The effect of B-vitamins on hyperhomocysteinemia in patients on antiepileptic drugs

Patients on antiepileptic drugs (AEDs) may have elevated levels of plasma total homocysteine (p-tHcy). The aim of this study was to assess the effect of B-vitamin supplementation on the levels of p-tHcy and markers of endothelial activation and lipid peroxidation. A total of 33 adult patients on AEDs were identified with either fasting (Group 1, n=23) or post methionine load (PML) (Group 2, n=10) hyperhomocysteinemia. Subjects were supplemented with B-vitamins for 30 days: folic acid 0.4 mg, pyridoxine 120 mg and riboflavin 75 mg per day. After supplementation, serum folate and pyridoxal phosphate had increased, while fasting and PML p-tHcy had decreased (P<0.0001) by 36 and 26%, respectively. Prior to supplementation, the Group 1 patients had elevated levels of P-selectin and von Willebrand factor (vWF) (P=0.05 and 0.03, respectively). After supplementation, the levels of intercellular cell adhesion molecules had decreased (P=0.01) and E-selectin decreased nonsignificantly (P=0.07). However, the levels of vascular cell adhesion molecules had increased (P<0.0001), while lipid peroxidation were unchanged. In conclusion, the combined supplementation with folic acid, pyridoxine and riboflavin reduced fasting and PML hyperhomocysteinemia in patients on AEDs. Patients with fasting hyperhomocysteinemia had elevated levels of P-selectin and vWF, which may indicate an increased risk of cardiovascular disease. Furthermore, B-vitamin supplementation influenced endothelial activation, although the clinical implication is uncertain.     

Protoporphyrin-IX accumulation and cutaneous tumor regression in mice using a ferrochelatase inhibitor

The use of endogenously created porphyrins as an alternative to photosensitizer injection for photodynamic therapy (PDT) of cancer is a rapidly evolving area of study. In-situ accumulation of protoporphyrin-IX (PpIX) by hemebiosynthesis inhibition represents a novel method for PDT of cancer cells. The kinetics of PpIX accumulation and cutaneous tumor regression in mice was studied using lead (a known and effective inhibitor of ferrochelatase). Cutaneous tumors were exposed to various doses of ferrochelatase enzyme inhibitor (lead) and to different durations and doses of visible light. The maximum increase in PpIX levels (blood, skin and tumor) was observed 48 h after the parenteral administration of second injection of lead within a period of 1 month. The maximum tumor regression was observed in mice that were exposed to visible light at a light dose of 648J/cm(2) (1h exposure in four sessions of 15 min, with a gap of 10 min between each exposure). Continuous treatment for 6 consecutive days resulted in almost complete regression of the tumors in most of the animals. Histopathological sections of tumors after light exposure showed necrotic tissue with degenerated lymphocytes, monocytes, and neutrophils. Since the ferrochelatase inhibitor (lead) used in the present study is toxic, the search must continue for a safe, non-toxic inhibitor to enhance sensitizer-mediated PDT.     

Dysfunction of the p53 tumor suppressor pathway in head and neck cancer

It is important to examine the abnormality of the entire p53 tumor suppressor pathway in head and neck cancer. We examined the mRNA expressions of p53 regulatory factors, p33ING1 and p14ARF, and a p53-target gene, p21WAF1 in head and neck cancer. Nine of 14 benign pleomorphic adenomas (PAs) and 7 of 8 malignant salivary gland tumors (MSGTs) expressed p33ING1 mRNA. Thirteen of 14 PAs expressed p14ARF mRNA, however, only 1 of 8 MSGTs expressed p14ARF mRNA. Eight of 14 PAs and 7 of 8 MSGTs expressed p21WAF1 mRNA. In salivary gland tumors, there was clear correlation between the expression of p33ING1 and p21WAF1 (p<0.0001, r2=0.53). However, there was no correlation between the expression of p14ARF and p21WAF1 (p=0.6543, r2=0.009). Twenty-six of 28 oral squamous cell carcinomas (SCCs) expressed p33ING1 mRNA. Nineteen of 28 oral SCCs expressed p14ARF mRNA. All of the oral SCCs expressed p21WAF1 mRNA. In oral SCCs, the expressions of both p33ING1 (p=0.009, r2=0.181) and p14ARF (p=0.0009, r2=0.271) correlated with the expression of p21WAF1. Interestingly, 24 of 26 oral SCCs (92%) showed either abnormality of p53 itself or loss of expression of p53 regulatory factors, p33ING or p14ARF. These results suggest that head and neck cancer often involve the dysfunction of p53 tumor suppressor pathway.     

