Problem based review: the patient with 'palpitations'.

Palpitations, or the sensation of a rapid or heavy heartbeat, are a common symptom in both primary and secondary care settings. Here we use a common presentation of palpitations to explore the best ways to assess and treat patients who present in this way. We hope that by using a structured approach to our assessment we will reduce the use of the 'scattergun' approach to diagnosis, thus preventing unnecessary investigation and hospital stay.

Novel p53 mutants selected in BRCA-associated tumours which dissociate transformation suppression from other wild-type p53 functions.

Inheritance of germ-line mutant alleles of BRCA1 and BRCA2 confers a markedly increased risk of breast cancer and we have previously reported a higher incidence of p53 mutations in these tumours than in grade matched sporadic tumours. We have now characterized these p53 mutants. The results of these studies identify a novel class of p53 mutants previously undescribed in human cancer yet with multiple occurrences in BRCA-associated tumours which retain a profile of p53-dependent activities in terms of transactivation, growth suppression and apoptosis induction which is close or equal to wild-type. However, these mutants fail to suppress transformation and exhibit gain of function transforming activity in rat embryo fibroblasts. These mutants therefore fall into a novel category of p53 mutants which dissociate transformation suppression from other wild-type functions. The rarity of these mutants in human cancer and their multiple occurrence in BRCA-associated breast tumours suggests that these novel p53 mutants are selected during malignant progression in the unique genetic background of BRCA1- and BRCA2-associated tumours.

Spectrum of p53 gene mutations suggests a possible role for ultraviolet radiation in the pathogenesis of advanced cutaneous lymphomas.

There is evidence that the incidence of primary cutaneous lymphoma, like other forms of non-Hodgkin's lymphoma, is increasing, yet little is known of the pathogenetic events involved in this group of disorders. In this study we examine the frequency and spectrum of P53 gene mutations in a large series of primary cutaneous lymphomas, with particular emphasis on tumor stage mycosis fungoides, as it is in these cases that p53 overexpression has previously been reported. Sixty-six samples from 55 patients with primary cutaneous B cell and T cell lymphomas were analyzed for mutations in exons 5-9 of the P53 gene using polymerase chain reaction/single strand conformational polymorphism, and subsequent cloning and sequencing of genomic DNA. Fourteen separate P53 mutations were identified in blood, skin, and lymph node samples in 13 patients (24%). Twelve of 14 mutations occurred at dipyrimidine sites, eight resulting in C-->T transitions and one in a CC-->TT tandem base transition, a mutation spectrum strikingly similar to that reported in nonmelanoma skin cancer and characteristic of DNA damage caused by ultraviolet B radiation. In the subset of patients with mycosis fungoides, P53 mutations were identified in six of 17 patients with tumor-stage but in none of 12 patients with plaque-stage disease (Fisher's exact test p = 0.027). These data suggest a role for ultraviolet radiation in the pathogenesis of primary cutaneous lymphomas and a possible ultraviolet B-related step in the progression of mycosis fungoides from plaque to tumor-stage disease.

p53 mutation with frequent novel condons but not a mutator phenotype in BRCA1- and BRCA2-associated breast tumours.

The status of p53 was investigated in breast tumours arising in germ-line carriers of mutant alleles of BRCA1 and BRCA2 and in a control series of sporadic breast tumours. p53 expression was detected in 20/26 (77%) BRCA1-, 10/22 (45%) BRCA2-associated and 25/72 (35%) grade-matched sporadic tumours. Analysis of p53 sequence revealed that the gene was mutant in 33/50 (66%) BRCA-associated tumours, whereas 7/20 (35%) sporadic grade-matched tumours contained p53 mutation (P<0.05). A number of the mutations detected in the BRCA-associated tumours have not been previously described in human cancer databases, whilst others occur extremely rarely. Analysis of additional genes, p16INK4, Ki-ras and beta-globin revealed absence or very low incidence of mutations, suggesting that the higher frequency of p53 mutation in the BRCA-associated tumours does not reflect a generalized increase in susceptibility to the acquisition of somatic mutation. Furthermore, absence of frameshift mutations in the polypurine tracts present in the coding sequence of the TGF beta type II receptor (TGF beta IIR) and Bax implies that loss of function of BRCA1 or BRCA2 does not confer a mutator phenotype such as that found in tumours with microsatellite instability (MSI). p21Waf1 was expressed in BRCA-associated tumours regardless of p53 status and, furthermore, some tumours expressing wild-type p53 did not express detectable p21Waf1. These data do not support, therefore, the simple model based on studies of BRCA-/- embryos, in which mutation of p53 in BRCA-associated tumours results in loss of p21Waf1 expression and deregulated proliferation. Rather, they imply that proliferation of such tumours will be subject to multiple mechanisms of growth regulation.

