Previous studies suggested that one or more genes on chromosome 5q21 are responsible for the inheritance of familial adenomatous polyposis (FAP) and Gardner's syndrome (GS), and contribute to tumor development in patients with noninherited forms of colorectal cancer. Two genes on 5q21 that are tightly linked to FAP (MCC and APC) were found to be somatically altered in tumors from sporadic colorectal cancer patients. One of the genes (APC) was also found to be altered by point mutation in the germ line of FAP and GS patients. These data suggest that more than one gene on chromosome 5q21 may contribute to colorectal neoplasia, and that mutations of the APC gene can cause both FAP and GS. The identification of these genes should aid in understanding the pathogenesis of colorectal neoplasia and in the diagnosis and counseling of patients with inherited predispositions to colorectal cancer.

Active ulcerative colitis (UC) is characterized by activation and infiltration of granulocytes and monocytes/macrophages into the colonic mucosa. The infiltrated leukocytes can cause mucosal damage by releasing degradative proteases, reactive oxygen derivatives, and proinflammatory cytokines. The aim of this trial (conducted in 14 specialist centers) was to assess safety and efficacy of granulocyte and monocyte adsorption apheresis in patients with active UC most of whom were refractory to conventional drug therapy. We used a new adsorptive type extracorporeal column (G-1 Adacolumn) filled with cellulose acetate beads (carriers) of 2 mm in diameter, which selectively adsorb granulocytes and monocytes/macrophages. Patients (n = 53) received five apheresis sessions, each of 60 minutes duration, flow rate 30 ml per minute for 5 consecutive weeks in combination with 24.4 +/- 3.60 mg prednisolone (mean +/- SE per patient per day, baseline dose). During 60 minutes apheresis, 26% of granulocytes, 19.5% of monocytes and 2% of lymphocytes adsorbed to the carriers. At week 7, 58.5% of patients had remission or improved, the dose of prednisolone was reduced to 14.2 +/- 2.25 mg (n = 37). The apheresis treatment was fairly safe, only eight non-severe side effects (in 5 patients) were reported. Based on our results, we believe that in patients with active severe UC, patients who are refractory to conventional drugs, granulocyte and monocyte adsorption apheresis is a useful adjunct to conventional therapy. This procedure should have the potential to allow tapering the dose of corticosteroids, shorten the time to remission and delay relapse.

We searched for germ-line mutations of the APC gene in 79 unrelated patients with familial adenomatous polyposis using a ribonuclease protection analysis coupled with polymerase chain reaction ampliflications of genomic DNA. Mutations were found in 53 patients (67%); 28 of the mutations were small deletions and 2 were 1-to 2-base-pair insertions; 19 were point mutations resulting in stop codons and only 4 were missense point mutations. Thus, 92% of the mutations were predicted to result in truncations of the APC protein. More than two-thirds (68%) of the mutations were clustered in the 5' halfof the last exon, and nearly two-fifths ofthe total mutations occurred at one of five positions. This information has significant implications for understanding the role of APC mutation in inherited forms of colorectal neoplasia and for designing effective methods for genetic counseling and presymptomatic diagnosis.

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Dental pulp stem cells (DPSCs) are mesenchymal stem cells (MSCs) that have multipotent differentiation and a self-renewal ability. They have been useful not only for dental diseases, but also for systemic diseases. Extensive studies have suggested that DPSCs are effective for various diseases, such as spinal cord injuries, Parkinson’s disease, Alzheimer’s disease, cerebral ischemia, myocardial infarction, muscular dystrophy, diabetes, liver diseases, eye diseases, immune diseases, and oral diseases. DPSCs have the potential for use in a cell-therapeutic paradigm shift to treat these diseases. It has also been reported that DPSCs have higher regenerative potential than the bone marrow-derived mesenchymal stem cells known as representative MSCs. Therefore, DPSCs have recently gathered much attention. In this review, the therapeutic potential of DPSCs, the latest progress in the pre-clinical study for treatment of these various systemic diseases, and the clinical applications of DPSCs in regenerative medicine, are all summarized. Although challenges, including mechanisms of the effects and establishment of cell processing and transplantation methods for clinical use, still remain, DPSCs could be promising stem cells sources for various clinical applications, because of their easy isolation by a noninvasive procedure without ethical concerns.

Mutation of hMLH1, a gene involved in DNA mismatch repair, is responsible for some families carrying the hereditary non-polypotic colorectal cancer (HNPCC) syndrome. To establish a basis for presymptomatic diagnosis of HNPCC patients who carry germline mutations in this gene, we determined the exon-intron organization of hMLH1. The results indicated that hMLH1 consists of 19 coding exons spanning approximately 100 kb, and that exons 1-7 contain a region that is highly conserved in the MLH1 and PMS1 genes of yeast. We used PCR-SSCP analysis and DNA sequencing to examine the entire coding region of the MLH1 gene in DNAs of 34 unrelated cancer patients who belong to HNPCC pedigrees. Germline mutations were detectable in eight (24%) of these patients; four of them were missense mutations, one had occurred in an intron where it would affect splicing, and the remaining three were frameshift mutations resulting in truncation of the gene product downstream of the mutation site.

Monitoring diabetes is critical for our understanding of the etiology and natural history of disease and for public health actions. However, traditional methods for monitoring are either too expensive (e.g., IDDM registries, NIDDM-OGTT prevalence surveys) or too inaccurate (routinely collected data or passive surveillance) for broad accurate, national programs for monitoring the incidence and prevalence of disease. We suggest that one technology called capture-recapture would considerably increase our ability to "count" diabetes, both nationally and globally. Implementation of this approach could lead to accurate inter- and intracountry data on rates of disease. Moreover, such tracking of diabetes could serve as the model for the monitoring of all disease in the 21st century and beyond.

Patients suffering from bone defects are often treated with autologous bone transplants, but this therapy can cause many complications. New approaches are therefore needed to improve treatment for bone defects, and stem cell therapy presents an exciting alternative approach. Although extensive evidence from basic studies using stem cells has been reported, very few clinical applications using stem cells for bone tissue engineering have been developed. We investigated whether injectable tissue-engineered bone composed of mesenchymal stem cells (MSCs) and platelet rich plasma was able to regenerate functional bone in alveolar deficiencies. We performed these studies in animals and subsequently carried out pilot trial cases in patients with long-term follow up; these showed good bone formation using minimally invasive MSC transplantation. All patients exhibited significantly improved bone volume with no side effects. Newly formed bone areas at 3 months was significantly higher than the pre-operation baseline (P <0.001) and reached levels equivalent to that of native bone. No significant bone resorption occurred during long term follow-up. Injectable tissue-engineered bone restored masticatory function in patients. This novel clinical approach represents an effective therapeutic utilization of bone tissue engineering.