Effect of acute on chronic liver failure over post-transplant survival.

INTRODUCTION AND OBJECTIVES: Acute-on-chronic liver failure (ACLF) is associated with reduced short-term survival, and liver transplantation is frequently the only therapeutic option. Nonetheless, the post-transplantation prognosis seems to be worse in ACLF patients. MATERIALS AND METHODS: The databases of two university centers were retrospectively evaluated, and adult patients with cirrhosis who underwent transplantation between 2013 and 2020 were included. One-year survival of patients with ACLF was compared to that of patients without ACLF. Variables associated with mortality were identified. RESULTS: A total of 428 patients were evaluated, and 303 met the inclusion criteria; 57.1% were male, the mean age was 57.1 ± 10.2 years, 75 patients had ACLF, and 228 did not. The main etiologies of ACLF were NASH (36.6%), alcoholic liver disease (13.9%), primary biliary cholangitis (8.6%) and autoimmune hepatitis (7.9%). Mechanical ventilation, renal replacement therapy, the use of vasopressors and the requirement of blood product transfusion during liver transplantation were significantly more frequent in ACLF patients. Among those recipients without and with ACLF, survival at 1, 3 and 5 years was 91.2% vs. 74.7%, 89.1% vs. 72.6% and 88.3% vs. 72.6%, respectively (p=0.001). Among pre-transplantation variables, only the presence of ACLF was independently associated with survival (HR 3.2, 95% CI: 1.46-7.11). Post-transplantation variables independently associated with survival were renal replacement therapy (HR 2.8, 95% CI: 1.1-6.8) and fungal infections (HR 3.26, 95% CI: 1.07-9.9). CONCLUSIONS: ACLF is an independent predictor of one-year post-transplantation survival. Importantly, transplant recipients with ACLF require the use of more resources than patients without ACLF.

Consequences of the exposome to gestational diabetes mellitus.

The exposome is the cumulative measure of environmental influences and associated biological responses throughout the lifespan, including those from the environment, diet, behaviour, and endogenous processes. The exposome concept and the 2030 Agenda for the Sustainable Development Goals (SDGs) from the United Nations are the basis for understanding the aetiology and consequences of non-communicable diseases, including gestational diabetes mellitus (GDM). Pregnancy may be developed in an environment with adverse factors part of the immediate internal medium for fetus development and the external medium to which the pregnant woman is exposed. The placenta is the interface between maternal and fetal compartments and acts as a protective barrier or easing agent to transfer exposome from mother to fetus. Under and over-nutrition in utero, exposure to adverse environmental pollutants such as heavy metals, endocrine-disrupting chemicals, pesticides, drugs, pharmaceuticals, lifestyle, air pollutants, and tobacco smoke plays a determinant role in the development of GDM. This phenomenon is worsened by metabolic stress postnatally, such as obesity which increases the risk of GDM and other diseases. Clinical risk factors for GDM development include its aetiology. It is proposed that knowledge-based interventions to change the potential interdependent ecto-exposome and endo-exposome could avoid the occurrence and consequences of GDM.

Do more hours in center-based care cause more externalizing problems? A cross-national replication study.

Whether high quantities of center-based care cause behavior problems is a controversial question. Studies using covariate adjustment for selection factors have detected relations between center care and behavior problems, but studies with stronger internal validity less often find such evidence. We examined whether within-child changes in hours in center-based care predicted changes in externalizing problems in toddlers and preschoolers (N = 10,105; 49% female; data collection 1993-2012) in seven studies, including from Germany, Netherlands, Norway, two from Canada and two from the U.S. Race/ethnicity data were only collected in the United States (57% and 80% White; 42% and 13% African-American; 1.2% and 5% Latinx). Meta-analyses showed no association (r = .00, p = .88) between hours in center-based care and externalizing problems.

The Apapacho Violence Prevention Parenting Program: Conceptual Foundations and Pathways to Scale.

