Impact of sharing Alzheimer's disease biomarkers with individuals without dementia: A systematic review and meta-analysis of empirical data.

INTRODUCTION: We conducted a systematic literature review and meta-analysis of empirical evidence on expected and experienced implications of sharing Alzheimer's disease (AD) biomarker results with individuals without dementia. METHODS: PubMed, Embase, APA PsycInfo, and Web of Science Core Collection were searched according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results from included studies were synthesized, and quantitative data on psychosocial impact were meta-analyzed using a random-effects model. RESULTS: We included 35 publications. Most personal stakeholders expressed interest in biomarker assessment. Learning negative biomarker results led to relief and sometimes frustration, while positive biomarkers induced anxiety but also clarity. Meta-analysis of five studies including 2012 participants (elevated amyloid = 1324 [66%], asymptomatic = 1855 [92%]) showed short-term psychological impact was not significant (random-effect estimate = 0.10, standard error = 0.23, P = 0.65). Most professional stakeholders valued biomarker testing, although attitudes and practices varied considerably. DISCUSSION: Interest in AD biomarker testing was high and sharing their results did not cause psychological harm. HIGHLIGHTS: Most personal stakeholders expressed interest in Alzheimer's disease biomarker assessment. Personal motivations included gaining insight, improving lifestyle, or preparing for the future. There was no short-term psychological impact of sharing biomarker status, implying it can be safe. Most professional stakeholders valued biomarker testing, believing the benefits outweigh the risk. Harmonized guidelines on biomarker testing and sharing results are required.

Comparison of median sternotomy closure-related complication rates using orthopedic wire or suture in dogs: A multi-institutional observational treatment effect analysis.

OBJECTIVE: To determine and compare median sternotomy (MS) closure-related complication rates using orthopedic wire or suture in dogs. STUDY DESIGN: Multi-institutional, retrospective observational study with treatment effect analysis. ANIMALS: 331 client-owned dogs, of which 68 were excluded. METHODS: Medical records of dogs with MS were examined across nine referral centers (2004-2020). Signalment, weight, clinical presentation, surgical details, complications, and outcomes were recorded. Follow-up was performed using patient records and email/telephone contact. Descriptive statistics, treatment effect analysis and logistic regression were performed. RESULTS: Median sternotomy closure was performed with wire in 115 dogs and suture in 148. Thirty-seven dogs experienced closure-related complications (14.1%), 20 in the wire group and 17 in the suture group. Twenty-three were listed as mild, four as moderate and 10 as severe. Treatment effect analysis showed a mean of 2.3% reduction in closure-related complications associated with using suture versus wire (95% CI: -9.1% to +4.5%). In multivariable logistic regression, the only factor associated with increased risk of closure-related complications was dog size (p = .01). This effect was not modified by the type of closure used (interaction term: OR = 0.99 [95% CI: 0.96/1.01]). CONCLUSION: The incidence of closure-related complication after MS was low compared to previous reports. The likelihood of developing a closure-related complication was equivalent between sutures and wires, independent of dog size, despite a higher proportion of complications seen in larger dogs (≥20 kg). CLINICAL SIGNIFICANCE: Use of either orthopedic wire or suture appear to be an appropriate closure method for sternotomy in dogs of any size.

Suggestions to Improve the Comprehensibility of Current Definitions of Scientific Authorship for International Authors.

Much has been said about the need for improving the current definitions of scientific authorship, but an aspect that is often overlooked is how to formulate and communicate these definitions to ensure that they are comprehensible and useful for researchers, notably researchers active in international research consortia. In light of a rapid increase in international collaborations within natural sciences, this article uses authorship of this branch of sciences as an example and provides suggestions to improve the comprehensibility of the definitions of authorship in natural sciences. It assesses whether the definition of authorship provided by the European Code of Conduct for Research Integrity can deal with current issues and problems of scientific authorship. Notably, problems that are experienced in project groups with researchers coming from multiple countries. Using theories developed by Jürgen Habermas and Robert Merton, a normative framework is developed to articulate ethical authorship in natural sciences. Accordingly, enriching the current definition of authorship with normative elements and using discipline-specific metaphors to communicate them are introduced as possible ways of improving the comprehensibility of the definition of authorship in international environments. Finally, this article provides a proposal to be considered in the future revisions of the European Code of Conduct for Research Integrity.

