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After the completion of a draft human genome sequence, the International Human Genome Sequencing Consortium has proceeded to finish and annotate each of the 24 chromosomes comprising the human genome. Here we describe the sequencing and analysis of human chromosome 3, one of the largest human chromosomes. Chromosome 3 comprises just four contigs, one of which currently represents the longest unbroken stretch of finished DNA sequence known so far. The chromosome is remarkable in having the lowest rate of segmental duplication in the genome. It also includes a chemokine receptor gene cluster as well as numerous loci involved in multiple human cancers such as the gene encoding FHIT, which contains the most common constitutive fragile site in the genome, FRA3B. Using genomic sequence from chimpanzee and rhesus macaque, we were able to characterize the breakpoints defining a large pericentric inversion that occurred some time after the split of Homininae from Ponginae, and propose an evolutionary history of the inversion.

Human chromosome 12 contains more than 1,400 coding genes and 487 loci that have been directly implicated in human disease. The q arm of chromosome 12 contains one of the largest blocks of linkage disequilibrium found in the human genome. Here we present the finished sequence of human chromosome 12, which has been finished to high quality and spans approximately 132 megabases, representing approximately 4.5% of the human genome. Alignment of the human chromosome 12 sequence across vertebrates reveals the origin of individual segments in chicken, and a unique history of rearrangement through rodent and primate lineages. The rate of base substitutions in recent evolutionary history shows an overall slowing in hominids compared with primates and rodents.

Objective: Anastomotic leak post-gastro-esophagectomy for esophageal carcinoma remains an important issue in immediate as well as late morbidity and mortality. Several predictive factors such as patient and technical variables have been suggested with inconsistent findings. Our aim was to compare these factors and the results of treatment of anastomotic dehiscence on short and longterm survival in our center to published data., Methods: A retrospective study of 276 consecutive patients post-Ivor-Lewis gastro-esophagogastrectomy for esophageal carcinoma between 1992 and 1999. Explanatory variables taken into account for predicting anastomotic leak included preoperative weight loss, neoadjuvant therapy, inkwelling of the anastomosis, gastric drainage procedure and involvement of longitudinal resection margins. Incidence variation over time was compared. 5-year survival was assessed using the Kaplan-Meier method., Results: The anastomotic leak rate was 5.1% with only minor variation over time. The 30-day mortality with anastomotic leak was 35.7% compared to 4.2% for patients without leak (P<0.05). None of the suggested explanatory variables analyzed reached statistical significance at a 5% level. On multiple logistic regression there was a trend towards gastric outlet drainage procedure which might decrease the relative risk by 61% (P=0.099). After excluding the 30-day mortality the 5-year survival with anastomotic leak was not different to those without., Conclusions: None of the factors reported in the literature reached statistical significance in our series. High institutional and high surgeon volume seem to outweigh any other contributing factor. Aggressive management for substantial leaks is advocated by the authors as long term palliation does not seem to be affected once the leak has been successfully treated.

Objective: To compare the effects of inhaled corticosteroid treatment with leukotriene modifier treatment on medical resource use and costs for asthma patients., Study Design: Meta-analysis combining results from published and unpublished studies., Data Sources: Studies were identified from the MEDLINE and EMBASE databases and the GlaxoSmithKline internal database study registers. Two independent reviewers evaluated the identified studies; studies meeting specified inclusion criteria were abstracted and summarized by meta-analysis with a random effects model., Outcomes Measured: Hospitalization rate, emergency department visit rate, emergency department costs, drug costs, total asthma-related costs, and total medical care costs., Results: Patients taking inhaled corticosteroids had: a significantly lower annual rate of hospitalization than those taking leukotriene modifiers (2.2% vs 4.3%, respectively; P<.05); a greater decline in hospitalization rate (before vs after therapy initiation) than those taking leukotriene modifiers (decline of 2.4% vs 0.55%; P<.01); a lower annual rate of emergency department visits than those taking leukotriene modifiers (6.2% vs 7.7%; P<.005); lower total asthma-related medical costs than those taking leukotriene modifiers (P<.05) and a 17% reduction in overall total medical care costs (P not significant)., Conclusions: Patients with asthma treated with inhaled corticosteroids have significantly fewer asthma-related hospitalizations and emergency department visits and lower total asthma-related health care costs than patients treated with leukotriene modifiers. These meta-analysis findings are consistent with results from randomized controlled trials showing improvements in lung function for patients taking inhaled corticosteroids as opposed to leukotriene modifiers.

