Rapidly declining trend of signet ring cell cancer of the stomach may parallel the infection rate of Helicobacter pylori.

BACKGROUND: Studies indicate that gastric cancer (GC) incidence has decreased, whereas signet ring cell carcinoma (SRC) incidence has increased. However, recent trends in GC incidence are unclear. We used our hospital cancer registry to evaluate the changes in the incidence of GC, SRC, and non-SRC (NSRC) over time in comparison to changes in the H. pylori infection rates over time. METHODS: We identified 2532 patients with GC enrolled in our registry between January 2007 and December 2018 and statistically analyzed SRC and NSRC incidence. The H. pylori infection rate in patients with SRC was determined by serum anti-H. pylori antibody testing, urea breath test, biopsy specimen culture, and immunohistochemical analysis (IHC) of gastric tissue. Additionally, genomic detection of H. pylori was performed in SRCs by extracting DNA from formalin-fixed paraffin-embedded gastric tissue and targeting 16S ribosomal RNA of H. pylori. RESULTS: Overall, 211 patients had SRC (8.3%). Compared with patients with NSRC, those with SRC were younger (P <  0.001) and more likely to be female (P <  0.001). Time series analysis using an autoregressive integrated moving average model revealed a significant decrease in SRC (P <  0.001) incidence; NSRC incidence showed no decline. There was no difference in H. pylori infection prevalence between the SRC and NSRC groups. IHC and genomic methods detected H. pylori in 30 of 37 (81.1%) SRCs. CONCLUSIONS: Reduction in H. pylori infection prevalence may be associated with the decrease in the incidence of SRC, which was higher than that of NSRC.

Validation of Tokyo Guideline 2013 as Treatment of Acute Cholecystitis by Real World Data.

BACKGROUND: The Tokyo Guidelines (TG; 2013) indicated that emergency cholecystectomy is an important early treatment option for acute cholecystitis; however, surgical intervention is not necessarily indicated in patients with advanced age. We evaluated percutaneous transhepatic gallbladder aspiration (PTGBA), percutaneous transhepatic gallbladder drainage (PTGBD), and the administration of antibiotics alone as treatment options for acute -cholecystitis. METHODS: From January 2010 to December 2017, 159 patients with acute cholecystitis were treated at our institution. The data from these patients were retrospectively analyzed. RESULTS: Of these 159 cases, 109 underwent PTGBA, 28 underwent PTGBD, and 22 were administered antibiotics alone. None of the 159 patients needed urgent (early) cholecystectomy, and all patients were discharged without mortality. PTGBA was unsuccessful in only 6 of 109 patients; PTGBD was performed in these 6 cases. Long-term follow-up was conducted in all cases. Of the 159 patients, 146 had gallbladder stones initially, while 13 had none at the time of presentation. Of these 146 patients with gallbladder stones, 84 underwent elective cholecystectomy, while 62 did not. Of the 84 patients who underwent elective cholecystectomy, 2 developed choledocholithiasis; of the 62 patients who did not undergo elective cholecystectomy, 5 developed choledocholithiasis and 2 developed acute cholecystitis. The incidences of choledocholithiasis and acute cholecystitis did not significantly differ between the 2 groups (p = 0.06). CONCLUSIONS: Despite the recommendations in the TG (2013), emergency cholecystectomy was not needed in any of the present patients with acute cholecystitis. Acute cholecystitis can be successfully treated with -PTGBA or PTGBD, which are simple procedures with good short- and long-term safety. These procedures are highly recommended for patients with acute cholecystitis, especially in the elderly population.

Factors Predicting Subsequent Hospitalization in Patients with Ulcerative Colitis: Total Colonoscopic Findings are the Strongest Predictor.

BACKGROUND/AIMS: Patients with ulcerative colitis suffer from long term impairment of quality of life, especially when subjected to repeated hospitalization. We aimed to identify factors that may predict future hospitalization. METHODOLOGY: We followed 139 consecutive patients with ulcerative colitis for average of 11.2 years (2.8 to 49.5 years) from the onset. Clinical and endoscopic stagings were determined by Japanese staging system, the extent of colitis by Montreal classification and endoscopic grading by Matts' grade. RESULTS: Overall hospitalization rate was 37% at 5 years, 47% at 10 years and 60% at 20 years from the onset. Of 5 parameters including demographic and staging scores, univariate analysis revealed clinical severity at onset (p = 0.003), total colonoscopic findings on severity (Matts' grade, p = 0.003), and total colonoscopic findings on sites of abnormality (p = 0.012) were significantly correlated with hospitalization. By multivariate analysis, total colonoscopic findings on sites of abnormality was the only baseline character significantly related to the need of hospitalization (p = 0.0007). In fact, 5/10/20 years hospitalization rates were only 18/26/33 percent for proctitis type, whereas those were 61/72/90 for total colitis type. CONCLUSIONS: The total colonoscopic finding on sites of abnormality at the onset is the only predictdr of hospitalization in patients with ulcerative colitis.

