A longitudinal study of the control of renal and uterine hemodynamic changes of pregnancy.

We have determined the sequence and extent of maternal renal and uterine adaptation to pregnancy and examined the role of hormonal factors in their regulation. Renal bipolar diameter (RBD), renal artery resistance index (RARI), uterine artery pulsatility index (UAPI), and plasma relaxin, human chorionic gonadotropin (hCG), progesterone, estradiol, urea, and creatinine were measured longitudinally in women with normal spontaneous singleton pregnancies, in vitro fertilization (IVF) singleton pregnancies, ovum donation (OD) singleton pregnancies, and multiple pregnancies from prepregnancy to postpartum. There was a progressive increase in the RBD and the RARI and a decrease in the UAPI during pregnancy. These changes reversed toward prepregnancy levels by 6 weeks post delivery. There was no difference in the rate of change of RBD, RARI, and UAPI between spontaneous singleton, IVF singleton, OD singleton, and multiple pregnancies (p < 0.05), but relaxin was directly correlated to the RARI (r = 0.654, p = 0.015), and progesterone was inversely correlated to uterine artery PI (r = 0.554, p = 0.049). These data show that renal size and resistance to blood flow increase with advancing gestation, whereas the uterine artery resistance declined with gestation. These changes may be influenced by relaxin and progesterone.

Local suppression of T cell responses by arginase-induced L-arginine depletion in nonhealing leishmaniasis.

The balance between T helper (Th) 1 and Th2 cell responses is a major determinant of the outcome of experimental leishmaniasis, but polarized Th1 or Th2 responses are not sufficient to account for healing or nonhealing. Here we show that high arginase activity, a hallmark of nonhealing disease, is primarily expressed locally at the site of pathology. The high arginase activity causes local depletion of L-arginine, which impairs the capacity of T cells in the lesion to proliferate and to produce interferon-gamma, while T cells in the local draining lymph nodes respond normally. Healing, induced by chemotherapy, resulted in control of arginase activity and reversal of local immunosuppression. Moreover, competitive inhibition of arginase as well as supplementation with L-arginine restored T cell effector functions and reduced pathology and parasite growth at the site of lesions. These results demonstrate that in nonhealing leishmaniasis, arginase-induced L-arginine depletion results in impaired T cell responses. Our results identify a novel mechanism in leishmaniasis that contributes to the failure to heal persistent lesions and suggest new approaches to therapy.

Mitochondrial dysfunction and the role of the non-specialist laboratory.

Each human cell contains at least 1,000 mitochondria, each containing several copies of mitochondrial DNA. This DNA is tiny compared with the nuclear genome, and its structure and products have been fully elucidated. Whilst oxidative phosphorylation depends on the polypeptides encoded by mitochondrial DNA, it also requires a huge number of nuclear DNA products. Inherited deleterious mutations of mitochondrial DNA leading to inefficient oxidative phosphorylation have been described as 'mitochondrial disorders', with a variety of clinical presentations. When similar clinical presentations occur with no discernible mutation of mitochondrial DNA, histological and biochemical evidence is required for diagnosis. The number of these laboratory-proven inherited mitochondrial disorders is growing. It is also becoming clear that mitochondrial DNA defects can be acquired, the most common cause being therapy with highly active antiretroviral therapy (HAART) for human immunodeficiency virus-1 (HIV-1) infection. Whilst definitive diagnosis of inherited or acquired mitochrondrial dysfunction requires access to specialist laboratory techniques, routine laboratories have a role to play in the initial investigation and monitoring of these conditions.

Placenta as a link between amino acids, insulin-IGF axis, and low birth weight: evidence from twin studies.

Current evidence suggests that reduced placental transport of amino acids regulates fetal growth. We determined the association between fetal nutrition and the insulin-IGF axis by measuring the plasma concentrations of amino acids, insulin, IGF-I and IGF-binding protein-1 (IGFBP-1) in maternal and cord blood from gestational age-matched dichorionic (DC) twins with (n = 10) and without discordant birth weights (n = 10). In the growth-restricted (IUGR) twins, fetal concentrations of total essential (P < 0.01), nonessential (P < 0.01), and branched chain amino acids (P < 0.01) were lower than those in the appropriate for gestational age co-twins and concordant twin pairs. The IUGR twins had lower fetal concentrations of insulin (P < 0.001) and IGF-I (P < 0.05) and higher concentrations of IGFBP-1 (P < 0.01) than their appropriate for gestational age co-twins. In the discordant group, fetal IGFBP-1 had a negative association with fetal insulin (r = 0.71; P < 0.001), total essential amino acids (r = 0.78; P < 0.001), and branched chain amino acids (r = 0.64; P < 0.01). There was a positive correlation between total essential amino acids (r = 0.63; P < 0.001) and branched chain amino acids (r = 0.58; P < 0.01) and plasma insulin. However, there were no associations among fetal insulin, IGFBP-1 and nonessential amino acids. These data demonstrate the link between the reduction in certain essential and nonessential amino acids and alterations in fetal circulating levels of insulin and IGFBP-1, in growth-restricted twins.