Biomedical subjects

T T Huang

Publications and source records attributed to T T Huang.

At least 19 recordsLinked to original sources

PubMed2001

Absence of mitochondrial superoxide dismutase results in a murine hemolytic anemia responsive to therapy with a catalytic antioxidant.

Manganese superoxide dismutase 2 (SOD2) is a critical component of the mitochondrial pathway for detoxification of O2(-), and targeted disruption of this locus leads to embryonic or neonatal lethality in mice. To follow the effects of SOD2 deficiency in cells over a longer time course, we created hematopoietic chimeras in which all blood cells are derived from fetal liver stem cells of Sod2 knockout, heterozygous, or wild-type littermates. Stem cells of each genotype efficiently rescued hematopoiesis and allowed long-term survival of lethally irradiated host animals. Peripheral blood analysis of leukocyte populations revealed no differences in reconstitution kinetics of T cells, B cells, or myeloid cells when comparing Sod2(+/+), Sod2(-/-), and Sod2(+/-) fetal liver recipients. However, animals receiving Sod2(-/-) cells were persistently anemic, with findings suggestive of a hemolytic process. Loss of SOD2 in erythroid progenitor cells results in enhanced protein oxidative damage, altered membrane deformation, and reduced survival of red cells. Treatment of anemic animals with Euk-8, a catalytic antioxidant with both SOD and catalase activities, significantly corrected this oxidative stress-induced condition. Such therapy may prove useful in treatment of human disorders such as sideroblastic anemia, which SOD2 deficiency most closely resembles.

Anemia, Hemolytic↗

PubMed2001

Manganese superoxide dismutase signals matrix metalloproteinase expression via H2O2-dependent ERK1/2 activation.

Manganese-superoxide dismutase (Sod2) removes mitochondrially derived superoxide (O(2)) at near-diffusion limiting rates and is the only antioxidant enzyme whose expression is regulated by numerous stimuli. Here it is shown that Sod2 also serves as a source of the intracellular signaling molecule H(2)O(2). Sod2-dependent increases in the steady-state levels of H(2)O(2) led to ERK1/2 activation and subsequent downstream transcriptional increases in matrix metalloproteinase-1 (MMP-1) expression, which were reversed by expression of the H(2)O(2)-detoxifying enzyme, catalase. In addition, a single nucleotide polymorphism has recently been identified (1G/2G) at base pair--1607 that creates an Ets site adjacent to an AP-1 site at base pair --1602 and has been shown to dramatically enhance transcription of the MMP-1 promoter. Luciferase promoter constructs containing either the 1G or 2G variation were 25- or 1000-fold more active when transiently transfected into Sod2-overexpressing cell lines, respectively. The levels of MMP-2, -3, and -7 were also increased in the Sod2-overexpressing cell lines, suggesting that Sod2 may function as a "global" redox regulator of MMP expression. In addition, Sod2(-/+) mouse embryonic fibroblasts failed to respond to the cytokine-mediated induction of the murine functional analog of MMP-1, MMP-13. This study provides evidence that the modulation of Sod2 activity by a wide array of pathogenic and inflammatory stimuli may be utilized by the cell as a primary signaling mechanism leading to matrix metalloproteinase expression.

Animals↗

PubMed2001

Growth of visceral fat, subcutaneous abdominal fat, and total body fat in children.

