Biomedical subjects

K Fu

Publications and source records attributed to K Fu.

At least 37 records · Page 2Linked to original sources

PubMed1998

The effect of twist on microvascular anastomotic patency and angiographic luminal dimensions.

BACKGROUND: Microvascular anastomoses must be constructed perfectly in order to be successful. One of the subtle technical errors that can occur during construction is twisting of the anastomosis. In the present study, we examined the effect of twist on the immediate, 2-h postoperative angiographic dimensions and patency of microvascular anastomoses. MATERIALS AND METHODS: Sixty-four Sprague-Dawley rats were assigned randomly to four groups. The femoral arteries were dissected for a distance sufficient to permit the application of an 8.5-mm-long microanastomotic approximator clamp. Microarteriorrhaphies were performed with twists of 0 degrees, 90 degrees, 180 degrees, or 270 degrees. Patency was assessed 2 h after surgery using transabdominal aortic arteriography with run-off. Measurements were recorded for each anastomosis, as well as for the narrowest and widest diameters of the vessels within 10 mm of the anastomosis. RESULTS: Fifty-nine of the 64 rats had technically satisfactory angiograms which permitted measurement of vascular dimensions. The cross-sectional areas of the narrowest areas and the anastomoses were inversely related to the degree of twist, and were significantly reduced at 270 degrees (P < 0.05). Two-hour patency rates were 86% with 0 degrees twist, 82% with 90 degrees twist, 71% with 180 degrees twist, and 33% with 270 degrees twist. The reduction in patency with 270 degrees twist was statistically significant (P < 0.05). CONCLUSIONS: Twists of 0 degrees, 90 degrees, and 180 degrees did not impair patency at a statistically significant level, but twists of 270 degrees did significantly reduce patency of microvascular anastomoses (P < 0.05).

Anastomosis, Surgical↗

PubMed1998

SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome.

Leigh Syndrome (LS) is a severe neurological disorder characterized by bilaterally symmetrical necrotic lesions in subcortical brain regions that is commonly associated with systemic cytochrome c oxidase (COX) deficiency. COX deficiency is an autosomal recessive trait and most patients belong to a single genetic complementation group. DNA sequence analysis of the genes encoding the structural subunits of the COX complex has failed to identify a pathogenic mutation. Using microcell-mediated chromosome transfer, we mapped the gene defect in this disorder to chromosome 9q34 by complementation of the respiratory chain deficiency in patient fibroblasts. Analysis of a candidate gene (SURF1) of unknown function revealed several mutations, all of which predict a truncated protein. These data suggest a role for SURF1 in the biogenesis of the COX complex and define a new class of gene defects causing human neurodegenerative disease.

Amino Acid Sequence↗

PubMed1998

Characterization of the mitochondrial DNA abnormalities in the skeletal muscle of patients with inclusion body myositis.

Inclusion body myositis (IBM) is a late-onset inflammatory myopathy with distinctive clinical and histopathological features. The molecular basis for the disease remains unknown, but abnormal nuclear morphology and the accumulation of a protein that binds single-stranded DNA in a sequence-independent fashion suggest a nuclear defect. Evidence of mitochondrial respiratory chain dysfunction (ragged-red fibers, multiple mtDNA deletions) has been reported in IBM muscle. Here we have investigated the relationship of the mtDNA abnormalities in sporadic and familial IBM patients to the pathogenesis of the disease. In situ hybridization analysis with mtDNA probes revealed several different mtDNA abnormalities in cytochrome c oxidase-negative muscle fibers including large-scale mtDNA deletions and mtDNA depletion, but no evidence for nonspecific DNA binding. Contrary to previous reports, we did not observe mtDNA deletions on Southern blot analysis, consistent with the presence of multiple different deleted mtDNA species demonstrated by single fiber PCR. There was no consistent correlation between the mitochondrial abnormalities and markers of muscle regeneration, inflammation, or microscopically detectable pathological alterations of myonuclei in the same fibers. Thus, early molecular abnormalities in IBM may simply accelerate the accumulation of mtDNA abnormalities that occurs with natural aging.