Demonstration of partially transparent thick metallic sodium in the vacuum ultraviolet spectral range.

We describe the direct measurement of actual transmittance of sodium samples with thickness of a 2 mm and 3 mm in a spectral range >115 nm, resulting in >50% transmittance of 3 mm thick solid and liquid sodium samples including transmission of a pair of the windows at the wavelength of 120 nm, giving an extinction coefficient of ~10(-6) to ~10(-7) which represents the sodium with a few cm thickness to be partially transparent for this wavelength. To confirm the measurement, we perform simple imaging experiments by the ultra-violet light passing through a 8 mm-thick sodium sample to illuminate a mesh as an object, resulting in obtaining a clear image.

A case of nemaline myopathy with associated dilated cardiomyopathy and respiratory failure.

Nemaline myopathy is a representative form of congenital myopathy, and is characterized by nemaline bodies in muscle fibers. Here we report a 47-year-old man with congenital nemaline myopathy complicated with dilated cardiomyopathy-related heart failure, and restrictive respiratory failure. The complication of dilated cardiomyopathy in nemaline myopathy has rarely been reported. In this case, nemaline bodies were detected in the cardiac muscle fibers, demonstrating the presence of underlying disease-related myocardial degeneration. The patient responded to the combination of conventional therapy for heart failure including ß-blocker and noninvasive continuous positive-pressure ventilation for respiratory failure. His general condition has been stable during a 10-month follow up period.

The Use of Electronic Medical Records-Based Big-Data Informatics to Describe ALT Elevations Higher than 1000 IU/L in Patients with or without Hepatitis B Virus Infection.

Hepatitis B virus (HBV) infection is one of the serious health problems in the world as HBV causes severe liver diseases. Moreover, HBV reactivation has occasionally been observed in patients with resolved HBV infection and patients using immunosuppression and anticancer drugs. Large-scale hospital data focused on HBV infection and severe liver function were analyzed at our hospital, located in an urban area adjacent to Tokyo, the capital city of Japan. A total of 99,932 individuals whose blood samples were taken at 7,170,240 opportunities were analyzed. The HBV surface antigen (HBsAg)-positive group had a more frequent prevalence of patients with higher transaminase elevations than the HBsAg-negative group. However, among the HBsAg-negative group, patients who were positive for anti-HBV surface antibody and/or anti-HBV core antibody, had more severe liver conditions and fatal outcomes. More careful attention should be paid to alanine transaminase (ALT) elevations higher than 1000 IU/L in patients who had current and previous HBV infection.

[A case of surfer's myelopathy with serial imaging examination from early stage after onset].

Surfer's myelopathy is non-traumatic spinal cord injury which develops in beginner surfers. The patient was a 17-year-old female who developed severe paraplegia with bilateral sensory dysfunction below the groin and bladder/rectal dysfunctions after her first surfing lesson. A spinal-cord MRI performed six hours after onset revealed an intramedullary hyperintensity area from T8 to the conus medullaris on the T2 weighted images. Expansion of this hyperintensity area was observed on Day 3 and showed a reduction on Day 8. After providing intravenous methylpredonisolone, intravenous glycerol and intravenous edaravone, motor function and bladder/rectal functions began to improve after approximately three weeks. In this study, the expansion of the lesion in the early stages of the disease course was observed by sequential spinal MRI. Furthermore, a time lag between improvement according to imaging and improvement in symptoms was also observed.

Molecular subtype switching in early-stage gastric cancers with multiple occurrences.