Objective: We estimate long-term health care costs of former smokers compared with continuing and never smokers using a retrospective cohort study of HMO enrollees. Previous research on health care costs associated with former smokers has suggested that quitters may incur greater health care costs than continuing smokers, therefore, getting people to quit creates more expensive health care consumers. We studied the trend in cost for former smokers over seven years after they quit to assess how the cessation experience impacts total health care cost., Data Sources/study Setting: Group Health Cooperative (GHC), a nonprofit mixed model health maintenance organization in western Washington state., Study Design: Retrospective cohort study using automated and primary data collected through telephone interviews., Principal Findings: We find that former smokers' costs are significantly greater (p<.05) in the year immediately following cessation relative to continuing smokers, but former smokers' costs fall in year two. This decrease maintains throughout the six-year follow-up period. Although former smokers cost more than continuing smokers in the year after cessation, this increase appears to be transient. Long-term costs for former smokers are not statistically different from those of continuing smokers and cumulative health care expenses are lower by the seventh year postquit. Our evidence suggests that smoking cessation does not increase long-term heath care costs., Conclusions: Health care costs among former smokers increase relative to continuing smokers in the year after cessation but fall to a level that is statistically indistinguishable in the second year postquit. Any net increase in costs among former smokers relative to continuing smokers appears compensated for within two years post-quit and is maintained for at least six years after cessation.

Objective: To review the evidence regarding antidepressant-induced sexual dysfunction and address implications for treatment strategy and health plan coverage policies for antidepressant medications., Data Sources: Primary articles were identified by a MEDLINE and HealthSTAR search to identify English-language studies published between January 1986 and July 2000. Search terms included sexual dysfunction or sexual function and antidepressants, fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, venlafaxine, nefazodone, bupropion, and mirtazapine. A cross-check of references cited in 10 published reviews yielded additional in-scope articles., Study Selection and Data Extraction: Approximately 200 articles were identified, including 8 randomized controlled trials and numerous open-label studies, case series, and case reports. Of the randomized controlled trials, only 5 were designed to evaluate the incidence of sexual dysfunction associated with antidepressant treatment. Three additional randomized controlled trials included a structured assessment of sexual dysfunction within an efficacy trial. Data extraction excluded case reports, letters, and other limited study designs. A panel survey augmented published reports., Data Synthesis: Sexual dysfunction is a relatively common adverse effect of many of the antidepressants in common use today. Rates of sexual dysfunction observed in clinical practice may be higher than those reported in the product information for several agents. Selective serotonin-reuptake inhibitors (SSRIs) appear to be the class of antidepressants most likely to cause sexual dysfunction. Published studies suggest that between 30% and 60% of SSRI-treated patients may experience some form of treatment-induced sexual dysfunction. Bupropion and nefazodone appear to be much less likely to cause sexual dysfunction (

Background: Although recurrent major depression in elderly individuals is a disabling condition, only a few studies have systematically examined the magnitude and specificity of quality-of-life (QOL) impairments in such patients in comparison with matched controls or the elderly population., Methods: We examined the variations in QOL scores of 100 elderly (age range 60-88 years) patients with moderate to severe recurrent major depression and compared them with published elderly population norms. Disease-specific Quality of Life in Depression Scale (QLDS) and generic Medical Outcomes Short Form-36 Health Survey (SF-36) QOL ratings obtained at baseline were analyzed., Results: Compared with published elderly population norms, depressed subjects showed significant QOL impairments in five of eight baseline SF-36 items (p <.01). Women rated their QOL as worse than men on physical functioning and role physical (p <.01) and showed similar trends on all other QOL items. Compared with younger subjects, subjects aged older than 70 years reported lower QOL on the summary physical component (p <.01) and a trend for higher QOL on the summary mental component (p <.05) of the SF-36. Depression symptom ratings were correlated with some QOL measures, but accounted for less than 10% of the variance., Conclusions: Despite limitations, such as a cross-sectional design and indirect comparisons with norms generated from another study, our findings confirm the disabling nature of recurrent late-life depression and the importance of targeting both depressive symptoms and broader QOL outcomes in intervention trials.