Adult↗

PubMed1998

Transplantation of lymph node fragments in a rabbit ear lymphedema model: a new method for restoring the lymphatic pathway.

The treatment of lymphedema by medical or surgical means remains a difficult task, and no technique is presently satisfactory. We established a rabbit ear chronic lymphedema model in which sequential lymph node fragments were transplanted to restore lymphatic pathways. Twenty New Zealand White rabbits were divided into two groups of 10 animals. One group served as the control, and the other was the transplantation group. A 3-cm-wide strip of skin and subcutaneous tissue including all the lymphatics was excised circumferentially from the root part of the right ear in each rabbit. The vascular pedicle in the control group was wrapped with a "bridge" strip of skin from the ventral ear to protect it from drying. In the transplantation group, the auricular lymph node was harvested from the contralateral ear, cut into 1- to 2-mm slices, and implanted next to the vascular pedicle where the lymph vessels had been resected. Water displacement measurements in both groups revealed significant edema (p < 0.001) compared with the contralateral ear at 3 days. Peak swelling was observed at 10 days in both groups. Volumes decreased in both groups postoperatively. The volume measured as percentage change in the lymph node transplantation group was significantly lower than in the control group at 2 months and continuing to the end of the experiment (p < 0.001). Indirect lymphographic examination revealed that the distal lymphatic vessels of the control group were increased in number, dilated, and did not allow proximal passage of dye. Light microscopy revealed the vascular pedicle to be surrounded by dense scar tissue in the "bridge." The transplantation group showed free passage of dye through the bridge. Microscopic examination showed regenerated lymphoid tissue with sinuses along the artery and vein of the "bridge." Many channels with a layer of endothelial cells were also noted. Electron microscopy confirmed these sites to be regenerated lymph vessels. Lymphatic tissue can regenerate after fragment transplantation. This lymph tissue seems to regenerate lymphatic vessels that may function for drainage. The results suggest that this simple technique may be applicable in a clinical situation to prevent or treat obstructive lymphedema.

Animals↗

PubMed1998

Metallothionein protects against cerulein-induced acute pancreatitis: analysis using transgenic mice.

Oxidative stress has been proposed to play a role in the early events of acute pancreatitis, and metallothionein (MT) can provide protection against oxidative stress. Using transgenic mice, we characterized the effects of depletion of MT-I and -II, or overexpression of MT-I, on pancreatic responses during cerulein-induced acute pancreatitis. In MT-I/-II knockout mice, repeated injections of cerulein caused (a) higher serum amylase levels at 3 and 7 h after the initiation of acute pancreatitis; (b) earlier and stronger upregulation of oxidative stress-responsive genes, including heme oxygenase (HO)-1 and c-fos; and (c) exacerbated tissue damage (edema and polymorphonuclear neutrophil infiltration) compared with nontransgenic 129/SvCPJ mice. Total pancreatic glutathione (GSH + GSSG) content was similar between the knockout and nontransgenic 129/SvCPJ mice. Interestingly, during acute pancreatitis, CD-1 mice pretreated with L-buthionine-[S,R]-sulfoximine (BSO), which dramatically depleted pancreatic GSH, also had more severe pancreatitis, based on the same three criteria listed above, relative to untreated controls. No effects were observed with BSO treatment alone. Finally, during cerulein-induced acute pancreatitis, MT-I overexpressing transgenic mice (>20-fold increase in pancreatic MT-I content) had lower serum alpha-amylase levels between 7 and 24 h and delayed upregulation of HO-1 mRNA levels, but no difference in c-fos mRNA induction relative to the appropriate strain of nontransgenic mice. Diminished tissue damage (particularly cellular necrosis) was noted in these MT-I overexpressing transgenic mice. Total pancreatic GSH content was similar in these transgenic and nontransgenic mice during cerulein-induced acute pancreatitis. These studies suggest that pancreatic MT can function as an intracellular antioxidant as does GSH and that these intracellular antioxidants play a protective role during cerulein-induced acute pancreatitis.

