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1.
Gene Ther ; 23(12): 846-856, 2016 12.
Article in English | MEDLINE | ID: mdl-27518705

ABSTRACT

Friedreich ataxia (FRDA) is a progressive neurodegenerative disease caused by deficiency of frataxin protein, with the primary sites of pathology being the large sensory neurons of the dorsal root ganglia and the cerebellum. FRDA is also often accompanied by severe cardiomyopathy and diabetes mellitus. Frataxin is important in mitochondrial iron-sulfur cluster (ISC) biogenesis and low-frataxin expression is due to a GAA repeat expansion in intron 1 of the FXN gene. FRDA cells are genomically unstable, with increased levels of reactive oxygen species and sensitivity to oxidative stress. Here we report the identification of elevated levels of DNA double strand breaks (DSBs) in FRDA patient and YG8sR FRDA mouse model fibroblasts compared to normal fibroblasts. Using lentivirus FXN gene delivery to FRDA patient and YG8sR cells, we obtained long-term overexpression of FXN mRNA and frataxin protein levels with reduced DSB levels towards normal. Furthermore, γ-irradiation of FRDA patient and YG8sR cells revealed impaired DSB repair that was recovered on FXN gene transfer. This suggests that frataxin may be involved in DSB repair, either directly by an unknown mechanism, or indirectly via ISC biogenesis for DNA repair enzymes, which may be essential for the prevention of neurodegeneration.


Subject(s)
Friedreich Ataxia/therapy , Genetic Therapy , Genomic Instability , Iron-Binding Proteins/genetics , Animals , Cells, Cultured , DNA Breaks, Double-Stranded , Fibroblasts/metabolism , Humans , Iron-Binding Proteins/metabolism , Lentivirus/genetics , Mice , Recombinational DNA Repair , Frataxin
2.
Br J Cancer ; 107(9): 1506-13, 2012 Oct 23.
Article in English | MEDLINE | ID: mdl-23093295

ABSTRACT

BACKGROUND: The objective of this study was to determine the molecular mechanisms responsible for cellular radiosensitivity in two human fibroblast cell lines 84BR and 175BR derived from two cancer patients. METHODS: Clonogenic assays were performed following exposure to increasing doses of gamma radiation to confirm radiosensitivity. γ-H2AX foci assays were used to determine the efficiency of DNA double-strand break (DSB) repair in cells. Quantitative PCR (Q-PCR) established the expression levels of key DNA DSB repair genes. Imaging flow cytometry using annexin V-FITC was used to compare artemis expression and apoptosis in cells. RESULTS: Clonogenic cellular hypersensitivity in the 84BR and 175BR cell lines was associated with a defect in DNA DSB repair measured by the γ-H2AX foci assay. The Q-PCR analysis and imaging flow cytometry revealed a two-fold overexpression of the artemis DNA repair gene, which was associated with an increased level of apoptosis in the cells before and after radiation exposure. Overexpression of normal artemis protein in a normal immortalised fibroblast cell line NB1-Tert resulted in increased radiosensitivity and apoptosis. CONCLUSION: We conclude that elevated expression of artemis is associated with higher levels of DNA DSB, radiosensitivity and elevated apoptosis in two radio-hypersensitive cell lines. These data reveal a potentially novel mechanism responsible for radiosensitivity and show that increased artemis expression in cells can result in either radiation resistance or enhanced sensitivity.


Subject(s)
Apoptosis/radiation effects , Fibroblasts/metabolism , Fibroblasts/radiation effects , Nuclear Proteins/biosynthesis , Apoptosis/physiology , Breast Neoplasms/pathology , Breast Neoplasms/radiotherapy , Cell Line , Cell Survival/physiology , Cell Survival/radiation effects , Clone Cells/radiation effects , DNA Breaks, Double-Stranded , DNA End-Joining Repair/genetics , DNA-Binding Proteins , Dose-Response Relationship, Radiation , Endonucleases , Female , Fibroblasts/pathology , Humans , Nuclear Proteins/genetics , Radiation Tolerance , Transfection
3.
Br J Radiol ; 79(942): 510-7, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16714754

