Factors influencing the occurrence of multicentric and 'recurrent' Warthin's tumour: a cross sectional study.

The multicentric nature of Warthin's tumour has been well recognised, though the factors predicting its occurrence and its influence on management remain speculative. In this cross sectional study, the authors analysed the presentation, management and outcome of solitary and multicentric Warthin's tumour, treated in the maxillofacial unit and investigated factors that could influence the occurrence of multicentric and recurrent tumours. Warthin's tumour was found in 24% (150/628) of patients presenting with parotid neoplasms and multicentric tumours were found in 13% (21/ 161) of parotidectomy specimens. Age, sex, side, site and smoking history were not predictors of multicentricity (P>0.40). Clinical examination (19%), imaging investigations (28%) and intra-operative palpation (33%) were poor at detecting multicentric tumours. Superficial parotidectomy was the most commonly performed operation. The recurrence rate was 0% in the solitary and 10% in the multicentric tumour group. Intra-operative rupture was not uncommon (11%), but was not associated with tumour recurrence (P= or >0.999). Incomplete excision (P=0.007) and multicentricity (P=0.026) were predictors of recurrence.

Conditional mutation of Rb causes cell cycle defects without apoptosis in the central nervous system.

Targeted disruption of the retinoblastoma gene in mice leads to embryonic lethality in midgestation accompanied by defective erythropoiesis. Rb(-/-) embryos also exhibit inappropriate cell cycle activity and apoptosis in the central nervous system (CNS), peripheral nervous system (PNS), and ocular lens. Loss of p53 can prevent the apoptosis in the CNS and lens; however, the specific signals leading to p53 activation have not been determined. Here we test the hypothesis that hypoxia caused by defective erythropoiesis in Rb-null embryos contributes to p53-dependent apoptosis. We show evidence of hypoxia in CNS tissue from Rb(-/-) embryos. The Cre-loxP system was then used to generate embryos in which Rb was deleted in the CNS, PNS and lens, in the presence of normal erythropoiesis. In contrast to the massive CNS apoptosis in Rb-null embryos at embryonic day 13.5 (E13.5), conditional mutants did not have elevated apoptosis in this tissue. There was still significant apoptosis in the PNS and lens, however. Rb(-/-) cells in the CNS, PNS, and lens underwent inappropriate S-phase entry in the conditional mutants at E13.5. By E18.5, conditional mutants had increased brain size and weight as well as defects in skeletal muscle development. These data support a model in which hypoxia is a necessary cofactor in the death of CNS neurons in the developing Rb mutant embryo.

Immigration medical screening and HIV infection in Canada.

HIV infection, particularly associated with AIDS, is often used by migrant screening nations to exclude entry into the country. The unique feature of the Canadian immigration HIV screening programme is that it was not primarily for determining inadmissibility of HIV-positive applicants, but for health promotion and disease prevention purposes. All applicants over 15 years of age for permanent residency or temporary residency from designated countries are HIV antibody tested. This includes persons seeking asylum from within Canada. The highest rates of HIV infection were found in migrant applicants from high prevalence areas of the world and reflected the demographic profile of the source region (predominately women). The majorities of HIV-positive persons are exempt from exclusion from Canada due to class of application (refugee, family) or are already in Canada (refugee claimant). Significant issues in notification, reporting and programme management have been identified as a consequence of this programme.

Multiple synchronous and metachronous neoplasms of the parotid gland: the Chichester experience.

Parotid neoplasms are usually solitary and multiple tumours occurring in an individual are uncommon. The incidence and implications of multiple synchronous and metachronous tumours remains relatively unknown. We reviewed the case notes of 606 patients who had parotidectomies for neoplastic lesions over a 30 year period and identified 30 patients (5%) with multiple primary tumours. There were 24 patients with synchronous tumours and 6 with metachronous tumours. Sixteen of the synchronous tumours (67%) were ipsilateral, whereas all six metachronous tumours were contralateral. Preoperative examination was effective at detecting bilateral tumours but poor at detecting multiple ipsilateral tumours. Multiple tumours were likely to be of the same histology (n=24, 80%) and Warthin's was by far the most common multiple tumour. Ipsilateral tumours of differing histological types and identical tumours other than Wartin's were uncommon. All but one patient had superficial parotidectomies and there were no recurrences.