Vibrio cholerae non-O1 bacteraemia: description of three cases in the Netherlands and a literature review.

Vibrio cholerae non-O1 serogroup (VCNO) bacteraemia is a severe condition with a high case-fatality rate. We report three cases diagnosed in the Netherlands, identified during a national microbiological congress, and provide a literature review on VCNO bacteraemia. A search strategy including synonyms for 'VCNO' and 'bacteraemia' was applied to PubMed, Medline, Web of Science and Embase databases. The three cases were reported in elderly male patients after fish consumption and/or surface water contact. The literature search yielded 82 case reports on 90 cases and six case series. Thirty case reports were from Asia (30/90; 33%), concerned males (67/90; 74%), and around one third (38/90; 42%) involved a history of alcohol abuse and/or liver cirrhosis The presenting symptom often was gastroenteritis (47/90; 52%) which occurred after seafood consumption in 32% of the cases (15/47).Aside from the most frequent symptom being fever, results of case series concurred with these findings. Published cases also included rare presentations e.g. endophthalmitis and neonatal meningitis. Based on the limited data available, cephalosporins seemed the most effective treatment. Although mainly reported in Asia, VCNO bacteraemia occurs worldwide. While some risk factors for VCNO were identified in this study, the source of infection remains often unclear. Clinical presentation may vary greatly and therefore a quick microbiological diagnosis is indispensable.

Factors associated with acceleration of clinical development for infectious diseases: a cross-sectional analysis of 10-year EMA registration data.

Background: Clinical trials feature centrally in the development of drugs and vaccines to determine safety and efficacy. Clinical development can be slow and may have a duration of more than ten years. Global public health threats such as Ebola virus disease (EVD) and COVID-19 have demonstrated that it is possible to accelerate clinical trials while maintaining safety and efficacy. We investigated acceleration in clinical trials over the past decade and identified factors associated with acceleration for drugs targeting infectious diseases. Methods: A cross-sectional study was performed of all medicinal compounds targeting infectious diseases that received marketing authorisation by the European Medicines Agency (EMA) between 2012 and 2022. We calculated median clinical development time in years between the first phase 1 trial enrolment date and the authorisation date. Multivariable linear regression analysis was performed to identify factors associated with shorter development times. Findings: Eighty-one trajectories were included. The median clinical development time was 7.3 years (IQR 4.4-12.3). The fastest times belonged to drugs and vaccines targeting COVID-19 (1.3 years, IQR 0.8-1.6), EVD (5.5 years, IQR 5.1-5.8), and Hepatitis A-E (5.5 years, IQR 3.9-8.2). Factors associated with shorter development times were outbreak setting (-5.4 years [95% CI, -8.2 to -2.6]), accelerated assessment status (-4.0 years [95% CI, -7.6 to -0.5]), and drugs with combined compounds (-2.7 years [95% CI, -4.9 to -0.4]). Interpretation: Clinical development time for infectious disease-related drugs and vaccines was relatively short, and outbreak setting and accelerated EMA assessment were associated with shorter development times. Funding: Amsterdam Public Health research institute.

[Digital transformation in general practitioner care: how do we maintain the core values of primary care?] / Digitale transformatie in de huisartsenzorg.

An increase in demand for care and a decrease in workforce puts pressure on general practitioner care. Digital transformation helps to maintain the core values of primary care - continuous, person oriented, medical generalist and together. Patients experience, even outside contacts at the practice, more person-oriented and continuous care through online access and availability of reliable online information. Services like eAppointment and eRepeat prescription save time for the doctor's assistant. Online care, such as a video consultation, provides flexibility and continuity. Both GP's and patients benefit from better data exchange and smart expert systems. Digital collaboration, for example with medical specialists, strengthens the central position of general practitioners. A digital transformation offers plenty of solutions, but can only succeed with high user-friendliness, increased knowledge and skills among patients and caregivers, and collaborative organization. Scientific research on the effect on the quality and effectiveness of care will have to play a role in choices of use.

Closure-related complications after median sternotomy in cats: 26 cases (2010-2020).