A transforming p53 mutant, which binds DNA, transactivates and induces apoptosis reveals a nuclear:cytoplasmic shuttling defect.

The DG75 Burkitt lymphoma-derived human B cell line is heterozygous for p53, carrying wild type (WT) and mutant (Arg283His) alleles. The cells constitutively express high levels of both p53 proteins and also Mdm2. Arg283His transactivates the p21Waf1, Mdm2, bax, cyclin G and IGF-BP3 promoters in transient transfection assays equally as well as, if not better than WT p53. It also suppresses the outgrowth of SAOS-2 cells and specifically binds DNA like wild type protein. However, in primary rodent fibroblasts Arg283His fails to suppress transformation by HPV16-E7 and (Ha-)ras and even has modest transforming activity when transfected alone with (Ha-)ras. When Arg283His is transiently transfected into SAOS-2 cells it efficiently induces apoptosis, so - unlike mutants such as Arg175Pro - its behaviour in transformation assays does not clearly correlate with loss of the apoptosis function. Immunofluorescence staining of both REF transformants and transiently transfected SAOS-2 revealed that this unusual mutant becomes excluded from the nucleus and produces striking cytoplasmic fluorescence. The best correlation with transformation, therefore, appears to be the lack of nuclear retention of Arg283His. Since this mutation does not map to any known nuclear localization signal and its presence seems to result in aberrant exclusion from the nucleus, then it may prove very useful in exploring mechanisms involved in the nuclear:cytoplasmic shuttling of p53.

Nuclear location and cell cycle regulation of the BRCA2 protein.

Women carrying a germ-line mutation in the BRCA1 or BRCA2 genes have a high risk of developing breast cancer, and loss of the wild-type allele in tumors suggests that these genes function as tumor suppressor genes. The BRCA2 gene encodes a 3418-amino acid protein with no significant sequence similarity to any known protein. To begin to elucidate the cellular role of BRCA2, we have raised antibodies to the BRCA2 protein and used these to study its subcellular localization and expression. We show that BRCA2 is a nuclear protein expressed in response to cell proliferation and that BRCA2 expression is initiated before DNA synthesis.

Molecular cloning and characterization of PTP pi, a novel receptor-like protein-tyrosine phosphatase.

Novel cDNAs encoding a receptor-like protein-tyrosine phosphatase (rPTP) have been isolated from human breast tumour cells and foetal brain. The predicted protein of approximately 160 kDa, called PTP pi, comprises an extracellular portion with a MAM (meprin-A5 antigen-PTP mu) domain, an IgG-like domain and four fibronectin III-like repeats, a hydrophobic transmembrane domain and an intracellular portion consisting of two PTP catalytic units. The predicted amino acid sequence shows high identity with those of the two homophilic binding rPTPs, PTP mu and PTP kappa. A variant of PTP pi potentially encoding a protein lacking three amino acids within the N-terminal tyrosine phosphatase domain has been identified. Reverse transcription-PCR has been used to confirm the expression of the variant in human foetal brain tissue. Expression analysis has shown that PTP pi is expressed in a variety of tissue types. Both forms of the N-terminal catalytic domain, the C-terminal catalytic domain and both catalytic domains in tandem were expressed in bacteria as fusion proteins. Intrinsic phosphatase activity was detected for all protein products with an artificial substrate. The fusion protein comprising both domains in tandem was also shown to dephosphorylate purified autophosphorylated epidermal growth factor receptor in vitro.

