Outcome after liver resection in patients presenting with simultaneous hepatopulmonary colorectal metastases.

BACKGROUND: The most common sites of metastasis from colorectal cancer (CRC) are hepatic and pulmonary; they can present simultaneously (hepatic and pulmonary metastases) or sequentially (hepatic then pulmonary metastases, or vice versa). Simultaneous disease may be aggressive, and thus may be approached with caution by the clinician. The aim of this study was to determine the outcomes following hepatic and pulmonary resection for simultaneously presenting metastatic CRC. METHODS: A retrospective review was undertaken of a prospectively maintained database to identify patients presenting with simultaneous hepatopulmonary disease who underwent hepatic resection. Patients' electronic records were used to identify clinicopathological variables. The log rank test was used to determine survival, and χ(2) analysis to determine predictors of failure of intended treatment. RESULTS: Fifty-nine patients were identified and underwent hepatic resection; median survival was 45·4 months and the 5-year survival rate 38 per cent. Twenty-two patients (37 per cent) did not have the intended pulmonary intervention owing to progression or recurrence of disease. Thirty-seven patients who progressed to hepatopulmonary resection had a median survival of 54·2 months (5-year survival rate 43 per cent). Those who had hepatic resection alone had a median survival of 24·0 months (5-year survival rate 30 per cent). Failure to progress to pulmonary resection was predicted by heavy nodal burden of primary colorectal disease and bilobar hepatic metastases. Redo pulmonary surgery following pulmonary recurrence did not confer a survival benefit. CONCLUSION: Selected patients with simultaneous hepatopulmonary CRC metastases should be considered for attempted curative resection, but some patients may not receive the intended treatment owing to progression of pulmonary disease after hepatic resection.

Prodrug activation in malaria parasites mediated by an imported erythrocyte esterase, acylpeptide hydrolase (APEH).

The continued emergence of antimalarial drug resistance highlights the need to develop new antimalarial therapies. Unfortunately, new drug development is often hampered by poor drug-like properties of lead compounds. Prodrugging temporarily masks undesirable compound features, improving bioavailability and target penetration. We have found that lipophilic diester prodrugs of phosphonic acid antibiotics, such as fosmidomycin, exhibit significantly higher antimalarial potency than their parent compounds (1). However, the activating enzymes for these prodrugs were unknown. Here, we show that an erythrocyte enzyme, acylpeptide hydrolase (APEH) is the major activating enzyme of multiple lipophilic ester prodrugs. Surprisingly, this enzyme is taken up by the malaria parasite, Plasmodium falciparum, where it localizes to the parasite cytoplasm and retains enzymatic activity. Using a novel fluorogenic ester library, we characterize the structure activity relationship of APEH, and compare it to that of P. falciparum esterases. We show that parasite-internalized APEH plays an important role in the activation of substrates with branching at the alpha carbon, in keeping with its exopeptidase activity. Our findings highlight a novel mechanism for antimicrobial prodrug activation, relying on a host-derived enzyme to yield activation at a microbial target. Mutations in prodrug activating enzymes are a common mechanism for antimicrobial drug resistance (2-4). Leveraging an internalized host enzyme would circumvent this, enabling the design of prodrugs with higher barriers to drug resistance.

Meta-analysis of prospective trials determining the short- and mid-term effect of elective open and endovascular repair of abdominal aortic aneurysms on quality of life.

BACKGROUND: Repair of an abdominal aortic aneurysm (AAA) is undertaken to prevent rupture. Intervention is by either open repair (OR) or a more minimally invasive endovascular repair (EVAR). Quality-of-life (QoL) analysis is an important health outcome and a number of single studies have assessed QoL following OR and EVAR. This was a meta-analysis of published studies to assess the effect of an intervention on QoL in patients with an AAA. METHODS: A systematic literature search was undertaken for studies prospectively reporting QoL analysis in patients with an AAA undergoing elective intervention. A multivariable meta-analysis model was developed in which the outcomes were mean changes in QoL scores over time, both for all AAA repairs (OR and EVAR) and comparing OR with EVAR. RESULTS: Data were collated from 16 studies (14 OR, 12 EVAR). The results suggested that treating an AAA had an effect on patient-reported QoL, evident from the statistically significant changes predominantly in domains assessing physical ability and pain. QoL was affected most within the first 3 months after any form of intervention, and was more pronounced following OR. Furthermore, a deterioration in the Physical Component Summary score following an AAA repair (either OR or EVAR) was evident at 12 months after intervention. CONCLUSION: Treating an AAA deleteriously affects patient-reported QoL over the first year following intervention.

