Primary familial brain calcification linked to deletion of 5' noncoding region of SLC20A2.

OBJECTIVES: Primary familial brain calcification (PFBC) is a rare neurological disease often inherited as a dominant trait. Mutations in four genes (SLC20A2, PDGFB, PDGFRB, and XPR1) have been reported in patients with PFBC. Of these, point mutations or small deletions in SLC20A2 are most common. Thus far, only one large deletion covering entire SLC20A2 and several smaller, exonic deletions of SLC20A2 have been reported. The aim of this study was to identify the causative gene defect in a Finnish PFBC family with three affected patients. MATERIALS AND METHODS: A Finnish family with three PFBC patients and five unaffected subjects was studied. Sanger sequencing was used to exclude mutations in the coding and splice site regions of SLC20A2, PDGFRB, and PDGFB. Whole-exome (WES) and whole-genome sequencing (WGS) were performed to identify the causative mutation. A SNP array was used in segregation analysis. RESULTS: Copy number analysis of the WGS data revealed a heterozygous deletion of ~578 kb on chromosome 8. The deletion removes the 5' UTR region, the noncoding exon 1 and the putative promoter region of SLC20A2 as well as the coding regions of six other genes. CONCLUSIONS: Our results support haploinsufficiency of SLC20A2 as a pathogenetic mechanism in PFBC. Analysis of copy number variations (CNVs) is emerging as a crucial step in the molecular genetic diagnostics of PFBC, and it should not be limited to coding regions, as causative variants may reside in the noncoding parts of known disease-associated genes.

Intrafamilial clinical variability in individuals carrying the CHCHD10 mutation Gly66Val.

OBJECTIVES: Mutations in the CHCHD10 gene, which encodes a mitochondrially targeted protein, have emerged as an important cause of motor neuron disease and frontotemporal lobar degeneration. The aim of this study was to assess the clinical variability in a large family carrying the p.Gly66Val mutation of the CHCHD10 gene. This mutation has recently been reported to cause late-onset spinal muscular atrophy (SMAJ) or sensorimotor axonal Charcot-Marie-Tooth neuropathy (CMT2) in the Finnish population. MATERIALS AND METHODS: Nine affected members of an extended Finnish pedigree were included in the study. Detailed clinical and neurophysiological examinations were performed. The CHCHD10 p.Gly66Val mutation was examined by Sanger sequencing. RESULTS: The heterozygous p.Gly66Val mutation was present in all affected individuals from whom a DNA sample was available. The clinical phenotype varied from proximal sensorimotor neuropathy to spinal muscular atrophy and in one case resembled motor neuron disease ALS at its early stages. The age of onset varied from 30 to 73 years. CONCLUSIONS: Our data demonstrate that even within the same family, the p.Gly66Val variant can cause variable phenotypes ranging from CMT2-type axonal neuropathy to spinal muscular atrophy, which may also present as an ALS-like disease. The spectrum of CHCHD10-related neuromuscular disease has widened rapidly, and we recommend keeping the threshold for genetic testing low particularly when dominant inheritance or mitochondrial pathology is present.

APOE and AGT in the Finnish p.Arg133Cys CADASIL population.

BACKGROUND: CADASIL is an inherited systemic small vessel disease, the affected status of brain vessels leading to subcortical vascular dementia. The defective gene is NOTCH3 in which over 230 different pathogenic mutations have been identified. The clinical course of CADASIL is highly variable even within families. Previous studies have shown that additional genetic factors modify the phenotype. AIMS AND METHODS: Altogether, 134 Finnish CADASIL patients with p.Arg133Cys mutation were analysed for possible associations between the apolipoprotein E (APOE) genotype, angiotensinogen (AGT) p.Met268Thr polymorphism or neutral p.Ala202Ala NOTCH3 polymorphism and earlier first-ever stroke or migraine. RESULTS: We found no association between the APOE genotypes, AGT polymorphism, NOTCH3 polymorphism and earlier first-ever stroke or migraine. CONCLUSIONS: The APOE, AGT and NOTCH3 polymorphism did not modify the onset of strokes or migraine in our CADASIL sample, which is one of the largest mutationally homogenous CADASIL populations published to date. International collaboration, pooled analyses and genomewide approaches are warranted to identify the genetic factors that modify the highly variable CADASIL phenotype.

Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease.