BACKGROUND: Multiple gastric cancers at the same time (synchronous) or recurrence after 1 year (metachronous) are frequently encountered. Since their genetic profiles were not well elucidated, we molecularly subtyped the genetic events of synchronous and metachronous early-stage gastric cancers. METHODS: We studied mismatch repair (MMR) genes in 84 tumors from 31 patients (15 synchronous and 16 metachronous) by immunohistochemistry. We performed microsatellite instability analysis and targeted sequencing of 58 significantly mutated genes (SMGs) in 35 tumors from thirteen patients. Genomic data from TCGA were used for comparisons with advanced-stage cancers. RESULTS: Among the 31 patients, at least one deficient-MMR (dMMR) tumor was observed in eight (26%). Of eight patients, seven showed a mixture of proficient-MMR (pMMR) and dMMR tumors. The one case with only dMMR had six recurrent tumors within 2 years. To further subtype, we sequenced 58 SMGs in 35 samples (25 pMMR and 10 dMMR) from thirteen patients. In 35 samples, 163 mutations were identified, but none matched in almost cases, strongly indicating different clonal origins, whether synchronous or metachronous occurrences. Of the 25 pMMR cases, 1 belonged to Epstein-Barr virus (EBV), 24 belonged to chromosomal instability (CIN) subtypes. Of the thirteen cases, repetitive CIN, a mixture of CIN and MSI, a mixture of CIN and EBV, and repetitive MSI were observed in nine (70%), two (15%), one (8%) and one (8%), respectively. CONCLUSIONS: Despite multiple tumors occurring in the same patient simultaneously or several years apart, clonal origin was totally different. 'Switching' or 'mixing' of dMMR and pMMR, EBV or CIN occurred, which had clinical relevance with regard to immunotherapy.

Deficiency of mismatch repair genes is less frequently observed in signet ring cell compared with non-signet ring cell gastric cancer.

Signet ring cell (SRC) gastric cancer at advanced stage has poor prognosis. While a recent study reported nearly one-third of SRC cases contain tumors with deficient mismatch repair (MMR) genes, other studies in SRC have been inconclusive. To re-analyze the results, we performed immunohistochemical staining of MLH1, MSH2, MSH6 and PMS2 proteins in 38 SRC gastric tumors compared with 109 non-SRC (NSRC) tumors from 94 patients. In contrast to the previous study, all SRC gastric tumors normally expressed MMR proteins, whereas 22 of 109 of NSRC (20%) showed deficient MMR proteins. To reinforce our results, we referred to the Cancer Genome Atlas (TCGA) genomic database and found that only 6 (6%) of 99 samples with diffuse gastric tumors showed deficient MMR, whereas 64 (21%) of 304 in intestinal gastric tumors showed deficient MMR. Our results as well as the TCGA database indicated that MMR genes are infrequently inactivated in SRC gastric cancer. These findings indicate that SRC patients may not be the best candidates for immuno-oncology therapy.

The efficacy and safety of lenvatinib for advanced hepatocellular carcinoma in a real-world setting.

BACKGROUND/PURPOSE: Lenvatinib (an inhibitor of vascular endothelial growth factor (GF) receptors 1-3, fibroblast GF receptors 1-4, platelet-derived GF receptor α, rearranged during transfection, and stem cell factor receptor) was non-inferior to sorafenib in a phase 3 (REFLECT) trial of advanced hepatocellular carcinoma. This study examined the efficacy and safety of lenvatinib in a real-world setting. METHODS: This was a retrospective, multicenter, observational study. Inclusion and exclusion criteria were based on the phase 3 trial, and participants were observed for at least 12 weeks. Therapeutic effect was determined using the modified Response Evaluation Criteria In Solid Tumors (m-RECIST) at the 8th week. Patients received oral lenvatinib 12 mg/day (body weight > 60 kg) or 8 mg/day (body weight < 60 kg). Dose interruptions followed by reductions for lenvatinib-related toxicities were permitted. Grades of adverse events (AEs) complied with the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: All 16 patients included in this study had prior treatment history, and a median 3.9 years had passed since the first treatment. Fatigue, hypertension, and proteinuria were the most frequent AEs, and were higher than Grade 2. AEs could be controlled by appropriate dose reduction, interruption, and symptomatic treatment according to the protocol. In the m-RECIST evaluation at the 8th week, 0, 6, 8, and 1 patients had achieved complete response, partial response, stable disease, and progressive disease, respectively. The objective response rate was 40%. CONCLUSION: Lenvatinib treatment could be accomplished with safety and good response in a real-world setting.