OBJECTIVE: To examine the patterns of growth of visceral fat, subcutaneous abdominal fat, and total body fat over a 3- to 5-year period in white and African American children. RESEARCH METHODS AND PROCEDURES: Children (mean age: 8.1 +/- 1.6 years at baseline) were recruited from Birmingham, Alabama, and those with three or more repeated annual measurements were included in the analysis (N = 138 children and 601 observations). Abdominal adipose tissue (visceral and subcutaneous) was measured using computed tomography. Total body fat and lean tissue mass were measured by DXA. Random growth curve modeling was performed to estimate growth rates of the different body fat compartments. RESULTS: Visceral fat and total body fat both exhibited significant growth effects before and after adjusting for subcutaneous abdominal fat and lean tissue mass, respectively, and for gender, race, and baseline age (5.2 +/- 2.2 cm(2)/yr and 1.9 +/- 0.8 kg/yr, respectively). After adjusting for total body fat, the growth of subcutaneous abdominal fat was not significant. Whites showed a higher visceral fat growth than did African Americans (difference: 1.9 +/- 0.8 cm(2)/yr), but there was no ethnic difference for growth of subcutaneous abdominal fat or total body fat. There were no gender differences found for any of the growth rates. DISCUSSION: Growth of visceral fat remained significant after adjusting for growth of subcutaneous abdominal fat, implying that the acquisition of the two abdominal fat compartments may involve different physiologic mechanisms. In contrast, growth of subcutaneous abdominal fat was explained by growth in total body fat, suggesting that subcutaneous fat may not be preferentially deposited in the abdominal area during this phase of growth. Finally, significantly higher growth of visceral fat in white compared with African American children is consistent with cross-sectional findings.

Abdomen↗

PubMed2001

Postrepression activation of NF-kappaB requires the amino-terminal nuclear export signal specific to IkappaBalpha.

One of the most prominent NF-kappaB target genes in mammalian cells is the gene encoding one of its inhibitor proteins, IkappaBalpha. The increased synthesis of IkappaBalpha leads to postinduction repression of nuclear NF-kappaB activity. However, it is unknown why IkappaBalpha, among multiple IkappaB family members, is involved in this process and what significance this feedback regulation has beyond terminating NF-kappaB activity. Herein, we report an important IkappaBalpha-specific function dictated by its amino-terminal nuclear export sequence (N-NES). The IkappaBalpha N-NES is necessary for the postinduction export of nuclear NF-kappaB, which is a critical event in reestablishing a permissive condition for NF-kappaB to be rapidly reactivated. We show that although IkappaBalpha and another IkappaB member, IkappaBbeta, can enter the nucleus and repress NF-kappaB DNA-binding activity during the postinduction phase, only IkappaBalpha allows the efficient export of nuclear NF-kappaB. Moreover, swapping the N-terminal region of IkappaBbeta for the corresponding IkappaBalpha sequence is sufficient for the IkappaB chimera protein to export NF-kappaB similarly to IkappaBalpha during the postinduction state. Our findings provide a mechanistic explanation of why IkappaBalpha but not other IkappaB members is crucial for postrepression activation of NF-kappaB. We propose that this IkappaBalpha-specific function is important for certain physiological and pathological conditions where NF-kappaB needs to be rapidly reactivated.

Active Transport, Cell Nucleus↗

PubMed2001

Knockout mice heterozygous for Sod2 show alterations in cardiac mitochondrial function and apoptosis.

Heart mitochondria from heterozygous (Sod2(-/+)) knockout mice have a 50% reduction in manganese superoxide dismutase (MnSOD) activity. The decrease in MnSOD activity was associated with increased mitochondrial oxidative damage as demonstrated by a decrease in the activities of iron sulfhydryl proteins sensitive to oxygen stress (aconitase and reduced nicotinamide adenine dinucleotide-oxidoreductase). Mitochondrial function was altered in the Sod2(-/+) mice, as shown by decreased respiration by complex I and an increase in the sensitivity of the permeability transition to induction by calcium and t-butylhydroperoxide. The increased induction of the permeability transition in heart mitochondria from Sod2(-/+.)mice was associated with increased release of cytochrome c and an increase in DNA fragmentation. Cardiomyocytes isolated from neonatal Sod2(-/+) and Sod2(-/-) mice were more sensitive to cell death than cardiomyocytes from Sod2(+/+) mice after t-butylhydroperoxide treatment, and this increased sensitivity was prevented by inhibiting the permeability transition with cyclosporin A. These experiments demonstrate that MnSOD may play an important role in the induction of the mitochondrial pathway of apoptosis in the heart, and this appears to occur primarily through the permeability transition.

Aconitate Hydratase↗

PubMed2001

Longitudinal changes in body fat in African American and Caucasian children: influence of fasting insulin and insulin sensitivity.

