Exploring the impact of antenatal micronutrients used as a treatment for maternal depression on infant temperament in the first year of life.

Antenatal depression and maternal nutrition can influence infant temperament. Although broad-spectrum-micronutrients (BSM: vitamins and minerals) given above Recommended Dietary Allowances during pregnancy can mitigate symptoms of antenatal depression, their associated effects on infant temperament are unknown. One hundred and fourteen New Zealand mother-infant dyads (45 infants exposed to BSM during pregnancy (range of exposure during pregnancy: 12-182 days) to treat antenatal depressive symptoms (measured by Edinburgh Postnatal Depression Scale) and 69 non-exposed infants) were followed antenatally and for 12 months postpartum to determine the influence of in utero BSM exposure on infant temperament. The Infant Behavior Questionnaire-Revised: Very Short-Form assessed temperament at 4 (T1), 6 (T2) and 12 (T3) months postpartum via online questionnaire. Latent growth curve modeling showed BSM exposure, antenatal depression and infant sex did not statistically significantly predict initial levels or longitudinal changes in orienting/regulatory capacity (ORC), positive affectivity/surgency (PAS) or negative affectivity (NEG). Higher gestational age was positively associated with initial PAS, and smaller increases between T1 and T3. Breastfeeding occurrence was positively associated with initial NEG. Although not significant, BSM exposure exerted small, positive effects on initial NEG (ß = -0.116) and longitudinal changes in ORC (ß = 0.266) and NEG (ß = -0.235). While BSM exposure did not significantly predict infant temperament, it may mitigate risks associated with antenatal depression. BSM-exposed infants displayed temperamental characteristics on par with typical pregnancies, supporting the safety of BSM treatment for antenatal depression.

Effect of antenatal micronutrient or antidepressant exposure on Brazelton neonatal behavioral assessment scale (NBAS) performance within one-month of birth.

BACKGROUND: Antenatal depression is a risk factor for poor infant outcomes. Broad-spectrum-micronutrients (vitamins and minerals) have shown efficacy in treating psychiatric symptoms in non-pregnant populations and are associated with reduced incidence of adverse birth outcomes, and improvements in neonatal development. We investigated the effects of treatment of antenatal depression with micronutrients above the Recommended Dietary Allowance on infant development compared to treatment with antidepressant medications and controls. METHOD: One-hundred-and-three infants were assessed using the Brazelton Neonatal Behavioral Assessment Scale (NBAS) within 28 days of birth: 37 exposed to micronutrients in-utero (50-182 days exposure), 18 to antidepressants in-utero (exposure for full gestation), and 48 controls whose mothers received neither treatment nor experienced depressive symptoms. RESULTS: Controlling for gestational age and parity, there were significant group differences on habituation, orientation, motor, state regulation, autonomic stability and reflexes (p < .05). Micronutrient-exposed performed better than antidepressant-exposed and controls on habituation, motor and autonomic stability (p < .05), effect sizes ranged 1.0-1.7 and 0.5-1.0, respectively. Antidepressant-exposed performed significantly worse on orientation and reflexes compared to micronutrient-exposed and controls. Micronutrient-exposed had significantly better state regulation compared to antidepressant-exposed. There was an association between micronutrient exposure length and better habituation (r = 0.41, p = .028). Micronutrient exposure was generally identified as a stronger predictor of neonatal performance over maternal depression, social adversity, gestational age and infant sex. CONCLUSION: In-utero micronutrient exposure appears to mitigate risks of depression on infant outcomes showing positive effects on infant behavior, on par with or better than typical pregnancies and superior to antidepressants. Limitations include differential exposure to micronutrients/antidepressants and lack of group blinding.

Mice with altered alpha-actinin-4 expression have distinct morphologic patterns of glomerular disease.

