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Biomedical subjects

P S Thorner

Publications and source records attributed to P S Thorner.

At least 19 recordsLinked to original sources
PubMed2005

Atypical and suspicious categories in fine needle aspiration cytology of the breast: histological and mammographical correlation and clinical significance.

INTRODUCTION: This study aims to correlate fine-needle aspiration specimens diagnosed as C3 (atypical, probably benign) and C4 (suspicious, probably malignant) with histology and mammography, and to evaluate these two cytology categories in terms of diagnostic usefulness and patient management. METHODS: All fine-needle aspiration (FNA) specimens in categories C3 or C4 at the Maharaj Nakorn Chiang Mai Hospital, Thailand between 2000-2004 were reviewed. Results were correlated with available histological and mammographical studies. RESULTS: 148 FNA specimens were identified, comprising 43 category C3 and 105 category C4. Histology was available in 90 cases. 14 (64 percent) C3 cases showed benign histology on biopsy and eight (36 percent) were malignant. 13 (19 percent) C4 cases were benign on biopsy, whereas 55 (81 percent) were malignant. Mammographical studies were available in 56 of the histologically-proven cases. All seven cases with benign mammograms had benign histology, and all 26 cases called "highly suggestive of malignancy" were malignant on histology (five C3 and 21 C4). Of the 23 cases called "suspicious abnormality" on mammography, 14 turned out to be malignant on biopsy (one C3 and 13 C4). CONCLUSION: Our study supports maintaining cytology categories C3 and C4. About two-thirds of C3 cases were benign on biopsy whereas 81 percent of C4 cases were malignant (p-value is less than 0.001). There was complete correlation between histological and mammographical studies except those with equivocal mammograms. Our study supports the combined use of clinical, mammographical and cytological findings for optimal patient management. This is especially important for patients with C3 aspiration results, in order to avoid unnecessary surgery for benign lesions.

Adult↗
PubMed2001

The inner ear of dogs with X-linked nephritis provides clues to the pathogenesis of hearing loss in X-linked Alport syndrome.

Alport syndrome is an inherited disorder of type IV collagen with progressive nephropathy, ocular abnormalities, and high-tone sensorineural deafness. In X-linked Alport syndrome, mutations in the COL4A5 gene encoding the alpha5 chain of type IV collagen lead to loss of the alpha3/alpha4/alpha5 network and increased susceptibility of the glomerular basement membrane to long-term damage. The molecular defects that underlie the otopathology in this disease remain poorly understood. We used a canine model of X-linked Alport syndrome to determine the expression of type IV collagen alpha-chains in the inner ear. By 1 month in normal adult dogs, the alpha3, alpha4, and alpha5 chains were co-expressed in a thin continuous line extending along the basilar membrane and the internal and external sulci, with the strongest expression along the lateral aspect of the spiral ligament in the basal turn of the cochlea. Affected dogs showed complete absence of the alpha3/alpha4/alpha5 network. The lateral aspect of the spiral ligament is populated by tension fibroblasts that express alpha-smooth muscle actin and nonmuscle myosin and are postulated to generate radial tension on the basilar membrane via the extracellular matrix for reception of high frequency sound. We propose that in Alport syndrome, the loss of the alpha3/alpha4/alpha5 network eventually weakens the interaction of these cells with their extracellular matrix, resulting in reduced tension on the basilar membrane and the inability to respond to high frequency sounds.

Animals↗
PubMed2001

Regulation of glomerular basement membrane collagen expression by LMX1B contributes to renal disease in nail patella syndrome.