Obesity is associated with hyperinsulinemia and reduced insulin sensitivity, both risk factors for type 2 diabetes. However, it is not clear whether these risk factors occur as a result of obesity or whether they contribute to the development of obesity. The aims of this study were to determine whether baseline (first visit) or changes in insulin measures over time were associated with longitudinal changes in body fat mass during growth in children. The study group consisted of 137 children (83 Caucasian and 54 African American) with a mean age of 8.1 yr at baseline. The children returned for 3-6 annual visits for measurement of fasting insulin, insulin sensitivity (Si), and acute insulin response (AIR) from the tolbutamide-modified frequent sampling iv glucose tolerance test and for determination of body composition by dual energy x-ray absorptiometry. Data were analyzed using SAS Proc mixed growth models. Total fat mass increased with time by 15.6%/yr (P = 0.013), but the rate of increase was not significantly influenced by race, sex, or Tanner stage. However, fasting insulin (positive effect), Si (negative effect), and AIR (positive effect) were significantly associated with the rate of increase in fat mass. In conclusion, in this cohort of children, growth-related increases in body fat were significantly associated with increases in fasting insulin and AIR and decreases in Si.

Adipose Tissue↗

PubMed2001

Upregulation of inducible nitric oxide synthase and cytokine secretion in peripheral blood monocytes from pulmonary tuberculosis patients.

SETTING: Peripheral blood monocytes (PBM) are the main source of alveolar macrophages, which have an upregulation of inducible nitric oxide synthase (iNOS) in pulmonary tuberculosis (TB). TNF-alpha and IL-1 beta are thought to be involved in the immune response to mycobacterial infection. OBJECTIVE: To identify whether iNOS expression and cytokine release of PBM are upregulated and have a connection in TB infection. DESIGN: The expression of iNOS immunoreactivity on PBM from TB patients and normal subjects was measured by loading with anti-macrophage iNOS polyclonal primary antibody analyzed by flow cytometry. Expression of iNOS mRNA in PBM was detected by RT-PCR. The spontaneous generation of nitrite and cytokines (IL-1 beta and TNF-alpha) by cultured monocytes was also determined. RESULTS: Compared to normal subjects, iNOS immuno-reactivity, the capacity for spontaneous nitrite generation and the level of TNF-alpha or IL-1 beta secretion of PBM were significantly higher in TB patients. The amount of nitrite, TNF-alpha and IL-1 beta released from PBM of TB patients was inhibited by NG-monomethyl-L-arginine (L-NMMA), a competitive inhibitor of NOS. The level of iNOS immunoreactivity on PBM was highly correlated with nitrite generation both in all the subjects studied and in TB patients alone. Spontaneous TNF-alpha production showed a stronger correlation with nitrite production than with IL-1 beta. CONCLUSION: The NO and cytokine synthase activities of monocytes appear to be concomitantly upregulated in response to mycobacterial infection. The enhanced NO generation by monocytes in TB patients may play an autoregulatory role in amplifying the synthesis of pro-inflammatory cytokines.

Female↗

PubMed2000

NF-kappaB activation by camptothecin. A linkage between nuclear DNA damage and cytoplasmic signaling events.

Activation of the transcription factor NF-kappaB by extracellular signals involves its release from the inhibitor protein IkappaBalpha in the cytoplasm and subsequent nuclear translocation. NF-kappaB can also be activated by the anticancer agent camptothecin (CPT), which inhibits DNA topoisomerase (Topo) I activity and causes DNA double-strand breaks during DNA replication to induce S phase-dependent cytotoxicity. Here we show that CPT activates NF-kappaB by a mechanism that is dependent on initial nuclear DNA damage followed by cytoplasmic signaling events. NF-kappaB activation by CPT is dramatically diminished in cytoplasts and in CEM/C2 cells expressing a mutant Topo I protein that fails to bind CPT. This response is intensified in S phase cell populations and is prevented by the DNA polymerase inhibitor aphidicolin. In addition, CPT activation of NF-kappaB involves degradation of cytoplasmic IkappaBalpha by the ubiquitin-proteasome pathway in a manner that depends on the IkappaB kinase complex. Finally, inhibition of NF-kappaB activation augments CPT-induced apoptosis. These findings elucidate the progression of signaling events that initiates in the nucleus with CPT-Topo I interaction and continues in the cytoplasm resulting in degradation of IkappaBalpha and nuclear translocation of NF-kappaB to attenuate the apoptotic response.