OBJECTIVES: The aim of this study was to determine closure-related complications and outcome after median sternotomy (MS) in cats. METHODS: This was a retrospective, multicentric study. The medical records of cats undergoing MS from six referral hospitals were reviewed (2010-2020). Data retrieved included signalment, history, presenting complaints, surgery, patient outcomes and complications. Follow-up was performed via patient records and email/telephone contact with both owners and referring veterinarians. Descriptive statistics were performed. RESULTS: Data on 36 cats were collected; four were excluded due to insufficient follow-up and six died less than 5 days after surgery. Twenty-six cats survived to discharge (survival rate 81%). Three cats had a full sternotomy (FS) performed and 23 cats a partial sternotomy (PS). Of the cats that underwent a PS, six included the manubrium (PSM) and three included the xyphoid process. For 14 cats, the length of sternotomy was unknown. Sternotomy closure was performed with suture in all cats. Two cats (7.7%) developed closure-related complications, both after PSM, during the long-term follow-up, one mild, slightly displaced sternal fracture and one severe, sternal dehiscence (without skin wound dehiscence) requiring revision surgery. No seroma, surgical site infection or wound dehiscence occurred. The most common reason for MS was the presence of a thoracic mass (17/26; 65%), with thymoma being the most common (11/17; 65%). CONCLUSIONS AND RELEVANCE: MS has a low closure-related complication risk in cats when compared with dogs. Complications in cats present differently to what has been previously described in dogs.

Chronic paronychia in cats with patellar fracture and dental anomaly syndrome.

CASE SERIES SUMMARY: The aim of this case series was to describe the clinical features and treatment of paronychia in cats diagnosed with patellar fracture and dental anomaly syndrome (PADS). Clinical records, photographs, microbiology, cytology and histopathology reports were collected, and follow-up was obtained. Five cats with paronychia were included. All five cats had multiple digits of multiple limbs affected and eventually underwent amputation of the third phalanx of one or multiple digits. A total of 36 digits were affected, 17% (n = 6/36) resolved with medical management and 83% (n = 30/36) were eventually treated successfully by amputation. The cats had treatment with numerous courses of antibiotics (range 7-20; mean 11 courses) over periods of time ranging from 10 to 67 months (mean 32 months). RELEVANCE AND NOVEL INFORMATION: Chronic paronychia may be an additional clinical feature of PADS and the probable mechanism involves poor integrity of osteopetrotic bone, loss of normal nailbed anatomy and secondary osteomyelitis of the distal phalanx. Medical management with antibiotics, anti-inflammatory therapy and steroid treatment may improve the clinical signs in the short term; however, in severe instances, amputation of the third phalanx of the affected digit seems to be necessary to resolve repeated recurrences and discomfort. Additional information on the long-term outcome is required. In any cat with atraumatic patellar fractures and/or retained deciduous teeth, paronychia may require surgical management if medical management is unsuccessful.

Predictive factors of high societal costs among chronic low back pain patients.

BACKGROUND: Societal costs of low back pain (LBP) are high, yet few studies have been performed to identify the predictive factors of high societal costs among chronic LBP patients. This study aimed to determine which factors predict high societal costs in patients with chronic LBP. METHODS: Data of 6,316 chronic LBP patients were used. In the main analysis, high societal costs were defined as patients in the top 10% of cost outcomes. Sensitivity analyses were conducted using patients in the top 5% and top 20% of societal costs. Potential predictive factors included patient expectations, demographic factors (e.g. age, gender, nationality), socio-economic factors (e.g. employment, education level) and health-related factors (e.g. body mass index [BMI], general health, mental health). The final prediction models were obtained using backward selection. The model's prognostic accuracy (Hosmer-Lemeshow X2 , Nagelkerke's R2 ) and discriminative ability (area under the receiver operating curve [AUC]) were assessed, and the models were internally validated using bootstrapping. RESULTS: Poor physical health, high functional disability, low health-related quality of life, high impact of pain experience, non-Dutch nationality and decreasing pain were found to be predictive of high societal costs in all models, and were therefore considered robust. After internal validation, the models' fit was good, their explained variance was relatively low (≤14.1%) and their AUCs could be interpreted as moderate (≥0.71). CONCLUSION: Future studies should focus on understanding the mechanisms associated with the identified predictors for high societal costs in order to design effective cost reduction initiatives. SIGNIFICANCE: Identifying low back pain patients who are at risk (risk stratification) of becoming high-cost users and making appropriate initiatives could help in reducing high costs.

CD28 and ICOS: similar or separate costimulators of T cells?

