Background. Previous studies have established an association between low birthweight (LBW) and future kidney disease, but few have explored the progression of kidney dysfunction through the pediatric years leading up through adolescence and young adulthood. Methods. To better understand the temporal effects of birthweight on kidney disease progression, we conducted a retrospective cohort study comparing the glomerular filtration rate (GFR) between LBW (<2500 grams) and normal birthweight (NBW) infants who were admitted to the neonatal intensive care unit (NICU) at our institution from 1992 to 2006. Results. Age at follow-up ranged 1-26 years old. GFR was found to be significantly lower in participants born with LBW than those born with NBW, with a mean difference of 5.5 mL/min/1.73 m(2) (P<0.01). These differences were found in the adolescent and young adult age group over 9 years of age, specifically in the extremely low birthweight group (ELBW) whose birthweight was less than 1000 grams. Conclusions. We recommend screening for CKD in ELBW individuals starting at the age of 9 years old, regardless of their previous medical history.

OBJECTIVE:To examine prospective parents' perceptions of management options and outcomes in the context of threatened periviable delivery, and the values they apply in making antenatal decisions during this period. STUDY DESIGN:Qualitative analysis of 46 antenatal interviews conducted at three tertiary-care hospitals with 54 prospective parents (40 pregnant women, 14 partners) who had received counseling for threatened periviable delivery (40 cases). RESULTS:Participants most often recalled being involved in resuscitation, cerclage, and delivery mode decisions. Over half (63.0%) desired a shared decision-making role. Most (85.2%) recalled hearing about morbidity and mortality, with many reiterating terms like "brain damage", "disability", and "handicap". The potential for disability influenced decision making to variable degrees. In describing what mattered most, participant spoke of giving their child a "fighting chance"; others voiced concerns about "best interest", a "healthy baby", "pain and suffering", and religious faith. CONCLUSIONS:Our findings underscore the importance of presenting clear information on disability and eliciting the factors that parents deem most important in making decisions about periviable birth.

Objective: When infants are at risk of being born at a very premature gestation (22-25 weeks), parents face important life-support decisions because of the high mortality for such infants. Concurrently, providers are challenged with providing parents a supportive environment within which to make these decisions. Practice guidelines for medical care of these infants and the principles of perinatal palliative care for families can be resources for providers, but there is limited research to bridge these medical and humanistic approaches to infant and family care. The purpose of this article is to describe how parents at risk of delivering their infant prior to 26 weeks gestation interpreted the quality of their interpersonal interactions with healthcare providers.Methods: Directed content analysis was employed to perform secondary analysis of data from 54 parents (40 mothers and 14 fathers) from the previously coded theme "Quality of Interactions." These categorized data described parents' encounters, expectations, and experiences of interactions that occurred prenatally with care providers. For this analysis, Swanson's theory of caring was selected to guide analysis and to delineate parents' descriptions of caring and uncaring interactions.Results: Parents' expectations for caring included: (a) respecting parents and believing in their capacity to make the best decisions for their family (maintaining belief); (b) understanding parents' experiences and their continued need to protect their infant (knowing); (c) physically and emotionally engaging with the parents (being with); (d) providing unbiased information describing all possibilities (enabling); and (e) helping parents navigate the system and creating a therapeutic environment for them in which to make decisions (doing for).Significance of Results: Understanding parents' prenatal caring expectations through Swanson's theory gives deeper insights, aligning their expectations with the palliative care movement.

1. A catheterized rat model was used to define the intestinal and hepatic components of oral bioavailability for an 11β-HSD1 inhibitor, AMG 221. These data were integrated with standard in vivo metabolism studies to elucidate the components contributing to the oral disposition of a novel drug candidate. 2. Intestinal and hepatic extraction ratios of AMG 221 obtained using a five-catheter rat model were 0.56 and 0.32, respectively. Therefore, both intestinal and hepatic extraction contributed to the first-pass component of oral bioavailability. There was no evidence for significant gut extraction of systemically administered drug. 3. Mass balance data and in vivo metabolite characterization obtained after administration of [(14)C] AMG 221 to rat showed that AMG 221 was completely absorbed from the gut lumen following an oral dose, primarily excreted in urine and was almost completely metabolized prior to excretion. 4. Hepatic bioavailability (FH), measured in two animals at various time points after oral dose administration was somewhat variable but generally characterized by an initial reduction during the absorption phase followed by an increase during the elimination phase, consistent with hepatic distribution of AMG 221. 5. The five-catheter rat model afforded estimates of hepatic and intestinal contribution to oral bioavailability that were used with other data to define the preclinical ADME characteristics of a drug candidate.