ABSTRACT

XP14BR is a cell line derived from a xeroderma pigmentosum (XP) patient from complementation group C. The patient was unusual in presenting with an angiosarcoma of the scalp, treated by surgical excision and radiotherapy. Following 38 Gy in 19 fractions with 6 MEV electrons, a severe desquamation and necrosis of the underlying bone ensued, and death followed 4 years later. The cell line was correspondingly hypersensitive to the lethal effects of gamma irradiation. We had previously shown that this sensitivity could be discriminated from that seen in ataxia-telangiectasia (A-T). The cellular response to ultraviolet radiation below 280 nm (UVC) was characteristic of XP cells, indicating the second instance, in our experience, of dual cellular UVC and ionizing radiation hypersensitivity in XP. We then set out to evaluate any defects in repair of ionizing radiation damage and to verify any direct contribution of the XPC gene. The cells were defective in repair of a fraction of double strand breaks, with a pattern reminiscent of A-T. The cell line was immortalized with the vector pSV3neo and the XPC cDNA transfected in to correct the defect. The progeny derived from this transfection showed the presence of the XPC gene product, as measured by immunoblotting. A considerable restoration of normal UVC, but not ionizing radiation, sensitivity was observed amongst the clones. This differential correction of cellular sensitivity is strong evidence for the presence of a defective radiosensitivity gene, distinct from XPC, which is responsible for the clinical hypersensitivity to ionizing radiation. It is important to resolve how widespread ionizing radiation sensitivity is amongst XP patients.


Subject(s)
Head and Neck Neoplasms/radiotherapy , Hemangiosarcoma/radiotherapy , Radiation Tolerance/genetics , Scalp , Skin Neoplasms/radiotherapy , Xeroderma Pigmentosum/complications , Cell Death/genetics , Cell Death/radiation effects , Cell Line, Tumor , DNA Damage/radiation effects , DNA Repair/radiation effects , DNA-Binding Proteins/genetics , Gamma Rays/adverse effects , Humans , Osteonecrosis/etiology , Parietal Bone/pathology , Parietal Bone/radiation effects , Radiation Injuries/genetics , Radiation Injuries/pathology , Transfection , Ultraviolet Rays/adverse effects , Xeroderma Pigmentosum/genetics
5.
West Indian Med J ; 49(3): 245-7, 2000 Sep.
Article in English | MEDLINE | ID: mdl-11076223

ABSTRACT

Complete non-puerperial uterine inversion is rare and when present is usually associated with a prolapsed submucous fibroid. The inversion in this case was associated with a uterine sarcoma in an 88 year old diabetic patient, gravida 13, who presented with a four month history of intermittent vaginal bleeding. She was successfully managed with a total abdominal hysterectomy and some of the difficulties with diagnosis and management are highlighted.


Subject(s)
Endometrial Neoplasms/pathology , Sarcoma/pathology , Uterine Inversion/pathology , Aged , Aged, 80 and over , Endometrium/pathology , Female , Humans , Uterus/pathology
6.
West Indian med. j ; 49(3): 245-7, Sept. 2000. gra
Article in English | MedCarib | ID: med-667

ABSTRACT

Complete non-puerperial uterine inversion is rare and when present is usually associated with a prolapsed submucous fibroid. The inversion in this case was associated with a uterine sarcoma in an 88 year old diabetic patient, gravida 13, who presented with a four month history of intermittent vaginal bleeding. She was successfully managed with a total abdominal hysterectomy and some of the difficulties with diagnosis and management are highlighted.(Au)


Subject(s)
Female , Humans , Uterine Inversion/blood , Leiomyoma , Jamaica , Hysterectomy, Vaginal
7.
West Indian med. j ; 49(3): 245-7, Sept. 2000. graf
Article in English | LILACS | ID: lil-291984

ABSTRACT

Complete non-puerperial uterine inversion is rare and when present is usually associated with a prolapsed submucous fibroid. The inversion in this case was associated with a uterine sarcoma in an 88 year old diabetic patient, gravida 13, who presented with a four month history of intermittent vaginal bleeding. She was successfully managed with a total abdominal hysterectomy and some of the difficulties with diagnosis and management are highlighted.