Acute Disease↗

PubMed1998

Pedigree analysis of French Canadian families with T14484C Leber's hereditary optic neuropathy.

We analyzed the clinical phenotype and determined the recurrence risks to relatives of patients with T14484C Leber's hereditary optic neuropathy (LHON). LHON is a maternally inherited optic neuropathy that primarily affects adolescent males. It is usually associated with one of three mtDNA mutations: G3460A, G11778A, or T14484C. Definition of recurrence risks for the T14484C mutation previously has not been possible due to the relative scarcity of families with this mutation. We obtained blood samples from index patients and their consenting family members, all of whom were of French Canadian ancestry and screened for LHON mutations in mtDNA. Referring ophthalmologists furnished clinical summaries and patients provided pedigree data. T14484C was the most common mutation in the pedigrees analyzed and was always homoplasmic. In these pedigrees, the ratio of affected males to females was 8:1. Median age at onset for males was 19 years (95th percentile, 40.8 years; range, 6 to 48 years). Some improvement of vision was observed in 58% of patients. Recurrence risks to brothers were 28%, sisters 5%, nephews 30%, nieces 3%, male matrilineal first cousins 19%, and female matrilineal first cousins 4%. Recurrence risks to brothers and nephews were not different; however, recurrence risks to brothers and male cousins and to nephews and male cousins were significantly different. There were no differences in recurrence risks to sisters and nieces or to either group compared with their female cousins. Affected females did not have more affected children than unaffected females. The clinical characteristics of French Canadian patients with T14484C LHON were strikingly similar to those in previous reports, suggesting that recurrence risks are generalizable to other T14484C LHON populations for genetic counseling of T14484C LHON families.

Adolescent↗

PubMed1998

[Ultrastructure of the synovial membrane and the articular cartilage in the temporomandibular joint of the rabbits with occlusal trauma].

OBJECTIVE: To study the effect of occlusal trauma on the ultra structure of rabbits' temporomandibular joints (TMJ) synovial membrane and articular cartilage. METHODS: TMJs from six rabbits with occlusal trauma and three control rabbits were studied by transmission electron microscopy. RESULTS: Degenerative changes of TMJ tissues were found. The articular surface of the condyle was damaged, and the chondrocytes showed signs of degeneration. The synovial lining cell consisted of a number of vimentin intermediate filaments (IFs) which were especially prevalent in the processes as well as paranuclearly. Microvilli on the cell membrane were commonly seen. The vermiform body in the deeper interstitium was also found. Our finding of punctate adherens between synoviocytes was firstly reported in the study. CONCLUSION: The occlusal trauma is really a factor inducing degenerative changes of the TMJ.

Animals↗

PubMed1998

[The interior relation between FDP and SHG].

The fluorescence-disappearing phenomenon (FDP) was used due to the nonlinear interaction between the laser and the matter, a universal phenomenon. It was often neglected during the research of surface-harmonic generation (SHG). Many experiments showed that there was a interior relation between FDP and SHG. In this paper, the mechanism of surface-harmonic generation has been discussed in detail, according to the fluorescence-disappear viewpoint and the fluorescence-disappear model (FDM) proposed also. The new mechanism was summarized by following three points: (a) The multiphoton absorption generated visible fluorescence spot, (b) Laser-heating effect and other effects promoted the conversion from spontaneous emission into quasi-stimulated emission, (c) Being accompanied by the fluorescence disappear, the part of laser energy which was initially used to cause fluorescence was now converted into developing the harmonic signal.

English Abstract↗

PubMed1997

Efficacy of pentasaccharide in a dog model of hemodialysis.

