The dietary glycemic index during pregnancy: influence on infant birth weight, fetal growth, and biomarkers of carbohydrate metabolism

During pregnancy, lower levels of maternal glucose before and during a glucose load have been associated with reduced infant birth weight and an increased risk of small-for-gestational-age births. A lower incremental area under the glucose response curve defines a low glycemic diet. Thus, during pregnancy the maternal diet, as measured by the glycemic index, may influence fetal growth and infant birth weight. A total of 1,082 gravidas who enrolled in the Camden Study between August 1996 and October 2002 were followed prospectively during pregnancy. The dietary glycemic index was computed from three 24-hour recalls in the course of pregnancy. Samples for plasma glucose and for glycosylated hemoglobin were obtained at 24-28 weeks' gestation. The glycemic index was positively and significantly related to maternal glycosylated hemoglobin and plasma glucose. There were as well significant linear trends for dietary fat intake to decrease and for intakes of carbohydrate, sucrose, fiber, and folate to increase as the glycemic index declined. Gravidas with a low dietary glycemic index had reduced infant birth weight and approximately a twofold increased risk of a small-for-gestational-age birth. Consistent with data on maternal plasma glucose, data in this study show that the type of carbohydrate in the diet of urban, low-income women influences fetal growth and infant birth weight.     

Pharmacokinetics and cellular uptake of imatinib and its main metabolite CGP74588

Despite the remarkable clinical response rates to imatinib in the treatment of bcr-abl leukemic patients, pharmacokinetic data on this relatively novel substance are needed to improve our understanding of the emergence of resistance, the interindividual variations of clinical response and the clinical and biologic relevance of its main metabolite N-desmethyl-imatinib. We present here pharmacokinetic data obtained with a newly designed HPLC approach in 97 patients with chronic myeloid leukemia or acute lymphatic leukemia (ALL) under treatment with imatinib that allowed us to calculate the AUC (39.5 g·h/ml for an oral dose of 400 mg daily), the t_1/2 (18.2 h) and the peak concentration (1.92 /ml for an oral dose of 400 mg daily) of imatinib in plasma. In a subgroup of patients, the same parameters were analyzed for N-desmethyl-imatinib. We also provide data on the imatinib concentration in the cerebrospinal fluid (CSF) of ALL patients and demonstrate that oral administration of imatinib resulted only in a marginal flux across the blood-brain barrier. Finally, in an in vitro setting, we determined cellular concentrations of imatinib in HL-60 cells and showed an over-proportional uptake both in RPMI medium and in human plasma. Using an arithmetical approach combining all parameters obtained in imatinib-treated patients, we finally provide a conclusive approximation of basic pharmacokinetic data for both imatinib and its main metabolite N-desmethyl-imatinib.     

Long-term effects of unilateral carotid endarterectomy on arterial baroreflex function

Abstract.Background and purpose: Carotid endarterectomy (CE) may be complicated by the clinical syndrome of baroreflex failure. Alterations of baroreflex function may also account for the frequently observed blood pressure lability in the first hours following surgery. We investigated the long-term effects of unilateral CE on baroreflex control of function and blood pressure.Methods: We investigated 14 patients after unilateral CE (13m:1f, 64.8 ± 6.5 years), 9 patients with a surgically untreated uni-/bilateral carotid stenosis (CS, 7m:2f, 57.6 ± 10.7 years) and 12 healthy controls (HC, 11m:1f, 60.9 ± 7.9 years) by means of Valsalva maneuver, active standing, forced breathing, cold face test, cold pressor test and mental arithmetic. Ambulatory blood pressure level and variability were determined from 24-hour Spacelabs and 5-hour beat-to-beat Portapres recordings.Results: Baroreflex sensitivity (derived from phase IV Valsalva maneuver) was significantly lower in CE (1.53 ± 0.83 ms/mmHg) than in CS (4.39 ± 2.27, p = 0.002) and HC (5.34 ± 3.78, p = 0.003). CE patients exhibited a decreased reflex control of heart rate in response to Valsalvas maneuver and active standing without orthostatic hypotension. Office blood pressure levels before and after endarterectomy were similar, as were ambulatory blood pressure levels in the three groups. Ambulatory blood pressure variability was higher in CE and CS than in HC, but not different between CE and CS.Conclusions: Unilateral CE causes a long-term impairment of baroreflex function, resulting in an attenuated reflex control of heart rate, but no hypertension or blood pressure lability.     

Fanconi syndrome caused by antiepileptic therapy with valproic Acid

PURPOSE: Valproic acid (VPA) is commonly used as an antiepileptic drug (AED). Regular screening for renal side effects is uncommon. Fanconi syndrome, a generalized dysfunction of renal proximal tubular cells, occurs with some inborn errors of metabolism. In addition, it can be acquired by exposure to several toxic substances. We report a case of Fanconi syndrome after long-term therapy with VPA. METHODS: An 8-year-old severely disabled and developmentally retarded boy with epilepsy was treated with VPA over a period of 7 years. He was hospitalized after a status epilepticus with laboratory findings suggesting a Fanconi syndrome. A PubMed-based worldwide review of the literature revealed that Fanconi syndrome is a rare side effect in children during long-term VPA treatment. We analyzed all 10 previously published cases by comparing age, underlying diseases, medication, and outcome. RESULTS: Examination revealed metabolic acidosis suggestive of renal tubular malfunction. Based on typical clinical and laboratory findings, an acquired Fanconi syndrome was diagnosed. This was treated with large doses of sodium bicarbonate. After discontinuation of VPA, renal function completely normalized within 2 months. CONCLUSIONS: Fanconi syndrome appears to be a rare but severe consequence of long-term VPA therapy. Therefore patients treated with VPA should be checked regularly for the possible development of VPA-induced Fanconi syndrome.     