High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten+/- mice.

PTEN is one of the most commonly mutated tumor suppressor genes in human cancer. PTEN mutations have been implicated in the development of a variety of human neoplasia, including high-grade glioblastoma, prostate, breast, endometrial, and thyroid carcinoma. Germ-line mutations of PTEN cause Cowden's syndrome (CS), a multiple hamartoma condition resulting in increased susceptibility for the development of cancer. When more than 6 months old, pten+/- mice develop a range of tumors, partially resembling the spectrum of neoplasia observed in CS patients. One-half (32 of 65) of pten+/- females developed breast tumors, whereas all (65 of 65) of the females had endometrial hyperplasia, and there was a high incidence (14 of 65) of endometrial cancer. Hamartoamous tumors of the gastrointestinal tract, as well as prostate and adrenal neoplasia, were also frequently observed. Significantly, the spectrum of neoplasia observed in pten+/- mice partially overlaps with the types of tumors frequently detected in CS patients. The majority of tumors in pten+/- mice exhibit loss of heterozygosity at the pten locus, which indicates the importance for loss of PTEN function in tumor formation. Consistent with the role of PTEN in negative regulation of PKB/Akt phosphorylation and activity, pten loss of heterozygosity is accompanied by hyperphosphorylation of PKB/Akt in tumors. Taken together, our results establish pten+/- mice as an excellent animal model system for the investigation of PTEN-related hamartoma syndromes, as well as the role of PTEN in breast and endometrial carcinogenesis.

Cell death attenuation by 'Usurpin', a mammalian DED-caspase homologue that precludes caspase-8 recruitment and activation by the CD-95 (Fas, APO-1) receptor complex.

Apoptotic cell suicide initiated by ligation of CD95 (Fas/APO-1) occurs through recruitment, oligomerization and autocatalytic activation of the cysteine protease, caspase-8 (MACH, FLICE, Mch5). An endogenous mammalian regulator of this process, named Usurpin, has been identified (aliases for Usurpin include CASH, Casper, CLARP, FLAME-1, FLIP, I-FLICE and MRIT). This protein is ubiquitously expressed and exists as at least three isoforms arising by alternative mRNA splicing. The Usurpin gene is comprised of 13 exons and is clustered within approximately 200 Kb with the caspase-8 and -10 genes on human chromosome 2q33-34. The Usurpin polypeptide has features in common with pro-caspase-8 and -10, including tandem 'death effector domains' on the N-terminus of a large subunit/small subunit caspase-like domain, but it lacks key residues that are necessary for caspase proteolytic activity, including the His and Cys which form the catalytic substrates diad, and residues that stabilize the P1 aspartic acid in substrates. Retro-mutation of these residues to functional caspase counterparts failed to restore proteolytic activity, indicating that other determinants also ensure the absence of catalytic potential. Usurpin heterodimerized with pro-caspase-8 in vitro and precluded pro-caspase-8 recruitment by the FADD/MORT1 adapter protein. Cell death induced by CD95 (Fas/APO-1) ligation was attenuated in cells transfected with Usurpin. In vivo, a Usurpin deficit was found in cardiac infarcts where TUNEL-positive myocytes and active caspase-3 expression were prominent following ischemia/reperfusion injury. In contrast, abundant Usurpin expression (and a caspase-3 deficit) occurred in surrounding unaffected cardiac tissue, suggesting reciprocal regulation of these pro- and anti-apoptotic molecules in vivo. Usurpin thus appears to be an endogenous modulator of apoptosis sensitivity in mammalian cells, including the susceptibility of cardiac myocytes to apoptotic death following ischemia/ reperfusion injury.

Temporal flow velocity profile in the descending aorta in coarctation.