Protective effect of ginsenosides Rg(2) and Rh(1) on oxidation-induced impairment of erythrocyte membrane properties.

The extract from Panax ginseng has been reported to improve the microcirculation in various organs. However, the mechanisms underlying this phenomenon are still poorly understood. In the present study, using the rheological properties of erythrocytes as an index, we have screened the components of Panax ginseng extract and identified Rg(2) and Rh(1) as the active ingredients. These two ginsenosides prevented the oxidative stress-induced elevation of erythrocyte suspension viscosity and the impairment of erythrocyte elongation in response to shear stress. Rg(2) and Rh(1) ginsenosides did not have antioxidant activity in an aqueous phase and did not inhibit the peroxidation of membrane lipids, either. However, they inhibited the oxidation-induced decrease of SH-groups in band 3 (anion exchanger-1), one of the important structural proteins of the erythrocyte membrane, but not in other structural proteins: bands 1 and 2 (spectrins), band 4.2 or band 5 (actin). These results suggest that ginsenosides Rg(2) and Rh(1) protect the rheological functions of erythrocytes against oxidative stress by preventing the oxidation of SH-groups in band 3 protein.

Influence of NUDT15 variants on hematological pictures of patients with inflammatory bowel disease treated with thiopurines.

AIM: The single nucleotide polymorphism (SNP) c.415C>T in exon 3 of NUDT15 affects thiopurine-induced leukopenia in Asian patients with Crohn's disease. Meanwhile, three additional genetic variants of NUDT15 were reported in patients with acute lymphoblastic leukemia. We evaluated the effects of these additional genetic variants of NUDT15 in patients with inflammatory bowel disease (IBD) treated with thiopurines. METHODS: Ninety-six Japanese patients with IBD were enrolled. Genotyping for the NUDT15 and TPMT genes was performed using Custom TaqMan SNP genotyping assays or Sanger sequencing. The changes in white blood cell (WBC) count, mean corpuscular volume (MCV), platelet count, hemoglobin, CRP, amylase, albumin, AST, ALT, and ESR were evaluated. RESULTS: Genetic variants of exon 1 and exon 3 of NUDT15 were identified in 24 of 96 patients (25.0%). C.52G > A and c.36_37insGGAGTC in exon 1 were found in three patients each. All three patients with c.36_37insGGAGTC in exon 1 were heterozygotes of p.Arg139Cys in exon 3. Eighteen patients had p.Arg139Cys in exon 3 alone. The WBC count gradually decreased after initiation of thiopurine treatment in the mutated cases (n = 24), and was significantly lower at 6, 8, 10, and 16 wk (P = 0.0271, 0.0037, 0.0051, and 0.0185, respectively). The WBC counts were also evaluated in patients with and without prednisolone treatment. In the patients with prednisolone treatment, the WBC count tended to show a greater decrease in the mutated cases, with significant differences at 8 and 10 wk (P = 0.012 and 0.029, respectively). In the patients without prednisolone treatment, the WBC count was significantly lower at 2, 4, 8, and 14 wk in mutated cases (P = 0.0196, 0.0182, 0.0237 and 0.0241, respectively). MCV increased after starting thiopurine treatment in the mutated cases, and was significantly higher at 10 wk (P = 0.0085). Platelet count, hemoglobin, CRP, amylase, albumin, AST, ALT and ESR did not differ significantly between the wild-type and mutated cases. TPMT mutations were not found in any of the patients. CONCLUSION: Mutations in exon 1 of NUDT15 also affect thiopurine-induced leukopenia in patients with IBD. To discuss thiopurine-induced leukopenia in more detail, investigation of SNPs in both exon 1 and exon 3 of NUDT15 is needed.

Participation of caspase-3-like protease in oxidation-induced impairment of erythrocyte membrane properties.

Erythrocytes are very susceptible to oxidative stress, having a high content of intracellular oxygen and hemoglobin. In the present study, exposure to oxidative stress resulted in a significant impairment of erythrocyte membrane functions, such as deformability and anion exchange. Band 3 protein, also known as anion exchanger-1, plays an important role in these two functions. We show that oxidative stress activated caspase-3 inside the erythrocytes, which resulted in band 3 protein cleavage. Interestingly, inhibition of the caspase-3 with its specific inhibitor not only suppressed the digestion of band 3 protein, but also blunted the functional damage to erythrocytes, such as deformability and anion exchange, without changing the level of peroxidation of membrane lipids. These results provide experimental evidence that activation of caspase-3 plays an important role in the oxidative stress-induced impairment of membrane functions of erythrocytes.