The Addiction Severity Index medical and psychiatric composite scores measure similar domains as the SF-36 in substance-dependent veterans: concurrent and discriminant validity

BACKGROUND: Recently attention has focused on the assessment of functional health status in substance-dependent individuals. The addiction severity index (ASI) is a widely used assessment instrument that includes scales to reflect current medical and psychiatric status. This study examines the concurrent validity of these ASI composite scores in relation to the short form 36-item health survey (SF-36), a well-established measure of health-related quality of life/functional health status. METHODS: Veterans (n=674) were assessed at admission to substance dependence treatment. Correlations were performed between ASI composite scores and SF-36 scales and the physical and mental summary components (PSC and MSC, respectively). Areas under receiver operating characteristic (ROC) curves determined the descriminative ability of the ASI composites to ascertain impairment. RESULTS: The ASI medical composite score demonstrated robust correlations with the four SF-36 scales that relate to physical health and with the PCS. The ASI psychiatric composite score had robust correlations with the four SF-36 scales related to mental health and with the mental component summary (MCS). ROC curves indicated that the ASI medical (AUC=0.83) and psychiatric composites (AUC=0.90) accurately detected subjects with impairment. CONCLUSIONS: ASI medical and psychiatric composite scores provide effective initial screening for patients with impaired functional status as measured by the corresponding SF-36 component summary scores.     

Both body and arm position significantly influence blood pressure measurement

The position of both the body and the arm during indirect blood pressure (BP) measurement is often neglected. The aim of the present study was to test the influence of the position of the patient on BP readings: (1) sitting with the arms supported precisely at the right atrium level and (2) supine: (a) with the arms precisely at the right atrium level and (b) with the arms on the examination bed. In a first group of 57 hypertensive patients, two sessions of BP and heart rate (HR) measurements were performed in two positions: sitting and supine with the arms supported precisely at right atrium level in both positions. BP was measured simultaneously at both arms, with a Hawksley Random Zero sphygmomanometer at the right arm, and with an automated oscillometric device (Bosomat) at the left arm. BP and HR readings obtained in the two positions were then compared. In a second group of 25 normo- and hypertensive persons, two sessions of BP and HR readings were performed in supine with the arms in two different arm positions: (a) the arm placed precisely at right atrium level and (b) the other arm on the examination bed. The measurements were performed at both arms with two automated devices (Bosomat). The readings taken in the two positions were compared. Both systolic BP (SBP; by 9.5 +/- 9.0 (standard deviation, s.d.); right arm) and diastolic BP (DBP; by 4.8 +/- 6.0 mmHg; right arm) were significantly higher in the supine than in the sitting position. When the two different arm positions (body continously supine) were compared in the second part of the study, significantly higher SBP (by 4.6 +/- 6.1 mmHg) and DBP (by 3.9 +/- 2.8 mmHg) were obtained when the arm of the patient was placed on the bed (below the right atrium level), than when the arm was placed at the level of the right atrium. BP readings in sitting and supine positions are not the same. When according to guidelines the arm of the patient is meticulously placed at the right atrium level in both positions, the difference is even greater than when the arm rests on the desk or on the arm support of the chair. Moreover, in the supine position small but significant differences in BP are measured between arm on a 5 cm-high pillow and arm on the bed. In every study reporting BP values, the position of both the body and especially the arm should be precisely mentioned.     

Claudin-4 expression decreases invasiveness and metastatic potential of pancreatic cancer

Claudin-4 has been identified as an integral constituent of tight junctions and has been found to be highly expressed in pancreatic cancer. The aim of the present study was to elucidate the effect of claudin-4 on growth and metastatic potential in pancreatic cancer cells, as well as the regulation of claudin-4 by oncogenic pathways. Claudin-4 was stably overexpressed in SUIT-2 pancreatic cancer cells, and its effect on invasion and growth in vitro was examined by using two-chamber invasion assays, soft agar assays, and fluorescence-activated cell sorter analysis. Claudin-4 localization was characterized by light and electron microscopy, and pulmonary colonization was analyzed in vivo after injection of claudin-4 overexpressing cells into the tail vein of nude mice. Overexpression of claudin-4 was associated with significantly reduced invasive potential in vitro and inhibited colony formation in soft agar assays. In vivo, tail vein-injected claudin-4 overexpressing cells formed significantly less pulmonary metastases in comparison with mock-transfected cells. These effects were not caused by changes in proliferation, cell cycle progression, or matrix metalloproteinase gelatinolytic activity, but were paralleled by increased cell contact formation. Moreover, proinvasive transforming growth factor beta was able to down-regulate claudin-4 in PANC-1 cells. Inhibition of Ras signaling by using dominant-negative Ras and specific inhibitors of both downstream effectors mitogen-activated protein/extracellular signal-regulated kinase kinase and phosphatidylinositol 3'-kinase also decreased claudin-4 expression. Our findings identify claudin-4 as a potent inhibitor of the invasiveness and metastatic phenotype of pancreatic cancer cells, and as a target of the transforming growth factor beta and Ras/Raf/extracellular signal-regulated kinase pathways.