A synthetic heparin pentasaccharide with sole anti-Xa actions has been evaluated for its antithrombotic efficacy in a dog model of hemodialysis. Various dosages of pentasaccharide, 400-800 nmol/kg, were compared with a single bolus dose of unfractionated heparin (250 U/kg). The primary endpoint in these studies was the duration of dialysis time. In addition, dialyzer filter content, venous trap protein, celite and saline ACT and hematocrit measurement. Pentasaccharide at dosages of 600 and 800 nmol/kg produced an extension of dialysis time (> 180 minutes) in contrast to unfractionated heparin at 250 U/kg which only produced antithrombotic effects for periods of up to 150 +/- 42 minutes (n = 5). At a lower dosage of 400 nmol/kg pentasaccharide produced weaker effects and the dialysis circuit was patent for periods of 122 +/- 14.8 (n = 5) minutes. The saline and celite ACT times were not extended at any dosage of pentasaccharide; however, at 250 U/kg, a strong effect was noted with unfractionated heparin (> 800 secs, 647 +/- 211 secs.), respectively. A dose dependent antithrombotic effect was also evident in the studies on the filter clots and venous trap protein content. No difference in the hematocrit was noted in any group. These results clearly suggest that despite the fact that pentasaccharide does not produce any prolongation of the coagulation times, it produces a dose dependent antithrombotic effect in this model of dog hemodialysis. Furthermore, these results also suggest that pentasaccharide at an appropriate dosage can be used as an alternate antithrombotic agent during hemodialysis.

Animals↗

PubMed1997

Human estrogen receptor-like 1 (ESRL1) gene: genomic organization, chromosomal localization, and promoter characterization.

Estrogen receptor-like 1a (ESRL1a; same as estrogen receptor-related orphan receptors, ERR1) belongs to a subfamily of the nuclear receptor superfamily. We have previously shown that human ESRL1a modulates estrogen responsiveness of the lactoferrin gene promoter in transiently transfected endometrial carcinoma RL95-2 cells. In this study, we cloned and characterized the human ESRL1 gene. Through the fluorescence in situ hybridization method, the ESRL1 gene was localized to the centromere region of chromosome 11q12. Partial sequencing, restriction mapping, and PCR analysis revealed that the ESRL1 gene consists of seven exons and is approximately 20 kb in length. We found that the smallest exon (exon 3) contains 117 bp and the largest exon (exon 7) has 1032 bp. The smallest intron (intron 5) is only 88 bp long and the largest intron (intron 2) is 8 kb long. All introns have the conserved GT and AG dinucleotides present at the donor and acceptor sites, respectively. Like the estrogen receptor, the highly conserved DNA-binding domain of hESRL1a is encoded by exon 2 and exon 3, and the intron/exon junctions (2 and 3) are well conserved between the two genes. Primer extension analysis revealed multiple transcription initiation start sites in human uterine (HeLa, HEC, and RL95-2) cell lines. However, one major initiation start site was found by RNase protection assay. The hESRL1a mRNA is differentially expressed in various human tissues. The nucleotide sequence adjacent to the transcription start sites of the ESRL1 lacks the typical TATA and CAAT boxes but is GC rich and contains 10 consensus Sp1-binding elements and two E boxes. The region that contains these transcription factor-binding elements showed a high level of promoter activity when transiently transfected into RL95-2 cells.

Blotting, Northern↗

PubMed1997

Topical application of low molecular weight heparin in a rabbit traumatic anastomosis model.

Low molecular weight heparins (LMWHs) are antithrombotic drugs composed of lower molecular weight components of heparin with an apparent molecular weight in the range of 4.0-8.0 KDA. These agents have been used clinically for several years. They have different mechanisms of action compared to heparin, a longer half-life and much higher bioavailability. Anticoagulant drugs such as heparin have been used topically in our previous studies to avoid bleeding complications observed with systemic administration. In this study, low molecular weight heparin (Certoparin, Sandoz) was topically administered in a rabbit ear arterial crush-avulsion thrombosis model and compared with heparin. The animals were divided into three groups: LMWH, heparin and saline control groups. In the LMWH group, the patency rate was 71% (10 of 14) at both 1 and 7 days. The patency rate in the heparin group was 95% (19 of 20) at 24 hrs and 80% (16 of 20) at 7 days. In the saline control group, the vessel patency rate was 17% at 24 hrs and 13% at 7 days. Clotting times such as ACT, PT and APTT performed on samples drawn one hour after drug administration were within the normal ranges for both the control and the treatment groups. The results suggest that topical administration of LMWH prevents the occurrence of thrombosis at the traumatic anastomosis site to a similar degree as heparin.