Simultaneous determination of electrical conductivity and thickness of nonmagnetic metallic foils using two-sided multifrequency eddy current techniques.

In this paper, we describe a simple method for performing multifrequency eddy current characterization of free-standing uniform-thickness metallic foils using a forked inductive coil arrangement. The method involves measuring the mutual inductance between two coils when a foil is present between the coils, and when it is not present; the ratio of these mutual inductances is compared with an analytical solution, and foil conductivity, thickness, and sheet resistance are simultaneously estimated using numerical inversion and least-squares fitting. This method was used to characterize 34 non-ferrous metallic samples with thicknesses between 50 and 640 µm and with conductivities between 0.8 × 107 and 5.8 × 107 S/m. The estimated thicknesses from eddy current characterization agreed well with those measured using confocal optical techniques; the two approaches agreed to within 1 µm for samples that were thinner than 200 µm, and to within 0.5% for samples that had a thickness of 200 µm or greater. The estimated conductivities from eddy current characterization were in close agreement with expected values, given knowledge of the materials used. A particular strength of this approach is that the instrumentation needed is broadly available in research and development laboratories and the associated fixturing is easy to manufacture and assemble. A calibration procedure is described that can be used to reduce errors from geometric uncertainties. This calibration requires a sample that has only a known conductivity or thickness; both do not need to be known. The method described herein is likely extensible to conductivities and thickness well outside the ranges measured as part of this work.

Hindlimb response to tactile stimulation of the pastern and coronet.

REASONS FOR PERFORMING STUDY: Lightweight tactile stimulators attached to the hind pasterns increase the height of the hind hoof flight arc but details of the induced changes in swing phase kinematics and kinetics have not been investigated. HYPOTHESES: Stimulators on the hind pasterns are associated with increased hindlimb joint flexions and increased positive work performed by the hip and tarsal musculature. MATERIALS AND METHODS: Nine nonlame horses trotted 4 times with and without 55 g tactile stimulators loosely attached around the hind pasterns. Height of the flight arc and peak flexion angles of the hindlimb joints were measured and net positive and negative work performed across each joint during the swing phase were calculated using inverse dynamics analysis and compared across paired conditions. RESULTS: Speed and stride duration did not change but stimulators were associated with a reduction in hind stance duration. The flight arc was higher with stimulators due to increased flexions of the stifle, tarsal, metatarsophalangeal and distal interphalangeal joints. Positive work increased in the tarsal musculature, but not in the hip musculature, and negative work increased across the stifle, metatarsophalangeal and distal interphalangeal joints. POTENTIAL RELEVANCE: The effects of tactile stimulation of the hind pasterns on joint motion and muscle activation may be used in physiotherapy and rehabilitation to restore or increase flexion of the hindlimb joints with the exception of the hip joint. The ability to stimulate concentric activity of the tarsal musculature may have therapeutic applications in conditions such as toe dragging.

Type A behavior and elevated physiological and neuroendocrine responses to cognitive tasks.

Qualitatively distinct patterns of cardiovascular and neuroendocrine responses were observed in male college students during mental work and during sensory intake task performance. During mental work, Type A (coronary-prone) subjects showed greater muscle vasodilatation and more enhanced secretion of norepinephrine, epinephrine, and cortisol than Type B subjects. During sensory intake, Type A hyperresponsivity was found for testosterone and, among those subjects with a positive family history of hypertension, for cortisol. As a demonstration of combined cardiovascular, sympathetic nervous system, and neuroendocrine hyperresponsivity to specific cognitive tasks in Type A subjects, this study breaks ground in the search for mechanisms mediating the increased coronary disease risk among Type A persons.