Mutations in ACTN4, encoding the actin-binding protein alpha-actinin-4, cause a form of familial focal segmental glomerulosclerosis. We had developed two strains of transgenic mice with distinct alterations in the expression of alpha-actinin-4. One strain carried a human disease-associated mutation in murine Actn4, whereas the other knockout strain did not express alpha-actinin-4 protein. Most adult homozygous Actn4 mutant and knockout mice developed collapsing glomerulopathy. Homozygous Actn4 mutant mice also exhibited actin and alpha-actinin-4-containing electron-dense cytoplasmic structures, that were present but less prominent in heterozygous Actn4 mutant mice and not consistently seen in wild-type or knockout mice. Heterozygous Actn4 mutant mice did not develop glomerulosclerosis, but did exhibit focal glomerular hypertrophy and mild glomerular ultrastructural changes. The ultrastructural abnormalities seen in heterozygous Actn4 mutant mice suggest low-level glomerular damage, which may increase susceptibility to injury caused by genetic or environmental stressors. Our studies show that different genetic defects in the same protein produce a spectrum of glomerular morphologic lesions depending on the specific combination of normal and/or defective alleles.

Leucine-rich repeat-containing G-protein-coupled receptor 8 in the rat brain: Enrichment in thalamic neurons and their efferent projections.

Leucine-rich repeat-containing G-protein-coupled receptor 8 (LGR8; also classified as relaxin family peptide 2 receptor; RXFP2) has been identified as a cognate receptor for the peptide hormone, insulin-like peptide 3 (INSL3) and INSL3-LGR8 signaling plays an essential role in testis descent and germ cell development in human and rodents. Lgr8 mRNA has been detected in human tissues including testis, kidney and brain, but its regional and cellular distribution in these tissues in human or other species is largely unknown. In an initial step to elucidate the physiological function of a putative INSL3-LGR8 system in rat brain, the localization of Lgr8 mRNA was investigated using in situ hybridization histochemistry, revealing a discrete distribution in forebrain, with expression highly enriched in the thalamus. High densities were detected in the parafascicular nucleus (Pf), the dorsolateral, ventrolateral and posterior thalamic nuclei, and in the medial habenula. Lgr8 transcripts were also detected in frontal and motor cortices. The comparative distribution of LGR8 (receptor protein) was examined by autoradiography of [125I]-human INSL3 binding sites, with high densities detected in the thalamus, especially in Pf, and in the entire striatum--the caudate putamen (CPmicro), islands of Calleja, olfactory tubercle, nucleus accumbens--with lower levels in distinct layers of cerebral cortex. Notably, these areas also receive dopaminergic projections. These findings demonstrate the existence of LGR8 in neuronal soma in the thalamus and axons/terminals in thalamic target areas such as the striatum and frontal cortex. LGR8 was also detected throughout the medial habenula-fasciculus retroflexus-interpeduncular nucleus pathway, further indicating that the receptor is transported from mRNA-expressing soma to remote axonal/terminal sites. These findings suggest the existence of a broadly distributed LGR8 signaling system in the rat involved in sensorimotor, limbic and cognitive functions. Further studies are now required to elucidate the precise function of LGR8, under normal and pathological conditions, as importantly, several of the equivalent receptor-positive areas in human brain are part of the pathology of neurodegenerative conditions including Parkinson's disease.

Neuroprotective effects of a selective N-methyl-D-aspartate NR2B receptor antagonist in the 6-hydroxydopamine rat model of Parkinson's disease.

