Molecular genetics of familial hypercholesterolemia in Israel

Recreational SCUBA diving exposes individuals to environmental stresses not often encountered in other types of activity. These stresses include increased ambient pressure, raised partial pressure of O(2), increased resistance to movement, added weight and drag of diving equipment, cold stress, and a higher breathing resistance. One means to understand how such stresses affect a diver is to employ the stress-strain-adaptive response model. Physiologic adaptations, like an increase in VO(2) in response to cold stress, will minimize the strain placed on thermal balance. Nonphysiologic adaptive responses include those behavioral and equipment interventions that isolate the diver from a particular stress. Self-contained underwater breathing apparatus (SCUBA) isolates the diver from the inability to extract O(2) from the water; dive garments minimize the stress of cold water immersion. This review will focus on cardiorespiratory and thermal responses to SCUBA diving, using the stress-strain-adaptive response model to illustrate the interaction between diver and environment. Some responses like hyperventilation, cardiac arrhythmias, or cold injury due to vasoconstriction are not considered adaptive but are realistic possibilities in diving environments.     

Managing cutaneous melanoma

Cutaneous melanoma represents the main cause of death among skin cancers. Early diagnosis gives, for the time being, the only possibility for high rate of curative treatment. Diagnosis is based on pathological findings, and at primary tumor stage. Breslow thickness of the lesion is the best prognostic index. At local stage of the disease, treatment is precisely codified by international recommendations and consensus conferences. Follow-up after surgical treatment is also well codified. Treatment of lymph node invasion or metastatic disease is, on the other hand, less codified. Despite recent advances, especially in immunotherapy, treatment of advanced stages of melanoma remains difficult.     

Narrow resection of cutaneous melanoma

We report the case of a young pregnant woman with a malignant tumour of the kidney suggestive of oncocytoma. Because of the pregnancy, preoperative staging consisted of abdominal ultrasound and magnetic resonance imaging. Caesarean section was performed. Several days later, surgical exploration of the kidney was performed with tumourectomy and frozen section analysis: radical nephrectomy was finally performed. The definitive histology was chromophobe renal cell carcinoma. This is a rare tumour of the kidney, with its own characteristics allowing histopathological diagnosis and with a better prognosis than renal cell carcinoma. In the literature, pregnancy, a situation of immune depression, does not increase the prevalence of malignant neoplasms.     

Clinical characteristics of early cutaneous melanoma

Clinical characteristics of the primary tumor in 786 patients with superficial spreading melanoma were studied in a prospective sequential series of patients from the Melanoma Clinical Cooperative Group. The most useful features for early diagnosis were change in size and change in color, present in 71% and 55% respectively of patients with level II lesions. Increase in height of lesion correlated with more advanced disease. Ulceration and bleeding were predominantly found in advanced primary lesions and are consequently of limited use in early recognition. Awareness of the historical and clinical features of the primary tumor should result in early recognition and cure of most primary superficial spreading melanomas.     

Molecular genetics. Introduction

While sharing the same techniques as the field at large, diagnostic molecular genetics is unique among the subdisciplines of molecular pathology in many of its aspects, from sample collection to ethical implications of the test results obtained. Yet, despite its many challenges, this branch of DNA diagnostics has already pervaded the practice of medical genetics to an extent unmatched in any other clinical specialty. Genetic disease also presents the most immediately obvious opportunities for extension from DNA-based diagnosis to DNA-based therapy.     