Subject(s)
Female , Humans , Uterine Inversion/blood , Leiomyoma , Hysterectomy, Vaginal , Jamaica
8.
Eur J Surg Oncol ; 26(1): 30-3, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10718176

ABSTRACT

BACKGROUND: Telomerase is a ribonucleoprotein enzyme that plays an important role in cell immortalization and carcinogenesis. Lymphovascular invasion (LVI) is a fundamental step in the process of breast cancer metastasis and is recognized as an important prognostic factor in patients with breast cancer. METHODS: Using a PCR-based assay, telomerase activity was determined in 34 prospectively collected infiltrating breast carcinomas. Adjacent sections of the specimens were examined histologically by two experienced breast pathologists using light microscopy and haematoxylin & eosin staining. RESULTS: Telomerase activity was detected in 24 (71%) of 34 breast tumours. Two (20%) of 10 telomerase-negative tumours had LVI compared with 14 (58.3%) of 24 telomerase-positive tumours. This association was statistically significant (P<0.05). Telomerase activity was also significantly associated with nodal metastases but not with tumour grade, tumour size or menopausal status. CONCLUSIONS: Telomerase reactivation is significantly associated with LVI in breast cancer and may reflect the metastatic potential of the disease.


Subject(s)
Biomarkers, Tumor/metabolism , Breast Neoplasms/enzymology , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/enzymology , Carcinoma, Ductal, Breast/secondary , Telomerase/metabolism , Vascular Neoplasms/enzymology , Vascular Neoplasms/secondary , Adult , Chi-Square Distribution , Female , Humans , Lymphatic Metastasis , Polymerase Chain Reaction , Prospective Studies
9.
Int J Surg Investig ; 1(6): 509-16, 2000.
Article in English | MEDLINE | ID: mdl-11729859

ABSTRACT

BACKGROUND: Telomerase is a ribonucleoprotein enzyme that seems to play an important role in cellular immortality and carcinogenesis. p53 mutations account for approximately 50% of human cancers and represent the most frequent genetic lesion in breast cancer. AIMS: This study aims to examine the association between telomerase reactivation and hormonal receptor status and p53 expression in invasive breast cancer. METHODS: Using a polymerase chain reaction-based assay, telomerase activity was determined in 47 invasive breast carcinomas and 21 adjacent non-cancerous breast tissue specimens (stored at -80 degrees C) prospectively collected from 47 women undergoing elective surgical treatment in our centre. The histopathological features of the tumour were determined by experienced breast pathologists using light microscopy and haematoxylin and eosin staining. Oestrogen receptor (ER), progesterone receptor (PR) and p53 expressions were determined using immunohistochemistry techniques. RESULTS: Telomerase activity was detected in 34 (72%) of 47 breast carcinomas and in none of the adjacent non-cancerous breast specimens. There was a significant association between telomerase reactivation, tumour size and nodal status. Telomerase positive tumours were more likely to be poorly differentiated (65% versus 46%), but this association failed to reach statistical significance. There was no significant difference in ER expression (68% versus 85%). PR expression (62% versus 62%) and p53 expression (19% versus 27%) between telomerase positive and telomerase negative cancers. CONCLUSION: Telomerase reactivation is associated with important prognostic factors such as tumour size and nodal status in invasive breast cancer and seems to be independent of hormonal receptor status and p53 expression.


Subject(s)
Breast Neoplasms/chemistry , Receptors, Estrogen/analysis , Receptors, Progesterone/analysis , Telomerase/metabolism , Tumor Suppressor Protein p53/analysis , Biopsy, Needle , Female , Humans , Immunohistochemistry , Polymorphism, Single-Stranded Conformational , Prospective Studies
10.
Am J Surg ; 178(1): 69-72, 1999 Jul.
Article in English | MEDLINE | ID: mdl-10456708

ABSTRACT

BACKGROUND: Telomerase is a ribonucleoprotein enzyme that appears to play an important role in carcinogenesis. Telomerase reactivation seems to be associated with immortalization and malignancy. METHODS: Using a polymerase chain reaction (PCR)-based assay known as the TRAP (telomeric repeat and amplification protocol) assay, we examined telomerase activity in 60 breast specimens prospectively collected from 39 patients undergoing elective breast surgery in our center. The specimens included adjacent noncancerous breast (n = 21), benign breast disease (n = 5), and infiltrating carcinoma (n = 34). Ki-67 expression was determined in 32 invasive breast cancer specimens using immunohistochemistry techniques. The histopathological features were determined by light microscopy by an experienced breast pathologist. RESULTS: Telomerase activity was detected in 24 (71%) of 34 infiltrating carcinomas. None of the adjacent noncancerous specimens nor the benign breast lesions expressed telomerase activity. Telomerase reactivation was significantly associated with nodal metastasis and Ki-67 expression. There was no significant association between telomerase activity and menopausal status, tumor grade, or tumor size. CONCLUSIONS: Telomerase reactivation is associated with the acquisition of malignancy in the human breast. Telomerase activity is significantly associated with nodal metastasis and cellular proliferation as measured by Ki-67 expression in human breast cancer.