The temporal blood flow velocity profile in the descending aorta at the diaphragm was investigated using pulsed Doppler echocardiography in patients with documented coarctation of the aorta and in control patients. The ratio of peak systolic to peak diastolic frequency shift, an angle-independent index of pulsatility derived from the Doppler curve, proved to be an excellent indicator of aortic arch obstruction in the absence of a patent ductus arteriosus. Control groups included patients with a systemic right ventricle, systemic ventricular dysfunction and aortic stenosis, to determine if these conditions would confound the test. None of these factors were found to influence significantly the frequency shift ratio. However, the Doppler curves in six patients with interrupted aortic arch or severe coarctation, whose descending aorta was supplied by way of a large patent ductus arteriosus, were similar to those seen in control patients. Two indexes of wave transmission velocity, the rate of acceleration and the time to peak velocity, discriminated less effectively between patients with coarctation and the control patients, particularly those with aortic stenosis. After surgery for coarctation, the Doppler indexes and contour of the Doppler curve discriminated completely between patients with and without residual coarctation.

Left ventricular diastolic function in elite athletes with physiologic cardiac hypertrophy.

Left ventricular hypertrophy due to aortic stenosis, hypertension and other forms of heart disease is associated with abnormalities of diastolic function. It is uncertain whether these changes are an inherent consequence of the hypertrophic process or represent additional pathologic factors. To investigate this issue, echocardiographic indexes of left ventricular early diastolic function in highly trained athletes were compared with those in age-matched normal control subjects. Athletes were equally classified into two groups: 11 swimmers who had a pattern of myocardial hypertrophy with normal wall thickness to dimension ratio and 11 power lifters whose wall thickness to dimension ratio was increased. The peak rates of left ventricular dimension increase and wall thinning in swimmers and power lifters were greater than in control subjects despite significantly higher left ventricular wall thickness and left ventricular mass index in the athletes. This increase in diastolic function indexes was associated with greater ventricular size and systolic performance. Normalization of the peak rate of dimension increase for end-diastolic dimension and adjustment of the peak rate of wall thinning for the fractional systolic thickening resolved any differences between groups. Thus, after the effects of ventricular size and systolic function were taken into consideration, diastolic function was normal in these subjects with considerable physiologic hypertrophy. This is in contrast to the findings in patients with hypertrophy associated with left ventricular pressure or volume overload, and suggests that abnormalities of diastolic function seen in pathologic hypertrophy are due to factors other than cardiac hypertrophy itself.

Hyperkalemia in outpatients using angiotensin-converting enzyme inhibitors. How much should we worry?

BACKGROUND: Hyperkalemia is a potentially life-threatening complication resulting from the use of angiotensin-converting enzyme (ACE) inhibitors; data to guide the intensity of monitoring for or responding to hyperkalemia in outpatients are limited. METHODS: Case-control methodological procedures were used to identify risk factors for hyperkalemia. Outpatients prescribed ACE inhibitors during 1992 and 1993 at a Veterans Affairs medical center general medicine clinic were identified. Case patients had a potassium level higher than 5.1 mmol/L on the day of clinic visit while using an ACE inhibitor; controls had a potassium level lower than 5.0 mmol/L on the day of clinic visit while using an ACE inhibitor and had no elevated potassium level during the study period. Predictor variables measured included type and dosage of ACE inhibitor; serum chemistries; comorbidities; concurrent drug use; and age. Case patients were followed up for 1 year after the index episode of hyperkalemia. Follow-up variables included changes in therapy with ACE inhibitor, maximum potassium for each change, and mortality. RESULTS: Of 1818 patients using ACE inhibitors, 194 (11%) developed hyperkalemia. Results of laboratory studies indicating a serum urea nitrogen level higher than 6.4 mmol/L (18 mg/dL), creatinine level higher than 136 mumol/L (1.5 mg/dL), congestive heart failure, and long-acting ACE inhibitors were independently associated with hyperkalemia; concurrent use of loop or thiazide diuretic agent was associated with reduced risk. After 1 year of follow-up, 15 (10%) of 146 case patients remaining on a regimen of an ACE inhibitor developed severe hyperkalemia (potassium level > 6.0 mmol/L). A serum urea nitrogen level higher than 8.9 mmol/L (25 mg/dL) and age more than 70 years were independently associated with subsequent severe hyperkalemia. CONCLUSIONS: Mild hyperkalemia is common in medical outpatients using ACE inhibitors, especially in those with renal insufficiency or congestive heart failure. However, once hyperkalemia is identified during the use of ACE inhibitors, subsequent severe hyperkalemia is uncommon in patients younger than 70 years with normal renal function.

