Biomedical subjects
Publications and source records attributed to S Kogan.
A 56-year-old woman had erosions due to pemphigus vulgaris in the inner thighs and perineum. The cutaneous lesions cleared following intramuscular gold therapy. However, because of complaints of dyspareunia, a colposcopic examination was performed and involvement of the cervix was demonstrated. The need for a vaginal examination in the monitoring of pemphigus vulgaris is emphasized.
Mutations leading to hemophilia A by substitution of amino acids in coagulation factor VIII may provide important clues to the structure and function of this large and enigmatic protein. To efficiently find missense mutations, hemophiliacs with mild and moderately severe forms of the disease were surveyed. DNA samples from affected individuals were assayed for mutations by denaturing gradient gel electrophoresis following DNA amplification of target regions, which included all coding regions except for that of the dispensable B domain. Missense mutations were observed in 20 of the 34 patients examined, with identical mutations found in five pairs of patients. All mutations were found in the repetitive A and C domains. By aligning these domains in factor VIII with homologous domains in factor V, ceruloplasmin, and the mouse milk fat globule membrane protein, it was determined that most mutations change amino acids in areas of strong sequence conservation. Three additional mutations were detected, including a point mutation in an intron, a stop codon mutation, and a silent base change. Ten of the 18 different mutations discovered in this patient population are reported here for the first time.
Since Idiopathic Parkinson's disease (IPD) was first described more than 170 years ago, there have been major advances in the understanding of the etiology of the disease as well as in its treatment. This article will review current knowledge concerning the role of the environment, genetic hypotheses and the aging factor in the etiology of IPD and proposes a complex interaction involving all these factors. Hypotheses regarding mitochondrial inhibition and free radical generation in IPD are discussed in relation to the mechanism of action of neurotoxins known to produce parkinsonian syndromes.
Hemophilia A results from mutations in the gene coding for coagulation factor VIII. We used denaturing gradient gel electrophoresis to screen for mutations in the region of the factor VIII gene coding for the first acidic domain. Amplification primers were designed employing the MELTMAP computer program to optimize the ability to detect mutations. Screening of amplified DNA from 228 unselected hemophilia A patients revealed two mutations and one polymorphism. Rescreening the same population by making heteroduplexes between amplified patient and control samples prior to electrophoresis revealed one additional mutation. The mutations include two missense and one 4-base-pair deletion, and each mutation was found in patients with severe hemophilia. The polymorphism, located adjacent to the adenine branch site in intron 7, is useful for genetic prediction in some cases where the Bcl I and Xba I polymorphisms are uninformative. These results suggest that DNA amplification and denaturing gradient gel electrophoresis should be an excellent strategy for identifying mutations and polymorphisms in defined regions of the factor VIII gene and other large genes.
Chyloperitoneum is an extremely rare complication of abdominal surgery in children and a combined occurrence of chylothorax and chyloperitoneum after abdominal surgery has never been reported in children. Chylous ascites usually occurs as a result of operative trauma to the thoracic duct, cisterna chyli, or its tributaries. About one third of all patients with chylous ascites after retroperitoneal lymph node dissection also develop secondary chylothorax. Diaphragmatic defects have been shown to be responsible for the occurrence of chylothorax secondary to chyloperitoneum. Congenital diaphragmatic weakness may result in evagination of the peritoneum causing diaphragmatic blebs, the rupture of which results in the movement of the peritoneal fluid into the pleural cavity. In the authors' patient, the rent in the diaphragm that occurred during surgery was probably responsible for the chylothorax. The role of chemotherapy, if any, in the pathophysiology of this complication is unknown. Total parenteral nutrition (TPN) is a simple and effective treatment for postoperative chylous effusions. Surgical treatments such as abdominal exploration for the repair of leaking lymphatics and peritoneovenous shunt should be reserved for patients who fail TPN.
We present the DNA sequence and a functional dissection of the 1483 residue yeast activator HAP1. Salient results are, first, a single DNA binding domain (1-148) specifies binding to the two target sites of different sequence, UAS1 and CYC7. This domain contains a cysteine-rich zinc finger, and mutation of either of two cysteines abolishes binding to both sites. Second, mutations that specifically abolish binding to UAS1 or to CYC7 exist. These changes lie either in the residue immediately amino-terminal to the finger or in sequences carboxyl to the finger. Thus, both the base of the finger and carboxyl flanking residues are involved in specific DNA binding. Third, a distinct region (residues 245-445) mediates heme induction by masking the DNA binding domain in the absence of inducer; heme counteracts this masking, perhaps by interacting with a repeat sequence of metal binding character in this region. While sequences between 445 and 1308 have no obvious function, a highly acidic carboxyl terminus mediates transcriptional activation by HAP1.