Numerous studies have revealed that the B7.1/B7.2-CD28 and B7RP-1-ICOS (Inducible COStimulator) pathways provide crucial costimulatory signals to T cells. We have compared the contribution of these pathways during primary and effector responses, in vitro and in vivo, molecularly as well as functionally. This comparison between CD28 an ICOS after initiation of T cell activation demonstrates that both CD28 and ICOS function similarly during expansion, survival and differentiation of T cells and that both CD28 and ICOS are necessary for proper IgG responses. The major differences between CD28 and ICOS are differences in expression of both receptors and ligands, and the fact that CD28 induces IL-2 production, whereas ICOS does not. In addition, ICOS is more potent in the induction of IL-10 production, a cytokine important for suppressive function of T regulatory cells. All data available at present indicate that both molecules are very suitable candidates for immunotherapy, each in their own unique way.

Bovine-heart NADH:ubiquinone oxidoreductase is a monomer with 8 Fe-S clusters and 2 FMN groups.

The availability of the amino-acid sequences of a number of mitochondrial and bacterial NADH:ubiquinone oxidoreductases (Complex I), the sequence similarities of five of the essential subunits of Complex I with subunits of [NiFe]hydrogenases and [Fe]hydrogenases, as well as some long-standing controversies about the precise EPR properties and stoichiometries of the iron-sulfur clusters in Complex I have led us to propose a new structural and functional model for this complicated enzyme. The functional unit is a monomer comprising 8 different Fe-S clusters and 2 FMN molecules as prosthetic groups. The electron-input pathway, as well as part of the electron-transfer components, seem largely inherited from bacterial NAD(+)-reducing hydrogenases. The essential electron-transfer components of the electron-output pathway are located in the TYKY subunit. This subunit is proposed to hold both iron-sulfur clusters 2 and to render the enzyme the ability to perform coupled electron transfer. Based on earlier observed similarities (Albracht. S.P.J. (1993) Biochim. Biophys. Acta 1144, 221-224) of the 49 kDa subunit and the PSST subunit with, respectively, the large and small subunits of [NiFe]hydrogenases, it is proposed that the 49 kDa/PSST subunit couple provides Complex I with an ancient proton-transfer pathway.

[Elderly patients presenting with fever and respiratory problems in an intensive care unit. Diagnostic, therapeutic and prognostic impact of a systematic infectious disease consultation]. / Patients âgés fébriles avec signes respiratoires dans un service d'urgences. Impact diagnostique, thérapeutique et pronostique d'une consultation systématique d'infectiologie.

OBJECTIVE: To measure the impact of an infectious disease consultation on the morbidity and mortality in patients aged over 75 presenting with fever and respiratory signs and treated with antibiotics in an intensive care unit. METHOD: Retrospective study comparing two groups of patients having been seen or not by an infectious disease specialist within the first 24 hours of hospitalisation. The data available before prescription of the antibiotherapy by the intensive care physician were collected, together with the diagnostic and therapeutic proposals of the infectious disease specialist. Morbidity and mortality were assessed from the medical files and nurses charts and included: duration of fever and hospitalisation, complications with antibiotherapy and venous catheters and the cause or causes of death. RESULTS: 169 patients were included, 115 of whom had been seen (study group) and 54 who had not bee seen (control group) by an infectious disease specialist. Sixty-six percent of the infectious disease specialists (76/115) proposed a differential diagnosis, although a diagnostic re-assessment was effective for only 22% of the patients in the control group (p< 0.01). A 50% reduction in antibiotic prescriptions was observed in the study group. The duration of hospitalisation was greater in the study group than in the control group (a mean of 10 versus 7 days, p<0.01), but was unrelated to the consultation with a specialist. The same result was observed with the complications of venous catheterism (16 versus 2 cases, p =0.04). The rate of mortality was of 13% in both groups. CONCLUSION: The over-zealous diagnoses of infection are the primary cause of over-prescription of antibiotics. Despite the population studied, considered as fragile, the 50% reduction in antibiotics is without any negative prognostic impact.

In vivo dynamics of stable chronic lymphocytic leukemia inversely correlate with somatic hypermutation levels and suggest no major leukemic turnover in bone marrow.