Molecular genetics of metachromatic leukodystrophy

Metachromatic leukodystrophy is an autosomal recessive inherited lysosomal storage disease. It can be caused by mutations in two different genes, the arylsulfatase A and the prosaposin gene. These genes encode two proteins that are needed for the proper degradation of cerebroside sulfate, a glycolipid mainly found in the myelin membranes. Deficiency of arylsulfatase A or of a proteolytic product of prosaposin leads to the accumulation of cerebroside sulfate, which causes a lethal progressive demyelination. Mutations in the arylsulfatase A gene are far more frequent than those of the prosaposin gene. So far 31 amino acid substitutions, one nonsense mutation, three small deletions, three splice donor site mutations, and one combined missense/splice donor site mutation have been identified in the arylsulfatase A gene. Two of these mutant alleles are frequent, accounting for about one-half of all mutant alleles, whereas the remainder are heterogeneous. Amino acid substitutions cluster in exons 2 and 3, a region that shows a high degree of conservation among sulfatases of different function and origin. Different mutations are associated with phenotypes of different severity, but there is a remarkable variability of severity when patients with identical genotypes are compared. Demonstration of an arylsulfatase A deficiency is not a proof of metachromatic leukodystrophy, since a substantial deficiency without any clinical consequences is frequent in the general population. This deficiency is caused by an arylsulfatase A allele, which due to certain mutations encodes greatly reduced amounts of functional enzyme. However, these amounts are sufficient to sustain a normal phenotype. In the diagnosis and genetic counseling, these deficiencies must be differentiated from those causing metachromatic leukodystrophy. So far only six patients with mutations in the prosaposin gene have been described, in which three defective alleles two with amino acid substitutions and one with a 33-bp insertion have been identified.     

Molecular genetics of peroxidase deficiency

Myeloperoxidase (MPO) belongs to a family of related proteins which also includes eosinophil, thyroid, and lactoperoxidase. The MPO gene is a 14-kb gene located on the long arm of chromosome 17. Thus far four mutations (R569W, Y173C, M251T and a 14-base deletion in exon 9) have been identified in patients with MPO deficiency. As in other genetically determined diseases, many more mutations will eventually be revealed that cause this disease. Present evidence shows that most patients are compound heterozygotes, i.e., they have inherited different mutations on their paternal and maternal MPO alleles. Understanding why some patients with this genetic deficiency develop clinical symptoms while others do not requires mutation analyses of a large number of patients. This includes the analysis of genotype-phenotype relationships. Genotyping has also been started in patients with EPO-deficiency.     

Molecular genetics of oculocutaneous albinism

Oculocutaneous albinism (OCA) is a group of autosomal recessive disorders characterized by deficient synthesis of melanin pigment. Type I (tyrosinase-deficient) OCA results from deficient enzymatic activity of tyrosinase, which catalyzes at least three steps in the melanin biosynthetic pathway. Type II (tyrosinase-positive) OCA results from abnormalities of the "P" polypeptide. Recent application of molecular genetic techniques to the study of these disorders has led to extraordinary advances in knowledge of their molecular pathogenesis, paving the way to improved diagnosis, carrier detection, and even treatment.     

Molecular genetics of long-QT syndrome

We have recently shown that spinal calmodulin inhibitors (W-7 and calmidazolium) dose-dependently inhibit the nociceptive reaction (biting, scratching, licking, BSL) evoked by intrathecal N-methyl-D-aspartate (NMDA) and septide, an agonist of the neurokinin (NK) NK1 receptor. To compare this effect with that induced by standard analgesics, we now report a study of the effects of calmidazolium (14420 nmol), bupivacaine (29-582 nmol) and morphine (26-260 nmol) when coadministered intrathecally with either NMDA (4 microg) or septide (0.5 microg). Calmidazolium had the highest potency for inhibiting septide-induced nociceptive behaviour, acting over a dose range of 34-130 nmol (dose eliciting a half-maximal response, ED50, 67 nmol) lower than that of bupivacaine [ED50 234 (115-475) nmol]. Only the highest dose of morphine (260 nmol) inhibited septide-evoked BSL [ED50=133 (69-255) nmol]. Higher doses of morphine could not be tested due to the appearance of an excitatory aversive reaction. Both calmidazolium [ED50=232 (138-388) nmol] and bupivacaine [ED50=123 (59-256) nmol] dose-dependently reduced NMDA-induced BSL reaching an almost maximal inhibition at the highest doses assayed (420 and 291 nmol, respectively). In contrast, morphine had less effect on NMDA-induced behaviour, inducing only a partial reduction of BSL even with the highest dose assayed (260 nmol). Overall, it can be concluded that the calmodulin inhibitor calmidazolium inhibits septide- and NMDA-evoked nociceptive behaviour with a potency and efficacy at least as high as those of morphine and bupivacaine.     