Violence against children (VAC) is a major global issue with long-lasting negative consequences on individuals and societies. The present study presents a review of the literature on drivers of VAC and the core components of evidence-based violence prevention programs. Moreover, it analyzes the existing services and social infrastructure in Colombia to rigorously inform the design of the Apapacho violence prevention parenting program for families with children younger than five targeted toward Colombia. Findings indicate that (1) VAC in Colombia is a multidimensional issue with roots at the individual, family, community, and society levels, (2) evidence-based violence prevention programs share a common set of content and delivery strategies that could inform the components of the Apapacho program, and (3) there is an urgent need for scalable and flexible violence prevention programs for families with young children in Colombia. Considering existing evidence, the Apapacho violence prevention parenting program will be designed using ecological, developmental, and neuroscience-informed perspectives. This article concludes by presenting the initial components of the theory of change and discussing future directions for the design of the Apapacho program and other violence prevention interventions in LMICs.

Measuring the quality of early childhood education: Associations with children's development from a national study with the IMCEIC tool in Colombia.

National-level monitoring of quality of early childhood education (ECE) is key to achieving inclusive and equitable education. Most countries report structural quality while process characteristics are rarely observed at the national level. This study examined the associations between ECE and children's development in a middle-income country using data from a nationally representative sample of public centers serving Colombian children (N = 3163; M = 4.3 years, 50% girls; 42% Mestizo, 16% White, 15% Afro-Colombian, 4% Indigenous, 23% not reported). Descriptive findings evidenced low to moderate quality. Multilevel models showed several positive associations between structural and process quality and child outcomes. Results have implications for the existing literature and highlight the feasibility of quality monitoring in low- and middle-income countries.

cG-CAOMECS-clinical-grade cultured autologous oral mucosal epithelial cell sheet.

The present study reports the feasibility and successful production of rabbit cG-CAOMECS, designed to reconstruct corneal epithelium of patients with bilateral limbal stem cell deficiency. To produce a safe, chemically defined and FDA compliant cG-CAOMECS, oral mucosal epithelial cells were isolated from a biopsy of rabbit buccal tissue and seeded on a cGMP-certified cell culture surface coated with GMP-grade extracellular matrix. A newly designed clinical-grade medium (KaFa™ medium) was utilized to carry out cell expansion. Detachment and harvesting of the produced cell sheet was accomplished using collagenase treatment. Live cell imaging and morphological analysis techniques were used to examine cell growth. Cells attached onto the surface and self-assembled into colony-forming units (CFUs). Microscopic examination showed that CFUs formed during the first 5 days, and basal monolayer cell sheet formed in less than 10 days. Cells expanded to form a multilayered epithelial cell sheet that was harvested after 17-19 days in culture. Immunostaining and Western blot analyses showed that deltaNp63 was expressed in the basal cells and K3/K12 was expressed in the apical cells, indicating the presence of corneal epithelial-like cells in the produced cell sheet. Adhesion molecules, E-cadherin, beta-catenin, and Cnx43 were also expressed and exhibited the epithelial integrity of the cell sheet. The expression of integrin-beta1 and beta4 confirmed that the collagenase treatment used for detaching and harvesting the cell sheet did not have adverse effects. Our results showed that the utilization of clinical-grade and FDA-approved reagents successfully supported the production of cG-CAMECS.

Algorithm to filter the noise in the spectral intensity of ultrashort laser pulses.

We have developed an algorithm to filter the noise in the spectral intensity of ultrashort laser pulses. The filtering procedure consists of smoothing the noise by using the Savitzky-Golay filter, removing the offset, and using a super-Gaussian window to truncate the frequencies of the spectrum. We have modeled bandwidth-limited ultrashort pulses with Gaussian modulated frequencies to show the estimation of the carrier wavelength, reconstruction of the intensity pulse profile, and pulse duration after applying the algorithm. Theoretical results are presented for pulse durations between 5 fs and 100 fs with a carrier wavelength of 825 nm and three different amounts of signal-to-noise ratio (SNR): 30 dB, 20 dB, and 15 dB, normally found in experiments. The algorithm is also applied to an experimental spectral intensity from a homemade Ti:sapphire laser that produces pulses of about 20 fs at 825 nm at 100 MHz. We will show that using only a low-pass Fourier filter and removing offset is not enough to recover the spectral intensity when a large SNR is present, which may be the case when the ultrashort laser beam has been manipulated to compensate for the group velocity dispersion of an external optical system. In cases like this, the use of the Savitzky-Golay filter prior to the super-Gaussian filter improves the recovery of the carrier wavelength and the spectral intensity. We will also show that the algorithm presented in this paper is suitable for experimental analysis and requires limited user intervention.