Administration, Topical↗

PubMed1997

Expression of oxidative stress-responsive genes and cytokine genes during caerulein-induced acute pancreatitis.

Oxidative stress and the inflammatory response may play roles in the pathogenesis of acute pancreatitis. Herein, we characterized pancreatic expression of oxidative stress-responsive genes [c-fos, heme oxygenase-1 (HO-1), and metallothionein-I (MT-I)] and cytokine genes [interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha)] during caerulein-induced acute pancreatitis in the mouse. c-fos, HO-1, and MT-I mRNAs were coordinately and rapidly (3-7 h) upregulated, and HO-1 and MT-I protein levels were increased slightly in the pancreas during acute pancreatitis. In addition, IL-1 beta, IL-6, and TNF-alpha mRNAs were rapidly (7 h) upregulated in the pancreas, and intrapancreatic IL-1 beta and IL-6 protein levels rapidly increased (3-fold and 6.4-fold, respectively) during acute pancreatitis. These studies suggest that oxidative stress and inflammation each occur in the pancreas during the early stages of acute pancreatitis. However, under a limited set of experimental conditions, we found that an insult that causes pancreatic oxidative stress (diethylmaleate) or one that induces an inflammatory response (bacterial lipopolysaccharide), or a combination of these agents, did not cause the changes characteristic of acute pancreatitis. Therefore, simply inducing oxidative stress and/or inflammation may be insufficient to initiate acute pancreatitis.

Acute Disease↗

PubMed1996

Phase III study of interstitial thermoradiotherapy compared with interstitial radiotherapy alone in the treatment of recurrent or persistent human tumors. A prospectively controlled randomized study by the Radiation Therapy Group.

PURPOSE: The objectives of this randomized trial were to determine if interstitial thermoradiotherapy (ITRT) improves tumor regression/control in accessible lesions in comparison with interstitial radiotherapy (IRT) alone and to assess the skin and soft tissue complications with either modality. METHODS AND MATERIALS: From January 1986 to June 1992, 184 patients with persistent or recurrent tumors after previous radiotherapy and/or surgery, which were amenable to interstitial radiotherapy, were accessioned to a protocol developed by the Radiation Therapy Oncology Group (RTOG). One hundred seventy-three cases were analyzed (87 patients in the IRT group and 86 in the ITRT arm). The two arms were well balanced regarding stratification criteria. Most tumors were in the head and neck (40% in the IRT group and 46% in the ITRT group), and pelvis (42% and 43%, respectively). Eighty-four percent of patients in both arms had prior radiation therapy (> or = 40 Gy); 50% and 40%, respectively, had prior surgery, and 34% in each arm had prior chemotherapy. The dose of radiation therapy administered was dependent on the previous radiation dose and did not exceed a total cumulative dose of 100 Gy. Hyperthermia was delivered in one or two sessions, either before or before and after interstitial implant. The intended goal of the hyperthermia was to maintain a minimal tumor temperature of 42.5 degrees C for 30 to 60 min. RESULTS: There was no difference in any of the study end points between the two arms. Complete response (CR) was 53% and 55% in both arms. Two-year survival was 34% and 35%, respectively. Complete response rate for persistent lesions was 69% and 63% in the two treatment arms as compared with 40% and 48% for recurrent lesions. A set of minimal adequacy criteria for the delivery of hyperthermia was developed. When these criteria were applied, only one patient had an adequate hyperthermia session. Acute Grade 3 and 4 toxicities were 12% for IRT and 22 % for ITRT. Late Grade 3 and 4 toxicities were 15% for IRT and 20% for ITRT. The difference was not significant. CONCLUSIONS: Interstitial hyperthermia, as applied in this randomized study, did not show any additional beneficial effects over interstitial radiotherapy alone. Delivery of hyperthermia remains a major obstacle (since only one patient met the basic minimum adequacy criteria as defined in this study). The benefit of hyperthermia in addition to radiation therapy still remains to be proven in properly randomized prospective clinical trials after substantial technical improvements in heat delivery and dosimetry are achieved.