Understanding racial variation in the use of coronary revascularization procedures: the role of clinical factors.

BACKGROUND: Black patients undergo coronary artery bypass grafting and percutaneous transluminal coronary angioplasty less often than white patients. It is unclear how racial differences in clinical factors contribute to this variation. METHODS: A retrospective cohort study was performed of 666 male patients (326 blacks and 340 whites), admitted to 1 of 6 Veterans Affairs hospitals from October 1, 1989, to September 30, 1995, with acute myocardial infarction or unstable angina who underwent cardiac catheterization. The primary comparison was whether racial differences in percutaneous transluminal coronary angioplasty and coronary artery bypass grafting rates persisted after stratifying by clinical appropriateness of the procedure, measured by the appropriateness scale developed by the RAND Corporation, Santa Monica, Calif. RESULTS: Whites more often than blacks underwent a revascularization procedure (47% vs 28%). There was substantial variation in black-white odds ratios within different appropriateness categories. Blacks were significantly less likely to undergo percutaneous transluminal coronary angioplasty (odds ratio, 0.30; 95% confidence interval, 0.14-0.63 [P<.01]) when the indication was rated "equivocal." Similarly, blacks were less likely to undergo coronary artery bypass grafting (odds ratio, 0.44; 95% confidence interval, 0.23-0.86 [P<.01]) when only coronary artery bypass grafting was indicated as "appropriate and necessary." Differences in comorbidity or use of cigarettes or alcohol did not explain these variations. Using administrative data from the Veterans Health Administration, we found no differences in 1-year (5.2% vs 7.4%) and 5-year (23.3% vs 26.2%) mortality for blacks vs whites. CONCLUSION: Among patients with acute myocardial infarction or unstable angina, variation in clinical factors using RAND appropriateness criteria for procedures explained some, but not all, racial differences in coronary revascularization use.

Changes in Doppler ultrasound sonagrams at varying distances from stenoses.

The effect of different degrees of arterial stenosis on Doppler ultrasound sonagrams recorded from various distances downstream has been investigated in a canine model. It has been found that even mild stenoses give rise to considerable disturbances close to the stenosis, and that more severe stenoses give rise to greater disturbances which propagate further downstream. The distance the disturbances travelled was not related to stroke volume, and it was only for stenoses of 88% area reduction and greater that such disturbances ever propagated beyond one stroke-length. Quantitative assessment of moderate degrees of proximal stenosis using continuous wave Doppler ultrasound will not be reliable unless the distance between the major stenosis and the recording site is known.

Genetic analysis of the rfbX gene of Shigella flexneri.

Analysis of the nucleotide sequence of the rfbX gene of Shigella flexneri revealed that it contained a high proportion of rare codons, as previously observed in the analysis of the O-antigen polymerase-encoding gene rfc [Morona et al., J. Bacteriol. 176 (1994) 733-747]. The rfbX gene encodes a hydrophobic, 46-kDa protein, with 12 potential transmembrane-spanning domains, that shows structural homology with gene products encoded in many rfb regions, and with Orf0416 of the rff region of Escherichia coli K-12 which has also been identified as a member of this class of proteins. Attempts to clone rfbX independent of other rfb genes, and to identify the protein product of rfbX have proven unsuccessful. Analysis of plasmids containing various deletions within the rfb region suggest that the 5' end of rfbX plays an indirect regulatory role in expression of the dTDP-rhamnose biosynthetic enzymes, encoded by rfbBCAD. We speculate that RfbX is a cytoplasmic membrane protein which functions in the transport of the O-antigen repeat unit.

Frequency of adverse reactions after influenza vaccination.