Subject(s)
Breast Neoplasms/physiopathology , Carcinoma, Ductal, Breast/physiopathology , Cell Transformation, Neoplastic , Ki-67 Antigen/biosynthesis , Telomerase/metabolism , Adult , Amino Acid Sequence , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/genetics , Carcinoma, Ductal, Breast/secondary , Female , Humans , Immunohistochemistry , Ki-67 Antigen/genetics , Lymphatic Metastasis , Molecular Sequence Data , Polymerase Chain Reaction , Prognosis , Prospective Studies
11.
Eur J Surg Oncol ; 25(4): 352-5, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10419703

ABSTRACT

AIMS: To investigate telomerase, a ribonucleoprotein that synthesizes telomeres. Recent evidence suggests that telomerase reactivation is associated with the acquisition of immortalization and malignancy. METHODS: Using a sensitive PCR-based assay (the TRAP assay), we examined telomerase activity in two recurrent phyllodes tumours in two patients. RESULTS: Both tumours expressed telomerase activity. Histological examination of the lesions, according to the criteria proposed by Azzopardi and Salvadori, revealed a malignant phyllodes tumour in one patient and a benign phyllodes tumour in the other patient. CONCLUSIONS: Our findings suggest that telomerase activity may have a potential role as a prognostic marker in predicting the clinical behaviour of these rare tumours.


Subject(s)
Biomarkers, Tumor/metabolism , Breast Neoplasms/enzymology , Phyllodes Tumor/enzymology , Telomerase/metabolism , Aged , Aged, 80 and over , Breast Neoplasms/pathology , Female , Humans , Middle Aged , Phyllodes Tumor/pathology
12.
Br J Cancer ; 79(1): 47-53, 1999 Jan.
Article in English | MEDLINE | ID: mdl-10408692

ABSTRACT

Telomeres are specialized structures consisting of repeat arrays of TTAGGGn located at the ends of chromosomes. They are essential for chromosome stability and, in the majority of normal somatic cells, telomeres shorten with each cell division. Most immortalized cell lines and tumours reactivate telomerase to stabilize the shortening chromosomes. Telomerase activation is regarded as a central step in carcinogenesis and, here, we demonstrate telomerase activation in premalignant skin lesions and also in all forms of skin cancer. Telomerase activation in normal skin was a rare event, and among 16 samples of normal skin (one with a history of chronic sun exposure) 12.5% (2 out of 16) exhibited telomerase activity. One out of 16 (6.25%) benign proliferative lesions, including viral and seborrhoeic wart samples, had telomerase activity. In premalignant actinic keratoses and Bowen's disease, 42% (11 out of 26) of samples exhibited telomerase activity. In the basal cell carcinoma and cutaneous malignant melanoma (CMM) lesions, telomerase was activated in 77% (10 out of 13) and 69% (22 out of 32) respectively. However, only 25% (3 out of 12) of squamous cell carcinomas (SCC) had telomerase activity. With the exception of one SCC sample, telomerase activity in a positive control cell line derived from a fibrosarcoma (HT1080) was not inhibited when mixed with the telomerase-negative SCC or CMM extracts, indicating that, overall, Taq polymerase and telomerase inhibitors were not responsible for the negative results. Mean telomere hybridizing restriction fragment (TRF) analysis was performed in a number of telomerase-positive and -negative samples and, although a broad range of TRF sizes ranging from 3.6 to 17 kb was observed, a relationship between telomerase status and TRF size was not found.


Subject(s)
Carcinoma, Basal Cell/enzymology , Carcinoma, Squamous Cell/enzymology , Melanoma/enzymology , Skin Neoplasms/enzymology , Telomerase/metabolism , Base Sequence , Carcinoma, Basal Cell/pathology , Carcinoma, Squamous Cell/pathology , DNA Primers , Enzyme Activation , Humans , Melanoma/pathology , Neoplasm Invasiveness , Skin/enzymology , Skin Neoplasms/pathology , Telomerase/antagonists & inhibitors
13.
Eur J Surg Oncol ; 25(3): 269-72, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10336806