Apoptosis↗

PubMed2000

A nuclear export signal in the N-terminal regulatory domain of IkappaBalpha controls cytoplasmic localization of inactive NF-kappaB/IkappaBalpha complexes.

Appropriate subcellular localization is crucial for regulation of NF-kappaB function. Herein, we show that latent NF-kappaB complexes can enter and exit the nucleus in preinduction states. The nuclear export inhibitor leptomycin B (LMB) sequestered NF-kappaB/IkappaBalpha complexes in the nucleus. Using deletion and site-directed mutagenesis, we identified a previously uncharacterized nuclear export sequence in residues 45-54 of IkappaBalpha that was required for cytoplasmic localization of inactive complexes. This nuclear export sequence also caused nuclear exclusion of heterologous proteins in a LMB-sensitive manner. Importantly, a LMB-insensitive CRM1 mutant (Crm1-K1) abolished LMB-induced nuclear accumulation of the inactive complexes. Moreover, a cell-permeable p50 NF-kappaB nuclear localization signal peptide also blocked these LMB effects. These results suggest that NF-kappaB/IkappaBalpha complexes shuttle between the cytoplasm and nucleus by a nuclear localization signal-dependent nuclear import and a CRM1-dependent nuclear export. The LMB-induced nuclear complexes could not bind DNA and were inaccessible to signaling events, because LMB inhibited NF-kappaB activation without affecting the subcellular localization of upstream kinases IKKbeta and NIK. Our findings indicate that the dominant nuclear export over nuclear import contributes to the largely cytoplasmic localization of the inactive complexes to achieve efficient NF-kappaB activation by extracellular signals.

Amino Acid Motifs↗

PubMed2000

Exposure to, and perceived usefulness of, school-based tobacco prevention programs: associations with susceptibility to smoking among adolescents.

PURPOSE: To examine the relationships of exposure to school-based tobacco prevention programs and perceived usefulness of such programs to smoking susceptibility. METHODS: An ethnically representative sample of 6929 Grade 10 students participated in a cross-sectional survey of tobacco-related activities and behaviors. Perceived usefulness of prevention programs was investigated according to two dimensions: perceived helpfulness of information received at school with regard to making decisions about tobacco use and perceived availability of social resources that might help students cope with tobacco-related issues. RESULTS: The extent of exposure to school prevention programs and both dimensions of perceived usefulness of these programs were inversely associated with susceptibility to smoking. In addition, perceived information helpfulness mediated the effect of program exposure on susceptibility status, whereas perceived availability of social resources moderated that effect. The study also presented evidence suggesting ethnic/cultural variability in the status of susceptibility to smoking at this age. CONCLUSIONS: The study indicates a need to examine the perceptions of students receiving school prevention programs. Perceived usefulness of school prevention programs may be used to identify youth at high risk for smoking susceptibility. Future studies, however, should investigate other dimensions of perceived usefulness as well as intrapersonal, interpersonal, and environmental correlates of this construct.

Adolescent↗

PubMed2000

Ubiquitous overexpression of CuZn superoxide dismutase does not extend life span in mice.

Oxidative damage has been implicated in the aging process and in a number of degenerative diseases. To investigate the role of oxygen radicals in the aging process in mammals, the life spans of transgenic mice on a CD-1 background expressing increased levels of CuZn superoxide dismutase (CuZnSOD), the enzyme that metabolizes superoxide radicals, were determined. Homozygous transgenic mice with a two- to five-fold elevation of CuZnSOD in various tissues showed a slight reduction of life span, whereas hemizygous mice with a 15- to 3-fold increase of CuZnSOD showed no difference in life span from that of the nontransgenic littermate controls. The results suggest that constitutive and ubiquitous overexpression of CuZnSOD alone is not sufficient to extend the life spans of transgenic mice.