Basement membrane (BM) morphogenesis is critical for normal kidney function. Heterotrimeric type IV collagen, composed of different combinations of six alpha-chains (1-6), is a major matrix component of all BMs (ref. 2). Unlike in other BMs, glomerular BM (GBM) contains primarily the alpha 3(IV) and alpha 4(IV) chains, together with the alpha 5(IV) chain. A poorly understood, coordinated temporal and spatial switch in gene expression from ubiquitously expressed alpha 1(IV) and alpha 2(IV) collagen to the alpha 3(IV), alpha 4(IV) and alpha 5(IV) chains occurs during normal embryogenesis of GBM (ref. 4). Structural abnormalities of type IV collagen have been associated with diverse biological processes including defects in molecular filtration in Alport syndrome, cell differentiation in hereditary leiomyomatosis, and autoimmunity in Goodpasture syndrome; however, the transcriptional and developmental regulation of type IV collagen expression is unknown. Nail patella syndrome (NPS) is caused by mutations in LMX1B, encoding a LIM homeodomain transcription factor. Some patients have nephrosis-associated renal disease characterized by typical ultrastructural abnormalities of GBM (refs. 8,9). In Lmx1b(-/-) mice, expression of both alpha(3)IV and alpha(4)IV collagen is strongly diminished in GBM, whereas that of alpha1, alpha2 and alpha5(IV) collagen is unchanged. Moreover, LMX1B binds specifically to a putative enhancer sequence in intron 1 of both mouse and human COL4A4 and upregulates reporter constructs containing this enhancer-like sequence. These data indicate that LMX1B directly regulates the coordinated expression of alpha 3(IV) and alpha 4(IV) collagen required for normal GBM morphogenesis and that its dysregulation in GBM contributes to the renal pathology and nephrosis in NPS.

Animals↗
PubMed1999

Acute plasmacytic interstitial nephritis in a child with Down syndrome.

A 7.5-year-old boy with Down syndrome presented in acute renal failure (ARF) needing dialysis. When 1.5 years old he had a neuroblastoma, was treated for 1 year with chemotherapy and radiotherapy, and off chemotherapy had since been in remission. Renal biopsy revealed an interstitial inflammation, principally of plasma cells with some lymphocytes and eosinophils. Immunofluorescence showed no deposition of immunoglobulins or complement (C3). The plasma cells were a mixture of kappa and lambda light chain-producing cells. The patient spontaneously improved a week after admission. Initial ultrasonography showed enlarged kidneys with loss of corticomedullary differentiation. We are unaware of a report of ARF in a child, resulting primarily from a polyclonal plasmacytic interstitial nephritis. The etiology remains unclear.

Acute Disease↗
PubMed1999

Absence of the alpha6(IV) chain of collagen type IV in Alport syndrome is related to a failure at the protein assembly level and does not result in diffuse leiomyomatosis.

X-linked Alport syndrome is a progressive nephropathy associated with mutations in the COL4A5 gene. The kidney usually lacks the alpha3-alpha6 chains of collagen type IV, although each is coded by a separate gene. The molecular basis for this loss remains unclear. In canine X-linked hereditary nephritis, a model for X-linked Alport syndrome, a COL4A5 mutation results in reduced mRNA levels for the alpha3, alpha4, and alpha5 chains in the kidney, implying a mechanism coordinating the production of these 3 chains. To examine whether production of alpha6 chain is under the same control, we studied smooth muscle cells from this animal model. We determined the canine COL4A5 and COL4A6 genes are separated by 435 bp, with two first exons for COL4A6 separated by 978 bp. These two regions are >/= 78% identical to the human sequences that have promoter activity. Despite this potential basis for coordinated transcription of the COL4A5 and COL4A6 genes, the alpha6 mRNA level remained normal in affected male dog smooth muscle while the alpha5 mRNA level was markedly reduced. However, both alpha5 and alpha6 chains were absent at the protein level. Our results suggest that production of the alpha6 chain is under a control mechanism separate from that coordinating the alpha3-alpha5 chains and that the lack of the alpha6 chain in Alport syndrome is related to a failure at the protein assembly level, raising the possibility that the alpha5 and alpha6 chains are present in the same network. The lack of the alpha6 chain does not obviously result in disease, in particular leiomyomatosis, as is seen in Alport patients with deletions involving the COL4A5 and COL4A6 genes.

Animals↗
PubMed1999

Effectiveness of the angiogenesis inhibitor TNP-470 in reducing the growth of human neuroblastoma in nude mice inversely correlates with tumor burden.

