Genetic and physiologic analysis of the role of uncoupling protein 3 in human energy homeostasis.

By virtue of its potential effects on rates of energy expenditure, uncoupling protein 3 (UCP3) is an obesity candidate gene. We identified nine sequence variants in UCP3, including Val9Met, Val102Ile, Arg282Cys, and a splice site mutation in the intron between exons 6 and 7. The splice mutation results in an inability to synthesize mRNA for the long isoform (UCP3L) of UCP3. Linkage (sib pair), association, and transmission disequilibrium testing studies on 942 African-Americans did not suggest a significant effect of UCP3 on body composition in this group. In vastus lateralis skeletal muscle of individuals homozygous for the splice mutation, no UCP3L mRNA was detectable; the short isoform (UCP3S) was present in an increased amount. In this muscle, we detected no alterations of in vitro mitochondrial coupling activity, mitochondrial respiratory enzyme activity, or systemic oxygen consumption or respiratory quotient at rest or during exercise. These genetic and physiologic data suggest the following possibilities: UCP3S has uncoupling capabilities equivalent to UCP3L; other UCPs may compensate for a deficiency of bioactive UCP3L; UCP3L does not function primarily as a mitochondrial uncoupling protein.

Prophylaxis in factor IX deficiency product and patient variation.

To determine the dosing needed to maintain a prophylactic level of factor IX (FIX) >/=2%, 15 non-inhibitor severe (/=2%. Based on pharmacokinetic analysis the median amount of concentrate needed to maintain a prophylactic level >/=2% for 30 days when administered every third day is 677 IU kg(-1) pd-FIX (range 388-6005 IU kg(-1) pd-FIX) compared with 1168 IU kg(-1) r-FIX (range 268-13085 IU kg(-1) r-FIX). The median cost for 30 days of prophylaxis of an average 25-kg 8-year-old child at the current University of Iowa Price (0.87 US dollars Mononine/0.86 US dollars BeneFix as of December 2002) if given every third day would be 19,972 US dollars and 34,456 US dollars for r-FIX. However, because of wide inter-patient variability in recovery and half-life, pharmacokinetic evaluation of each patient is necessary to determine the appropriate dosing schedule and product best suited for prophylaxis.

Interphase fluorescence in situ hybridization studies of ovarian adenocarcinomas using the midisatellite probe.

The genes involved in ovarian carcinogenesis are largely unknown. Cytogenetic studies have shown a large number of chromosomal abnormalities in ovarian cancers. Molecular studies have additionally found abnormalities. Few in situ hybridization studies have been performed on ovarian cancer tissues. We chose to study the distal region of chromosome 1p with the midisatellite probe and interphase fluorescence in situ hybridization. A total of 35 patient samples, including various controls and cancers, was collected from our pathology archives. Our cancer cases included some patients with stage I disease, in whom tumors arose in endometriotic cysts. In these cases, both tumor tissue and areas in the cyst distant from the tumor mass were examined. Results showed clear cell carcinoma nuclei to have an increase in both number and size of probe signals, interpreted as representing amplification of the probed region of chromosome 1. Serous carcinomas showed an increase in the number of signals, up to four. We felt this could be a result of amplification, or, because these cells exhibited the highest mitotic counts, to DNA doubling in preparation for mitosis. Endometrioid carcinomas resembled controls in showing up to two small probe signals, but not more. We conclude that amplification in distal chromosome 1p occurs in ovarian clear cell, and possibly serous, carcinomas and may not be important in endometrioid carcinomas. Because alteration was not found in the various control epithelia, including nonmalignant-looking areas from cysts which also contained cancer, we believe that the change, when present, may not be an early step in carcinogenesis.

Biology and pharmacology of hematopoietic growth factors.

Several glycoproteins that control blood formation have recently been characterized. Through their overlapping, synergizing, and antagonistic effects, they regulate hematopoiesis in a highly differentiated network. Large scale production of these colony stimulating factors (CSFs) has been made available by recombinant DNA technology, and a series of clinical studies in a variety of indications has been finished. In general, the subcutaneous application seems to be superior to the intravenous injection and causes less toxicity. Erythropoietin has been shown to be a highly effective treatment for anemia in patients with chronic renal failure. Granulocyte colony stimulating factor and granulocyte-macrophage colony stimulating factor are capable of ameloriating the chemotherapy induced neutropenia, and to abbreviate the time span of myeloaplasia after bone marrow transplantation. The potentials of other colony stimulating factors like Interleukin 1 and Interleukin 3, and combination regimens of several CSFs will be discussed.