The hematopoietic-specific transmembrane protein tyrosine phosphatase CD45 functions to regulate Src kinases required for T- and B-cell antigen receptor signal transduction. So far, there have been no reports to our knowledge of a human deficiency in a tyrosine-specific phosphatase. Here, we identified a male patient with a deficiency in CD45 due to a large deletion at one allele and a point mutation at the other. The point mutation resulted in the alteration of intervening sequence 13 donor splice site. The patient presented at 2 months of age with severe combined immunodeficiency disease. The population of peripheral blood T lymphocytes was greatly diminished and unresponsive to mitogen stimulation. Despite normal B-lymphocyte numbers, serum immunoglobulin levels decreased with age. Thus, CD45 deficiency in humans results in T- and B-lymphocyte dysfunction.

A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1.

We describe a novel variant of Alzheimer's disease (AD) in a Finnish pedigree with 17 affected individuals of both sexes in three generations. The disease is characterized by progressive dementia which is, in most cases, preceded by spastic paraparesis. Neuropathological investigations revealed numerous, distinct, large, round and eosinophilic plaques as well as neurofibrillary tangles and amyloid angiopathy throughout the cerebral cortex. The predominant plaques resembled cotton wool balls and were immunoreactive for Abeta but lacked a congophilic dense core or marked plaque-related neuritic pathology. Molecular genetic analysis revealed that the disease was caused by a deletion of exon 9 (delta9) of the presenilin 1 (PS1) gene from the mRNA: unlike previous examples of the delta9 variant, the deletion was not caused by a splice acceptor site mutation.

Extensive somatic microsatellite mutations in normal human tissue.

Microsatellite (MS) instability occurs in tumors with DNA mismatch repair (MMR) deficiencies but is typically absent in adjacent normal tissue. However, MS mutations have been observed in normal tissues from rare individuals with congenital MMR deficiencies. Autopsy tissues from a 4-year-old with congenital MMR deficiency (MLH1-/-) were examined for MS mutations. Insertions and deletions were observed in CA-repeat MS loci. Approximately 0.26 to 1.4 mutations per MS locus per cell were estimated to be present in normal heart, lymph node, kidney, and bladder epithelium. These findings illustrate that phenotypically normal MMR-deficient cells commonly accumulate MS mutations. Loss of MMR and the accumulation of some MS mutations may occur early in MMR-deficient tumor progression, even before a gatekeeper mutation.

New function for NF1 tumor suppressor.

The expression and subcellular localization of neurofibromatosis type 1 tumor suppressor was studied in keratinocytes induced to differentiate by increased Ca2+ concentration of the culture medium. Differentiating keratinocytes became intensely immunoreactive for neurofibromatosis type 1 protein, which was apparently associated with cellular fibrils. Double immunolabeling with antibodies to cytokeratin 14 and neurofibromatosis type 1 protein suggested an association of intermediate type cytoskeleton and neurofibromatosis type 1 protein. The presence of neurofibromatosis type 1 protein in cell preparations treated with cytoskeletal buffer indicated a high affinity interaction between intermediate filaments and neurofibromatosis type 1 protein. Further studies utilizing double immunolabelings revealed that the intense neurofibromatosis type 1 tumor suppressor signal on intermediate filaments was temporally limited to the period in keratinocyte differentiation in which the formation of desmosomes takes place. Keratinocytes were also cultured from nine patients with type 1 neurofibromatosis and were studied with respect to cell morphology, and association of neurofibromatosis type 1 protein with intermediate cytoskeleton. The results showed that keratinocytes cultured from patients with neurofibromatosis type 1 displayed a highly variable cell size and morphology compared to controls. The latter findings represent predicted alterations in a situation where cytoskeletal organization is disturbed. Furthermore, differentiating neurofibromatosis type 1 keratinocytes were characterized by a reduced number of cytokeratin bundles that were decorated neurofibromatosis type 1 protein. The results of this study suggest that neurofibromatosis type 1 tumor suppressor exerts its effects in part by controlling organization of cytoskeleton during the formation of cellular contacts.

Phenotype of a homozygous CADASIL patient in comparison to 9 age-matched heterozygous patients with the same R133C Notch3 mutation.