Thrombosis of fetal intracranial dural sinuses is a rare entity. A specific type of midline dural sinus thrombosis (DST) at the torcular Herophili with extension into the superior sagittal sinus (SSS) was initially seen on fetal US and was referred to fetal MRI for definite diagnosis and better delineation.

This study evaluated parents' and health care providers' (HCPs) descriptions of hope following counseling of parents at risk of delivering an extremely premature infant. Data came from a longitudinal multiple case study investigation that examined the decision making and support needs of 40 families and their providers. Semistructured interviews were conducted before and after delivery. Divergent viewpoints of hope were found between parents and many HCPs and were subsequently coded using content analysis. Parents relied on hope as an emotional motivator, whereas most HCPs described parents' notions of hope as out of touch with reality. Parents perceived that such divergent beliefs about the role of hope negatively shaped communicative interactions and reduced trust with some of their providers. A deeper understanding of how varying views of hope might shape communications will uncover future research questions and lead to theory-based interventions aimed at improving the process of discussing difficult news with parents.

Most deaths of extremely premature infants occur in the perinatal period. Yet, little is known about how parents make life support decisions in such a short period of time. In the paper, how parents make life support decisions for extremely premature infants from the prenatal period through death from the perspectives of parents, nurses, and physicians is described. Five cases, comprised of five mothers, four neonatologists, three nurses, and one neonatal nurse practitioner, are drawn from a larger collective case study. Prenatal, postnatal and end-of-life interviews were conducted, and medical record data were obtained. In an analysis by two research team members, mothers were found to exhibit these characteristics: desire for and actual involvement in life support decisions, weighing pain, suffering and hope in decision making, and wanting everything done for their infants. All mothers received decision making help and support from partners and family, but relationships with providers were also important. Finally, external resources impacted parental decision making in several of the cases. By understanding what factors contribute to parents’ decision making, providers may be better equipped to prepare and assist parents when making life support decisions for their extremely premature infants.

The prediction of in vivo drug-drug interactions from in vitro enzyme inhibition parameters remains challenging, particularly when time-dependent inhibition occurs. This study was designed to examine the accuracy of in vitro-derived parameters for the prediction of inhibition of CYP3A by erythromycin (ERY). Chronically cannulated rats were used to estimate the reduction in in vivo and in vitro intrinsic clearance (CL(int)) of midazolam (MDZ) after single and multiple doses of ERY; in vitro recovery of CL(int) was determined at 1, 2, 3, and 4 days after discontinuation of ERY. Enzyme inhibition parameters (k(inact), K(I), and K(i)) of ERY were estimated in vitro by using untreated rat liver microsomes. In vivo enzyme kinetic analysis indicated that single and multiple doses of ERY (150 mg/kg i.v. infusion over 4 h) reduced MDZ CL(int) by reversible and irreversible mechanisms, respectively. CYP3A inactivation after multiple doses of ERY treatment reflected metabolic intermediate complex formation without a significant change in hepatic CYP3A2 mRNA. A physiologically based pharmacokinetic model of the interaction between ERY and MDZ predicted a 2.6-fold decrease in CYP3A activity after repeated ERY treatment using in vitro-estimated enzyme inhibition parameters and in vivo degradation half-life of the enzyme (20 + or - 6 h). The observed -fold decreases were 2.3-fold and 2.1-fold for the in vitro-estimated CYP3A activity and the in vivo CL(int), respectively. This study demonstrates that in vivo DDIs are predictable from in vitro data when the appropriate model and parameter estimates are available.

Departments of Pharmacy Practice (X.Z.) and Industrial & Physical Pharmacy (R.E.G.),School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana, Section of Neonatology, Department of Pediatrics, Rush University Medical Center, Chicago, Illinois (R.E.K.) and Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana (X.Z., R.E.G., S.K.Q., D.R.J., S.D.H ) DMD Fast Forward. Published on October 1, 2009 as doi:10.1124/dmd.109.028290