1. Current pharmacotherapies for the treatment of Parkinson's disease (PD) are largely symptomatic and do not attenuate the characteristic nigral (dopamine) cell loss. 2. Using the 6-hydroxydopamine (6-OHDA) rat model of PD, we investigated the novel, potentially neuroprotective compound BZAD-01, which is an N-methyl-D-aspartate (NMDA) glutamate receptor antagonist selective for the NR2B subunit. 3. Forty female Sprague-Dawley rats were pretreated with either 10 mg/kg BZAD-01 or vehicle (5% sucrose and 0.1% ascorbate) in their drinking water for 11 days prior to and for 3 days following 6-OHDA surgery. During surgery, rats received an injection of either a toxic dose of 16 microg 6-OHDA or a non-toxic dose of 1 microg 6-OHDA (sham) into the medial forebrain bundle. A series of behavioural tests, including curling (measuring body axis bias), head position bias and narrow beam, was performed fortnightly for 8 weeks after surgery to assess the effects of BZAD-01 pretreatment on parkinsonism. Drug-induced rotational asymmetry was also assessed just before rats were killed. Post-mortem immunohistochemistry was performed to quantify the degree of nigral dopamine cell loss. 4. Pretreatment of 6-OHDA-lesioned rats with BZAD-01 significantly reduced the amount of dopamine cell loss and significantly improved all behavioural measures. Furthermore, there was no significant difference in any of the behavioural measures between lesioned rats pretreated with BZAD-01 and rats that underwent sham surgery.

Developing a preclinical model of Parkinson's disease: a study of behaviour in rats with graded 6-OHDA lesions.

Injection of increasing concentrations of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB) can be used to establish a graded model of different clinical stages of Parkinson's disease (PD). We investigated the relationship between behavioural alterations and loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Forty female Sprague-Dawley rats were injected with either (i) 4 microg (ii) 8 microg or (iii) 16 microg 6-hydroxydopamine (6-OHDA) to mimic the preclinical, mild and advanced clinical stages of PD, respectively. Vehicle was injected in a separate control group. Behaviours analysed included postural asymmetry, balance, locomotion, sensorimotor deficits and apomorphine rotation. At post-mortem the degree of tyrosine immunoreactive dopaminergic cell (TH-ir) loss was then estimated. There was a graded and consistent trend in each of the behaviours studied with respect to cell loss between the different sized lesion groups when examined using correlation analysis (all comparisons, r > 0.8, p < 0.001). Rats with large lesions demonstrated more significant behavioural changes over 8 weeks of testing than those with intermediate and smaller lesions (group comparisons p < 0.001). PD symptomatology became overt when cell loss reached 70%, however some significant changes can be observed with as little as 40% dopaminergic cell loss. Thus, injection with increasing concentrations 6-OHDA into the MFB can produce increasing extents of cell loss and behavioural changes, which were well correlated. This graded model can be useful for testing potential neuroprotective compounds for PD.

Patient and disease factors predictive of adverse perioperative outcomes after nephrectomy.

INTRODUCTION: The aim of this study was to determine the patient and disease factors predictive of adverse perioperative outcomes after nephrectomy using the British Association of Urological Surgeons (BAUS) audit database. METHODS: All nephrectomies entered on the BAUS database for the year 2012 were included and ten patient or disease factors were selected for analysis. Logistic regression was used to calculate the area under the receiver operating characteristic curve (AUC) (0.5 = no better than chance, 1.0 = perfect prediction) for each variable and 500 bootstrap samples were used to determine variable selection. RESULTS: Data were captured for 6,031 nephrectomies in 2012. World Health Organization performance status (WHO-PS) (AUC: 0.733) and anaemia (AUC: 0.696) were the most significant predictors of 30-day mortality in univariate analysis. WHO-PS (AUC: 0.626) and anaemia (AUC: 0.590) also predicted complications classified as Clavien-Dindo grades III-V. Anaemia (AUC: 0.722) and clinical T stage (AUC: 0.713) predicted need for transfusion. CONCLUSIONS: Adverse perioperative outcomes after nephrectomy are predicted by clinical presentation with haematuria, poor WHO-PS and higher TNM (tumour, lymph nodes, metastasis) stage. This study used surgeon collected data as opposed to an administrative database, which may have advantages in terms of accuracy and breadth of data fields. These data form a basis for preoperative patient counselling and informed consent for nephrectomy. They can also be used as a standard against which surgeons and hospitals can compare their own results.

Behavioural effects of parafascicular thalamic lesions in an animal model of parkinsonism.