BACKGROUND AND PURPOSE: CADASIL is an autosomal dominant arteriopathy, characterized by multiple brain infarcts, cognitive decline, and finally dementia, which is caused by mutations in Notch3 gene encoding a Notch3 receptor protein. We describe the clinical, neuropsychological, imaging, genetic, and skin biopsy findings in a CADASIL patient homozygous for the C475T mutation resulting in R133C amino acid substitution, in comparison to 9 age-matched heterozygous patients with the same mutation. METHODS: The patients were examined clinically and neuropsychologically and with MRI and positron emission tomography for assessment of cerebral blood flow. The gene defect was analyzed by sequencing the products of polymerase chain reaction of exons 3 and 4 of the Notch3 gene. Dermal arteries were analyzed electron microscopically. RESULTS: The homozygous patient had his first-ever stroke at age 28 years. This is markedly earlier than the average, but the patient's heterozygous son had his first transient ischemic attack-like episode at the same age and another heterozygous patient had his first-ever stroke when only 2 years older. He was neuropsychologically more severely deteriorated than all but 1 of the heterozygous patients. These 2 patients had the most severe (confluent grade D) white matter MRI changes. Positron emission tomography showed markedly reduced cerebral blood flow. Skin biopsy revealed profuse deposits of granular osmiophilic material. The progression of disease in the homozygous case was, however, slower than in the most severely affected heterozygous patient. CONCLUSIONS: Our homozygous patient's phenotype is within the clinical spectrum of CADASIL, although at its severe end. Thus, CADASIL may follow the classic definition of a dominant disease, according to which the heterozygous and homozygous patients are clinically indistinguishable.

Urinary excretion of polyamines: importance of circadian rhythm, age, sex, menstrual cycle, weight, and creatinine excretion.

The urinary excretion of putrescine, spermidine, spermine, and N1- and N8-acetylspermidines was measured in 95 volunteers. The 24-h excretion, split in four consecutive periods, was analyzed for circadian rhythm in eight volunteers. Circadian rhythm was observed in total polyamine and in N1- and N8-acetylspermidine excretions. The excretion rates of these polyamines were highest in the morning. The normal values for 24-h urinary excretion of polyamines were determined in 87 volunteers. Men excreted significantly more spermidine (P less than 0.001), N8-acetylspermidine (P less than 0.05), and spermine (P less than 0.001) than did women; putrescine excretion was higher in women (P less than 0.001). This variation was only partially explained by differences between sexes in body or muscle mass because most differences remained significant even after normalization for creatinine excretion and body weight. No correlation between the polyamine excretions and age or menstrual cycle was found.

Gliomas presenting after age 10 in individuals with neurofibromatosis type 1 (NF1).

Children with neurofibromatosis 1 (NF1) often develop low-grade gliomas, but brain tumors are infrequently encountered in adults with NF1. The authors present evidence from two clinical series, one including patients known to have NF1 and another focusing on adults with new onset brain tumors, that suggests an association between NF1 and symptomatic gliomas in older individuals. They also summarize the clinical data on 17 adolescents or adults with NF1 and symptomatic gliomas. The findings suggest that individuals with NF1 are at increased risk of developing gliomas throughout their lives.

Cardiovascular malformations and other cardiovascular abnormalities in neurofibromatosis 1.

Although it is well recognized that a peripheral vasculopathy may occur in patients with neurofibromatosis 1 (NF1), it is unclear whether cardiovascular abnormalities are more common. We reviewed the frequency of cardiovascular abnormalities, in particular, cardiovascular malformations (CVMs), among 2322 patients with definite NF1 in the National Neurofibromatosis Foundation International Database from 1991-98. Cardiovascular malformations were reported in 54/2322 (2.3%) of the NF1 patients, only 4 of whom had Watson syndrome or NF1-Noonan syndrome. There was a predominance of Class II "flow" defects [Clark, 1995: Moss and Adams' Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult. p 60-70] (43/54, 80%) among the NF1 patients with CVMs. Pulmonic stenosis, that was present in 25 NF1 patients, and aortic coarctation, that occurred in 5, constitute much larger proportions of all CVMs than expected. Of interest was the paucity of Class I conotruncal defects (2 patients with tetralogy of Fallot), and the absence of atrioventricular canal, anomalous pulmonary venous return, complex single ventricle and laterality defects. Besides the 54 patients with CVMs, there were 27 patients with other cardiac abnormalities (16 with murmur, 5 with mitral valve prolapse, 1 with intracardiac tumor, and 5 with electrocardiogram abnormalities). No patient in this study had hypertrophic cardiomyopathy. There were 16 patients who had a peripheral vascular abnormality without an intracardiac CVM, plus an additional 4 patients among those with a CVM who also had a peripheral vascular abnormality.