Molecular genetics of breast cancer

During 1994, 129 specimens of chub (Leuciscus cephalus L.) from two localities, polluted--Bolelouc, 80th river kilometer, near the city of Olomouc, and unpolluted--Brodské, 225th river kilometer, near the Lanzhot on the Morava river, were examined for metazoan parasites. Altogether 38 metazoan parasite species including helminths, leeches and glochidia belonging to 14 genera were found, 34 in the case of unpolluted locality (Brodské) and 28 in the polluted one (Bolelouc). In both localities, 24 parasite species (Dactylogyrus folkmanovae, D. naviculoides, D. prostae, D. vistulae, D. vranoviensis, Gyrodactylus carassii, G. gasterostei, G. gracilihamatus, G. scardiniensis, G. vimbi, Gyrodactylus sp., Paradiplozoon ergensi, P. homoion, P. megan, Paradiplozoon sp., Caryophyllaeus brachycollis, Diplostomum spathaceum--larval stage, Philometra abdominalis, Acanthocephalus anguillae, Pomphorhynchus laevis and Glochidium sp.) were found, 10 (D. crucifer, D. nanoides, G. hemibarbi, G. lamberti, G. leucisci, G. lomi, P. rutili, C. fennica, A. imitans, S. bramae) were identified solely in the unpolluted locality Brodské and 4 (D. fallax, G. laevis, P. ovata, G. kearni) parasite species were found only in the polluted locality Bolelouc. Differences in parasite species richness, the level of dominance, the structure of core and in satellite species were observed. Current methods of statistical evaluation were used.     

Molecular genetics of Wilms'' tumour

The cardiopulmonary response elicited by intravenous bacteria or endotoxin is well characterized in swine and has two major components. The first represents the acute pulmonary and broncho-constrictive phase (0-2 h) and the second phase (3-8 h) represents increased microvascular permeability, hypotension, and enhanced leukocyte-endothelial adhesion. The pulmonary vasoconstriction and bronchoconstriction of phase 1 results in acute pulmonary hypertension and airway dysfunction, which may result in rapid mortality. Because this acute pulmonary response may not mimic the development of human septic shock, we sought to block this early phase and examine the role of tumor necrosis factor in the latter septic phase (3-8 h). Employing a thromboxane A2 (TXA2) receptor antagonist (BAY U 3405) in the presence of LD100 Escherichia coli challenge, we blocked the acute pulmonary hypertensive phase and prevented early mortality, however, TXA2 blockade did not affect the latter development of septic shock and death. This latter lethal phase, characterized by prolonged leukopenia, was blocked in a dose-dependent manner by tumor necrosis factor monoclonal antibody. We conclude that the TXA2-blocked E. coli-challenged swine may provide a novel animal model in which to investigate the pathophysiology of acute septic shock.     

Molecular genetics of acute leukaemia

The outlook for patients with acute promyelocytic leukaemia has improved vastly with the use of all-trans retinoic acid. The development of this therapeutic agent stemmed from the finding that an abnormality of the retinoic acid receptor is involved in this disease. In the search for other molecular abnormalities in the acute leukaemias that might serve as therapeutic targets, the chromosomal translocations associated with this group of disorders have been helpful in indicating where to look for potential cancer genes. Some common signal-transduction pathways through which different such genes act have been identified, and compounds that interfere with these pathways are already being screened for.     