Short-term habituation of equine limb kinematics to tactile stimulation of the coronet.

UNLABELLED: A lightweight bracelet that provides tactile stimulation to the horse's pastern and coronet induces a higher flight arc of the hoof. This study addresses the pattern of habituation to these devices. OBJECTIVE: To evaluate short-term habituation to tactile stimulation of the pastern and coronet in trotting horses. METHODS: Tactile stimulation was provided by a lightweight (55 g) device consisting of a strap with seven chains that was attached loosely around the pastern. Reflective markers were fixed to the dorsal hoof wall, the forehead and over the tenth thoracic vertebra of eight sound horses. The horses trotted in hand 10 times at a consistent velocity along a 30 m runway under three conditions applied in random order at two-hour intervals: no stimulators, stimulators on both front hooves or stimulators on both hind hooves. One stride per trial was analyzed to determine peak hoof heights in the swing phase. Sequential trials with stimulators were compared with unstimulated trials using a nested ANCOVA and Bonferronni's post hoc test (P < 0.005). RESULTS: Peak hind hoof height increased significantly for all 10 trials when wearing hind stimulators, whereas peak fore hoof height increased during the first six trials only when wearing fore stimulators. The first trial with stimulators showed the greatest elevation, followed by a rapid decrease over the next three trials and then a more gradual decrease. CONCLUSIONS: If the goal is to facilitate a generalized muscular response, a short burst of tactile stimulation is likely to be most effective, whereas longer periods of stimulation will be more effective for strength training.

An aerosol challenge model of tuberculosis in Mauritian cynomolgus macaques.

BACKGROUND: New interventions for tuberculosis are urgently needed. Non-human primate (NHP) models provide the most relevant pre-clinical models of human disease and play a critical role in vaccine development. Models utilising Asian cynomolgus macaque populations are well established but the restricted genetic diversity of the Mauritian cynomolgus macaques may be of added value. METHODS: Mauritian cynomolgus macaques were exposed to a range of doses of M. tuberculosis delivered by aerosol, and the outcome was assessed using clinical, imaging and pathology-based measures. RESULTS: All macaques developed characteristic clinical signs and disease features of tuberculosis (TB). Disease burden and the ability to control disease were dependent on exposure dose. Mauritian cynomolgus macaques showed less variation in pulmonary disease burden and total gross pathology scores within exposure dose groups than either Indian rhesus macaques or Chinese cynomolgus macaques. CONCLUSIONS: The genetic homogeneity of Mauritian cynomolgus macaques makes them a potentially useful model of human tuberculosis.

Therapeutic potential of ACAT inhibitors as lipid lowering and anti-atherosclerotic agents.

Hypercholesterolemia is one of the few independent risk factors definitively linked to increased morbidity and mortality due to myocardial infarction. One possible therapy of current interest is the prevention of the absorption of dietary cholesterol by inhibiting the enzyme, acyl-CoA: cholesterol acyltransferase (ACAT), which catalyses the intracellular formation of cholesterol esters. Evidence is now accumulating that suggests that ACAT inhibition may not only lower plasma cholesterol levels, but may also have a direct effect at the artery wall, where ACAT has been shown to be responsible for the accumulation of cholesterol esters in arterial lesions. Drago Sliskovic and Andrew White discuss the importance of ACAT in the lipid transport system and the consequences of its inhibition in a variety of tissues, with emphasis on both lipid-lowering and anti-atherosclerotic effects.

Inconsistent reporting of minimally invasive surgery errors.