Aging↗

PubMed2000

Cellular and molecular responses to topoisomerase I poisons. Exploiting synergy for improved radiotherapy.

The efficacy of topoisomerase (Topo) I-active drugs may be improved by better understanding the molecular and cellular responses of tumor compared to normal cells after genotoxic insults. Ionizing radiation (IR) + Topo I-active drugs (e.g., Topotecan) caused synergistic cell killing in various human cancer cells, even in cells from highly radioresistant tumors. Topo I poisons had to be added either during or immediately after IR. Synergy was caused by DNA lesion modification mechanisms as well as by concomitant stimulation of two pathways of cell death: necrosis (IR) + apoptosis (Topo I poisons). Cumulative data favor a mechanism of synergistic cell killing caused by altered DNA lesion modification and enhanced apoptosis. However, alterations in cell cycle regulation may also play a role in the synergy between these two agents in certain human cancers. We recently showed that NF-kappa B, a known anti-apoptotic factor, was activated in various cancer cells after poisoning Topo I using clinically active drugs. NF-kappa B activation was dependent on initial nuclear DNA damage followed by cytoplasmic signaling events. Cytoplasmic signaling leading to NF-kappa B activation after Topo I poisons was diminished in cytoplasts (lacking nuclei) and in CEM/C2 cells that expressed a mutant Topo I protein that did not interact with Topo I-active drugs. NF-kappa B activation was intensified in S-phase and blocked by aphidicolin, suggesting that activation was a result of double-strand break formation due to Topo I poisoning and DNA replication. Dominant-negative I kappa B expression augmented Topo I poison-mediated apoptosis. Elucidation of molecular signal transduction pathways after Topo I drug-IR combinations may lead to improved radiotherapy by blocking anti-apoptotic NF-kappa B responses. Recent data also indicate that synergy caused by IR + Topo I poisons is different from radiosensitization by beta-lapachone (beta-lap), a "reported" Topo I and II-alpha poison in vitro. In fact, beta-lap does not kill cells by poisoning either Topo I or II-alpha in vivo. Instead, the compound is "activated" by an IR (damage)-inducible enzyme, NAD(P)H:quinone oxidoreductase (NQO1), a gene cloned as x-ray-inducible transcript #3, xip3. Unlike the lesion modification pathway induced by IR + Topo I drugs, beta-lap kills cells via NQO1 futile cycle metabolism. Downstream apoptosis caused by beta-lap appears to be noncaspase-mediated, involving calpain or a calpain-like protease. Thus, although Topo I poisons or beta-lap in combination with IR both synergistically kill cancer cells, the mechanisms are very different.

Animals↗

PubMed2000

Genetic dissection of region associated with behavioral abnormalities in mouse models for Down syndrome.

Two animal models of Down syndrome (human trisomy 21) with segmental trisomy for all (Ts65Dn) or part (Ts1Cje) of human chromosome 21-homologous region of mouse chromosome 16 have cognitive and behavioral abnormalities. To compare these trisomies directly and to assess the phenotypic contribution of the region of difference between them, Ts65Dn, Ts1Cje, and a new segmental trisomic (Ms1Ts65) for the region of difference (APP: to Sod1) have been generated as littermates and tested in parallel. Although the performance of Ts1Cje mice in the Morris water maze is similar to that of Ts65Dn mice, the reverse probe tests indicate that Ts65Dn is more severely affected. By contrast, the deficits of Ms1Ts65 mice are significantly less severe than those of Ts65Dn. Therefore, whereas triplication of Sod1 to Mx1 plays the major role in causing the abnormalities of Ts65Dn in the Morris water maze, imbalance of APP: to Sod1 also contributes to the poor performance. Ts65Dn mice are hyperactive and Ts1Cje mice are hypoactive; the activity of Ms1Ts65 mice is not significantly above normal. These findings indicate that genes in the Ms1Ts65 trisomic region must interact with others in the Ts1Cje region to produce hyperactivity in Ts65Dn mice.