[Systemic neurolymphomatosis complicated in diffuse large B-cell lymphoma].

A 73-year-old woman was diagnosed with diffuse large B-cell lymphoma of the uterus (Stage IVB). After 3 courses of CHOP therapy, right abducens nerve paralysis appeared and was diagnosed as central nervous system infiltration with lymphoma cells. Although partial remission was obtained by chemotherapy with methotrexate, numbness and muscle weakness of all four limbs appeared asymmetrically and progressed subacutely. Nerve conduction velocity examination revealed mononeuritis multiplex, but we could not reach a final diagnosis. Steroid pulse therapy, chemotherapy including high-dose methotrexate, and radiation therapy were ineffective. On autopsy, histological examination of the peripheral nerves revealed systemic neurolymphomatosis.

Triglyceride in plasma: prospective effects on microcirculatory functions.

The effect of triglyceride in plasma on RBC aggregation was examined, and the prospective influence on the flow of RBCs in microcirculation and the O2 release was discussed. To minimize the individual differences, blood samples were collected from one subject 2 hrs after high-fat and low fat meals. Triglyceride content in plasma was measured by an enzymatic method, and the rate of rouleaux formation was measured with a low shear rheoscope. The rate of rouleaux formation was increased with the increase of triglyceride concentration. Our previous findings suggested some functional impairment in microcirculation. (1) The enhanced RBC aggregation tends to reduce flow resistance in arterioles, but results in inhomogeneous flow of RBCs in capillaries. (2) The sclerotic change of microvessels alters flow behavior of RBCs, and thereby flow resistance is increased. (3) The enhanced RBC aggregation reduces O2 release from RBCs flowing in microvessels. In conclusion, high triglyceride level in plasma not only changes flow behavior of RBCs in microcirculation and thus increases flow resistance, but also prevents homogeneous tissue oxygenation.

Connective tissue growth factor is released from platelets under high shear stress and is differentially expressed in endothelium along atherosclerotic plaques.

Connective tissue growth factor (CTGF) is overexpressed in atherosclerotic blood vessels. To further investigate the role of CTGF in atherosclerosis, we examined whether CTGF is released from platelets by high shear stress, and whether the expression of CTGF along the atherosclerotic lesions depends on local hemodynamic conditions. Human platelets were subjected to 10 dyn/cm2 or 120 dyn/cm2 and analysed by Western blotting. Furthermore, longitudinal sections of 25 carotid plaques were immunohistochemically analysed for the endothelial expression of CTGF. A very low CTGF amount was secreted from platelets at low shear stress (11.4 +/- 3.9% of total CTGF in platelets). On the contrary, high shear stress caused a markedly increased CTGF release from platelets (29 +/- 13.8%, p = 0.07 vs low shear stress, n = 4). Immunohistochemical analyses showed that the mean numbers of CTGF-positive endothelial cells were significantly higher up-stream as compared with down-stream regions of the luminal surface of atherosclerotic vessels (21.3 +/- 3.6 vs 13.9 +/- 2.8 down-stream, p < 0.001). Moreover, in plaques undergoing intimal neovascularization, newly formed vessels accumulated particularly in up-stream parts of the lesions. In conclusion, this study demonstrated that CTGF is released from platelets by high shear stress. Furthermore, disturbed flow along atherosclerotic vessels may induce endothelial CTGF expression and contribute to the progress of atherosclerotic lesions.

Energy expenditure in males with mental retardation.

Previously, we reported that males with mental retardation (MR) (MR group) expended more energy than males without MR (control group) at a given work load. The precise physiological mechanisms for this difference remain unclear. Using the same set of subjects (23 age-, height-, and weight-matched male pairs, mean age: 36.3 y), we examined possible causes for the observed metabolic difference by monitoring physical movements and evaluating the metabolic capability of the skeletal muscles. In the supine position when no body movements were detected for any subjects, oxygen consumption (VO2) and heart rate (HR) were not markedly different between the MR and the control groups. By contrast, in the sitting and standing positions and during walking at 30 and 50 m/min, when significantly larger body movements were monitored in the MR group, VO2 and HR were significantly higher in this group than in the control group. Linear regression analyses, performed separately in the MR and control groups, revealed that the slope of the regression line of HR on relative exercise intensity (%VO2max) during walking, that of VO2 on walking speeds, and that of VO2 on the number of steps in the MR group were almost identical with those in the control group. These results suggest that the capability of skeletal muscles was not so different between the two groups. Thus, the high energy expenditure in the MR group was suggested to be a result of excessive body movements rather than an intrinsic incapability of skeletal muscles.