PURPOSE: Although concern about side effects constitutes a major deterrent to patient compliance with recommendations for influenza vaccination, there is a paucity of data about the frequency of adverse reactions to newer trivalent vaccines. Our aim was to determine the frequency of adverse reactions to influenza vaccine in older, chronically ill persons, many of whom are at high risk for influenza-related morbidity. PATIENTS AND METHODS: We conducted a telephone survey of 40% of the patients who were vaccinated at a walk-in flu shot clinic. The subjects were randomly assigned to two groups. To determine postvaccine symptom rates, Group I was interviewed seven days after vaccination. Group II was interviewed 21 days after vaccination in order to control for baseline symptom rates. Both groups were queried about fever, disability, and flu-like illness in the week preceding the interview. RESULTS: Of 816 patients selected, 650 (79.6%) completed the interview. The mean age of the subjects was 63, and more than two thirds were at risk for influenza-related morbidity. The frequencies of self-reported fever (5.3% versus 5.1%, p = 0.91) and disability (10.4% versus 9.3%, p = 0.65) were similar in the two groups. However, a significantly higher proportion of Group I subjects reported a flu-like illness compared to the Group II subjects (14.2% versus 8.7%, p = 0.03). Although Group I subjects were more likely to report flu-like illness within two days of vaccination compared to a similar time interval for Group II subjects, there was no corresponding clustering of disability after vaccination. CONCLUSION: We conclude that the overall frequency of symptoms in both groups was low; however, the absolute risk of a flu-like illness was 5.5% higher during the first week following influenza vaccination when compared with the third week after the injection. These symptoms did not result in a decreased ability to perform usual daily activities.

Use of the indirect axillary pulse tracing for noninvasive determination of ejection time, upstroke time, and left ventricular wall stress throughout ejection in infants and young children.

The use of indirect axillary pulse tracings was investigated as an alternative method to record the carotid pulse in infants and young children. Simultaneous high-speed recordings of ascending aortic pressure and indirect axillary pulse tracings with noninvasive peripheral blood pressures were recorded in 30 young children (aged 1 day to 48 months, median 9 months) during cardiac catheterization. In 15 patients, simultaneous left ventricular (LV) M-mode echocardiograms and phonocardiograms were also performed. Systolic ejection time (SET) and the half-time of the pulse upstroke determined by both methods were compared. Computer analysis of digitized echocardiographic and pulse tracing data was used to generate plots of LV wall stress throughout ejection. Values for wall stress derived from calibrated indirect axillary pulse tracings were compared with those derived from central aortic pressure. SET calculated from axillary tracings was within 5% of the aortic value in 91% of cases, with a mean error for all subjects of -1 +/- 3%. The half-time of the pulse upstroke was within 15% of the aortic value in 91% of cases, with a mean error for all subjects of 6 +/- 12%. LV wall stress was compared at the onset of ejection, peak wall stress, midsystole, and endsystole for each patient, and 98% of values calculated from axillary data were within 10% of the wall stress values calculated from aortic pressure measurements. Thus, indirect axillary pulse tracings provide an excellent representation of the aortic pressure contour and can be used for accurate calculation of SET.(ABSTRACT TRUNCATED AT 250 WORDS)

Noninvasive determination of systolic, diastolic and end-systolic blood pressure in neonates, infants and young children: comparison with central aortic pressure measurements.

Noninvasive determinations of systolic and diastolic blood pressure using the oscillometric method for pressure measurement were combined with externally recorded axillary pulse tracings to estimate end-systolic pressure in 32 neonates, infants and young children. Results were compared with central aortic pressure measurements made at the time of central aortic catheter placement. Studies were performed in patients aged 1 day to 48 months who weighed 0.9 to 18.1 kg. A wide range of systolic (41 to 141 mm Hg), diastolic (22 to 73 mm Hg) and end-systolic (30 to 111 mm Hg) pressure values were found. The mean absolute pressure differences and percent errors (pressure difference divided by central aortic pressure) were 1.8 mm Hg and 2.5% for systolic, 0.8 mm Hg and 0.8% for diastolic and 1.4 mm Hg and 2.1% for end-systolic pressure. No correlation was noted between percent error and age, weight, heart rate, cardiac index or systemic vascular resistance. The ability to perform reliable noninvasive pressure measurements should prove invaluable for clinical and research purposes. In addition, this method of end-systolic blood pressure determination enables sensitive indexes of left ventricular contractility to be measured noninvasively in small children.