Objectives: To: evaluate the impact of smoking status on objective productivity and absenteeism measures; evaluate the impact of smoking status on subjective measures of productivity; and assess the correlation between subjective and objective productivity measures., Design: Prospective cohort study in a workplace environment., Subjects: Approximately 300 employees (100 each of former, current, and never smokers) at a reservation office of a large US airline., Main Outcome Measures: Objective productivity and absenteeism data were supplied by the employer. Subjective assessments of productivity were collected using a self report instrument, the Health and Work Questionnaire (HWQ)., Results: Current smokers had significantly greater absenteeism than did never smokers, with former smokers having intermediate values; among former smokers, absenteeism showed a significant decline with years following cessation. Former smokers showed an increase in seven of 10 objective productivity measures as compared to current smokers, with a mean increase of 4.5%. While objective productivity measures for former smokers decreased compared to measures for current smokers during the first year following cessation, values for former smokers were greater than those for current smokers by 1-4 years following cessation. Subjective assessments of "productivity evaluation by others" and "personal life satisfaction" showed significant trends with highest values for never smokers, lowest for current smokers, and intermediate for former smokers., Conclusions: Workplace productivity is increased and absenteeism is decreased among former smokers as compared to current smokers. Productivity among former smokers increases over time toward values seen among never smokers. Subjective measures of productivity provide indications of novel ways of productivity assessment that are sensitive to smoking status.

The authors examined patterns of improvement in quality of life (QOL) in elderly patients with recurrent major depression (MDD) after acute treatment. One hundred elderly (age 60-88 years) patients with recurrent MDD were randomized to receive either bupropion sustained-release (100 mg-300 mg/day) or paroxetine (10 mg-40 mg/day) for 6 weeks. Treatment with both paroxetine and bupropion was associated with improvements in QOL. Lower perceived Physical- and Social-Functioning QOL ratings at baseline were associated with lower treatment response. Improvement in depression symptom ratings correlated significantly with improvement in QOL on many domains, but accounted for less than one-quarter of the total variance. Remitters showed significantly (P<0.001) greater improvement than both Partial Responders and Nonresponders on various measures. Findings support the importance of treating elderly depressed patients to full remission to maximize impact on both emotional and physical QOL domains.

Objective: The objective of this study was to evaluate the health care costs associated with the treatment of a new episode of depression with bupropion sustained release (SR) rather than with other antidepressants (selective serotonin reuptake inhibitors [SSRIs], tricyclic antidepressants [TCAs], and serotonin norepinephrine reuptake inhibitors [SNRIs])., Methods: This was a retrospective cohort study based on the private-pay, fee-for-service 1997 and 1998 MEDSTAT MarketScan databases. Individuals were included if they were 18 years of age or older, had an initial prescription for an antidepressant under study with an index prescription date between July 1997 and June 1998, and had a claim for a diagnosis of depression diagnosis within 30 days of the index date. All patients' claims from six months before and after receiving their index antidepressant prescription were examined. Total, outpatient, and pharmacy costs were compared among antidepressant groups using an intent-to-treat analysis with exponential regression models and bootstrapped 95% confidence intervals., Results: A total of 1771 patients were included in the study cohort. The mean age was 41.6 years, and 69.5% of subjects were female. Most patients (75%) continued with the index antidepressant during the 6-month follow-up period. Although the drug acquisition cost was lowest for TCAs, total costs were significantly higher for patients treated with TCAs than for those treated with bupropion SR (p < .05). In comparison with bupropion SR, patients initiating therapy with sertraline had significantly higher mental health payments (p < .05)., Conclusions: Initiating treatment of depression with bupropion SR was associated with lower total mental health care costs compared with TCAs and with sertraline. This study reaffirms that formulary and medical decision-makers should consider the overall impact of antidepressant treatment, including but not limited to drug acquisition costs, other health care costs, and drug efficacy and safety.