Although accumulating evidence indicates that chronic lymphocytic leukemia (CLL) is a disease with appreciable cell dynamics, it remains uncertain whether this also applies to patients with stable disease. In this study, (2)H(2)O was administered to a clinically homogeneous cohort of nine stable, untreated CLL patients. CLL dynamics in blood and bone marrow were determined and compared with normal B-cell dynamics in blood from five healthy individuals who underwent a similar (2)H(2)O labeling protocol. Average CLL turnover rates (0.08-0.35% of the clone per day) were approximately 2-fold lower than average B-cell turnover rates from healthy individuals (0.34-0.89%), whereas the rate at which labeled CLL cells in blood disappeared (0.00-0.39% of B cells per day) was approximately 10-fold lower compared with labeled B cells from healthy individuals (1.57-4.24% per day). Leukemic cell turnover variables inversely correlated with the level of somatic hypermutation of the CLL clone (IgVH mutations). Although CLL cells in bone marrow had a higher level of label enrichment than CLL cells in blood, no difference between proliferation rates and proapoptotic and antiapoptotic profiles of CLL cells from these compartments was observed. These data suggest that, in stable disease, there is a biological relationship between the degree of somatic hypermutation of the CLL clone and its dynamics in vivo. Furthermore, in contrast to lymph nodes, the bone marrow does not seem to be a major CLL proliferation site.

T cell activation and proliferation characteristic for HIV-Nef transgenic mice is lymphopenia induced.

The HIV-Nef protein has been implicated in generating high viral loads and T cell activation. Transgenic (tg) mice with constitutive T cell-specific Nef expression show a dramatic reduction in T cell number and highly increased T cell turnover. Previous studies in Nef tg mice attributed this T cell activation to a direct effect of Nef at the cellular level. Given the strongly reduced peripheral T cell numbers, we examined whether this enhanced T cell division might instead be lymphopenia induced. Adoptively transferred naive wild-type T cells into lymphopenic Nef tg mice showed high T cell turnover and obtained the same effector/memory phenotype as the autologous Nef tg T cells, supporting the idea that the microenvironment determines the phenotype of the T cells present. Moreover, in bone marrow chimeras from mixtures of wild-type and Nef tg bone marrow, with a full T cell compartment containing a small proportion of Nef tg T cells, Nef tg T cells kept a naive phenotype. These results demonstrate that T cell activation in the Nef tg mice is lymphopenia induced rather than due to a direct T cell-activating effect of Nef.

A critical contribution of both CD28 and ICOS in the adjuvant activity of Neisseria meningitidis H44/76 LPS and lpxL1 LPS.

The development of novel vaccines against Neisseria meningitidis recently gained momentum by the generation of penta-acylated lpxL1 LPS which has similar adjuvant activity, but reduced endotoxic activity as compared to hexa-acylated wild type (H44/76) LPS. We investigated the costimulation requirements for the adjuvant activity of both forms of LPS by immunizing CD28-, ICOS- and B7.1/2/ICOS-deficient mice. Both ICOS and CD28 appeared essential for optimal adjuvant activity of H44/76 LPS or lpxL1 LPS. Interestingly, ICOS-mediated costimulation predominates in the adjuvant activity of lpxL1 LPS, while both ICOS and CD28 are required for H44/76 LPS adjuvant activity.

Naive transgenic T cells expressing cartilage proteoglycan-specific TCR induce arthritis upon in vivo activation.

Proteoglycan (PG)-induced arthritis (PGIA), a murine model for rheumatoid arthritis (RA), is driven by antigen (PG)-specific T and B cell activation. In order to analyze the pathogenic role of antigen-specific T cells in the development of autoimmune arthritis, we have generated a transgenic (Tg) mouse. The CD4(+) T cells of this TCR-5/4E8-Tg line express a functional T cell receptor (TCR) composed of the Valpha1.1 and Vbeta4 chains with specificity for the dominant arthritogenic T cell epitope of human cartilage PG. Adoptive transfer of naive TCR-5/4E8-Tg cells induced arthritis with severe clinical symptoms in syngeneic immunodeficient BALB/c.RAG2(-/-) mice. In vivo activation of TCR-5/4E8-Tg CD4(+)Vbeta4(+) cells with cartilage PG seemed to be critical for arthritis induction. Arthritis never developed after transfer of naive wild-type cells. The arthritis was characterized as a chronic progressive disease with intermittent spontaneous exacerbations and remissions. Inflamed joints showed extensive cartilage damage and bone erosions leading to massive ankylosis in peripheral joints. These PG epitope-specific TCR-5/4E8-Tg mice can be valuable research tools for studying antigen-driven T cell regulation in arthritis, and migration of T cells to the joints. In addition the model may be used for the development of immune modulating strategies in T cell-mediated autoimmune diseases.