Adult↗

PubMed1996

Activation of the complete mouse metallothionein gene locus in the maternal deciduum.

The mouse metallothionein (MT) gene family consists of four known members (MT-I through IV) clustered on chromosome 8. Studies reported herein examine the expression and regulation of the MT-III and MT-IV genes in specific cell types in the maternal reproductive tract, developing embryo, and fetus known to express the MT-I and -II genes. MT-III and MT-IV mRNAs were absent from the visceral yolk sac, placenta, and fetal liver, tissues with high levels of MT-I and MT-II mRNAs. In contrast, MT-III and MT-IV mRNAs were both abundant in the maternal deciduum, and in experimentally induced deciduoma on 7 and 8 days postcoitum (1 dpc = vaginal plug), as are MT-I and -II mRNAs. The abundance of each of these MT mRNAs increased coordinately during development of the deciduum (6-8 dpc), and in situ hybridization localized MT-I, MT-III, and MT-IV mRNAs to the secondary decidual zone of the antimesometrial region on 8 dpc, where in some regions all of the cells were apparently positive. Thus, all of the known mouse MT genes are co-expressed in at least some of the cells in the secondary decidual zone. Electrophoretic analysis of decidual MT suggested that the MT-I, -II, and -III isoforms are abundant proteins in the secondary deciduum. Bacterial endotoxin-lipopolysaccharide (LPS) and Zn are powerful inducers of MT-I and MT-II gene expression in many adult organs, whereas these agents apparently have little effect on MT-III and MT-IV gene expression. Neither of these agents significantly effected levels of decidual MT-III or MT-IV mRNAs in vivo or in primary cultures of decidual cells in vitro, and only modest effects of Zn on MT-I mRNA levels were noted. During 2 days of in vitro culture, decidual cell MT-I and MT-III mRNA levels remained elevated while MT-IV mRNA levels decreased. Thus, expression of the mouse MT gene locus in the deciduum appears to be developmentally regulated, and in this tissue, the MT genes are refractory to induction by Zn or inflammation.

Animals↗

PubMed1996

Transgenic mouse blastocysts that overexpress metallothionein-I resist cadmium toxicity in vitro.

The role of metallothionein with regard to cadmium toxicity in vitro was investigated using preimplantation mouse blastocysts derived from a transgenic strain that constitutively overexpresses metallothionein-I transgenes (MT-I*). Northern blot and in situ hybridization revealed high levels of MT-I mRNA in transgenic blastocysts when compared with control blastocysts, and reverse transcriptase-polymerase chain reaction-amplified MT-I mRNA was almost exclusively MT-I*. Moreover, pulse-labeling experiments showed that the relative rate of synthesis of MT was 9-fold higher in transgenic blastocysts. Cadmium (Cd2+) toxicity was assessed after incubating blastocysts for 4 hr in Whitten's medium containing 50 microM Cd2+. Embryos that displayed abnormal morphology were judged "sensitive". Transgenic blastocysts were more resistant to cadmium-induced morphological changes than were control blastocysts. "Sensitive" and "resistant" blastocysts were individually genotyped by polymerase chain reaction, or they were transferred to foster mothers, and embryonic development to midterm was monitored. Of the blastocysts derived from mating heterozygous transgenic males with control females, 56% were transgenic before incubation with Cd2+, whereas 95% of the blastocysts that retained normal morphology after incubation were transgenic. Moreover, after Cd2+ exposure, transgenic blastocysts with normal morphology were nine times more likely to develop to midterm than were control blastocysts with normal morphology. Blastocysts with abnormal morphology failed to develop to midterm. These studies indicate that MT plays a central role in protection from Cd2+ toxicity within the physiological context of the developing mouse embryo.