Direct medical costs and medically related transportation costs incurred by patients in long-term-care facilities (LTCFs) as a result of influenza-like illness (ILI) were studied. The study was conducted from the payer's perspective. Charts were reviewed retrospectively for all patients who were residents of four Richmond, Virginia, LTCFs between January 1 and May 31, 1999. Consultant pharmacists gathered data on patient demographics, ILI status, vaccination for influenza and streptococcal pneumonia, diagnosis of asthma or chronic obstructive pulmonary disease, and utilization of health care services related to ILI. Services included the use of antimicrobials, antivirals, and respiratory drugs; emergency room visits; diagnostic tests; hospitalizations; and medically related transportation. Costs were based on average wholesale prices (for drugs) and Medicare or Medicaid reimbursement rates. Data were collected for 551 patients. Of these, 112 patients had been diagnosed with 128 cases of ILI during the study period. Twenty-two patients with ILI had 28 visits to emergency rooms, and 30 patients with ILI had 36 hospitalizations. The mean +/- S.D. cost per case of ILI was $1341 +/- $2063; inpatient hospital costs accounted for 84% of this amount. Centers for Disease Control and Prevention criteria for ILI provided a lower incidence of ILI and, consequently, a lower mean +/- S.D. cost of $968 +/- $1806 per case. ILI in patients in four LTCFs in Richmond, Virginia, generated substantial costs, the bulk of which resulted from hospitalization. A substantial percentage of the patients apparently were not immunized.

BACKGROUND: This open-label portion of a 2-phase study assessed the effects of the antidepressant bupropion sustained release (SR) on health-related quality of life (QOL) and workplace productivity in patients with major depression. METHOD: Patients (N = 816) with DSM-IV major depression were treated with bupropion SR, 300 mg/day, for 8 weeks. The Clinical Global Impressions scale for Improvement of Illness (CGI-I) was completed at weekly clinic visits. At baseline and week 8, QOL and productivity were assessed. QOL was assessed using the Quality of Life in Depression Scale (QLDS). RESULTS: QOL and productivity were significantly improved from baseline after 8 weeks of treatment with bupropion SR. Mean QLDS scores were 18.98 and 10.36 at baseline and week 8, respectively (mean change = 8.62; p <.001). At week 8 compared with baseline, patients working at a paid job reported missing 1.58 fewer hours of work because of depression during the past 7 days, being 14.6% more effective on the job, working at reduced effectiveness less often, and incurring 6.37 fewer hours of overall lost productivity (p <.001 each variable). Improvements in QOL and productivity were significantly (p <.001) greater in bupropion SR responders (i.e., those with CGI-I scores of "very much improved" or "much improved" during the last 3 weeks of open-label therapy) than in nonresponders. CONCLUSION: Effective treatment of major depression with bupropion SR for 8 weeks is associated with improvements in QOL and reductions in lost workplace productivity. Patients who responded clinically to bupropion SR showed significantly greater improvements in these variables than those who did not respond.

Objective: The purpose of this study was to assess the costs and treatments associated with influenza patients with and without secondary viral or bacterial infections in a managed care setting., Methods: Patients with influenza diagnoses (ICD-9 = 487) were identified in the PharMetrics database between January 1, 1997 and June 30, 1998. Patients were placed into 3 cohorts: influenza only (INF), influenza plus a secondary bacterial respiratory infection (BRI), and influenza plus a secondary viral respiratory infection (VRI). The index date was defined as the date of the first occurrence of an influenza diagnosis during the study period. Medical claims were assessed from the index date to the end of the influenza episode, which was defined as the date of the last claim for influenza followed by a 90-day "clean period" during which no influenza-related charges occurred., Results: A total of 18,000 patients met the inclusion criteria. The mean age was 29 years, and 54% were female. Approximately 93% of patients were placed in the INF cohort, and 3% each in the BRI and VRI groups. The BRI cohort had the highest mean total cost ($5593* SD = 10,939), compared with the VRI cohort ($847 SD = 1782) and INF cohort ($602 SD = 2813) (P less than.0001 vs INF; P less than.0001 vs VRI). This total cost disparity was primarily driven by differences in inpatient costs: BRI ($3509, SD = 9474); VRI ($208, SD = 1327); INF ($138, SD = 2145). Patients in the BRI cohort averaged 0.5 hospitalizations per patient vs 0.06 in the VRI cohort and 0.03 in the INF cohort., Conclusions: Subjects in the BRI cohort were significantly more costly and had an increased risk of hospitalization as compared with subjects in the VRI or INF cohorts. Early intervention with antiviral agents and/or antibiotics, where appropriate, could result in significant cost savings for managed care organizations.