We recently reported that the centromedian-parafascicular thalamic complex (CM-Pf) degenerates in Parkinson's disease and progressive supranuclear palsy. The contribution of such thalamic pathology to disease symptoms has not yet been established. The present study therefore investigated the behavioural impact of lesioning the corresponding thalamic region (termed Pf) on a range of behaviours present in rodents. There were four surgical groups: (1) sham medial forebrain bundle (mfb)+sham Pf, (2) 6-OHDA mfb lesion+sham Pf, (3) sham mfb+NMDA Pf lesion, (4) 6-OHDA+NMDA Pf lesions. Posture, sensory functions and apomorphine-induced rotational asymmetry were assessed before and after each surgery. Other assessments performed including a timed motivational task, grooming behaviours and piloerection. 6-OHDA lesions induced postural (ipsilateral curling and head position biases), sensorimotor (increased latency to respond to tactile stimulation of the contralateral side when eating or grooming) and rotational abnormalities (contralateral circling after apomorphine). The main effects of combined 6-OHDA+Pf lesions were improved performance in a motivational task (decreased latency to retrieve reward) but worsened piloerection, relative to animals with either 6-OHDA or Pf lesions alone. The thalamic zone common to all lesioned animals involved the posterior Pf. Our data suggests that the posterior CM-Pf may be involved in motivational responses and autonomic dysfunction in parkinsonian disorders.

Enteral hyperalimentation in undernourished patients with cirrhosis and ascites.

Available enteral hyperalimentation solutions used to treat undernourished cirrhotic, ascitic patients with protein intolerance are excessive in water, sodium, and in some cases protein. This study investigated the use of enteral formulae tailored to the water, sodium, and protein tolerance of 10 undernourished subjects with ascites due to alcoholic liver disease (n = 8) and postnecrotic cirrhosis (n = 2). During a 10- to 60-day (mean +/- 80 = 37 +/- 19) hyperalimentation period, three subjects were treated with a low Na (1g Na/2000 kcal), high caloric density formula (2 kcal/ml); previous encephalopathy in seven remaining subjects required infusion of a low Na, low protein (40 g/day) modular high caloric density formula. The high caloric density formula protein content in 6/7 subjects was increased to 80 to 143 g without adverse effect. Nine subjects tolerated the program well and showed improvement in the following indices: serum albumin, creatinine/height, and midarm muscle and fat areas. In selected cases, enteral hyperalimentation solutions with appropriate composition can be safely and effectively administered to cachectic cirrhotic subjects with ascites.

Activities of the hepatic enzymes of vitamin B6 metabolism for patients with cirrhosis.

Patients with cirrhosis and other hepatic diseases frequently exhibit lower concentrations of plasma pyridoxal 5'-phosphate (PLP), which is derived primarily from liver. To determine the biochemical basis for this abnormality, the enzymes of vitamin B6 metabolism--pyridoxal kinase, pyridoxine (pyridoxamine) 5'-phosphate oxidase, PLP phosphatase(s), and pyridoxal oxidase(s)--were analyzed in liver. The activities of the two biosynthetic enzymes, pyridoxal kinase and pyridoxine (pyridoxamine) 5'-phosphate oxidase were similar for both. The phosphatase activities were significantly higher (mean +/- SD of 9.55 +/- 8.03 versus 3.97 +/- 2.36 nmol X min X mg protein, p less than 0.05) for cirrhotics. Pyridoxal oxidase activities appeared slightly lower for cirrhotics. There was considerable variation in many indices of liver function, which suggests that the defects contributing to altered vitamin B6 metabolism may be complex and individualistic. These analyses have shown that cirrhotics are capable of apparently normal PLP synthesis and that increased hepatic dephosphorylation may be responsible for low levels of plasma PLP.

Lesion of thalamic centromedian--parafascicular complex after chronic deep brain stimulation.

A patient with PD who exhibited disabling tremor and prominent dyskinesia underwent deep brain stimulation (DBS) of the left thalamic ventral intermediate nucleus. The electrode migrated and was replaced but with suboptimal clinical response. Two years later, postmortem analysis found the second electrode tip had entered the thalamic centromedian-parafascicular complex. There was a small thalamotomy and cell loss exceeding that found in PD. Thalamic damage may occur in association with DBS for PD.