Maternal knowledge, stimulation, and early childhood development in low-income families in Colombia.

Theoretical models assume that parental knowledge about child development and caregiving motivates parental stimulation, shaping child development. Evidence supporting these models is scarce in low- and middle-income countries (LMICs). This study tests the relations between maternal knowledge, stimulation, and child development in a Colombian sample of 1,277 low-income mothers and their children under the age of five. Mothers showed diverse knowledge about child development and caregiving. Moreover, maternal knowledge when children were 9-26 months old indirectly predicted growth in children's cognitive, receptive language, and gross motor skills at ages 27-46 months, partially through maternal engagement in stimulating activities with the child.

Maternal, paternal, and other caregivers' stimulation in low- and- middle-income countries.

BACKGROUND AND OBJECTIVES: Globally, studies have shown associations between maternal stimulation and early child development. Yet, little is known about the prevalence of paternal and other caregivers' stimulation practices, particularly in low- and- middle-income countries (LMICs). METHODS: Data from the Multiple Indicators Cluster Survey (MICS) and the Demographic and Health Survey (DHS) were combined across 62 LMICs (2010-2018). The sample included 205,150 mothers of children aged 3 and 4 years. High levels of stimulation were defined as caregiver engagement in at least 4 out of 6 possible activities with the child. The proportion of mothers, fathers, and other caregivers providing high levels of stimulation was calculated by country, region, and for the whole sample. Socioeconomic disparities within and between countries were estimated. RESULTS: On average, 39.8% (95% CI 37.4 to 42.2) of mothers, 11.9% (95% CI 10.1 to 13.8) of fathers, and 20.7% (95% CI 18.4 to 23.0) of other adult caregivers provided high levels of stimulation. Stimulation varied by region, country income group, and Human Development Index (HDI), with higher levels of maternal and paternal-but not other caregivers'-stimulation in high-income and high-HDI countries. Within countries, stimulation levels were, on average, lower in the poorest relative to the richest households, and some but not all countries exhibited differences by child sex (i.e., boys vs. girls) or area (i.e., urban vs. rural). CONCLUSIONS: Results suggest a need for intervention efforts that focus on increasing caregiver stimulation in LMICs, particularly for fathers and in low-income contexts.

Simultaneous measurement of DC two-photon absorption signal offset and amplitude of the intensity autocorrelation in the focusing of femtosecond pulses.

In this work, the DC two-photon absorption signal offset (${{\rm DC}_{\rm TPA}}$DCTPA) and the amplitude of the autocorrelation (${{\rm A}_{\rm AC}}$AAC) are measured simultaneously around the focal point of an apochromatic microscope objective using the z-scan autocorrelation technique. The ${{\rm A}_{\rm AC}}$AAC is obtained from the nonlinear sensor response given by the two-photon-absorption, generated in a GaAsP photodiode, for femtosecond laser pulses. We verify that the change in the ${{\rm DC}_{\rm TPA}}$DCTPA signal along $z$z is coincident with the amplitude of the intensity autocorrelation, and that the highest amplitude of the AC is reached at the same position as the highest amplitude of the ${{\rm DC}_{\rm TPA}}$DCTPA signal. The ${{\rm DC}_{\rm TPA}}$DCTPA signal is typically used as a reference for the alignment in a collinear intensity autocorrelator, and we show that it can also be used as a practical procedure to estimate the depth of focus. The ${{\rm DC}_{\rm TPA}}$DCTPA signal measurement allows us to locate the optimum spatial-temporal coupling given by the highest amplitude of the intensity autocorrelation. Additionally, we find a variation in the pulse duration within the same region due to the radially varying group delay dispersion.