The development and application of an economic model designed to assess the specific costs and benefits of health plan coverage of smoking-cessation programs involving sustained-release bupropion hydrochloride are described. A cohort of 100,000 employees or health plan members and 60,000 adult dependents was followed from the start of the model to either retirement at age 65 or death at age 85. The model was used to compare outcomes for coverage versus no coverage of sustained-release bupropion hydrochloride as a component of a smoking-cessation benefit under four managed care plan scenarios and four employer scenarios. For the managed care scenarios involving coverage of bupropion sustained-release the overall decrease in health care costs over a 20-year period ranged from $7.9 million to $8.8 million; for every dollar spent covering smoking cessation, $4.10-$4.69 in health care costs was saved. For the employer scenarios, health care costs over 20 years decreased by $8.3 million to $14.0 million, and smoking-related indirect costs decreased an additional $5.1 million to $7.7 million; for every dollar spent covering smoking cessation, $5.04-$6.48 was saved. A model developed to assess the specific costs and benefits of covering sustained release bupropion hydrochloride as a component of a smoking-cessation benefit indicated cost savings for health plans and employers.

In this era of cost containment, outcomes research is becoming more prevalent. Therefore, various technologies allowing for flexibility in study design and the capture of specific clinical information need to be examined and used. These technologies include fax data systems, pocket scanners, automated telephone equipment, and hand-held computer devices. Fax data systems convert a fax machine into an automated data-entry system. Data-filled forms are faxed to a computer, the fax is converted, and the data are entered into preset fields in a database. Applications for fax systems include acute care-based and ambulatory care-based drug-use evaluations, drug recall systems, and patient-completed surveys of health status. Pocket scanners are hand-held instruments for rapid data entry and transport. Applications for pocket scanning include patient interview responses, procedure and disease analysis, and procedure coding. Options for automated telephone equipment include surveys with interactive voice-mail responses or keypad data entry, pharmacist-monitored drug information and survey services, fax-back and mail-out services, and patient-generated disease intervention programs. Hand-held computer technology is a source of information on multiple protocols and care pathways. All these technologies improve data collection with respect to accuracy and speed, facilitate data analysis, and promote cost-efficient information sharing. The purpose of this study was to evaluate the use of fax technology in data collection for a prospective, multicenter study of the outcomes and cost-effectiveness of two drugs used in the treatment of cancer. Details for the pharmacoeconomic study can be found elsewhere. Fax technology was selected because of the ease with which those responsible for managing the data collection could be trained to use it, the affordability and efficiency of the technology, the ease with which data could be analyzed, and the accuracy of data collection.