Hyperamylasemia after cardiopulmonary bypass: pancreatic cellular injury or impaired renal excretion of amylase?

BACKGROUND: Postoperative hyperamylasemia and even acute pancreatitis are associated with coronary artery bypass grafting (CABG). The mechanism of hyperamylasemia and pancreatic acinar cell damage was studied in 20 patients undergoing CABG. METHODS: Serial blood and urine samples at eight time points before, during, and 24 hours after the CABG were collected. Salivary and pancreatic isoamylases, the fractional clearance of isoamylases (i.e., relative to creatinine clearance), pancreatic phospholipase A2 (a specific serum marker of pancreatic acinar cell injury), and cystatin C (a sensitive marker of glomerular filtration rate) were measured. RESULTS: Mild serum hyperamylasemia (300 to 1000 units/L) was found in 11 of 20 (55%) and severe (> 1000 units/L) in 6 of 20 (30%) patients with no signs of clinical acute pancreatitis. Hyperamylasemia occurred from 6 to 24 hours after the CABG and was mainly caused by pancreatic isoamylase. Serum pancreatic phospholipase A2 concentration remained unchanged, which excludes acinar cell damage. Although renal glomerular filtration was normal during CABG as measured by serum cystatin C and creatinine clearance, the fractional clearance of isoamylases decreased. CONCLUSIONS: The decreased rate of excretion into urine, rather than pancreatic cellular damage, is the major source of hyperamylasemia after CABG.

Urinary excretion of polyamines in patients with surgical and accidental trauma: effect of total parenteral nutrition.

Excretion of polyamines first increases and then decreases in patients with multiple trauma receiving total parenteral nutrition (TPN). To separate the effects of trauma and TPN on polyamine excretion, we studied 12 patients with multiple trauma and 14 patients after surgery for colorectal malignancy. Patients were randomized to receive either TPN or hypocaloric glucose infusion. Urinary excretion of total and free polyamines, putrescine (PU), spermidine (SPD), and spermine (SP), and their metabolites, N1-acetylspermidine (N1-AcSPD) and N8-acetylspermidine (N8-AcSPD), and energy and nitrogen balance were measured. Polyamine excretion, excluding SP, markedly increased after trauma and surgery, exceeding the normal values by twofold to 10-fold. In patients receiving TPN, the excretion of total polyamines was 48% higher (P < .01), PU was 34% higher (P < .05), SPD was 35% higher (P < .05), and SP was 350% higher (P < .05) than in patients receiving hypocaloric glucose. Urinary excretion of SP was only 17% of the reference value during hypocaloric glucose (P < .05), but was normal during TPN. The difference in polyamine excretion between nutrition groups was more pronounced when normalized for nitrogen or energy balance. Patients receiving TPN were more hypermetabolic than patients receiving hypocaloric glucose (resting energy expenditure, 1.36 +/- 0.06 [SE] and 1.16 +/- 0.04 times predicted values, respectively; P < .025). Statistically, energy expenditure could explain the difference in polyamine excretion between nutrition groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Occult neurofibroma and increased S100 protein in the skin of patients with neurofibromatosis type 1: new insight to the etiopathomechanism of neurofibromas.

BACKGROUND: Neurofibromas represent proliferation of the connective tissue cells of peripheral nerves and deposition of collagenous extracellular matrix. There is evidence that the appearance and growth of neurofibromas may be associated with prior or ongoing mechanical trauma in patients with neurofibromatosis type 1 (NF1). OBJECTIVE: To study the histologic characteristics of apparently healthy skin of patients with NF1. DESIGN: The histologic features of healthy-looking skin of patients with NF1 were analyzed. SETTING: University hospital. PATIENTS: Ten patients who fulfilled the criteria for NF1. INTERVENTIONS: Punch biopsy specimens of healthy-looking skin of the forearm from 9 volunteer patients and of the upper eyelid during cosmetic operation from 1 volunteer patient were obtained. MAIN OUTCOME MEASURES: The main outcomes were not predicted, and the hypothesis was formulated during data collection. RESULTS: Apparently unaffected skin of 5 patients with NF1 was studied by routine histologic testing with respect to expression of S100 protein. Unexpectedly, analysis of the samples revealed the presence of a small neurofibroma tumor in one of the samples. The tumor was located in deep dermis around a hair follicle. In addition, neurofibromatous tissue not large enough to be called a tumor was found on the same anatomical location in another patient. In further studies, 10 punch biopsy specimens of apparently healthy skin from patients with NF1 were similarly sectioned and analyzed. No tumors were found in these additional samples. In 4 patients, however, abundant S100 protein-positive cells were located within collagenous extracellular matrix surrounding hair follicles. CONCLUSIONS: The skin of patients with NF1 might be more widely affected than previously thought and occult neurofibromas are not rare.