Early childhood exposure to non-violent discipline and physical and psychological aggression in low- and middle-income countries: National, regional, and global prevalence estimates.

BACKGROUND: Advocates for children's rights have recommended the elimination of all forms of violent discipline given its detrimental effects on children's development. Yet, little is known about the global prevalence of various forms of discipline, including physical and psychological aggression, as well as alternative forms of non-violent discipline, especially in low- and middle-income countries (LMICs). OBJECTIVE: This study aims to obtain national, regional, and global prevalence estimates of the percentage and number of 2- to- 4-y-olds in LMICs exposed to these disciplinary practices by their caregivers. PARTICIPANTS AND SETTING: We use data collected between 2010 and 2016 from 107,063 2- to- 4-y-old children living in 49 LMICs as part of the Multiple Indicator Cluster Survey (MICS). METHODS: Using the best-fitting model based on cross-validation techniques, we performed predictive modeling to generate country-level prevalence estimates for 131 LMICs in 2013, as well as 95% confidence intervals around these estimates. RESULTS: We estimate that 296.2 million 2- to- 4-y-olds (95% CI 256.9, 300.9) were exposed to non-violent discipline in 2013, which corresponds to 83.9% of the population. Furthermore, 220.4 million (95% CI 138.1, 283.7) and 230.7 million (95% CI 128.4, 300.6) children were exposed to aggressive physical and psychological discipline, respectively, which corresponds to prevalence of 62.5% and 65.4%. We also identify a high heterogeneity in the estimates across and within regions, finding a higher prevalence of both violent disciplinary methods in South Asia and Sub-Saharan Africa. CONCLUSIONS: These results suggest the need for new policies and programs to minimize violent discipline around the world.

Mode-coupling enhancement by pump astigmatism correction in a Ti:Sapphire femtosecond laser.

To pump a solid-state femtosecond laser cavity, a beam from a CW laser is focused by a single lens into the laser crystal. To increase the output power of the laser, the overlap of the laser mode with the pump mode should be maximized. This is particularly important in the so-called mode coupling and the Kerr-lens mode locking (KLM) operation, where the change in beam waist at the position of the gain medium is exploited to enhance the mode overlap with the pump laser in the crystal. In this paper, the astigmatism in the pump beam is reduced by tilting the pump lens. A Gaussian beam is propagated through the complete focusing system-pump lens, tilted spherical mirror, and crystal cut at Brewster's angle-to show the astigmatism inside the crystal as a function of the tilt of the pump lens. A genetic algorithm is presented to optimize the mode coupling between the pump and laser beam inside the crystal by tilting the pump lens. Experimental results are presented to verify the design, showing an increase in the output power of the laser cavity of about 20%.

Teflon Injection into the Trachea Causes Predictable Fibroblastic Response and Collagen Deposition: A Pilot Study.

BACKGROUND: Expiratory central airway collapse is an increasingly recognized abnormality of the central airways and may be present in as many as 22% of patients evaluated for chronic obstructive pulmonary disease and/or asthma. Many current treatment options require invasive procedures that have been shown to cause significant morbidity and mortality. To test the hypothesis that Teflon injection will induce sufficient fibroblast proliferation and collagen deposition, we evaluated the time course on the effect of Teflon injection in the posterior membranous trachea on the histopathology of the tracheobronchial tree. METHODS: Six Yucatan Pigs were assigned to undergo general anesthesia and injection of 0.3 to 0.5 mL of sterile Teflon paste in 50% glycerin into the posterior membranous tracheal wall. A control pig received an equivalent volume of glycerin. Animals were euthanized in predefined intervals and tracheas were excised and examined under light microscopy for identifying fibroblast proliferation and collagen deposition. RESULTS: Compared with the control pig, the Teflon injection site showed tissue reaction of fibrohistiocytic proliferation and subsequent collagen deposition in all animals. Furthermore, the increased fibroblast proliferation and collagen deposition were time dependent (P<0.01). CONCLUSION: This pilot study demonstrates histopathologic changes in the trachea after Teflon injection, comprised of increased fibroblast activity and collagen deposition that could be of potential use in creating greater airway rigidity in patients with sever diffuse excessive dynamic airway collapse.