Cefpodoxime proxetil in the treatment of skin and soft tissue infections.

Patients with skin and soft tissue infections were enrolled in a study comparing 2 dosage regimens of orally administered cefpodoxime proxetil; 204 patients with mild to moderate infections received cefpodoxime proxetil 200mg twice daily and 47 patients with severe infections received 400mg twice daily. Both dosage regimens were given for 7 to 14 days. 132 of 142 (93.0%) evaluable patients in the 200mg group and 22 of 29 (75.9%) in the 400mg group were clinically cured post-therapy, the remainder in both groups being classified as improved. The pathogen eradication rate at the end of therapy in the 200mg group was 161 of 165 (97.6%), and 38 of 38 (100%) in the 400mg group. Adverse reactions (drug-related) were reported by 20 (8.0%) patients overall, and there was no apparent relationship between the dosage group and the incidence of adverse reactions. The most commonly reported reactions involved the gastrointestinal tract (diarrhoea) or female genital tract (vaginitis). Cefpodoxime proxetil appears to be a useful and safe agent in the therapy of skin and soft tissue infections.

Use of a three-channel electrocardiographic recorder for limited intracardiac electrocardiography during single- and double-chamber pacemaker implantation.

A technique for making unipolar intracardiac recordings with a three-channel electrocardiograph during permanent pacemaker insertion is described.

Carcinoma of the right colon: a change in characteristic configuration?

Carcinoma of the colon occurring to the right of the middle colic vessels is usually described as morphologically and clinically distinctive from cancers occurring in the left colon. Cancers of the right colon are characterized as polypoid tumors that are discovered in the search for occult blood loss, whereas carcinomas of the left and sigmoid colon are described as scirrhous and often annular in configuration, giving rise to obstruction as the characteristic clinical presentation. A personal experience with constricting annular lesions of the right colon that were considered atypical has led to a review of the total experience in colonic resections for cancer (excluding abdominoperineal resections for carcinoma of the rectum) at one metropolitan university medical center. Of 152 colonic resections for cancer within 39-month interval, 57 resections were for cancer of the right colon and 95 for cancer of the left colon. One half of the cancers of the right colon were annular, whereas only one third of those of the left colon were so described by operative, pathologic, and radiologic criteria. Differences in clinical presentation of cancers of the right and left colon are probably attributable more to the form and function of the colon in each anatomic region than to any characteristic configuration of the tumor itself.

Aortic insufficiency requiring valve replacement in Whipple's disease.

Reviews of postmortem reports on patients with Whipple's disease (intestinal lipodystrophy) describe gross valvular deformity in more than 50% with characteristic histological findings of macrophages containing periodic acid-Schiff-positive, diastase-resistant granules. Frequently, congestive heart failure characterizes the terminal stages. In a 58-year-old man with well-documented Whipple's disease for 5 years, gastrointestinal, joint, and pericardial involvement apparently resolved with medical therapy. However, 10 years later, severe aortic insufficiency necessitated prosthetic valve replacement, at which time gross and histological examination of the excised valve demonstrated characteristic changes of Whipple's disease. Clinical recognition of the importance of cardiac valvular abnormalities and of possible late cardiac decompensation mandates close observation of patients with Whipple's disease. Corrective operation should improve the patient's chances of survival.

Complications of radial artery catheterization.

Sixty patients, representing a ten per cent incidence of complications, developed ischaemic or necrotic changes in the involved hand following radial artery cannulation. The loss of digits or hands could have been avoided by adequate evaluation of the vascular status of the hand both before and after cannulation.

A new wire-supported shunt for carotid endarterectomy.

An intraarterial shunt for cerebral protection during carotid endarterectomy is described. It combines the features of the U-shaped shunt of Hallin and the straight shunt of Sundt, and incorporates a side-arm that can be used for perfusion, irrigation, and intraarterial pressure. The shunt is a molded Silastic tube with wire coils at each end to prevent collapse, and its funicular collar and rim obviate sudden expulsion. Its use allows endarterectomy to be performed in a deliberate manner, permitting careful attention to prevention of an intimal flap and unhurried repair of the arteriotomy.