Large-Scale pathology-based cancer data - a reflection of population-based cancer data

Pathology-based cancer data is a high quality reflection of the patterns of cancer in the population it represents, provided the demographic details of the patients are carefully recorded. Relative frequency data is neither a replacement for population-based data nor a suggested alternative; it simply enhances the quality of population data and in very large data sets reflects the cancer patterns observed in the representative populations. Aware of the standard shortfalls of pathology-based data, the department of pathology, The Aga Khan University Hospital (AKUH) standardized its data, representing 53.4% of the cancer data of Karachi Division (Pakistan) and also reflecting the cancer pattern of other provinces of Pakistan. This data was compared with 4 different population and institutional-based data sets. The findings substantiate the observation that despite the problems of interpretation of data from pathology laboratories, they are an invaluable source of information on cancer patterns in much of the world where incidence data are unavailable . If developing countries, unable to organize National Population- Based Registry should as an alternate develop National Pathology-based Registers a well targeted and monitored, a Cancer Control Program would be possible. A good quality, large-scale pathology data with demographic details of the patient recorded can also be extended to give coverage to the population.     

Gastric cancers overexpress S100A calcium-binding proteins

Serial analysis of gene expression provides quantitative and comprehensive expression profiling in a given cell population. In our efforts to define the genes overexpressed in carcinoma of the stomach, we performed serial analysis of gene expression analyses on dissected neoplastic and normal gastric epithelia. We identified 91,334 expressed tags, including 26,633 that were unique. The 20 most up-regulated genes (P < 0.01) in gastric cancer (GC) compared with normal gastric epithelia included several keratins that are specific for epithelial cells such as keratin 6A, 13, and 17. Interestingly, five calcium-binding proteins (S100A2, S100A7, S100A8, S100A9, and S100A10) were overexpressed. Quantitative real-time PCR on primary GC samples demonstrated overexpression of S100A2 in 18 of 20 tumors (90%). The other calcium-binding proteins were overexpressed in 25-45% of the GC samples that we studied. Our results indicate that S100A proteins may be important for gastric tumorigenesis. Additional investigations are required to elucidate the biological role of calcium-binding proteins in cancer.     

Association of chromosome 19q13.2-3 haplotypes with basal cell carcinoma: tentative delineation of an involved region using data for single nucleotide polymorphisms in two cohorts

We have previously used single nucleotide polymorphisms to detect an association of basal cell carcinoma (BCC) in Caucasian Americans and Danes with the genome region 19q13.2-3, which contains several genes involved in the nucleotide excision repair of DNA. In this exploratory paper we have extended the data and used them in a chromosomal scan. The results indicate the presence of a gene variation modulating the risk of developing BSS in a submegabase region including and surrounding the gene RAI. Specifically, persons that are homozygous for the haplotype RAI intron 1(A) RAI exon 6(A) appear at increased risk for BCC. In addition, we have looked for possible synergisms between all pairs of markers. We find that a marker in GLTSCR1, presumably separated from RAI by several million bases, supplements the most significant marker in RAI in separating cases from controls, which may suggest the presence of an independent, risk-modulating variation in this second gene region.     

Effect of transient hippocampal inhibition on amygdaloid kindled seizures and amygdaloid kindling rate

In this study the effect of transient inhibition of the CA1 region of the dorsal hippocampus by lidocaine on amygdala kindling rate and amygdaloid kindled seizures was investigated. In experiment 1, rats were divided into four groups. In group 1, animals were implanted only with a tripolar electrode into the amygdala but in groups 2-4, two guide cannulae were also implanted into the CA1 regions of the dorsal hippocampi. Animals were stimulated daily to be kindled. In groups 3 and 4, saline or 2% lidocaine (1 microl/2 min) was also injected respectively into the hippocampus, 5 min before each stimulation. Results obtained showed that amygdala kindling rate and the number of stimulations to receive from stage 4 to stage 5 seizure were significantly increased in group 4. In experiment 2, lidocaine (1% and 2%) was infused (1 microl/2 min) into the hippocampus of amygdala kindled rats bilaterally and animals were stimulated at 5, 15 and 30 min after drug injection. Twenty four h before lidocaine injection, saline was also infused (1 microl/2 min) into the hippocampus as control. Obtained results showed that afterdischarge duration was reduced 5 min after lidocaine (1% and 2%) injection. Stage 5 seizure duration was also decreased 5 and 15 min after 2% lidocaine. Thus, it may be suggested that in amygdala kindling, activation of the hippocampal CA1 region has a role in seizure acquisition and seizure severity so that inhibition of this region results in decreasing of seizure severity and retards amygdala kindling rate.