ICOS contributes to T cell expansion in CTLA-4 deficient mice.

Both CD28 and ICOS are important costimulatory molecules that promote Ag-specific cellular and humoral immune reactions. Whereas CD28 is generally thought to be the most important molecule in the initiation of a T cell response, ICOS is considered to act during the effector phase. We have investigated the contribution of ICOS to T cell responses in the absence of CTLA-4-mediated inhibition. Mice lacking CTLA-4, which show spontaneous CD28-mediated CD4(+) T cell activation, expansion and differentiation, were treated with antagonistic alphaICOS antibodies. Blocking the interaction between ICOS and its ligand B7RP-1 significantly reduced this aberrant T cell activation and caused a reduction in T cell numbers. In vitro analysis of CD4(+) T cells from treated mice revealed that ICOS blockade significantly reduced Th1 differentiation, while Th2 differentiation was only moderately inhibited. Further in vitro stimulation experiments demonstrated that ICOS is able to induce proliferation of murine CD4(+) and CD8(+) T cells but only in the presence of IL-2. These results indicate that ICOS is not only important for T cell effector function but also contributes to the expansion phase of a T cell response in the presence of CD28 signaling.

Should we promote influenza vaccination of health care workers in nursing homes? Some ethical arguments in favour of immunization.

Although studies show the relation between influenza immunization of health care workers and the benefits for residents in nursing homes, compliance to vaccination is still low. In this article we explore and discuss two specific moral reasons for nursing home professionals to accept vaccination. These special reasons derive from two sources: the responsibilities they have as health professionals, and the responsibilities they have as a member of the collective.

The Weber-curve pitfall: effects of a forced introduction on reporting rates and reported adverse reaction profiles.

BACKGROUND: In May 1999 Losec MUPS (MUPS) were granted a marketing authorization in the Netherlands, followed by the withdrawal of the Losec capsules (capsules) in September 1999. Both formulations contain omeprazole as active substance. This forced switch resulted in a large number of spontaneous reports of adverse drug reactions (ADRs) to the Netherlands Pharmacovigilance Centre Lareb. METHODS: We calculated and compared the reporting rate of both formulations and grouped the reported adverse reactions into system and organ classes (SOCs) in order to analyse possible differences in the type of reported ADRs. RESULTS: Lareb received 480 reports on omeprazole formulations between May 1997 and December 2000. A quarter of the reports concerned a decrease in therapeutic effect. The reporting rate on MUPS showed a sharp rise after withdrawal of the capsules, but did not differ significantly from the reporting rate on the capsules. A comparison of the type of reported ADRs showed differences in six SOCs. Elimination of the reports concerning a decreased therapeutic effect reduced the number of different SOC reporting rates. Certain gastrointestinal complaints were reported more frequently as an ADR of MUPS. CONCLUSION: The forced switch caused an increase in reports resembling an early Weber effect rather than a decrease in safety of the newer formulation. However, our analysis cannot exclude differences in pharmacokinetic, pharmacodynamic or safety characteristics.

CTLA-4 regulates cell cycle progression during a primary immune response.

Engagement of CTLA-4 is critical for inhibiting T cell immune responses. Recent studies have shown that CTLA-4 plays a key role in regulating peripheral T cell tolerance. It has been suggested that one mechanism by which CTLA-4 performs this function is by regulating cell cycle progression. Here, we investigate in depth the role of CTLA-4 in regulating cell cycle progression in naive T cells by comparing the immune responses in the absence or presence of CTLA-4. In the absence of CLTA-4, T cells exhibit marked increases in T cell proliferation, IL-2 mRNA and protein secretion, and cells cycling in the S and G2-M phase. Analyses of cyclins, cyclin-dependent kinases, and cell cycle inhibitors involved in the transition from the G1 to S phase reveal that cell cycle progression is prolonged in the absence of CTLA-4. This is due to the early exit from the G1 phase, entry into the S phase, and prolonged S phase period. Re-expression of the cell cycle inhibitor p27(kip1) is delayed in the absence of CTLA-4. These studies demonstrate that the B7 : CTLA-4 pathway exerts its major effects on T cell immune responses via regulation of the cell cycle.