Itraconazole (ITZ) is a substrate of CYP3A and both ITZ and hydroxyitraconazole (OH-ITZ), a major metabolite formed by CYP3A, are potent inhibitors of CYP3A. The concentration- and time-dependent changes in the hepatic availability (FH) of ITZ were evaluated in rats after oral doses of 5 and 40 mg/kg. Simultaneous blood samples were obtained from the aorta, portal vein, and hepatic vein for 24 h following duodenal ITZ administration, and concentrations of ITZ and OH-ITZ determined by LC/MS. During the absorption phase, the FH of ITZ increased from 0.2 to 1.0, reflecting the time course of hepatic CYP3A inhibition. A counterclockwise hysteresis was observed between ITZ concentrations entering the liver (CIN,ITZ) and FH, whereas there was no time delay observed between the change in FH and the OH-ITZ concentrations entering the liver (CIN,OH-ITZ). The direct relationship between CIN,OH-ITZ and FH suggested that OH-ITZ was mainly responsible for the inhibition of CYP3A. A positive portal venous-aortic gradient for OH-ITZ was measured after duodenal administration of ITZ, indicating intestinal formation of OH-ITZ. The in vivo Ki for OH-ITZ (38 ± 3 nM) was estimated from CIN,OH-ITZ versus FH of ITZ, and is similar to values obtained from inhibition of midazolam hydroxylation in CYP3A4 supersomes (Drug Metab Dispos 32:1121–1131, 2004). The data suggest that OH-ITZ, formed by intestinal CYP3A, controls the time course of hepatic CYP3A inhibition and is mainly responsible for the observed increase in FH of ITZ.

A 10-week-old female infant developed hypertension. The elevated blood pressure was associated with metabolic alkalosis and urinary chloride wastage. The family history was unremarkable. Her urinalysis, blood urea nitrogen (BUN), and serum creatinine concentrations were all normal. A renal ultrasound was normal. A technetium-99m diethylenetriaminopentoacetic acid (DTPA) renal scan with captopril showed normal blood flow bilaterally. The head ultrasound and echocardiogram were normal. Blood epinephrine, norepinephrine, catecholamines, thyroxine, and steroid levels were also normal. Treatment with various combinations of labetalol, hydralazine, captopril, methyldopa, nifedipine, and spironolactone, all at high doses, failed to control the elevated blood pressure. Serum aldosterone level and peripheral plasma renin activity were low. The lack of therapeutic response to spironolactone, with a good response to amiloride and recurrence of hypertension and metabolic alkalosis after amiloride cessation that was subsequently treated with amiloride, established the diagnosis of Liddle syndrome. To our knowledge, this is the youngest patient with Liddle syndrome that has been reported in the literature.

The use of high-dose pancreatic enzymes by patients with cystic fibrosis was associated with the development of fibrosing colonopathy. Preliminary studies indicated that the infusion of high-dose pancreatic enzymes alone did not cause intestinal damage. We hypothesized that cystic fibrosis patients that developed fibrosing colonopathy had increased intestinal permeability. Our goal was to develop a rat model for pancreatic enzyme-induced fibrosing colonopathy by increasing intestinal permeability with the use of indomethacin. Pancreatic enzymes, 150,000 units/kg/day, and indomethacin, 3 mg/kg/day, alone and in combination were administered via duodenal catheter to rats for 10 days. Indomethacin and pancreatic enzymes caused intestinal damage, resulting in significant increases in the total number of ulcers (P < 0.007), the number of severe ulcers (P < 0.003), and ulcers in the cecum and colon (P < 0.0007). We conclude that the combination of indomethacin and pancreatic enzymes acts synergistically to cause damage to the intestine.

We previously showed that endotoxin-induced lactic acidemia is initially caused by a decrease in clearance of lactic acid (L) and not by an increase in production (Pediatr Res 41:1997, 38A). Previous investigators have shown that hepatocellular function is impaired early in the course of sepsis (Wang et. al. Shock 3:1995). Because the liver is a major site of L metabolism, we hypothesized that impaired hepatic extraction of L would contribute to endotoxin-induced lactic acidemia. To test this hypothesis, we measured simultaneous hepatic venous (HV), portal venous (PV) and aortic (A) lactic acid concentrations after 2 mg/kg LPS was infused into the IVC in chronically catheterized rats (n=3). Blood L concentrations (nmol/ml) were analyzed using an enzymatic assay. The extraction of L by the liver, non-hepatic splanchnic organs, and the entire splanchnic system was determined from the hepatic venous-portal venous (HV-PV), portal venous-aortic (PV-A), and hepatic venous-aortic (HV-A) concentration gradients, respectively. Values in table are mean (SD). Aortic L concentration increased 4.5 fold peaking at 90 min post LPS infusion. The positive L(PV-A) remained unchanged indicating that the non-hepatic splanchnic organs are net producers of L but do not contribute to the increase in L after LPS. The increasingly negative L(HV-PV) after LPS indicates that the liver retains the ability to extract L from the PV after LPS. The increasingly negative L(HV-A) indicates that the splanchnic system as a whole is a net clearer of L after LPS. We conclude that the ability of the liver to extract lactate is not impaired by LPS. However, the net hepatic flux of L is related both to the concentration gradient of L across the liver and blood flow through the liver. Since L(HV-PV) becomes increasingly negative, we speculate that the decreased net extraction of lactate after LPS may be related to a decrease in hepatic blood flow.