Animals↗

PubMed1996

Random genetic drift in the female germline explains the rapid segregation of mammalian mitochondrial DNA.

Mitochondrial DNA (mtDNA) is maternally inherited in mammals. Despite the high genome copy number in mature oocytes (10(5)) and the relatively small number of cell divisions in the female germline, mtDNA sequence variants segregate rapidly between generations. To investigate the molecular basis for this apparent paradox we created lines of heteroplasmic mice carrying two mtDNA genotypes. We show that the pattern of segregation can be explained by random genetic drift occurring in early oogenesis, and that the effective number of segregating units for mtDNA is approximately 200 in mice. These results provide the basis for estimating recurrence risks for mitochondrial disease due to pathogenic mtDNA mutations and for predicting the rate of fixation of neutral mtDNA mutations in maternal lineages.

Animals↗

PubMed1996

Effects of traumatic brain injury on the cholinergic system in the rat.

Rats subjected to a mild to moderate fluid percussion injury exhibit memory deficits that are similar to rats that have received lesions of the septohippocampal system. Because the cholinergic system plays a major role in septohippocampal function, we studied the kinetics of the synthetic enzyme for acetylcholine, choline acetyltransferase (ChAT), at 1 h, 24 h, or 5 days after a fluid percussion injury. Decreases in ChAT activity were found in the dorsal hippocampus (25%), frontal (32%), and temporal (23%) cortices 1 h after injury. In the parietal cortex, a greater than 50% increase in ChAT activity was observed at all time intervals assessed. At 5 days after TBI, there was an 18% increase in ChAT activity in the medial septal area. These data provide evidence that a mild to moderate fluid percussion injury produces changes in the cholinergic system in brain areas related to memory.

Analysis of Variance↗

PubMed1996

A novel heteroplasmic tRNAleu(CUN) mtDNA point mutation in a sporadic patient with mitochondrial encephalomyopathy segregates rapidly in skeletal muscle and suggests an approach to therapy.

A novel mtDNA point mutation was detected in the tRNAleu(CUN) gene (G to A at position 12315) in a sporadic patient with chronic progressive external ophthalmoplegia, ptosis, limb weakness, sensorineural hearing loss and a pigmentary retinopathy. The mutation disrupts base pairing in the T psi C stem at a site which has been conserved throughout evolution. Although the other mtDNA tRNAleu gene (UUR) is a hotspot for mutation, this is the first pathogenic mutation to be reported in the gene coding for tRNAleu(CUN). MtDNAs carrying the mutation constituted 94% of total mtDNAs in two separate muscle biopsies. Single fibre analysis showed that skeletal muscle fibres without detectable cytochrome c oxidase activity (COX-ve fibres) contained predominantly mutant mtDNAs (93-98%) while fibres with apparently normal COX activity had up to 90% mutant mtDNAs, demonstrating that the G12315A mutation is functionally recessive. Immunofluorescence studies with specific antibodies to mtDNA- or nuclear-encoded subunits of COX were consistent with a defect in mitochondrial protein translation. The mutation was not present in blood cells or cultured fibroblasts and surprisingly, it could not be detected in satellite cells cultured from the patient's muscle. This pattern, which may by typical of patients who have inherited new germline pathogenic mtDNA mutations, possibly reflects loss of the mutation by random genetic drift in mitotic tissues and proliferation of mitochondria containing the mutant mtDNA in post-mitotic cells. The absence of mtDNA carrying the mutation in satellite cells suggests that regeneration of skeletal muscle fibres from satellite cells could restore a wild-type mtDNA genotype and normal muscle function.

Base Sequence↗