Spontaneous decrease of a pilocytic astrocytoma in neurofibromatosis type 1.

A patient with type 1 neurofibromatosis was followed up with neuroimaging over a period of 12 years. A spontaneous decrease in the size of a histologically verified pilocytic astrocytoma was documented on serial CT and MR examinations. Subsequent studies showed the development of a lesion in the contralateral hemisphere with mass effect and contrast enhancement. Results of a biopsy disclosed normal brain tissue; follow-up imaging showed a spontaneous decrease in the size of this abnormality.

Nitrogen and energy balance in septic and injured intensive care patients: response to parenteral nutrition.

We studied energy and nitrogen balance in 50 intensive care patients with sepsis (n = 18) or multiple trauma (n = 32). Most patients were mechanically ventilated during the study. Within 72h of admission the patients were randomised to receive one of 5 infusion regimens for 48h (group n = 9-11). The control group received hypocaloric glucose, two groups received 1.5g/kg/day of amino-acids, either with hypocaloric glucose on both days or with energy adjusted to pre-nutrition REE on the second day. The fourth group received 0.6g/kg/day of amino-acids and energy at REE, and the fifth group a high nitrogen (18g/day) regimen with a stepwise increase in energy intake from day 1 to day 2. Baseline REE was 118 +/- 18.9% of predicted. No significant differences in REE were observed between the diagnostic groups, treatments or measurements performed during mechanical or spontaneous ventilation. Nitrogen balance in the control group was -250.3 +/- 83.3 mg/kg on day 1 and 218.6 +/- 95.3 mg/kg on day 2. Nitrogen balance remained negative in all groups throughout the study (range of group means-218.6 to -48.5 mg/kg/day). Increasing energy intake equal to prenutrition REE at an amino-acid dosage of 1.5g/kg/day decreased the negative nitrogen balance by 66%. Further increase in energy balance had only a marginal effect on nitrogen balance.

Accelerated splanchnic amino acid uptake after cardiac surgery.

Energy expenditure increases after cardiac surgery, but changes in peripheral tissue metabolism do not explain this increase. We hypothesized that the splanchnic region is a major contributor to the postoperative hypermetabolism, and this should be reflected in the exchange of amino acids across the splanchnic bed. We measured systemic and regional (splanchnic and leg) amino acid exchange, oxygen uptake and hemodynamics in 22 elective coronary bypass grafting patients postoperatively after arrival to the intensive care unit, 2 h later, and after stabilization of hemodynamics. Splanchnic uptake of glutamine (50 +/- 37 micromol/min/m2 to 78 +/- 37 micromol/min/m2, P < 0.05) and three of the gluconeogenetic amino acids, alanine (115 +/- 52 micromol/min/m2 to 183 +/- 70 micromol/min/m2, P < 0.05), serine (18 +/- 10 micromol/min/m2 to 26 +/- 13 micromol/min/m2) and threonine (20 +/- 8 micromol/min/m2 to 28 +/- 8 micromol/min/m2) increased during the observation period. Similarly, the oxygen consumption by the splanchnic region increased while splanchnic blood flow remained stable. A correlation between oxygen and amino acid uptake by the splanchnic bed was observed during the study period. Femoral exchange of glutamine and alanine did not change, although femoral blood flow and oxygen consumption increased during rewarming. High metabolic activity was observed in the splanchnic region during the early postoperative phase after hypothermic cardiac surgery. The increased plasma amino acid concentration indicates a release of amino acids from other sources than the peripheral muscle.

Nitrogen and energy balance in depleted patients undergoing major gastrointestinal surgery: response to TPN.