ABSTRACT

AIMS: Telomerase is a ribonucleoprotein enzyme which appears to play an important role in carcinogenesis. Its reactivation is associated with the acquisition of immortalization and malignancy. The present study aims to examine the association between telomerase activity and prognosis in breast cancer. METHODS: Using a PCR-based assay, we retrospectively examined telomerase activity in 45 frozen human breast cancer specimens. Telomerase activity was compared with histopathological and clinical data. RESULTS: Telomerase activity was detected in 20 (44%) of 45 cases and was associated with advanced histopathological grade and tumour type (ductal vs. lobular). The association with these histological parameters was statistically significant (chi-squared test P<0.05). There was no significant difference in the overall survival rate (78 vs. 77%) or disease-free survival (73 vs. 69%) at 5 years (Kaplan-Meier method, log-rank test P>0.05). CONCLUSIONS: The present results indicate that telomerase activity in human breast cancer is not associated with nodal status or disease outcome.


Subject(s)
Breast Neoplasms/enzymology , Telomerase/metabolism , Adult , Aged , Breast Neoplasms/mortality , Female , Frozen Sections , Humans , Middle Aged , Polymerase Chain Reaction , Predictive Value of Tests , Prognosis , Retrospective Studies , Survival Analysis
14.
Cancer Res ; 59(3): 516-20, 1999 Feb 01.
Article in English | MEDLINE | ID: mdl-9973191

ABSTRACT

Losses of heterozygosity involving chromosomes 9 and 10 are frequent events in the development and progression of cutaneous malignant melanoma. To investigate whether specifically deleted chromosomal regions encode tumor suppressor genes (TSGs), we introduced normal chromosome 10 into the tumorigenic human metastatic melanoma cell line UACC-903 by microcell fusion. In addition, two chromosome 9 derivatives that were microdeleted in the region of the p16INK4A/p15INK4B locus were transferred to determine whether an additional melanoma TSG or TSGs reside on chromosome 9p, as indicated by previous melanoma allele loss studies. In comparison to parental cells, microcell hybrids generated with chromosomes 9 (microdeleted) and 10 displayed reduced anchorage-independent growth in soft agar and markedly reduced tumorigenicity in athymic (nu/nu) mice. These data define a TSG or TSGs that function independently of p15/p16 on chromosome 9 and provide evidence for a TSG (or TSGs) on chromosome 10 that may be important in melanoma development.


Subject(s)
Cell Cycle Proteins , Cyclin-Dependent Kinase Inhibitor p16 , Genes, Tumor Suppressor , Melanoma/genetics , Skin Neoplasms/genetics , Tumor Suppressor Proteins , Agar , Animals , Carrier Proteins/genetics , Cell Division/physiology , Chromosome Deletion , Chromosome Mapping , Chromosomes, Human, Pair 10 , Chromosomes, Human, Pair 9 , Cloning, Molecular , Cyclin-Dependent Kinase Inhibitor p15 , Female , Genes, p16 , Humans , Melanoma/pathology , Mice , Mice, Nude , Neoplastic Stem Cells/pathology , Phenotype , Skin Neoplasms/pathology , Tumor Cells, Cultured
15.
Breast ; 8(4): 208-11, 1999 Aug.
Article in English | MEDLINE | ID: mdl-14731443

ABSTRACT

Telomerase is a ribonucleoprotein enzyme which appears to play an important role in carcinogenesis. Telomerase reactivation seems to be associated with immortalization and malignancy. Using a PCR-based assay, we examined telomerase activity in 50 breast tissue specimens, prospectively obtained from 37 women undergoing elective breast surgery. The specimens examined included normal breast (n=13), benign breast lesions (n=5), ductal carcinoma in situ (n=8) and infiltrating ductal carcinoma (n=24). All normal breast, benign breast and DCIS specimens lacked telomerase activity. Sixteen (67%) of 24 infiltrating carcinomas. In infiltrating ductal cancer, there was a statistically significant association between telomerase activity and nodal metastasis. The present results indicate that telomerase activity is associated with acquisition of invasive malignancy in the human breast and may have a role in complementing cytopathological diagnosis. Telomerase activity as a prognostic marker should be included in future validation studies. In DCIS, telomerase activity may be a late event associated with invasion of the basement membrane.