Angiogenesis plays an important role in the growth and metastasis of malignant tumors. We have previously reported that in children with neuroblastoma (NB), tumor vascularity directly correlates with metastatic disease, MYCN amplification, and poor outcome. The angiogenesis inhibitor TNP-470 has been shown to reduce the rate of NB growth in rodents with macroscopic tumors without ultimately impacting survival. To investigate whether TNP-470 could more effectively inhibit NB growth in animals with a low tumor burden, we treated 30 nude mice with minimal disease with this angiogenesis inhibitor (supplied by TAP Pharmaceuticals, Inc.). Therapy was initiated before tumors were clinically evident after s.c. inoculation of 5 x 10(6) cells from the MYCN-amplified NB cell line NBL-W-N. TNP-470 was administered 3 days/week, and after 12 weeks of treatment, 53% of the treated mice remained tumor free, whereas 100% of the control mice developed tumors (P < 0.0001). To further assess the relationship between the efficacy of TNP-470 treatment and tumor burden, TNP-470 was also administered s.c., 3 days/week, to mice with clinically evident small (<400 mm3; n = 15) and large (>400 mm3; n = 11) tumors. For animals with small tumors, the mean rate of growth was significantly decreased in the treated mice compared to the controls (P = 0.02). In contrast, there was no difference in the mean rate of tumor growth between animals with large tumors treated with TNP-470 and controls (P = 0.64). Our studies demonstrate that the effectiveness of TNP-470 inversely correlates with tumor burden. We speculate that TNP-470 may most effectively inhibit NB tumor growth in children with a low tumor burden.

Angiogenesis Inhibitors↗
PubMed1998

Role of distinct type IV collagen networks in glomerular development and function.

BACKGROUND: In X-linked Alport syndrome, mutations in the COL4A5 gene encoding the alpha 5 chain of type IV collagen result in progressive renal failure. This nephropathy appears to relate to the arrest of a switch from an alpha 1/alpha 2 to an alpha 3/alpha 4/alpha 5 network of type IV collagen in the developing glomerular basement membrane (GBM; Kalluri et al, J Clin Invest 99:2470, 1997). METHODS: We examined the role of this switch in glomerular development and function using a canine model of X-linked nephritis with a COL4A5 mutation. The electron microscopic appearance and the expression of the alpha 1-alpha 6 chains of type IV collagen in the GBM was correlated with glomerular function. RESULTS: In normal neonatal glomeruli, once capillary loops were present, there was staining of GBM for the alpha 1-alpha 5 chains. Prior to this stage, only alpha 1 and alpha 2 chains were present, with rare glomeruli positive for the alpha 5 chain. As glomeruli matured, the alpha 1 and alpha 2 chains tended to disappear from the GBM, with the alpha 3-alpha 5 chains remaining. In affected male dogs, only the alpha 1 and alpha 2 chains were detected at any stage. GBM ultrastructure in these dogs remained normal until one month and proteinuria did not appear until two months. CONCLUSION: Our results show that normal glomerular development involves a switch in type IV collagen networks. In affected male dogs, a failure of this switch results in an absence of the alpha 3/alpha 4/alpha 5 network and a persistence of the alpha 1/alpha 2 network in GBM. GBM ultrastructure and glomerular function remain normal for one month, indicating that GBM deterioration in Alport syndrome begins as a postnatal process. Hence, only the alpha 1/alpha 2 network is essential for normal glomerular development, whereas the alpha 3/alpha 4/alpha 5 network is essential for long-term maintenance of glomerular structure and function.

Aging↗
PubMed1998

Prognostic significance of age, MYCN oncogene amplification, tumor cell ploidy, and histology in 110 infants with stage D(S) neuroblastoma: the pediatric oncology group experience--a pediatric oncology group study.