In patients with sepsis, high blood lactate concentrations ([L]) have been associated with increased mortality. Previous studies indicate that endotoxin(LPS)-induced lactic acidemia is caused by a decrease in lactate extraction rather than increased production. Since lactate extraction is dependent on perfusion, we theorize that LPS causes a decrease in perfusion. Because perfusion is partially controlled by nitric oxide (NO), modulation of nitric oxide synthase (NOS), which exists in two forms, inducible (iNOS) and endothelial constitutive (ecNOS), may mediate LPS-induced changes in perfusion. Studies indicate that LPS induces iNOS and inhibits ecNOS. We hypothesize that further NOS inhibition will exacerbate LPS-induced lactic acidemia. We measured the effects of N-ω-nitro-L-arginine methyl ester(L-NAME), an inhibitor of both iNOS and ecNOS, and S-methylisothiourea (SMT), an iNOS inhibitor, on the lactic acidemia induced by LPS in non-stressed catheterized rats. LPS (6 μg/kg) and either L-NAME (0.3 mg/kg bolus, 0.3 mg/kg/hr) or SMT (0.1 mg/kg) were infused into the IVC. Aortic blood was sampled every 30 min for 4 hours and [L] were measured enzymatically. [L] did not significantly change with the infusion of L-NAME or SMT without LPS. Inhibition of both iNOS and ecNOS by L-NAME increased LPS-induced [L] while selective inhibition of iNOS by SMT decreased the LPS-induced lactic acidemia(p<0.02, repeated measures ANOVA). The apparent paradoxical effect of inhibiting iNOS alone compared to both ecNOS and iNOS on LPS-induced lactic acidemia suggests that NO produced by ecNOS may increase tissue perfusion. In contrast, NO produced by iNOS decreases tissue perfusion. We speculate that selective inhibition of iNOS may benefit patients with sepsis. Values represent mean (SE) in μmol/ml. Table

In patients with sepsis, high serum [lactate] have been associated with increased mortality. Lactic acidemia can be caused by an increase in the production of lactate or a decrease in clearance. Previous studies attempting to differentiate these two mechanisms of endotoxin (LPS) induced increase in serum [lactate] are inconclusive. In order to delineate between these two possiblities, we constantly infused tracer amounts of [14C]lactate into the IVC of chronically catheterized rats and determined the initial effect of LPS on blood [lactate] and the [14C]lactate. If there is an increase in production of lactate, the ratio of [14C]lactate:lactate ([14C]L/L) will decrease as blood [lactate] increases. However, if one assumes that [14C] lactate and endogenous lactate are similarly cleared, then a constant [14C]L/L associated with an increase in blood [lactate], will indicate a decrease in the clearance of lactate. 45 minutes after the start of the constant infusion of[14C]lactate (0.03 μCl/min) into the IVC, 6 μg/kg of LPS was infused into the IVC. Aortic blood samples were obtained -45, -15, -8, 0, 15, 30, 60, and 90 min after the LPS infusion. Aortic blood was deproteinized and analyzed for blood [lactate] (nmol/ml) using an enzymatic assay. [14C]lactate was isolated using a Dowex exchange column and [14C] was measured. In the four study rats, the serum [TNF] were elevated, 87±21 ng/ml indicating a response to LPS. Raw data were analyzed by ANOVA for repeated measures. In the following table values (mean±sem) were normalized to the average of the pre LPS levels.

At 1-2 weeks of age, a high proportion of extremely low birth wt infants(ELBW, 0.35 on of age were treated with DEX. We analyzed the use of steroids in the 25 (P1) and 44 (P2) surviving infants with BW between 500-800g Table