16.
Mol Cell Biol ; 16(11): 6553-62, 1996 Nov.
Article in English | MEDLINE | ID: mdl-8887684

ABSTRACT

ERCC4 is an essential human gene in the nucleotide excision repair (NER) pathway, which is responsible for removing UV-C photoproducts and bulky adducts from DNA. Among the NER genes, ERCC4 and ERCC1 are also uniquely involved in removing DNA interstrand cross-linking damage. The ERCC1-ERCC4 heterodimer, like the homologous Rad10-Rad1 complex, was recently found to possess an endonucleolytic activity that incises on the 5' side of damage. The ERCC4 gene, assigned to chromosome 16p13.1-p13.2, was previously isolated by using a chromosome 16 cosmid library. It corrects the defect in Chinese hamster ovary (CHO) mutants of NER complementation group 4 and is implicated in complementation group F of the human disorder xeroderma pigmentosum. We describe the ERCC4 gene structure and functional cDNA sequence encoding a 916-amino-acid protein (104 kDa), which has substantial homology with the eukaryotic DNA repair and recombination proteins MEI-9 (Drosophila melanogaster), Rad16 (Schizosaccharomyces pombe), and Rad1 (Saccharomyces cerevisiae). ERCC4 cDNA efficiently corrected mutants in rodent NER complementation groups 4 and 11, showing the equivalence of these groups, and ERCC4 protein levels were reduced in mutants of both groups. In cells of an XP-F patient, the ERCC4 protein level was reduced to less than 5%, consistent with XPF being the ERCC4 gene. The considerable identity (40%) between ERCC4 and MEI-9 suggests a possible involvement of ERCC4 in meiosis. In baboon tissues, ERCC4 was expressed weakly and was not significantly higher in testis than in nonmeiotic tissues.


Subject(s)
DNA Repair , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/genetics , Drosophila Proteins , Nuclear Proteins , Recombination, Genetic , Amino Acid Sequence , Animals , Base Sequence , CHO Cells , Cell Survival/radiation effects , Cloning, Molecular , Cosmids , Cricetinae , DNA Damage , DNA Repair Enzymes , DNA-Binding Proteins/chemistry , Drosophila melanogaster/genetics , Endonucleases/chemistry , Exons , Fungal Proteins/chemistry , Humans , Introns , Molecular Sequence Data , Open Reading Frames , Papio , Proteins/chemistry , Recombinant Proteins/biosynthesis , Restriction Mapping , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae Proteins , Schizosaccharomyces/genetics , Schizosaccharomyces pombe Proteins , Sequence Homology, Amino Acid , Transfection , Ultraviolet Rays
17.
Clin Transplant ; 9(3 Pt 1): 185-9, 1995 Jun.
Article in English | MEDLINE | ID: mdl-7549058

ABSTRACT

Hypomagenesemia is frequently encountered early after kidney transplantation, especially in patients receiving cyclosporine (CsA). However, there have been no studies addressing the natural history of this disorder in adult transplant recipients. We conducted this investigation to study the change in the prevalence of hypomagnesemia over time in renal transplant patients as well as to determine the factors associated with this change. Three patient groups were studied: 24 CsA-treated patients followed longitudinally at 1, 3 and 6 months post-transplant (Group 1a, 1b, 1c); 33 CsA-treated patients at least 2 years post-transplant (Group 2; mean follow-up 55 +/- 25 months); and 31 non-CsA-treated patients at least 2 years post-transplant (Group 3; mean follow-up 132 +/- 57 months). The following parameters were monitored: serum and urine magnesium levels; serum potassium; creatinine clearance; fractional excretion of magnesium; and trough CsA levels. In group 1 patients, longitudinal follow-up showed a significant linear trend for improvement in the serum magnesium over time (1.6 +/- 0.3, 1.7 +/- 0.2, 1.8 +/- 0.2 mg/dl; p = 0.0015) as well as a decline in the whole blood CsA level (316 +/- 103, 251 +/- 82, 194 +/- 67 ng/ml; p = 0.0015) at 1, 3 and 6 months, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Cyclosporine/blood , Hypertension/etiology , Immunosuppressive Agents/blood , Kidney Transplantation/adverse effects , Magnesium/blood , Adult , Cross-Sectional Studies , Cyclosporine/therapeutic use , Female , Humans , Hypertension/blood , Immunosuppressive Agents/therapeutic use , Longitudinal Studies , Magnesium/urine , Male , Middle Aged
18.
J Otolaryngol ; 24(1): 46-50, 1995 Feb.
Article in English | MEDLINE | ID: mdl-7769645

ABSTRACT

Changes in atmospheric pressure may result in barotrauma to a variety of head and neck structures including the middle and inner ears, the sinus cavities, the teeth and some cranial nerves. This article outlines the pathophysiology of these injuries and suggestions are offered for prevention and treatment.