Objective: To conduct an economic analysis on the use of carboplatin versus cisplatin over multiple courses in patients with lung [nonsmall cell lung cancer (NSCLC) and small cell lung cancer (SCLC)] or ovarian cancer., Design: This 1-year study was a prospective, multicentre, cost-minimisation evaluation. Direct medical resource utilisation and costs associated with carboplatin and cisplatin administration over 3 to 6 courses of treatment were measured and compared. The perspective of this evaluation was that of the payer., Setting: A convenience sample of 16 sites representing a mix of cancer centres, outpatient clinics, medical centres and managed-care sites in a general practice oncology setting participated., Patients and Interventions: Patients were included in this study if they were newly diagnosed with NSCLC, SCLC or ovarian cancer, had not received prior chemotherapy, received either carboplatin or cisplatin as their treatment (additional chemotherapy agents were allowed), and received at least 3 courses of carboplatin or cisplatin therapy up to a maximum of 6 courses. Patients receiving more than 6 courses of therapy were included in this study, but data collection on those patients stopped after the sixth course. Individuals involved with data collection at all sites were trained via on-site and/or teleconference training. Site visits were made to assure reliability of at least 0.80. Data were collected and compiled via a fax transmission process that scans directly through optical mark and character recognition into a computer database. Outcome measures included costs of: medications, emergency room visits, physician/clinic/laboratory visits, home healthcare visits, transfusions, special procedures, consultations, hospitalisations and other/miscellaneous costs., Main Outcome Measures and Results: Of 220 patients, 164 met the study criteria (response rate = 74.2%) with 95 patients in the carboplatin group (NSCLC = 45, SCLC = 18, ovarian = 32) and 69 in the cisplatin group (NSCLC = 36, SCLC = 21, ovarian = 12). The average number of courses were: NSCLC = 4.3 and 4.2, SCLC = 4.3 and 4.8, and ovarian = 4.7 and 5.1, respectively, for carboplatin and cisplatin. The total costs (treatment and toxicity) associated with the use of carboplatin were higher in NSCLC, similar in SCLC but lower in ovarian cancer., Conclusions: These results indicate that overall treatment costs may vary depending on cancer type, even when the same drugs are used. The total costs (treatment plus toxicity costs) associated with the use of carboplatin were higher than those of cisplatin in patients with NSCLC, similar in SCLC, but lower in ovarian cancer.

Controversy surrounds the use of models in economic evaluations of pharmaceuticals. Many believe that modeling is a way of manipulating results and is not credible, whereas others consider modeling a valuable tool in economic evaluations. The purpose of this article is to provide a historical perspective on modeling, focus on the controversy and policy implications of using models, and review the suggested framework and guidelines for modeling practices. Models can be used to extrapolate beyond intermediate end points, predict costs and consequences of alternative therapies, generalize data to other settings, pose questions instead of providing answers when no data exist, design an evaluation to reduce uncertainty, and perform direct comparisons that are not currently available. We believe that a useful model should document the detailed inner workings, assumptions, and inherent bias during production (and at publication time), so that its reviewers and users can evaluate the appropriateness of the model's outcomes. The acceptability of models in the future rests with the researchers constructing them. If constructed appropriately, modeling economic evaluations is not a manipulation but rather a valuable tool.

Atypical fibroxanthoma is a malignant fibrohistiocytic neoplasm that develops most commonly on sun-exposed skin of elderly individuals. A number of different variants have been described, ranging from a purely spindle cell type to a xanthomatous form. We recently observed an unusual variant of atypical fibroxanthoma in which there were numerous osteoclast-like multinucleated giant cells. Histologically, there was a diffuse spindle cell neoplasm in the dermis exhibiting fibrohistiocytic differentiation associated with inflammatory cells. The neoplastic spindle cells were markedly pleomorphic and many were in mitosis, some being tripolar and tetrapolar. In addition to these features, which are common in atypical fibroxanthoma, there were numerous multinucleated giant cells scattered throughout the lesion with features resembling normal osteoclasts. Epithelioid cells with features of histiocytes were seen in association with these cells. No osteoid was observed, however, that suggested monocyte-macrophage differentiation. The histologic appearance of this lesion was reminiscent of the giant cell variant of malignant fibrous histiocytoma, also termed malignant giant cell tumor of soft parts. Thus, osteoclast-like giant cells may be seen in atypical fibroxanthoma. These cells probably represent multinucleated histiocytes rather than true osteoclasts. It is important to recognize this variant to avoid confusion with other malignant soft tissue neoplasms.

The histopathologic diagnosis of mycosis fungoides (MF), even when clinical manifestations of the disease seem convincing, is often tenuous. The observation that practically all patients with MF harbor human T cell lymphotropic virus type I (HTLV-I) proviral sequences in their circulating lymphocytes raised the possibility that such viral footprints could be detected in their cutaneous infiltrates. Application of in situ polymerase chain reaction (PCR) to skin biopsies of 11 of 12 patients demonstrated this assumption to be correct. In addition, cells suspected to be keratinocytes were also positive. None of 10 skin biopsies from a variety of sources used as controls, nor 3 lymph node biopsies from patients with B-cell lymphomas, showed any HTLV proviral sequences on in situ PCR. On the basis of these observations, it is concluded that in situ PCR carried out on skin biopsies of patients with presumptive MF may help to established the diagnosis.