Thalamic mediation of hypoxic respiratory depression in lambs.

Immaturity of respiratory controllers in preterm infants dispose to recurrent apnea and oxygen deprivation. Accompanying reductions in brain oxygen tensions evoke respiratory depression, potentially exacerbating hypoxemia. Central respiratory depression during moderate hypoxia is revealed in the ventilatory decline following initial augmentation. This study determined whether the thalamic parafascicular nuclear (Pf) complex involved in adult nociception and sensorimotor regulation (Bentivoglio M, Balerecia G, Kruger L. Prog Brain Res 87: 53-80, 1991) also becomes a postnatal controller of hypoxic ventilatory decline. Respiratory responses to moderate isocapnic hypoxia were studied in conscious lambs. Hypoxic ventilatory decline was compared with peak augmentation. Pf and/or adjacent thalamic structures were destroyed by the neuron-specific toxin ibotenic acid (IB). IB lesions involving the thalamic Pf abolished hypoxic ventilatory decline. Lesions of adjacent thalamic nuclei that spared Pf and control injections of vehicle failed to blunt hypoxic respiratory depression. Our findings reveal that the thalamic Pf region is a critical controller of hypoxic ventilatory depression and thus a key target for exploring molecular concomitants of forebrain pathways regulating hypoxic ventilatory depression in early development.

Intra-articular enzyme replacement therapy with rhIDUA is safe, well-tolerated, and reduces articular GAG storage in the canine model of mucopolysaccharidosis type I.

BACKGROUND: Treatment with intravenous enzyme replacement therapy and hematopoietic stem cell transplantation for mucopolysaccharidosis (MPS) type I does not address joint disease, resulting in persistent orthopedic complications and impaired quality of life. A proof-of-concept study was conducted to determine the safety, tolerability, and efficacy of intra-articular recombinant human iduronidase (IA-rhIDUA) enzyme replacement therapy in the canine MPS I model. METHODS: Four MPS I dogs underwent monthly rhIDUA injections (0.58 mg/joint) into the right elbow and knee for 6 months. Contralateral elbows and knees concurrently received normal saline. No intravenous rhIDUA therapy was administered. Monthly blood counts, chemistries, anti-rhIDUA antibody titers, and synovial fluid cell counts were measured. Lysosomal storage of synoviocytes and chondrocytes, synovial macrophages and plasma cells were scored at baseline and 1 month following the final injection. RESULTS: All injections were well-tolerated without adverse reactions. One animal required prednisone for spinal cord compression. There were no clinically significant abnormalities in blood counts or chemistries. Circulating anti-rhIDUA antibody titers gradually increased in all dogs except the prednisone-treated dog; plasma cells, which were absent in all baseline synovial specimens, were predominantly found in synovium of rhIDUA-treated joints at study-end. Lysosomal storage in synoviocytes and chondrocytes following 6 months of IA-rhIDUA demonstrated significant reduction compared to tissues at baseline, and saline-treated tissues at study-end. Mean joint synovial GAG levels in IA-rhIDUA joints were 8.62 ± 5.86 µg/mg dry weight and 21.6 ± 10.4 µg/mg dry weight in control joints (60% reduction). Cartilage heparan sulfate was also reduced in the IA-rhIDUA joints (113 ± 39.5 ng/g wet weight) compared to saline-treated joints (142 ± 56.4 ng/g wet weight). Synovial macrophage infiltration, which was present in all joints at baseline, was abolished in rhIDUA-treated joints only. CONCLUSIONS: Intra-articular rhIDUA is well-tolerated and safe in the canine MPS I animal model. Qualitative and quantitative assessments indicate that IA-rhIDUA successfully reduces tissue and cellular GAG storage in synovium and articular cartilage, including cartilage deep to the articular surface, and eliminates inflammatory macrophages from synovial tissue. CLINICAL RELEVANCE: The MPS I canine IA-rhIDUA results suggest that clinical studies should be performed to determine if IA-rhIDUA is a viable approach to ameliorating refractory orthopedic disease in human MPS I.