The prevalence of coronary artery disease in liver transplant candidates over age 50.

The prevalence of angiographically proven coronary artery disease (CAD) in adults with end-stage liver disease who undergo evaluation for liver transplantation is unknown; also it is unclear if cholestatic liver disease represents an independent risk factor. Patients with end-stage liver disease over age 50 having liver transplantation were studied using coronary angiography. Arterial stenosis was graded as normal, mild (< 30%), moderate (30 to 70%), or severe (> 70%). Risk factors for CAD were also assessed (male sex, smoking, hypertension, diabetes, family history of premature heart disease). Complications related to the angiography and decision making based on the findings were recorded. Thirty seven patients (23 females) with a median age of 61 years (range 50 to 71) underwent angiography. Thirteen patients (35.1%) had cholestatic liver disease. Thirty patients had no history of heart disease. The overall prevalence of severe coronary artery disease was 16.2% (95% confidence interval [CI] = 6.2% to 32.0%). No association was detected between CAD and cholestatic liver disease (P = 0.72). After eliminating seven patients with a prior history of angina (n = 1), myocardial infarction (n = 1), or coronary revascularization (n = 5), the frequency of moderate or severe CAD was 13.3% (95% CI = 3.8% to 30.7%). No association was detected between unsuspected CAD and cholestatic liver disease (P = 0.61). Diabetes was the most important risk factor for moderate or severe disease (P = 0.01). Patients without risk factors had significantly less CAD than the group as a whole regardless of the liver disease type (P = 0.02). Two patients experienced transient renal insufficiency after the angiography. Three patients with severe CAD were denied transplantation. We conclude that CAD represents a significant problem in patients over age 50 undergoing liver transplant evaluation. Cholestatic liver disease was not associated with a significantly higher prevalence of moderate or severe CAD in our population. Diabetes was the most predictive risk factor, and those without risk factors do not require extensive preoperative cardiac evaluation.

Salvage therapies for refractory variceal hemorrhage.

Refractory variceal bleeding is defined as bleeding that continues through adequate pharmacologic and endoscopic therapy. In patients with end-stage liver disease, the only option for long-term salvage is liver transplantation. In patients with well-preserved liver function (Child's class A and class B-7), other salvage options such as surgical shunt, TIPS, and devascularization procedures can achieve good outcome. The long-term survival depends on the underlying liver disease, rather than on the variceal bleeding per se.

The role of surgery in the treatment of portal hypertension.

The role of surgery in the treatment of portal hypertension continues to evolve. Pharmacologic and endoscopic therapies are the primary treatment modalities for the prophylaxis and treatment of variceal bleeding and ascites. Failure of these therapies is the indication for invasive intervention such as TIPS, surgical shunt, or devascularization. Distal splenoreal shunting provides selective variceal decompression with less encephalopathy and accelerated hepatic failure than portal decompression. Liver transplantation remains the treatment of choice for patients with poor hepatic function.

Two representational systems in dynamic visual identification.

How does the visual system retain and combine information about an object across time and space? This question was investigated by manipulating the spatiotemporal continuity and form continuity of 2 perceptual objects over time. In Experiment 1 the objects were viewed in central vision within a single eye fixation, in Experiment 2 they were viewed across a saccadic eye movement, and in Experiment 3 they were viewed at different spatial and retinal locations over time. In all 3 experiments some information about the object was found to be linked to its spatiotemporal continuity, and some information was found to be independent of spatiotemporal continuity. Form continuity was found to produce no effect. The results support a theory of dynamic visual identification according to which information is maintained over time both by episodic object representations and long-term memory representations, neither of which necessarily code specific sensory information.

Does consistent scene context facilitate object perception?