PURPOSE: Although a high rate of spontaneous regression is observed in infants with stage D(S) neuroblastoma (NB), survival is not uniform. To determine the prognostic relevance of age at diagnosis, therapy, and tumor biology in infants with stage D(S) NB, we reviewed the Pediatric Oncology Group (POG) experience. PATIENTS AND METHODS: A review of patients diagnosed with stage D(S) NB registered on POG protocols was performed. Survival according to age at diagnosis, treatment, and tumor biology was determined. RESULTS: Between 1987 and 1996, 110 infants with stage D(S) NB had an estimated 3-year survival rate of 85% +/- 4%; survival rate was 71% +/- 8% for infants 2 months of age or younger, and 68% +/- 12%, 44% +/- 33%, and 33% +/- 19% for patients with diploid, MYCN-amplified, and unfavorable histology tumors, respectively. Survival rates were similar for patients who received adjuvant chemotherapy versus those who did not (82% +/- 5% v 93% +/- 6%, respectively; P = .187). Furthermore, there was no statistical difference in survival rate for patients who underwent complete resection of their primary tumor compared with those who underwent partial resection or biopsy only (90% +/- 5% v 78% +/- 7%, respectively; P = .083). CONCLUSION: Our review confirmed that the survival of infants with stage D(S) NB is excellent. However, subsets of patients with poor prognosis can be identified by young age and unfavorable biologic factors. More effective therapy is needed for the group of stage D(S) infants who show unfavorable clinical and biologic features.

Age Factors↗
PubMed1996

Coordinate gene expression of the alpha3, alpha4, and alpha5 chains of collagen type IV. Evidence from a canine model of X-linked nephritis with a COL4A5 gene mutation.

Canine X-linked hereditary nephritis is an animal model for human X-linked hereditary nephritis with a premature stop codon in the alpha5(IV) gene of collagen type IV. We used this model to examine the other alpha(IV) chains at the mRNA and protein level in the kidney, since in human X-linked hereditary nephritis, the alpha3(IV) and alpha4(IV) chains are often absent from the glomerular basement membrane, although both are encoded by autosomal genes. cDNA probes for the alpha1(IV)-alpha6(IV) chains were generated from normal dog kidney using the polymerase chain reaction. Sequences were >/=88% identical at the DNA level and >/=92% identical at the protein level to the respective human alpha(IV) chains. By Northern analysis, transcripts for the alpha1(IV), alpha2(IV), and alpha6(IV) chains were detected at comparable levels in both normal and affected male dog kidney RNA. As previously shown, the transcript for the alpha5(IV) chain was reduced to approximately 10% of normal. Unexpectedly, the alpha3(IV) and alpha4(IV) transcripts were both decreased >/=77% in affected male dog kidney, suggesting a mechanism coordinating the expression of these three basement membrane components. The NC1 domain of collagen type IV isolated from normal dog glomeruli was positive for the alpha3(IV), alpha4(IV), and alpha5(IV) chains by Western blotting. In contrast, in the NC1 domain isolated from affected dog glomeruli, these three chains were not detectable, except for a trace of alpha3(IV) dimer. In X-linked hereditary nephritis, the absence of the alpha3(IV) and alpha4(IV) chains from glomerular basement membrane may reflect factors acting at the transcriptional and/or translational level in addition to the protein assembly level.

Amino Acid Sequence↗
PubMed1996

Discoid meniscus in children: magnetic resonance imaging characteristics.

OBJECTIVE: To describe the magnetic resonance imaging (MRI) appearance and associated abnormalities of discoid menisci in children. PATIENTS AND METHODS: The MRI findings for a total of 30 knees (in 20 children ranging in age from 4.5 to 16 [mean 9] years) in which discoid meniscus had been diagnosed were reviewed and correlated with clinical symptoms and arthroscopy findings. RESULTS: The symptoms, bilateral in 5 patients and unilateral in 15, included pain in 15 knees, snapping or clunking in 8, reduced mobility in 8, locking in 2 and "giving-way" in 2; there were flexion contractures in 2 patients. Five patients had unilateral symptoms but bilateral discoid menisci. The transverse diameter of the meniscus ranged from 18 to 37 mm and the depth from 14 to 36 mm. The lateral meniscal height was significantly greater than the medial meniscal height (p = 0.0001). On T1-weighted and T2-weighted images the meniscal signal was increased heterogeneously in 11 knees, in a central, horizontal, linear fashion in 9, diffusely in 6 and in a partly linear, partly diffuse fashion in 3. Thirteen joint effusions, 10 lateral meniscal tears and 4 meniscal cysts were identified. Eight arthroscopy procedures were performed in six of the children (for seven knees). Discoid meniscus was confirmed in six knees (with one initial false-negative result), tears were confirmed in four, and an additional tear was identified in one; in addition, one meniscus was characterized as Wrisberg type. CONCLUSIONS: Discoid meniscus commonly occurs bilaterally. High intrameniscal signal is found, especially in symptomatic patients. The size criteria for diagnosing this condition in children are similar to those for adults.