INTRODUCTION: Minimally invasive surgery (MIS) is a complex task requiring dexterity and high level cognitive function. Unlike surgical 'never events', potentially important (and frequent) manual or cognitive slips ('technical errors') are underresearched. Little is known about the occurrence of routine errors in MIS, their relationship to patient outcome, and whether they are reported accurately and/or consistently. METHODS: An electronic survey was sent to all members of the Association of Surgeons of Great Britain and Ireland, gathering demographic information, experience and reporting of MIS errors, and a rating of factors affecting error prevalence. RESULTS: Of 249 responses, 203 completed more than 80% of the questions regarding the surgery they had performed in the preceding 12 months. Of these, 47% reported a significant error in their own performance and 75% were aware of a colleague experiencing error. Technical skill, knowledge, situational awareness and decision making were all identified as particularly important for avoiding errors in MIS. Reporting of errors was variable: 15% did not necessarily report an intraoperative error to a patient while 50% did not consistently report at an institutional level. Critically, 12% of surgeons were unaware of the procedure for reporting a technical error and 59% felt guidance is needed. Overall, 40% believed a confidential reporting system would increase their likelihood of reporting an error. CONCLUSION: These data indicate inconsistent reporting of operative errors, and highlight the need to better understand how and why technical errors occur in MIS. A confidential 'no blame' reporting system might help improve patient outcomes and avoid a closed culture that can undermine public confidence.

Evaluation of the Immunogenicity of Mycobacterium bovis BCG Delivered by Aerosol to the Lungs of Macaques.

Nine million cases of tuberculosis (TB) were reported in 2013, with a further 1.5 million deaths attributed to the disease. When delivered as an intradermal (i.d.) injection, the Mycobacterium bovis BCG vaccine provides limited protection, whereas aerosol delivery has been shown to enhance efficacy in experimental models. In this study, we used the rhesus macaque model to characterize the mucosal and systemic immune response induced by aerosol-delivered BCG vaccine. Aerosol delivery of BCG induced both Th1 and Th17 cytokine responses. Polyfunctional CD4 T cells were detected in bronchoalveolar lavage (BAL) fluid and peripheral blood mononuclear cells (PBMCs) 8 weeks following vaccination in a dose-dependent manner. A similar trend was seen in peripheral gamma interferon (IFN-γ) spot-forming units measured by enzyme-linked immunosorbent spot (ELISpot) assay and serum anti-purified protein derivative (PPD) IgG levels. CD8 T cells predominantly expressed cytokines individually, with pronounced tumor necrosis factor alpha (TNF-α) production by BAL fluid cells. T-cell memory phenotype analysis revealed that CD4 and CD8 populations isolated from BAL fluid samples were polarized toward an effector memory phenotype, whereas the frequencies of peripheral central memory T cells increased significantly and remained elevated following aerosol vaccination. Expression patterns of the α4ß1 integrin lung homing markers remained consistently high on CD4 and CD8 T cells isolated from BAL fluid and varied on peripheral T cells. This characterization of aerosol BCG vaccination highlights features of the resulting mycobacterium-specific immune response that may contribute to the enhanced protection previously reported in aerosol BCG vaccination studies and will inform future studies involving vaccines delivered to the mucosal surfaces of the lung.

X-ray structure of human stromelysin catalytic domain complexed with nonpeptide inhibitors: implications for inhibitor selectivity.

Effective inhibitors of matrix metalloproteinases (MMPs), a family of connective tissue-degrading enzymes, could be useful for the treatment of diseases such as cancer, multiple sclerosis, and arthritis. Many of the known MMP inhibitors are derived from peptide substrates, with high potency in vitro but little selectivity among MMPs and poor bioavailability. We have discovered nonpeptidic MMP inhibitors with improved properties, and report here the crystal structures of human stromelysin-1 catalytic domain (SCD) complexed with four of these inhibitors. The structures were determined and refined at resolutions ranging from 1.64 to 2.0 A. Each inhibitor binds in the active site of SCD such that a bulky diphenyl piperidine moiety penetrates a deep, predominantly hydrophobic S'1 pocket. The active site structure of the SCD is similar in all four inhibitor complexes, but differs substantially from the peptide hydroxamate complex, which has a smaller side chain bound in the S'1 pocket. The largest differences occur in the loop forming the "top" of this pocket. The occupation of these nonpeptidic inhibitors in the S'1 pocket provides a structural basis to explain their selectivity among MMPs. An analysis of the unique binding mode predicts structural modifications to design improved MMP inhibitors.