Effects of rapid saline infusion on orthostatic intolerance and autonomic tone after 20 days bed rest.

To test whether acute volume expansion can normalize orthostatic intolerance and autonomic tone after prolonged bed rest (BR), 23 men were subjected to 20 days BR. Left ventricular (LV) echocardiography was performed during the lower body negative pressure (LBNP) test before and after BR with and without preceding rapid infusion of saline (1,500 ml/30 min). Saline infusion restored heart rate, LV dimension, and stroke volume during LBNP, increased cardiac output (from 4.1 +/- 1 to 5.3 +/- 1 L/min), and normalized LBNP tolerance time (from 11 +/- 4 to 23 +/- 6 minutes). In 9 men, a Holter electrocardiogram was recorded on the day before BR, the fourth and twentieth days of BR, and the day after BR. The high-frequency component of heart rate variability during sleep gradually decreased and reached the lowest level on the day after BR (100%, 66 +/- 16%, 39 +/- 18%, 10 +/- 8%). Thus, restoring decreased blood volume is an effective countermeasure for orthostatic intolerance after BR. However, decreased vagal tone persisted, suggesting reset autonomic tone.

Reduced oxygen release from erythrocytes by the acceleration-induced flow shift, observed in an oxygen-permeable narrow tube.

The oxygen release from flowing erythrocytes under accelerational force (0-4 g) was examined using an oxygen-permeable, fluorinated ethylenepropylene copolymer tube (25 microm in inner diameter). The narrow tube was fixed vertically on the rotating disk of a new centrifuge apparatus, and erythrocyte suspension was perfused in the direction of Earth gravity. The accelerational force was applied perpendicularly to the flow direction of cells by centrifugation. The microscopic images of the flowing cells obtained at five different wavelengths were analyzed, and marginal cell-free layer and oxygen saturation of the cells were measured. By lowering oxygen tension around the narrow tube, erythrocytes were deoxygenated in proportion to their traveling distance, and the deoxygenation was enhanced with decreasing flow velocity and hematocrit. With increase of the g-value, the shift of flowing erythrocyte column to the centrifugal side was increased, the column was compressed, and the oxygen release from the cells was suppressed. Qualitatively, similar results were obtained by inducing erythrocyte aggregation with Dextran T-70 (MW = 70,400), without accelerational force. These results conclude that both the accumulation of erythrocytes under accelerational force and the enhancement of erythrocyte aggregation by macromolecules lead to the reduction of oxygen release from the flowing cells.

Glucose and oxygen hypometabolism in aceruloplasminemia brains.

OBJECTIVE: Aceruloplasminemia is an iron metabolic disorder caused by mutations in the ceruloplasmin gene. It is characterized by progressive neurodegeneration in association with iron accumulation. Excess iron functions as a potent catalyst of biologic oxidation. Previously we showed that an increased iron concentration is associated with the products of lipid peroxidation in the serum, cerebrospinal fluid, and brain tissues. To clarify the free radical-mediated tissue injury caused by intracellular iron accumulation through mitochondrial dysfunction. PATIENTS AND METHODS: We have measure brain oxygen and glucose metabolisms using positron emission tomography (PET) and examined brains at autopsy for iron contents and activities of the mitochondrial respiratory chain in two affected patients who had different truncation mutations of the ceruloplasmin gene. RESULTS: PET showed a marked decrease in glucose and oxygen consumption in the entire brain of aceruloplasminemia patients, with a preponderance of metabolic reduction in basal ganglia. Enzyme activities in the mitochondrial respiratory chain of the basal ganglia were reduced to approximately 45% and 42% respectively for complexes I and IV. An inverse relationship was shown between the amounts of iron accumulated and the levels of mitochondrial enzyme activities in all the brain regions examined. CONCLUSION: Iron-mediated free radicals may contribute to the impairment of mitochondrial energy metabolism in aceruloplasminemia.