Adolescent↗
PubMed1995

Co-amplification of MYCN and a DEAD box gene (DDX1) in primary neuroblastoma.

DEAD box proteins are putative RNA helicases that have been implicated in cellular processes involving alteration of RNA secondary structure, such as translation initiation and splicing. These proteins share eight conserved amino acid motifs, including Asp(D)-Glu-(E)-Ala(A)-Asp(D) which is part of a more extended motif. Recently, we have shown that the novel DDX1 gene containing a DEAD box motif maps to the same chromosome band as MYCN at 2p24 and is co-amplified with MYCN in retinoblastoma cell lines. Here, we show that the DDX1 gene is co-amplified with the MYCN gene in 2 of three neuroblastoma cell lines and that DDX1 RNA levels correlate with DDX1 gene copy number. Since amplification of MYCN is an indicator of poor prognosis in neuroblastoma, it was of interest to determine whether co-amplification with DDX1 occurred in clinical samples of neuroblastoma and whether such a finding carried any additional prognostic significance. We determined the gene copy number of DDX1 in 32 neuroblastoma patient samples (representative of all stages): 13 were MYCN amplified and 19 had normal copy numbers of the MYCN gene. Of the 13 neuroblastomas that were MYCN amplified, seven were also DDX1 amplified. Of the 19 that were not MYCN amplified, none were DDX1 amplified. This is the first example of a gene that is co-amplified with MYCN at a high frequency in neuroblastoma. While there was a trend towards a worse clinical outcome with co-amplification, the numbers were too small to reach significance.

Child↗
PubMed1995

Bilateral congenital midureteral adynamic segments.

Two cases of congenital midureteral adynamic segments are presented. Both children were successfully managed with excision of the lesions and primary reanastomosis. Pathologic examination revealed probe-patent ureters with muscular disarray, suggesting functional obstruction. Appropriate management of the anomaly was dependent on precise radiographic localization of the area of narrowing, and for this retrograde urography was essential. Primary ureteroureterostomy was successful in both cases. In this report we discuss the diagnosis, embryology, radiographic evaluation, and management of this rate situation.

Humans↗
PubMed1995

Histologic studies of intravesical oxybutynin in the rabbit.

Intravesically applied oxybutynin has been reported to have no significant systemic anticholinergic side effects, with excellent efficacy in the treatment of neurogenic bladder dysfunction. Currently, the morphologic effects of intravesical oxybutynin on the local bladder tissue are not well established. It is the purpose of this study to address this issue in an animal model. Thirty-nine New Zealand White female rabbits were catheterized daily and intravesical solutions instilled for as long as 30 days. In part A of the study, the overall histologic effects of intravesical oxybutynin were examined by comparing oxybutynin with saline administration. Part B of this study compared the relative effects of crushed oxybutynin tablets and pure oxybutynin powder. The bladder histology and urine microbiological studies were analyzed in a blinded fashion. We found that the crushed oxybutynin tablets and saline administered intravesically produced similarly mild inflammation in the bladders (p < 0.05). When we compared the crushed oxybutynin tablets and pure oxybutynin powder, however, the crushed tablet group was found to have a mild eosinophilic infiltrate seen in 5 of 9 animals, which was not observed in any of the animals in the other groups (p = 0.029). Qualitative and quantitative analyses of the microbiological findings were not different among the different groups (p > 0.05). Our findings support the clinical use of intravesical oxybutynin as being safe for local tissue. However, consideration should be given to the use of the pure powdered form of oxybutynin, since the crushed oxybutynin tablets may lead to allergic reactions.