Heterocyclic amides: inhibitors of acyl-CoA:cholesterol O-acyl transferase with hypocholesterolemic activity in several species and antiatherosclerotic activity in the rabbit.

A series of heterocyclic amides were synthesized and evaluated as inhibitors of acyl-CoA: cholesterol O-acyltransferase (ACAT) in vitro and for cholesterol lowering in cholesterol-fed rats. Compounds were evaluated for cell-based macrophage ACAT inhibition, bioactivity, and adrenal toxicity. Candidates were selected for evaluation in cholesterol-fed dogs and, ultimately, the injured cholesterol-fed rabbit model of atherosclerosis. The heterocyclic amides potently inhibited rabbit liver ACAT (IC50's = 0.014-0.11 microM), and the majority of compounds significantly lowered plasma cholesterol (42-68%) in an acute cholesterol-fed rat model at 3 mg/kg. The most efficacious compounds in the rat were evaluated for bioactivity in vivo and arterial ACAT inhibition in a cell-based macrophage ACAT assay. Two highly bioactive analogs, (+/-)-2-(3-dodecylisoxazol-5-yl)-2-phenyl-N-(2,4,6-trimethoxypheny l) acetamide (13a) and (+/-)-2-(5-dodecylisoxazol-3-yl)-2-phenyl-N-(2,4,6-trimethoxypheny l) acetamide (16a), were selected for further study and were found to be nontoxic in a guinea pig model of adrenal toxicity. Compounds 13a and 16a lowered total cholesterol in the cholesterol-fed rat, rabbit, and dog models of pre-established hypercholesterolemia. Compound 13a in the injured cholesterol-fed rabbit model of atherosclerosis was effective in slowing the development of cholesteryl ester-rich thoracic aortic lesions, reducing lesion coverage by 53% at a dose of 1 mg/kg.

Heterocyclic ureas: inhibitors of acyl-CoA:cholesterol O-acyltransferase as hypocholesterolemic agents.

A series of diaryl-substituted heterocyclic ureas was prepared, and their ability to inhibit acyl-CoA: cholesterol O-acyltransferase (ACAT) in vitro and to lower plasma total cholesterol in cholesterol-fed animal models in vivo was examined. N-(2,6-Diisopropylphenyl)-N'-tetrazole or isoxazole-substituted heterocyclic ureas proved optimal. A carbon chain of 11-14 carbons substituted 1,3 with respect to the amine provided the optimal side chain. Substitution of the alkyl chain generally lowered activity. Tetrazole urea 2i dosed at 3 mg/kg lowered plasma total cholesterol (TC) 67% in an acute, cholesterol-fed (C-fed) rat model of hypercholesterolemia and 47% in C-fed dogs. Tetrazole 2i, dosed at 10 mg/kg, also lowered TC 52% and raised HDL cholesterol 113% in rats with pre-established hypercholesterolemia.

Inhibitors of acyl-CoA:cholesterol O-acyltransferase. synthesis and pharmacological activity of (+/-)-2-dodecyl-alpha-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5- acetamide and structurally related tetrazole amide derivatives.