The conclusion that scene knowledge interacts with object perception depends on evidence that object detection is facilitated by consistent scene context. Experiment 1 replicated the I. Biederman, R. J. Mezzanotte, and J. C. Rabinowitz (1982) object-detection paradigm. Detection performance was higher for semantically consistent versus inconsistent objects. However, when the paradigm was modified to control for response bias (Experiments 2 and 3) or when response bias was eliminated by means of a forced-choice procedure (Experiment 4), no such advantage obtained. When an additional source of biasing information was eliminated by presenting the object label after the scene (Experiments 3 and 4), there was either no effect of consistency (Experiment 4) or an inconsistent object advantage (Experiment 3). These results suggest that object perception is not facilitated by consistent scene context.

Vitamin B6 metabolism by human liver.

The B6 vitamers (pyridoxine, pyridoxamine, and pyridoxal) are primarily metabolized in liver to pyridoxal 5'-phosphate (PLP) and the deadend catabolite 4-pyridoxic acid. We have built on the elegant early work of Snell and others to describe the activities of the human liver enzymes responsible for vitamin B6 metabolism and to develop a model of the relative rates of these interconversions in vivo. This model is consistent with changes in plasma B6 after a load, the clearance of different vitamers (e.g., pyridoxine versus pyridoxal), and with the low plasma PLP in patients with cirrhosis. Because cirrhotics were found to be capable of PLP synthesis, we have used oral supplementation with pyridoxine to restore plasma PLP to the normal range, and have evaluated the effects of this intervention on amino acid metabolism. No significant differences were observed in plasma or urinary clearance of methionine (or cystathionine) after an oral load, nor in amino acid clearance from circulation after a protein load for cirrhotic patients before and after restoration of normal plasma PLP. Hence, the abnormal metabolism of vitamin B6 does not appear to be an important factor in the deranged amino acid metabolism in this disease. Nonetheless, this approach may be generally useful in assessing the importance of PLP in other abnormalities.

Surgical shunts and TIPS for variceal decompression in the 1990s.

BACKGROUND: In the 1990s, liver transplantations and transjugular intrahepatic portosystemic shunts (TIPS) have become the most common methods to decompress portal hypertension. This center has continued to use surgical shunts for variceal bleeding in good-risk patients who continue to bleed through endoscopic and pharmacologic treatment. This article reports this center's experience with surgical shunts and TIPS shunts from 1992 through 1999. METHODS: Sixty-three patients (Child A, 43 patients; Child B, 20 patients) received surgical shunts: distal splenorenal, 54 patients; splenocaval, 4 patients; coronary caval, 1 patient; and mesocaval, 4 patients. Sixty-two patients had refractory variceal bleeding, and 1 patient had ascites with Budd-Chiari syndrome. Two hundred patients (Child A, 24 patients; Child B, 62 patients; Child C, 114 patients) received TIPS shunts. One hundred forty-nine patients had refractory variceal bleeding, and 51 patients had ascites, hydrothorax, or hepatorenal syndrome. Data were collected by prospective databases, protocol follow-up, and phone contact. RESULTS: The 30-day mortality rate was 0% for surgical shunts and 26% for TIPS shunts; the overall survival rate was 86% (median follow-up, 36 months) for surgical shunts and 53% (median follow-up, 40 months) for TIPS shunts. For surgical shunts, the portal hypertensive rebleeding rate was 6.3%; the overall rebleeding rate was 14.3%. For TIPS shunts, the overall rebleeding rate was 25.5% (30-day, 9.4%; late, 22.4%). There were 4 reinterventions for surgical shunts (6.3%); the reintervention rate for TIPS shunts in the bleeding group was 33%, and the reintervention rate in the ascites group was 9.5%. Encephalopathy was severe in 3.1% of the shunt group and mild in 17.5%; this was not systematically evaluated in the TIPS shunts patients. CONCLUSIONS: Surgical shunts still have a role for patients whose condition was classified as Child A and B with refractory bleeding, who achieve excellent outcomes with low morbidity and mortality rates. TIPS shunts have been used in high-risk patients with significant early and late mortality rates and have been useful in the control of refractory bleeding and as a bridge to transplantation. The comparative role of TIPS shunts versus surgical shunt in patients whose condition was classified as Child A and B is under study in a randomized controlled trial.