Administration, Intravesical↗
PubMed1994

Canine X chromosome-linked hereditary nephritis: a genetic model for human X-linked hereditary nephritis resulting from a single base mutation in the gene encoding the alpha 5 chain of collagen type IV.

Many families with X-chromosome linked hereditary nephritis (HN) have mutations in the gene on the X chromosome that codes for the alpha 5 chain of collagen type IV. Canine X-linked HN is an animal model for human X-linked HN. To study the alpha 5(IV) gene in this model, we used the nucleotide sequence published for the human alpha 5(IV) cDNA to construct sets of primers covering approximately 95% of the complete cDNA. cDNA from both affected and normal dog kidneys was amplified by PCR in nine overlapping regions. The nucleotide sequence encoding the noncollagenous domain NC1 hybridized to the human X chromosome and was 93% identical at the DNA level and 97% identical at the protein level to the human alpha 5(IV) NC1 domain, confirming that the canine alpha 5(IV) cDNA had been amplified. Sequence analysis of the alpha 5(IV) cDNA detected a single nucleotide substitution, G-->T, in affected dogs, changing a codon for a conserved glycine residue (GGA) to a stop codon (TGA). When genomic DNA was amplified, the same abnormality was found in exon 35. Using the canine NC1 domain cDNA as a probe for Northern analysis, two transcripts of approximately 8.6 kb and approximately 6.7 kb were identified in both normal and affected male dog kidney RNA. However, the abundance of both transcripts was decreased by a factor of approximately 10 in the affected dog. These results establish at the molecular level that canine X-linked HN is a model for human X-linked HN. This model provides an opportunity to determine the efficacy of new therapies and to investigate the role of the alpha 5(IV) chain in type IV collagen assembly.

Amino Acid Sequence↗
PubMed1994

MYCN gene amplification in rhabdomyosarcoma.

BACKGROUND: Amplification of the MYCN oncogene, formerly known as N-myc, has been seen in several malignant tumors, particularly neuroblastoma, where its association with a poor clinical outcome is the clearest example of a clinically relevant oncogene mutation in any human cancer. METHODS: The incidence and clinical significance of MYCN amplification in rhabdomyosarcoma (RMS) was assessed by Southern blot analysis in this retrospective study of seven alveolar RMS and six embryonal RMS. RESULTS: MYCN amplification (4- to 13-fold) was present in three of seven alveolar RMS (42.9%) but in none of the embryonal RMS. There was no significant difference between the clinical behavior of the MYCN-amplified and unamplified tumors, and no correlation was found with the light microscopic appearances of the tumors or with desmin immunoreactivity. CONCLUSIONS: The findings are compatible with previous studies that demonstrated cytogenetic evidence of gene amplification in RMS, and help to clarify conflicting reports in the literature about MYCN amplification in alveolar and embryonal RMS. The results raise the possibility of important biologic differences between these subtypes of RMS, differences that warrant further investigation.

Blotting, Southern↗
PubMed1994

Localized scleroderma in childhood: a report of 30 cases.

Localized scleroderma (LS), a rare disease that occurs primarily in the pediatric age group, differs from systemic sclerosis (SSc) in that it is usually limited to the skin and subcutaneous tissue and is only rarely associated with systemic manifestations. The authors' experience with pediatric LS seen in 30 patients at a tertiary care center was reviewed: 26 had linear scleroderma, 19 on an extremity and 7 on the face; 3 had morphea; and 1 had generalized morphea. Antinuclear antibodies were present in 76% and rheumatoid factor in 39%. Five of 19 patients with linear scleroderma that involved an extremity had growth failure in that limb, and 1 required surgery. Sclerodermatous involvement over a joint resulted in limited range of movement in 6 patients, and 1 required surgery. One of the 30 patients developed SSc and polymyositis. There was difficulty in evaluating disease activity and hence in evaluating treatment. This experience with a large patient population suggests that LS, although usually a self-limiting disease, can result in significant morbidity.

Adolescent↗