Mutations in the hepatocyte nuclear factor-1alpha/MODY3 gene in Japanese subjects with early- and late-onset NIDDM

Recent studies have shown that mutations in the hepatocyte nuclear factor (HNF)-1alpha gene are the cause of maturity-onset diabetes of the young type 3 (MODY3). We have screened 193 unrelated Japanese subjects with NIDDM for mutations in this gene: 83 with early-onset NIDDM (diagnosis at <30 years of age) and 110 with late-onset NIDDM (diagnosis > or = 30 years of age). All of the members of the latter group also had at least one sibling with NIDDM. The 10 exons, flanking introns, and promoter region were amplified using polymerase chain reaction and were sequenced directly. Mutations were found in 7 of the 83 (8%) unrelated subjects with early-onset NIDDM. The mutations were each different and included four missense mutations (L12H, R131Q, K205Q, and R263C) and three frameshift mutations (P379fsdelCT, T392fsdelA, and L584S585fsinsTC). One of the 110 subjects with late-onset NIDDM was heterozygous for the missense mutation G191D. This subject, who was diagnosed with NIDDM at 64 years of age, also had a brother with NIDDM (age at diagnosis, 54 years) who carried the same mutation, suggesting that this mutation contributed to the development of NIDDM in these two siblings. None of these mutations were present in 50 unrelated subjects with normal glucose tolerance (100 normal chromosomes). Mutations in the HNF-1alpha gene occur in Japanese subjects with NIDDM and appear to be an important cause of early-onset NIDDM in this population. In addition, they are present in about 1% of subjects with late-onset NIDDM.     

Optimization of hydrolysis of protein substrates by yeast proteases from Saccharomyces carlsbergenis

Maximizing efficiency of staff and resources is one method of reducing costs without affecting quality. Using a methodology similar to that used to maximize efficiency of airline-gate use, we developed a model with which to evaluate nursing support staff and clinical examining-room resources in a general otolaryngology clinic. For 144 patients over 7 consecutive clinic days, with four otolaryngologists and various combinations of support staff and examining rooms, we measured space and staff resource use, including total clinic time, number of patients seen, patient waiting time, physician and nurse productivity, and examining-room use. A simulation model was used as the medium of analysis to define parameters of the patient encounter. We identified optimal efficiency when there were three examining rooms and one and one-half nursing staff per physician or five examining rooms and three nursing staff for two simultaneously practicing physicians. Compared with a model of two rooms and one nursing staff member, our ideal model increased the percentage of the physicians' time spent in direct contact with patients from 84% to 92%. Visit length decreased from 81 minutes to 57 minutes, the average time from check-in to examination decreased from 47 to 16 minutes, and it became possible for three additional patients to be seen each day. Additional rooms and support staff, in comparison with the optimally efficient distribution, did not significantly affect these parameters. Maximizing efficiency with the use of this methodology can decrease waiting times for patients, resulting in greater patient satisfaction, improved physician productivity, total number of patients seen, and increased total contact time between physicians and patients.     

Alterations in nail pigment with cancer chmotherapy

Three patients developed different nail color alterations after they had received chemotherapy for cancer. Many anticancer drug combinations are associated with similar findings. Transverse pigmented bands are most common, and these changes should not be confused with those attributable to systemic disease.     

Structural elucidation by electrospray mass spectrometry: an approach to the in vitro metabolism of the macrolide immunosuppressant SDZ RAD

SDZ RAD [40-O-(2-hydroxyethyl)rapamycin] is a macrolide immunosuppressant that is currently under clinical investigation after organ transplantation. The elucidation of its metabolic pathway is essential to improve the understanding of its therapeutic potentials and safety. In this article we describe investigations on the structural identification of some major metabolites of the drug produced by human liver microsomes in vitro. The principles described may be generally applicable for the structural elucidation of complex compound mixtures in biological matrices. Under the conditions of electron impact ionization, SDZ RAD undergoes extensive fragmentation and no information sufficient for structural elucidation is obtained. Therefore, mass spectrometry based on soft electrospray ionization (ESI) in conjunction with collision-induced fragmentation was the method of choice. High-performance liquid chromatography coupled to an ESI mass spectrometer resulted in separation and identification of 16-O-demethyl-SDZ RAD, the ring-opened form of SDZ RAD, and its dehydrate. Additionally, we characterized several demethylated and hydroxylated metabolites.     

An evaluation of the prognostic significance of antigen CD95(Fas/APO-1) expression on the cells of patients with a myelodysplastic syndrome, acute myeloid leukemia and chronic myeloleukemia

AIM: The expression of CD95(Fas/APO-1) antigen was studied on bone marrow cells of 19 MDS patients, peripheral blood blast cells of 15 acute myeloid leukemia (AML) patients, blast cells and granulocytes of 68 patients with chronic myeloid leukemia (CML)--24 in chronic, 9 in accelerated phase and 35 in blastic crisis (BC)--by indirect surface immunofluorescence assay using flow cytometry (FACScan, Becton Dickinson, USA). RESULTS: CD95(Fas/APO-1) antigen was revealed on bone marrow cells of 8 out of 19 (36.8%) MDS patients; the percentage of antigen-positive cells was 38.1 +/- 19.2%; on 45.5 +/- 22.8% of cells in 6(45%) of 15 AML patients. Fas/APO-1 antigen was totally absent in CML chronic stage; its expression was found in 34% (12 of 35) of our patients with CML BC on peripheral blood blasts and in 56% (5 of 9) on peripheral blast cells of CML patients in acceleration phase. CONCLUSION: The data on overall survival of CD95-positive MDS patients suggest that the presence of Fas antigen is a favorable prognostic sign for patients with MDS. The patients from CD95-negative group represent a risk group both for survival and AML transformation. In CML BC group the survival does not depend upon Fas-antigen expression.     

Antigenic activity of angiotensin II and its fragments

The antigenic activity of angiotensin and its seven fragments has been studied in cross-reaction with specific antibodies, elicited to angiotensin and its fragments: C-terminal hexapeptide and middle tetrapeptide. It has been found that all the fragments studied possess certain affinity for antibodies elicited to angiotensin, C-terminal hexapeptide and middle tetrapeptide. The middle tetrapeptide was identified to be the immunologically active centre of the angiotensin molecule.     

A safer and more effective treatment regimen for eclampsia

The purpose of our investigation was twofold: to provide normative data for the ratios between head circumference and cerebellum, abdominal circumference and cerebellum, and femur length and cerebellum; and to evaluate the predictive accuracy of an abnormal ratio in the detection of growth retardation and macrosomia. Data on 675 women with normal gestations between 14 and 42 weeks were used to estimate reference curves for the three ratios to be evaluated. We then compared the ratios of 34 fetuses with intrauterine growth retardation and 28 macrosomic fetuses to the control group. Of the three ratios that we investigated, abdominal circumference to transverse cerebellar diameter was the most efficacious. However, the sensitivity of this ratio for the detection of intrauterine growth retardation and macrosomia was only 52.9% and 46.6%, respectively. A ratio between head circumference, abdominal circumference, or femur length and the transverse cerebellar diameter cannot reliably distinguish between normally growing fetuses and those that are growth retarded or macrosomic.