Animals↗

PubMed2000

Urinary tract infection in febrile infants younger than eight weeks of Age.

OBJECTIVE: To assess the usefulness of laboratory parameters, including peripheral white blood cell (WBC) count, C-reactive protein (CRP) concentration, erythrocyte sedimentation rate (ESR), and microscopic urinalysis (UA), for identifying febrile infants younger than 8 weeks of age at risk for urinary tract infection (UTI), and comparison of standard UA and hemocytometer WBC counts for predicting the presence of UTI. METHODS: A total of 162 febrile children <8 weeks of age were enrolled in this prospective study. All underwent clinical evaluation and laboratory investigation, including WBC count and differential; ESR; CRP; blood culture; a lumbar puncture for cell count and differential, glucose level, protein level, Gram stain, and culture; and a UA and urine culture. All urine specimens were obtained by suprapubic aspiration and microscopically analyzed with standard UA as well as with hemocytometer WBC counts. Quantitative urine cultures were performed. Sensitivity, specificity, accuracy, likelihood ratios, and receiver operating characteristic (ROC) curves were determined for each of the screening tests. RESULTS: There were 22 positive urine culture results of at least 100 colony-forming unit/mL. Eighteen of these 22 patients were males, and all were uncircumcised. There were significant differences for pyuria >/=5 WBCs/hpf, pyuria >/=10 WBC/microL, CRP >20 mg/L, and ESR >30 mm/hour between culture-positive and culture-negative groups (P <.05). The ROC area for hemocytometer WBC count, standard UA, peripheral WBC count, ESR, and CRP concentration were.909 +/-.045,.791 +/-.065,.544 +/-.074,. 787 +/-.060, and.822 +/-.036, respectively. The ROC curve analysis indicates that the CRP, ESR, and standard UA were powerful but imperfect tools with which to discriminate for UTI in potentially infected neonates. Hemocytometer WBC counts had the highest sensitivity, specificity, accuracy, and likelihood ratios for identifying very young infants with positive urine culture results. For all assessments, hemocytometer WBC counts were significantly different, compared with the standard urinalysis. ESR, CRP, and peripheral WBC counts were not helpful in identifying UTI in febrile infants. CONCLUSION: UTI had a prevalence of 13.6% in febrile infants <8 weeks of age. The CRP, ESR, and standard UA were imperfect tools in discriminating for UTI, and the sensitivity of these laboratory parameters was relatively low. Hemocytometer WBC count was a significantly better predictor of UTI in febrile infants.

Female↗

PubMed1999

Serotonin-inducible transcription of interleukin-1alpha in uterine smooth muscle cells requires an AP-1 site: cloning and partial characterization of the rat IL-1alpha promoter.

Interleukin-1 has been shown to contribute to infection-induced inflammatory processes during pregnancy. Prior work from this laboratory has demonstrated that serotonin-induced IL-1alpha also is required for the in-vitro production of collagenase in uterine smooth muscle cells, a normal, non-inflammatory process that occurs in-vivo during post-partum uterine involution. To understand the molecular mechanisms that regulate transcription of the IL-1alpha gene in these cells, we isolated and characterized 1.6 kilobases of the 5'-flanking region of the rat IL-1alpha gene. Sequencing and primer extension identified a single transcription start site and multiple potential regulatory elements, including a TATA box at - 30 bp, a CAAT box at - 74 bp, and a conserved AP-1 site at - 9 bp. This 5'-flanking DNA exhibited low basal promoter activity that was inducible by serotonin. Serotonin-induced promoter activity was unaffected or induced by either medroxyprogesterone or IL-1 receptor antagonist. This occurred despite the ability of both of these hormones to markedly decrease IL-1alpha mRNA. Deletional analysis revealed a strong repressor in the region between - 147 and - 98 bp; removal of this sequence resulted in a fivefold higher basal promoter activity that was still serotonin responsive. Constitutive promoter activity appeared to reside between - 97 and - 22 bp. Deletion of this promoter region, which contained the TATA and CAAT boxes and an NF-IL-6/PEA-3 site, resulted in decreased basal transcriptional activity to the low level seen in larger constructs. Mutational analysis showed that serotonin-inducible transcriptional activity was mediated, at least in part, by the conserved AP-1 site at - 9 bp. This site is located within a larger extended palindromic region: 5'-AAGCCTGACTCAGACTT-3', that together effects both the basal and serotonin-inducible expression of the IL-1alpha gene.