Deciding to restrain medical patients.

To determine when and why patients are placed in mechanical restraints, we surveyed the nurse and physician caring for each of 102 restrained patients from the general medical floors of an acute-care hospital. Ninety-three percent of the questionnaires were completed. Nursing questionnaires indicated that over half of patients were restrained during the evening shift. Nurses initiated the use of restraints in 75% of cases. Fifteen percent of the patients' physicians were unaware that the patient had been restrained. In the majority of cases, the nurse and physician believed that restraint was the best alternative for managing the patient although more physicians (11%) than nurses (2%) thought an alternative intervention would be better (P less than .02). As a group, physicians and nurses restrained patients for similar reasons, most often to prevent falls from bed (69%) or to protect medical devices (36%). However, there was poor agreement between the nurse and physician as to the reason for restraint in an individual patient (kappa statistic range from .02 to .43). These findings suggest that nurse and physician communication regarding restraint is poor. We recommend that acute-care hospitals adopt policies to promote communication between nurses and physicians concerning restraints to ensure that use of this potentially hazardous intervention is used only when necessary.

Biotransformation of genistein in the rat: elucidation of metabolite structure by product ion mass fragmentology.

Biotransformation of the phytoestrogen [14C]genistein was investigated in male and female rats by application of narrow-bore radio-HPLC-MSn (LCQ, Finnigan) to determine intermediates in metabolism. Urine contained five metabolites, Gm1-Gm5, 24 h after dosing by gavage with [14C]genistein (4 mg kg(-1)). Structural analysis following ESI revealed molecular ions [M+H]+ of m/z 447, 449, 273, and 271 for metabolites Gm2, Gm3, Gm5 and genistein, respectively and an [M-H]- of m/z 349 for Gm4. Metabolite structure was deduced by evaluation of product ion spectra derived from unlabelled and [14C]-labelled ions and sensitivity to treatment with beta-glucuronidase. These studies indicated identity of metabolites with genistein glucuronide (Gm2), dihydrogenistein glucuronide (Gm3), genistein sulphate (Gm4) and dihydrogenistein (Gm5). Detection of the beta-glucuronidase resistant major metabolite Gm1 by ESI was poor and so was analysed by negative ion APCI; this revealed a deprotonated molecular ion of m/z 165 which had chromatographic and mass spectral properties consistent with authentic 4-hydroxyphenyl-2-propionic acid, a novel metabolite of genistein. In vitro metabolism studies with anaerobic caecal cultures derived from male and female rats revealed metabolism of genistein to Gm1 via Gm5 and an additional metabolite (Gm6) which was identified from product ion spectra as 6'-hydroxy-O-desmethylangolensin. Biotransformation of genistein by both isolated hepatocytes and precision-cut liver slices was limited to glucuronidation of parent compound. Commonality of genistein metabolites found in rats with those reported in man suggest similar pathways of biotransformation, primarily involving gut micro-flora.

Preoperative laboratory testing: should any tests be "routine" before surgery?

Routine preoperative testing of all patients before elective surgery is unjustified. The frequency of unanticipated abnormalities or abnormalities shown to change patient management is too low to justify a practice pattern of testing all patients. Furthermore, little evidence exists that test result abnormalities are associated with perioperative morbidity. Table 12 lists a compilation of the findings from this article and recommendations regarding routine testing.

Intestinal parasites in returned travelers.

Parasites in the returned traveler can present in any organ system and at time periods quite distant from the activity or geographic exposure that created the risk for infection. All clinicians need to be aware that the most efficient approach to these unusual diseases starts with taking a travel history. The exciting challenge to the diagnostician and the laboratorian is to be able to respond to these clinical demands.