Epididymal abnormalities have long been found in conjunction with cryptorchid testicles. The aim of this study was to document the different types of epididymal and ductal anomalies in relation to the position of the cryptorchid testis and to determine their clinical significance. Exploration was performed on 187 cryptorchid testes in 174 boys. The position of the testis and the epididymal and ductal anomalies were documented at operation. A biopsy was taken from the testis or atretic spermatic cord structures for light microscopy. Epididymal, ductal and/or testicular anomalies were detected in 43 per cent of the 187 testes, including anomalies of ductal fusion, anomalies of ductal suspension and anomalies associated with absent or vanishing testes. Biopsy of the testes with severe anomalies of ductal fusion showed preservation of germ cells in 69 per cent and diminished germ cells in 31 per cent. The higher the arrest of testicular descent, the more grossly abnormal was the associated ductal system. Early successful orchiopexy alone may not ensure subsequent fertility despite the presence of normal germ cells.
Aggressive chemotherapy in patients with acute lymphoblastic leukemia has resulted in a marked upsurge in patient survival. In the course of their management, testicular biopsy and rebiopsy have an important role. We evaluated the histological findings in 50 sets of open wedge and simultaneous needle core biopsy specimens from 44 testes of children with acute lymphoblastic leukemia to determine the accuracy of the needle biopsy technique in the evaluation of testis involvement in acute lymphoblastic leukemia. We conclude that needle biopsy of the testis in acute lymphoblastic leukemia is highly accurate and correlates well with the conventional open wedge biopsy, and it may have a role in the management of children with acute lymphoblastic leukemia.
A case of knotting of a bladder catheter inserted to closely monitor a critically ill child is presented. The literature is reviewed, revealing knotting to be an unusual complication of this common pediatric procedure. Risk factors for knotting are discussed, and precautionary recommendations are presented.
Novel oligonucleotide primers are described for the convenient and internally controlled detection of the BclI factor VIII polymorphism on agarose gels. The primers were used for prenatal diagnosis in a family in which only one individual was affected with hemophilia A. In such families, it is important for the mother to understand that uncertainty about the point of origin of the mutation precludes the accurate diagnosis of affected fetuses but does allow the accurate diagnosis of unaffected fetuses in many cases.
Moderate and even severe dilatation of the urinary tract in the absence of vesicoureteric reflux may remain stable or show spontaneous resolution. Two such cases are described. Twenty-five children with dilated urinary systems were studied to correlate the radiological, isotope, pressure perfusion and surgical findings. A positive Whitaker test correlated well with the surgical findings and post-operative improvement in renal function in all patients with pelviureteric junction (PUJ) and vesicoureteric junction (VUJ) obstruction. High flow rates of 8.6 and 12 ml are required even in neonates and infants in order to demonstrate obstruction by Whitaker testing.
Hemophilia A is caused by a defect in coagulation factor VIII, a protein that undergoes extensive proteolysis during its activation and inactivation. To determine whether some cases of hemophilia are caused by mutations in important cleavage sites, we screened patient DNA samples for mutations in these sites by a two-step process. Regions of interest were amplified from genomic DNA by repeated rounds of primer-directed DNA synthesis. The amplified DNAs were then screened for mutations by discriminant hybridization using oligonucleotide probes. Two cleavage site mutations were found in a survey of 215 patients. A nonsense mutation in the activated protein C cleavage site at amino acid 336 was discovered in a patient with severe hemophilia. In another severely affected patient, a mis-sense mutation results in a substitution of cysteine for arginine in the thrombin activation site at amino acid 1689. This defect is associated with no detectable factor VIII activity, but with normal levels of factor VIII antigen. The severe hemophilia in this patient was sporadic; analysis of the mother suggested that the mutation originated in her gametes or during her embryogenesis. The results demonstrate that this approach can be used to identify factor VIII gene mutations in regions of the molecule known to be important for function.
We report on a child with xanthogranulomatous pyelonephritis--an uncommon entity in children. A review of the literature revealed that in only 18 per cent was the diagnosis made correctly preoperatively. In children the disease is of a focal nature rather than a diffuse one, suggesting that possibly radical surgery would be less necessary for adequate treatment.
We investigated the mechanisms of injury involved in unilateral testis torsion as well as the interventional effects of orchiectomy at 48 h and immunosuppression with corticosteroids in rats. Torsion was associated with abnormal contralateral testis histology and raised antilymphocytes and antisperm antibody titers. Both orchiectomy and steroid administration lessened these findings, suggesting that an immunological process underlies the abnormality seen in this experiment model.
The Klippel-Trenaunay syndrome is composed of the triad of unilateral limb hypertrophy, abnormalities of the deep venous system, and port-wine hemangiomas. An interesting case is presented in which there were multiple abnormalities of the renal veins and intrarenal hemangiomas resulting in renal failure in addition to the usual peripheral abnormalities.
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A twelve year old boy presented with sudden onset of severe hypertension and oligo-anuria. A diagnosis of Takayasu's Arteritis was made by aortography which demonstrated irregular narrowing of the lumbar aorta and renal arteries. Severe renal insufficiency necessitated maintenance hemodialysis. Hyperreninemic hypertension was intractable despite aggressive dialysis and multiple drug therapy. Renal biopsy after eight months of dialysis showed preservation of glomerular architecture. After nine months GFR improved spontaneously to 32 ml/min/1.73 m2 despite no improvement in his hypertension. This case report emphasizes the remarkable ability of renal parenchyma to recover function after sustained ischemia.