BALB/c mice are about 2,000 times less susceptible to sporozoites of Plasmodium berghei than to Plasmodium yoelii. Associated with this is the innate cellular response mounted after injection with P. berghei. Host inflammatory cells do not normally attack P. yoelii during their development as exoerythrocytic forms (EEFs) in the liver. We used P. berghei sporozoites to induce host inflammation that might act against developing P. yoelii EEFs. Mice injected with P. berghei sporozoites followed 1 hr later with P. yoelii had a 58% reduction in P. yoelii EEFs. To establish whether this was due to events that occurred before vs. after invasion of hepatocytes by P. yoelii sporozoites, mice received P. yoelii sporozoites that were allowed to invade for 1 hr before subsequent injection with P. berghei; these mice showed minimal reduction in P. yoelii EEFs. Thus, most of the deleterious effects of P. berghei sporozoites appear to have been directed against P. yoelii sporozoites prior to their invasion of hepatocytes. Plasmodium yoelii that had already invaded were relatively unaffected. Further timing experiments showed that this effect was induced only by viable P. berghei sporozoites, which may thus induce rapid changes in sinusoid physiology leading to host resistance against P. yoelii sporozoites.

We compared immunization of BALB/c mice with radiation-attenuated versus killed sporozoites of the rodent malaria parasite, Plasmodium yoelii. We employed a suboptimal schedule of only two immunizations, in expectation that some parasites might break through the resultant low level immunity and that it might thus be possible to study the response of the host against these 'breakthrough' schizonts. As a measure of protective immunity, we used histological means to determine the percentages of challenge sporozoites prevented from completing development into hepatic schizonts within the liver. Immunization with attenuated sporozoites led to almost complete protection, whereas immunization with similar dosages of killed sporozoites led to approximately a 75% protection. Fluorescent antibody titers against sporozoites were similar in both sets of immunized animals. However, serum from mice immunized with attenuated sporozoites had a protective effect upon passive transfer into immunologically naive mice subsequently challenged with normal sporozoites; serum from mice immunized with killed sporozoites had no such effect. When mice suboptimally immunized with attenuated sporozoites were challenged, we observed breakthrough schizonts being infiltrated with inflammatory cells, primarily mononuclear cells, and neutrophils; partial depletion of CD4+ or CD8+ cells within these mice prior to challenge prevented the infiltration of breakthrough schizonts. Thus, cellular infiltration of schizonts was apparently secondary to earlier action by lymphocytes. This infiltration was also not observed in mice immunized with killed sporozoites. The more effective protective immunity induced by attenuated sporozoites could be due to their ability to release antigen into the cytoplasm of hepatocytes that they invade or their ability to continue differentiating, thereby presenting new antigens that are not seen after immunization with killed sporozoites.

After injection of Plasmodium berghei sporozoites into Norway-Brown rats, we were able to localize these sporozoites and the early hepatic trophozoites developing from them in histological sections of the liver stained with a sensitive immunogold-silver procedure. Sporozoites invading hepatocytes released substantial quantities of circumsporozoite protein into the hepatocyte cytoplasm. This intrahepatic cytoplasmic distribution reached a maximal level at about 4 h post-sporozoite injection. As the hepatic parasites continued to differentiate, circumsporozoite protein became undetectable within the cytoplasm of the hepatocytes and became localized around the periphery of each parasite. There was generalized cellular inflammation within the liver of the host, which first became evident at around 4 h post-sporozoite injection and progressed to the formation of well-defined granulomas by 24 h. Such histopathological changes were not seen in rats injected with killed sporozoites, indicating that the cellular inflammation was induced by viable, infective sporozoites. We did not observe cellular infiltration specifically associated with any of the developing hepatic stages that we observed, even up to 28 h post-sporozoite inoculation. These results indicate that viable sporozoites induced rapid and generalized hepatic inflammation in host rats. However, sporozoites that successfully invaded hepatocytes and then proceeded to develop further did not appear to be the target of inflammatory cells until a period beginning at around 40 h post-sporozoite inoculation.