We studied energy and nitrogen balance during pre- and post-operative parental nutrition in 16 malnourished patients undergoing major abdominal surgery due to suspected gastrointestinal malignancy. The response to amino-acids alone (1.5g/kg; group AA) and energy alone (energy intake equal to pre-nutrition energy expenditure; group REE) was studied during the first day of pre- and post-operative nutrition. On the second day of parental nutrition both groups received amino-acids (1.5g/kg) and non-protein energy equal to pre-nutrition energy expenditure. Energy expenditure (EE) was increased both pre- and post-operatively (EE 112 +/- 15 and 121 +/- 14% of predicted, respectively). Nitrogen balance in group REE was more positive than in group AA on pre-operative day 2 (81.1 +/- 35.8 vs. 17.8 +/- 60.5 mg/kg; p < 0.05). N balance was better pre- than post-operatively on day 2 in both groups (17.8 +/- 60.5 vs. -49.6 +/- 49.2 mg/kg; group AA and 81.1 +/- 35.8 vs. 7.8 +/- 82.6 mg/kg; group REE; p < 0.05). Pre-operatively, administration of energy alone reduced EE (1489 +/- 301 vs. 1403 +/- 312 kcal/day; p < 0.05). We conclude that: 1) The patients were hypermetabolic both pre- and post-operatively. 2) Surgical trauma had a minor effect on EE. 3) Good nitrogen retention could be obtained both pre- and post-operatively at close to zero energy balance. 4) EE increased during the infusion of amino-acids more post-operatively than pre-operatively; non-protein energy at EE had no thermogenic effect. 5) Priming with energy improved nitrogen balance on the following day.

Branched-chain and mixed amino acid solutions and thermogenesis in postoperative patients.

The effect of amino acid composition on the thermogenic response to amino acid infusion was studied in 20 spontaneously breathing postoperative coronary bypass patients and 6 healthy volunteers. On the 1st postoperative day, patients received either a balanced amino acid solution (2510 kJ/24 h) or an amino acid solution consisting primarily (88.8%) of branched-chain amino acids (BCAAs; 2510 kJ/24 h) for 6 h. Another group of patients receiving only hypocaloric glucose served as control subjects. The volunteers randomly received the same balanced amino acid solution (2510 kJ/24 h) or the same BCAA-enriched solution (2510 kJ/24 h) for 6 h. In the coronary bypass patients, both infusion regimens resulted in an increase in resting energy expenditure (REE) (p < 0.01). The thermogenic response to nutrition was 28.5 +/- 5.8 and 46.9 +/- 4.3% (mean +/- SE) in the patients receiving the balanced and BCAA-enriched solutions, respectively (p < 0.05). REE did not change in the control group. Alveolar ventilation increased in both groups (p < 0.05), and the change was more prominent in patients receiving the BCAA-enriched solution. PaCO2 decreased significantly in both nutrition groups. In the healthy subjects, REE increased only during the balanced amino acid infusion (p < 0.05). The thermogenic response to the balanced amino acid solution was 20.7 +/- 4.2% (p < 0.05), whereas no thermogenic response to the BCAA-enriched solution was observed (-5.6 +/- 3.3%, NS). This difference was probably due to the smaller energy cost of BCAA metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Nutrition status, severity of illness, and thermogenic response to parenteral nutrition.

The effect of the degree of metabolic stress on the thermogenic response to parenteral nutrition was studied in surgical and intensive-care patients. Indirect calorimetry was measured before and 3 h after the start of parenteral nutrition. The following patient groups were studied: depleted ward patients before and after surgery for gastrointestinal malignancy (n = 16), mechanically ventilated sepsis/injury patients (n = 21), and spontaneously breathing intensive-care sepsis/injury patients (n = 8). The patients received either nonprotein energy alone (glucose/fat 30/70%) at a rate corresponding to 1.4-1.6x baseline resting energy expenditure (REE) or amino acids (1.5 g.kg-1.day-1) and hypocaloric glucose. There was no correlation between the thermogenic effect of nutrition and the degree of hypermetabolism or degree of malnutrition. There was no significant thermogenic response to either amino acids or hypercaloric lipids and glucose preoperatively. In the depleted patients, REE increased because of the operation (p < 0.05); postoperatively, only amino acids increased REE significantly (p < 0.05). The operation enhanced the thermogenic response, which was higher to amino acids than to nonprotein energy (27.2 +/- 9 vs. 5.3 +/- 2.2%, means +/- SE, p < 0.05). In the sepsis/trauma patients, REE increased in both nutrition groups (p < 0.05). The thermogenic response (19.7 +/- 6.5 and 8.0 +/- 3.2% in patients receiving amino acids and nonprotein energy, respectively) was similar to that of the depleted patients postoperatively and was similar in sepsis and trauma patients. We conclude that the thermogenic response to parenteral amino acids and nonprotein energy is minor in depleted patients.(ABSTRACT TRUNCATED AT 250 WORDS)