Subject(s)
Barotrauma/physiopathology , Ear, Middle/physiopathology , Atmospheric Pressure , Barotrauma/complications , Barotrauma/prevention & control , Hearing Loss, Sensorineural/etiology , Humans , Round Window, Ear/injuries , Tinnitus/etiology , Valsalva Maneuver , Vertigo/etiology
19.
J Invest Dermatol ; 103(5 Suppl): 96S-101S, 1994 Nov.
Article in English | MEDLINE | ID: mdl-7963692

ABSTRACT

Xeroderma pigmentosum, Cockayne syndrome, the xeroderma pigmentosum-Cockayne syndrome complex, and trichothiodystrophy cells have defects in DNA repair and are associated with clinical and cellular hypersensitivity to ultraviolet radiation (UV). Familial dysplastic nevus syndrome cells have UV hypermutability. Although xeroderma pigmentosum and dysplastic nevus syndrome have markedly increased cancer risk. Cockayne syndrome and trichothiodystrophy do not. At the molecular level, these disorders are associated with several different genetic defects as evidenced by the existence of multiple overlapping complementation groups. Recent progress has been made in identifying the chromosomal location and cloning the defective genes in these disorders. Using plasmid shuttle vectors we have shown abnormal repair and mutagenesis of DNA damaged by 254-nm (UVC) or 295-nm (UVB) radiation or the chemical carcinogen aflatoxin in cells from patients with xeroderma pigmentosum. Although xeroderma pigmentosum cells are defective in repair of all photoproducts, Cockayne syndrome cells appear to be defective in repair of cyclobutane dimers and have normal repair of nondimer photoproducts. DNS cells have post UV plasmid hypermutability. These diseases may serve as models for examining molecular mechanisms of carcinogenesis in humans.


Subject(s)
DNA Repair , Genetic Linkage , Neoplasms/genetics , Xeroderma Pigmentosum/genetics , Cockayne Syndrome/genetics , Dysplastic Nevus Syndrome/genetics , Hair/abnormalities , Humans
20.
Cancer Res ; 54(14): 3837-44, 1994 Jul 15.
Article in English | MEDLINE | ID: mdl-8033104

ABSTRACT

To determine the contribution of a human DNA repair gene, ERCC2 (XPD), to mutagenesis in human cells, two ERCC2 (XPD)-transformed xeroderma pigmentosum complementation group D (XPD) cell lines with increased UV survival compared to XP6BE(SV40), the original XPD line, were studied: D6BE-ER2-2 with slightly increased UV survival; and D6BE-ER2-9 with normal UV survival. ERCC2 (XPD) antibody-reactive protein levels were elevated 4.8-fold in D6BE-ER2-2 and 17.6-fold in D6BE-ER2-9 relative to XP6BE(SV40). DNA repair ability was assessed by measuring the ability of the cells to restore expression to UV-treated plasmids. Transfection of pRSVcat exposed to 1000 J/m2 UV resulted in 0.3% chloramphenicol acetyltransferase activity in XP6BE(SV40) cells but 20-80% in D6BE-ER2-2, D6BE-ER2-9, and repair-proficient cells compared to untreated control plasmids. The UV hypersensitivity of the mutagenesis shuttle vector pSP189 in XP6BE(SV40) cells was partially corrected and the UV hypermutability and excess of G:C-->A:T mutations of pSP189 fell to the normal range in D6BE-ER2-2 and D6BE-ER2-9 cells. However, the frequency of plasmids recovered with multiple base substitution mutations was significantly reduced with XP6BE(SV40) cells and remained low in D6BE-ER2-2 and D6BE-ER2-9 cells, when compared with the normal fibroblasts. The human DNA excision repair gene, ERCC2 (XPD), substantially corrected the plasmid UV hypersensitivity and UV hypermutability of xeroderma pigmentosum complementation group D cells; however, the dose response relationship varied for different end points.


Subject(s)
DNA Helicases , DNA Repair , DNA-Binding Proteins , Mutation , Proteins/genetics , Transcription Factors , Xeroderma Pigmentosum/genetics , Adult , Base Sequence , Cell Line , Cell Survival , Chloramphenicol O-Acetyltransferase/metabolism , Female , Genetic Vectors , Humans , Molecular Sequence Data , Plasmids , Ultraviolet Rays , Xeroderma Pigmentosum Group D Protein
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