A series of tetrazole amide derivatives of (+/-)-2-dodecyl-alpha-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5- acetamide (1) was prepared and evaluated for their ability to inhibit acyl-CoA: cholesterol O-acyltransferase (ACAT) in vitro and to lower plasma total cholesterol in vivo. For this series of compounds, our objective was to systematically replace substituents appended to the amide and tetrazole moieties of 1 with structurally diverse functionalities and assess the effect that these changes have on biological activity. The ensuing structure-activity relationship (SAR) studies identified aryl (7b) and heteroaryl (7f,g) replacements for 2,4,6-trimethoxyphenyl that potently inhibit liver microsomal and macrophage ACAT in vitro and exhibit good cholesterol lowering activity (56-66% decreases in plasma total cholesterol at 30 mg/kg), relative to 1, when compared in the acute rat model of hypercholesterolemia. Replacement of the alpha-phenyl moiety with electron-withdrawing substituents (13e-h), however, significantly reduced liver microsomal ACAT inhibitory activity (IC50 > 1 microM). This is in contrast to electron-donating substituents (13ij,m-q), which produce IC50 values ranging from 5 to 75 nM in the hepatic microsomal assay. For selected tetrazole amides (1, 7b, 13n,o), reversing the order of substituents appended to the 2- and 5-positions in the tetrazole ring (36a-d), in general, improved macrophage ACAT inhibitory activity and provided excellent cholesterol-lowering activity (ranging from 65% to 77% decreases in plasma total cholesterol at 30 mg/kg) in the acute rat screen. The most potent isomeric pair in this set of unsubstituted methylene derivatives (13n and 36a) caused adrenocortical cell degeneration in guinea pigs treated with these inhibitors. In contrast, adrenal glands taken from guinea pigs treated with the corresponding alpha-phenyl-substituted analogs (7b and 36c) were essentially unchanged compared to untreated controls. Subsequent evaluation of 7b and 36c in a rabbit bioassay showed that both compounds and/or their metabolities were present in plasma after oral dosing. Unlike 7b and 36c, compound 1 and related 2,4,6-trimethoxyanilides (13j, 30c,d) showed poor oral activity in the rabbit bioassay. Nevertheless, in cholesterol-fed rabbits, both systemically available (7b, 36c) and poorly absorbed inhibitors (1, 36d) were more effective in lowering plasma total cholesterol than the fatty acid amide CI-976.

Serum cholesterol and 20-year mortality in black and white men and women aged 65 and older in the Evans County Heart Study.

Serum cholesterol and 20-year mortality rates were studied in 396 Evans County black and white men and women who were 65 years and older and free of prevalent coronary heart disease (CHD) at baseline examination in 1960 to 1962. Previous reports on Evans County men and women younger than 65 found cholesterol levels to be significantly associated with all-cause and CHD mortality in white men, with CHD mortality in black men, and with cardiovascular disease mortality in white women. The independent role of total serum cholesterol as a predictor of CHD and all-cause mortality in the 65-and-older age group was evaluated using Cox proportional hazards models. Among white men, serum cholesterol level was positively associated with CHD mortality (relative risk of 1.54, P < 0.05 for an increment of 40 mg/dL [1.03 mmol/L], or one standard deviation in cholesterol). A significant J-shaped relationship of cholesterol with all-cause mortality was found among white men. Among black women, cholesterol was negatively associated with all-cause mortality. Neither all-cause nor CHD mortality was related to serum cholesterol among black men or white women. Although based on small numbers, the results of this study suggest that in Evans County, total serum cholesterol is an independent predictor of mortality in white men aged 65 and over, while these results should not be generalized to other race-gender groups in this cohort.

Community surveillance of coronary heart disease in the Atherosclerosis Risk in Communities (ARIC) Study: methods and initial two years' experience.

The community surveillance component of the Atherosclerosis Risk in Communities (ARIC) Study is designed to estimate patterns and trends of coronary heart disease (CHD) incidence, case fatality, and mortality in four U.S. communities. Community surveillance involves ongoing review of death certificates and hospital discharge records to identify CHD events in community residents aged 35-74 years. Interviews with next of kin and questionnaires completed by physicians and medical examiners or coroners were used to collect information on deaths, and review and abstraction of hospital records were used to collect information on possible fatal and nonfatal myocardial infarctions (MIs). Events were classified using standardized criteria. The initial 2-years' experience with case ascertainment and availability of information needed for classification of events is described. Average annual age-adjusted attack rates of definite MI and CHD mortality rates for blacks in two communities and whites in the four communities are presented and compared with rates based on unvalidated hospital discharge data and vital statistics. Age-adjusted rates based on ARIC classification of definite MI were lower than those based on hospital discharge diagnosis code 410 (e.g., 5.60/1000 and 11.50/1000 among Forsyth County white men, respectively). Age-adjusted rates of definite fatal CHD based on ARIC classification were similarly lower than rates based on underlying cause of death code 410; for example, Jackson black men had rates of 2.82/1000 and 4.52/1000 for definite fatal CHD and UCOD 410-414 or 429.2, respectively.