The accuracy of a semi-automated ambulatory blood pressure monitoring device (the Instrumedix 'Personal Blood Pressure Transmitter') was assessed in 36 patients undergoing diagnostic cardiac catheterisation. Blood pressure readings measured by the device and by a standard manual sphygmomanometer were compared with simultaneous intra-aortic pressure measured directly via the catheter. No measurement size trends were identified for either of the two comparisons. Compared to direct intra-aortic pressure measurement, the manual sphygmomanometer gave lower systolic (p less than 0.05), and higher diastolic readings (p less than 0.01), while the semi-automated device gave slightly higher readings for both systolic (not significant: p greater than 0.05) and diastolic (p greater than 0.05) pressure. In this assessment the semi-automated device provided at least as accurate a reflection of intra-aortic pressure as did standard manual sphygmomanometry. This device is an accurate tool for the ambulatory assessment of blood pressure where adequacy of treatment or correctness of the diagnosis is in question.

Cardioverter defibrillators were implanted in 26 patients at Charleston Area Medical Center for management of cardiac arrest (7 patients), and drug refractory sustained ventricular tachycardia (19 patients). A variety of operative approaches and concomitant surgical procedures were utilized in the implantation of these devices. No operative deaths occurred. A superficial wound infection was the only operative complication. During the follow-up period (9.3 +/- 5 months), 11 of 26 patients (46 percent) had a defibrillator discharge and one death occurred (3 percent), which was due to heart failure. Patients with malignant ventricular arrhythmias may present with sustained monomorphic ventricular tachycardia with associated syncope, pre-syncope or without any associated symptoms. Unfortunately, cardiac arrest may be the initial presentation. The use of antitachycardia devices such as implantable cardioverter defibrillators and antitachycardia pacemakers has allowed physicians to more successfully treat patients with malignant ventricular arrhythmias. In a significant number of patients with these arrhythmias, such devices are now used as first-line therapy.

Inflammatory responses to Plasmodium hepatic schizonts within the livers of non-immunized animals have long been assumed to be initiated only after the parasites have matured and begun to burst. However, recent reports of inflammatory responses around hepatic schizonts suggested a re-examination of this issue. We injected Norway-Brown rats of various ages intravenously with Plasmodium berghei sporozoites and studied subsequent liver histopathology. We found that the ability of these rats to mount an inflammatory response is age-dependent. Young (4 weeks) rats had weak inflammatory responses against hepatic schizonts, whereas older (8-10 weeks) rats mounted a strong response. Older rats had many granulomatous reactions within the liver; eosinophils represented a pioneer component of the cellular infiltrate. There was a reduction in the numbers of surviving hepatic schizonts in the older rats, suggesting that these granulomatous and eosinophilic reactions had effectively destroyed some of the hepatic schizonts. We found clear evidence of inflammatory cells (eosinophils) infiltrating hepatic schizonts as early as 40 hours post-injection with sporozoites, a time well before any hepatic schizonts could have burst within the liver. This presents histological evidence that inflammatory cells can recognize and infiltrate intact hepatocytes containing schizonts in immunologically naive animals.

We found BALB/c mice to be on the order of 2,000 times more susceptible to Plasmodium yoelii than Plasmodium berghei sporozoites, as measured by the ability of these sporozoites to differentiate into microscopically detectable hepatic schizonts in the livers of immunologically naive mice. One of the factors that determine the relative insusceptibility of mice to P. berghei sporozoites is the innate cellular inflammatory response that the mice mount after injection with sporozoites. The cellular inflammatory response against P. berghei is initiated soon after sporozoite injection; by 24 h, substantial histopathological changes have developed within the liver. There is considerably less of a cellular inflammatory response against P. yoelii; significant histopathological changes within the liver are not observed until well after hepatic schizonts have begun to rupture at around 44 h postinjection of sporozoites. These differences in the cellular inflammatory response against two different, closely related species of sporozoites are of considerable interest. The data strongly suggest that the BALB/c-P. berghei sporozoite system is a relatively poor biological model for sporozoite immunization studies.