90% hepatectomy with a porto-hepatic shunt in a canine model: a feasibility study.

BACKGROUND: We postulated that a surgical shunt between the portal and hepatic veins (portohepatic shunt) could improve the function and regeneration of the liver remnant after extensive hepatic resection. Using a canine model, we designed a survival study to test the feasibility of 90% hepatectomy with a portohepatic shunt. Of eight mixed-hound canines, it was necessary to sacrifice two animals for postmortem study of hepatic anatomy; we used the results to design a procedure for removing all of the liver except portions of two lobes. We tested this 90% hepatectomy procedure under general anesthesia in the remaining animals, with (N=3) or without (N=3) a portohepatic shunt. We monitored animals postoperatively with serial liver biochemical testing, and sacrificed on postoperative day 48. Assessment of liver regeneration was by weight after complete postmortem hepatectomy. Extended hepatectomy removed four complete lobes and portions of the right lateral and caudate lobes. For the portohepatic shunt, we anastomosed the left portal vein branch to the left hepatic vein branch. All procedures were performed successfully. One no-shunt animal expired on the second postoperative day. We thus confirmed the feasibility of 90% hepatectomy with portohepatic shunt in the canine model. If the efficacy of shunting is validated in a larger study population, it may increase the indications for extensive resection in patients with advanced hepatic malignancy.

Glycosaminoglycan storage in neuroanatomical regions of mucopolysaccharidosis I dogs following intrathecal recombinant human iduronidase.

Intrathecal (IT) recombinant human α-l-iduronidase (rhIDU) has been shown to reduce mean brain glycosaminoglycans (GAGs) to normal levels in mucopolysaccharidosis I (MPS I) dogs. In this study, we examined storage in neuroanatomical regions of the MPS I dog brain, including frontal lobe, cerebellum, basal ganglia, thalamus, hippocampal formation, and brainstem, to determine the response of these functional regions to treatment with IT rhIDU. GAG storage in untreated MPS I dogs was significantly different from normal dogs in all examined sections. GAG levels in normal dogs varied by region: frontal lobe (mean: 2.36 ± 0.54 µg/mg protein), cerebellum (2.67 ± 0.33), basal ganglia and thalamus (3.51 ± 0.60), hippocampus (3.30 ± 0.40), and brainstem (3.73 ± 1.10). Following IT treatment, there was a reduction in GAG storage in each region in all treatment groups, except for the brainstem. Percent reduction in GAG levels from untreated to treated MPS I dogs in the deeper regions of the brain was 30% for basal ganglia and thalamus and 30% for hippocampus, and storage reduction was greater in superficial regions, with 61% reduction in the frontal lobe and 54% in the cerebellum compared with untreated MPS I dogs. Secondary lipid storage in neurons was also reduced in frontal lobe, but not in the other brain regions examined. Response to therapy appeared to be greater in more superficial regions of the brain, particularly in the frontal lobe cortex.

Early versus late treatment of spinal cord compression with long-term intrathecal enzyme replacement therapy in canine mucopolysaccharidosis type I.