Liver resection using total vascular exclusion.

BACKGROUND: Total vascular exclusion (TVE) is a technique of liver resection that includes controlling both the suprahepatic and infrahepatic vena cava in addition to portal inflow at the time of parenchymal transection. We report a series of 61 liver resections in 60 patients using this technique. METHODS: A retrospective review of 61 procedures in 60 patients using TVE between 1990 and 1997 was carried out. No patient had cirrhosis. Parameters analyzed included age, gender, diagnosis, procedure, operative time, clamp time, intraoperative transfusion requirements, postoperative laboratory studies, length of stay (intensive care unit, ward), mortality, and morbidity. RESULTS: TVE was sustained hemodynamically in all patients. The mean age of the 34 men and 27 women was 56 years (+/- 15 years); 21% were older than 70 years. Eleven percent of the patients had benign lesions; 70% of the malignant tumors were metastatic. Seventy-five percent of the procedures were major or extended lobectomies. The mean operative and clamp times were 330 +/- 83 and 39 +/- 13.2 minutes, respectively; 68% had clamp times of < 45 minutes. The mean intraoperative red blood cell units was 1.45 +/- 1.93, with a range of 0 to 8 units; 48% required no transfusion and 80% received 2 units or less. There was 1 perioperative death for a mortality rate of 1.6%. The morbidity rate was 36%, which included 4 patients with postoperative liver dysfunction. Complications were not associated with transfusion but with clamp times exceeding 45 minutes. Liver dysfunction occurred with clamp times more than 60 minutes, particularly if the remaining liver parenchyma was histologically abnormal or the remnant was small. CONCLUSIONS: TVE is hemodynamically safe, even in patients older than 70 years. Blood loss during parenchymal transection is minimal; mortality and morbidity are low. The optimal clamp time is less than 45 minutes. Liver dysfunction is associated with clamp times exceeding 1 hour, particularly if the remaining parenchyma is abnormal or small.

In vivo measurement of leucine metabolism with stable isotopes in normal subjects and in those with cirrhosis fed conventional and branched-chain amino acid-enriched diets.

Low plasma levels of branched-chain amino acids, leucine, isoleucine, and valine are postulated to play an etiologic role in hepatic encephalopathy. Supplementation is advocated to reverse encephalopathy and improve nutritional status and survival. We measured in vivo leucine metabolism in normal individuals (n = 5) and in two groups of patients with cirrhosis (n = 8) with a primed continuous infusion of L-[15N, 1-13C] leucine to quantitate the following parameters of leucine metabolism: nitrogen and carbon fluxes, oxidation, contribution to protein synthesis, breakdown of endogenous protein to leucine, deamination and reamination to/from ketoisocaproate. Studies were performed in the fasting and fed states with a conventional enteral diet (Propac) and a branched chain-enriched diet (one third Propac plus two thirds Hepatic-Aid). In vivo leucine metabolism was similar in the fasting and fed states in normal individuals in patients with cirrhosis and with both diets when studied at a protein intake of 0.6 gm/kg ideal body weight/day. When fed these diets, oxidation increased (p less than 0.05) and breakdown decreased (p less than 0.05). The Hepatic-Aid diet increased (p less than 0.05) nitrogen and carbon fluxes significantly more than did the standard diet. Four additional patients with cirrhosis on a diet with more protein were studied (0.75 gm/kg ideal body weight/day). Carbon and nitrogen fluxes, oxidation, synthesis, and deamination were increased (p less than 0.05) when patients with cirrhosis were fed the Propac diet compared with those who fasted. The Hepatic-Aid diet further increased (p less than 0.05) all parameters except synthesis and did not decrease protein breakdown. These data show that patients with cirrhosis metabolize leucine in vivo in a manner identical to that of normal subjects and that leucine-enriched formulas increase oxidation to CO2 without improving protein synthesis.