Complete regression of primary cutaneous malignant melanoma

While partial spontaneous histopathological regression is a common finding in invasive primary melanoma, proven complete regression is rare, with only 33 cases having been documented. None of the patients in these reported cases had a biopsy specimen taken from the original lesion, which would unequivocally prove the diagnosis of complete regressing melanoma. Over 4 years, we saw a 62-year-old white man who refused treatment of a biopsy specimen-proved superficial spreading melanoma (Breslow thickness, 0.7 mm) that eventually regressed completely. A biopsy specimen confirmed complete histopathological regression. There was no clinical evidence of regional or distant metastases throughout the 4 years. To our knowledge, this is the first documented case of a biopsy specimen-proved primary melanoma completely regressing. We present sequential photographic documentation and review the literature about this phenomenon. While the prevalence of such an event is unknown, evidence is presented that it may be more common than previously thought.     

Molecular pathology of melanoma

There has long been a clinical need for improved molecular pathology in melanoma, particularly in the histopathology laboratory where the differentiation of melanoma from its benign counterparts is commonly difficult. The need for improved molecular pathology has recently increased as immunotherapeutic options for the treatment of the tumour evolve. It seems likely that in the relatively near future tumour typing before and during immunotherapy will be needed. The identification of the tumour suppressor gene coding for the protein p16 as an important gene in the pathogenesis of melanoma is of great interest but the identification of oncogenes having a significant role in melanoma carcinogenesis has been slow.     

The genetics of melanoma: the UK experience

The eighties and nineties are characterized by potent development of transplantology. Despite this the number of patients with organ failures waiting for a suitable organ is steadily increasing. Due to the permanent shortage of donors transplantation surgery tries to implement the maximum possible multiple organ collection. In the conclusion the authors emphasize the importance of satisfactory cooperation of the anaesthesiologist attending donors and the organ collection teams.     

Malignant cutaneous melanoma associated with neurofibromatosis in two sisters from a family with familial atypical multiple mole melanoma syndrome. Case reports and review of the literature

Two cases of malignant melanoma associated with neurofibromatosis in two first-degree female relatives from a family with familial atypical multiple mole melanoma (FAMMM) syndrome are presented. The types of neurofibromatosis and the FAMMM syndrome are discussed in relation to these cases and the family genealogic tree. Although the FAMMM syndrome could probably be seen as the underlying disease in the current cases, review of literature has failed to establish a clear relation. Research into pigmentary disturbance in neurofibromatosis is necessary to give a final explanation. To our knowledge, this is the first report in literature describing the familial occurrence of both diseases and it might present an addition to the tumor spectrum in the FAMMM syndrome.     

Molecular genetics of C1 inhibitor

More than 100 different C1 inhibitor gene mutations have been described in hereditary angioedema (HAE) patients. Sixty-nine mutations have been reported in patients with the quantitative C1 inhibitor defect (type 1 HAE) in two recent large-scale studies. These changes were found distributed over all exons and exon/intron boundaries. The molecular defects can be divided as follows: Alu-repeat-mediated deletions or duplications (accounting for 21% of all cases), missense mutations (> 36%), frameshifts (14%), Stop codon mutations (10%), promoter variants (4%), splice site mutations (7-10%), deletions of a few amino acids (less than 3%). Several recent studies indicate that up to 25% of these changes are found in patients without a family history of angioedema and represent de novo mutations. Pathogenic amino acid substitutions were found distributed over the entire length of the coding sequence, except for the 100 amino-acid-long glycosylated amino-terminal extension, whose sequence tolerates extensive variation, as indicated by comparisons across species. Functional studies have been carried out only on a fraction of these amino acid substitutions and indicate that defects affecting intracellular transport are often at the basis of type 1 hereditary angioedema. An interesting promoter variant (a C to T transition at position -103) was found in an exceptional family with recessive transmission of the disease. Regulatory elements in the promoter region and in intron 1 were revealed by their sequence conservation in mouse and man and by functional studies. C1 inhibitor "minigene" constructs directing correct mRNA and protein synthesis in transgenic mice have provided valuable information on hormonal control and cell-type specificity of gene expression.