Enzyme replacement therapy (ERT) with intravenous recombinant human alpha-l-iduronidase (IV rhIDU) is a treatment for patients with mucopolysaccharidosis I (MPS I). Spinal cord compression develops in MPS I patients due in part to dural and leptomeningeal thickening from accumulated glycosaminoglycans (GAG). We tested long-term and every 3-month intrathecal (IT) and weekly IV rhIDU in MPS I dogs age 12-15months (Adult) and MPS I pups age 2-23days (Early) to determine whether spinal cord compression could be reversed, stabilized, or prevented. Five treatment groups of MPS I dogs were evaluated (n=4 per group): IT+IV Adult, IV Adult, IT + IV Early, 0.58mg/kg IV Early and 1.57mg/kg IV Early. IT + IV rhIDU (Adult and Early) led to very high iduronidase levels in cervical, thoracic, and lumber spinal meninges (3600-29,000% of normal), while IV rhIDU alone (Adult and Early) led to levels that were 8.2-176% of normal. GAG storage was significantly reduced from untreated levels in spinal meninges of IT + IV Early (p<.001), IT+IV Adult (p=.001), 0.58mg/kg IV Early (p=.002) and 1.57mg/kg IV Early (p<.001) treatment groups. Treatment of dogs shortly after birth with IT+IV rhIDU (IT + IV Early) led to normal to near-normal GAG levels in the meninges and histologic absence of storage vacuoles. Lysosomal storage was reduced in spinal anterior horn cells in 1.57mg/kg IV Early and IT + IV Early animals. All dogs in IT + IV Adult and IV Adult groups had compression of their spinal cord at 12-15months of age determined by magnetic resonance imaging and was due to protrusion of spinal disks into the canal. Cord compression developed in 3 of 4 dogs in the 0.58mg/kg IV Early group; 2 of 3 dogs in the IT + IV Early group; and 0 of 4 dogs in the 1.57mg/kg IV Early group by 12-18months of age. IT + IV rhIDU was more effective than IV rhIDU alone for treatment of meningeal storage, and it prevented meningeal GAG accumulation when begun early. High-dose IV rhIDU from birth (1.57mg/kg weekly) appeared to prevent cord compression due to protrusion of spinal disks.

Programmed syndrome of hypernatremic hypertension in ovine twin lambs.

OBJECTIVE: An increased risk of adult hypertension, obesity, and coronary heart disease occurs in low birth weight or intrauterine growth-restricted newborn infants as a result of fetal programming. Human twins represent a natural model of low birth weight and intrauterine growth restriction because they are significantly smaller at birth than singleton infants because of both earlier delivery and reduced intrauterine growth. Increased blood pressure has been reported in several epidemiologic studies of human twin offspring, although this has not been confirmed in an animal model. Because the sheep pregnancy consists of singleton and twin litters, we sought to determine the impact of ovine twin gestation and twin nursing on the cardiovascular and renal function of the offspring. STUDY DESIGN: Newborn lambs (n = 12) were studied at 21 +/- 2 day of life. Both singleton (n = 6) and twin lambs (n = 6) were born to ewes provided ad libitum water and food throughout gestation. After the delivery, ewes were provided ad libitum water and food, and newborn lambs were allowed ad libitum nursing with the maternal ewe. At 15 +/- 2 days of age, the lambs were prepared with vascular and renal catheters and studied at 21 +/- 2 days. After a 2-hour basal period, lambs received an intravenous infusion of hypotonic (0.075 mol/L) NaCl (0.15 ml/kg/hr) for an additional 2 hours. Newborn arterial blood pressure, heart rate, and urine flow were monitored continuously, and arterial blood samples were obtained before, during, and after the infusion. RESULTS: At birth, twin lambs weighed 30% less than singleton lambs (3.5 +/- 0.1 kg vs 5.0 +/- 0.2 kg; P < .05), although 50% less at 21 days (5.2 +/- 0.6 vs 10.8 +/- 1.2 kg). There were marked differences in basal arterial blood values between twin and singleton lambs at 21 days, with twins having significantly increased plasma sodium and systolic, diastolic, and mean arterial pressures and reduced glomerular filtration rates, urine osmolality, osmolar excretion, and osmolar clearance (per kg body weight) compared with singleton lambs. In response to hypotonic saline solution infusion, the plasma composition and blood pressure differences between twin and singleton lambs persisted. CONCLUSION: These results indicate that ovine twin gestation and nursing markedly reduced body weight at 21 days of age, with evidence of plasma hypernatremia, hypertension, and reduced glomerular filtration rates, which persisted throughout hypotonic saline solution infusion. Consistent with epidemiologic studies of humans, these results demonstrate that gestational/newborn nutrient stress may program hypertension in offspring.