Animals↗

PubMed1999

Characterization of the antioxidant status of the heterozygous manganese superoxide dismutase knockout mouse.

The antioxidant status of several tissues (liver, kidney, lung, brain, heart, muscle, stomach, and spleen) from heterozygous manganese superoxide dismutase (MnSOD) mutant mice (Sod2-/+) was characterized. The activity of MnSOD was decreased (30 to 80%) in all tissues examined. The levels of mRNA coding for the major antioxidant enzymes (CuZnSOD, catalase, and glutathione peroxidase) were not significantly altered in liver, kidney, heart, lung, or brain in the Sod2-/+ mice. The activities of the enzymes were not altered in any of these tissues, with the exception of a decrease in glutathione peroxidase activity in muscle in the Sod2-/+ mice compared to the Sod2+/+ mice. Thus, there was no up-regulation of the activities of the major antioxidant enzymes to compensate for the decrease in MnSOD activity. Reduced glutathione levels were 30 to 50% lower in the lung, brain, and muscle of the Sod2-/+ mice compared to the wild-type Sod2+/+ mice. In addition, the ratio of GSH/GSSG was decreased approximately 50% in Sod2-/+ muscle, indicating that the decrease in MnSOD activity in the Sod2-/+ mice results in some degree of oxidative stress in this tissue.

Animals↗

PubMed1999

Mitochondrial disease in superoxide dismutase 2 mutant mice.

Oxidative stress has been implicated in many diseases. The chief source of reactive oxygen species within the cell is the mitochondrion. We have characterized a variety of the biochemical and metabolic effects of inactivation of the mouse gene for the mitochondrial superoxide dismutase (CD1-Sod2(tm1Cje)). The Sod2 mutant mice exhibit a tissue-specific inhibition of the respiratory chain enzymes NADH-dehydrogenase (complex I) and succinate dehydrogenase (complex II), inactivation of the tricarboxylic acid cycle enzyme aconitase, development of a urine organic aciduria in conjunction with a partial defect in 3-hydroxy-3-methylglutaryl-CoA lyase, and accumulation of oxidative DNA damage. These results indicate that the increase in mitochondrial reactive oxygen species can result in biochemical aberrations with features reminiscent of mitochondrial myopathy, Friedreich ataxia, and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.

Aconitate Hydratase↗

PubMed1999

Penile reconstruction: combined use of an innervated forearm osteocutaneous flap and big toe pulp.

The use of a radial forearm flap has become the most popular method to reconstruct a phallus in recent years. This method of reconstruction, however, is plagued with problems such as urethral fistula and loss of phallic girth as a result of tissue atrophy, rendering a phallic contour that is cosmetically unsatisfactory. We had the opportunity of modifying the technique of penile reconstruction using a forearm osteocutaneous flap to minimize these problems. Specifically, a segment of the big toe pulp is used to reconstruct a glans penis. Sensory restoration in the "glans" and "penile shaft" is restored by coapting the digital and the antebrachial nerves to the penile nerve remnants. A segment of flexor carpi radialis muscle is included in the design of a forearm flap to reinforce the coaptation site of the urethral tract. An arteriovenous shunt is incorporated in the shaft as a mechanism to elicit erection of the penis by compressing the root of the neophallus. We had used these technical modifications in a 51-year-old man who had undergone penile amputation because of cancer. The cosmetic appearance and erotic and tactile sensation in the shaft and glans were proper and satisfactory at the end of fourth year after the surgery. The coital function was also satisfactory.

Amputation, Surgical↗