Experience of healthcare workers taking postexposure prophylaxis after occupational HIV exposures: findings of the HIV Postexposure Prophylaxis Registry.

OBJECTIVE: To collect information about the safety of taking antiretroviral drugs for human immunodeficiency virus (HIV) postexposure prophylaxis (PEP). DESIGN: A voluntary, confidential registry. SETTING: Hospital occupational health clinics, emergency departments, private physician offices, and health departments in the United States. RESULTS: 492 healthcare workers (HCWs) who had occupational exposures to HIV, were prescribed HIV PEP, and agreed to be enrolled in the registry by their healthcare providers were prospectively enrolled in the registry. Three hundred eight (63%) of 492 of the PEP regimens prescribed for these HCWs consisted of at least three antiretroviral agents. Of the 449 HCWs for whom 6-week follow-up was available, 195 (43%) completed the PEP regimen as initially prescribed. Forty-four percent (n=197) of HCWs discontinued all PEP drugs and did not complete a PEP regimen. Thirteen percent (n=57) discontinued > or =1 drug or modified drug dosage or added a drug but did complete a course of PEP Among the 254 HCWs who modified or discontinued the PEP regimen, the two most common reasons for doing so were because of adverse effects attributed to PEP (54%) and because the source-patient turned out to be HIV-negative (38%). Overall, 340 (76%) HCWs with 6-week follow-up reported some symptoms while on PEP: nausea (57%), fatigue or malaise (38%), headache (18%), vomiting (16%), diarrhea (14%), and myalgias or arthralgias (6%). The median time from start of PEP to onset of each of the five most frequently reported symptoms was 3 to 4 days. Only 37 (8%) HCWs with 6-week follow-up were reported to have laboratory abnormalities; review of the reported abnormalities revealed that most were unremarkable. Serious adverse events were reported to the registry for 6 HCWs; all but one event resolved by the 6-month follow-up visit. Fewer side effects were reported by HCWs taking two-drug PEP regimens than by HCWs taking three-drug PEP regimens. CONCLUSIONS: Side effects from HIV PEP were very common but were rarely severe or serious. The nature and frequency of HIV PEP toxicity were consistent with information already available on the use of these antiretroviral agents. Clinicians prescribing HIV PEP need to counsel HCWs about PEP side effects and should know how to manage PEP toxicity when it arises.

Peripheral blood chromosome aberrations in MDS.

The frequency of non-clonal structural and numerical chromosome aberrations in peripheral blood lymphocytes of 51 patients with MDS and 37 age-matched hematologically normal subjects is assessed. The frequency of aneuploid cells (p less than 0.001) and of structural aberrations (p less than 0.005) was significantly higher in MDS patients than in normal subjects, but showed no relationship with FAB type or with the presence of clonal karyotype abnormalities in the bone marrow. Exchange configurations were only observed in MDS patients (27.5%). The data also suggest that there may be an association between high peripheral blood aberration levels and rapidly progressive disease. This may indicate increased mutagen sensitivity and have implications for treatment.

Isochromosome (6p) in Waldenstrom's macroglobulinemia.

Cytogenetic data on two cases of previously treated Waldenstrom's macroglobulinemia (WM) are presented. An i(6p) was identified in 60 and 56% of bone marrow (BM) metaphases from each patient, respectively. In both cases, i(6p) occurred as part of a complex karyotype but was also observed as the sole abnormality in a proportion of metaphases. The literature on the cytogenetics of WM and the relevance of i(6p) is discussed.