Familial Variability of Disease Severity in Adult Patients With ADPKD.

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic nephropathy and has striking familial variability of disease severity. Methods: To better comprehend familial phenotypic variability, we analyzed clinical and pedigree data on 92 unrelated ADPKD kindreds with ≥2 affected individuals (N = 292) from an Irish population. All probands underwent genetic sequencing. Age at onset of kidney failure (KF), decline in estimated glomerular filtration rate (eGFR), predicting renal outcome in polycystic kidney disease (PROPKD) score, and imaging criteria were used to assess and grade disease severity as mild, intermediate, or severe. One mild and 1 severe case per family defined marked intrafamilial variability of disease severity. Results: Marked intrafamilial variability was observed in at least 13% of the 92 families, with a higher proportion of families carrying PKD1-nontruncating (PKD1-NT) variants. In families with ≥2 members affected by KF, the average intrafamilial age difference was 7 years, and there was no observed difference in intrafamilial variability of age at KF between allelic groups. The prespecified criteria showed marked familial variability in 7.7%, 8.4%, and 24% for age at KF, the PROPKD score, and imaging criteria, respectively. In our multivariate mixed-effects model, the intrafamilial variability in kidney survival was independent of the measured genotypic factors associated with prognosis and survival (P = <0.001). Conclusion: Using objective measures, we quantified marked intrafamilial variability in ADPKD disease phenotype in at least 13% of families. Our findings indicate that intrafamilial phenotypic variability remains incompletely understood and necessitates a more thorough identification of relevant clinical and genotypic factors.

Metastases from gastric cancer presenting as colorectal lesions: a report of two cases and systematic review.

Gastric cancer is common with well-established routes of spread. Metastasis to the colon or rectum is rare; however, we have recently managed two patients with this clinical picture. We present these cases together with a literature review of current practice. A systematic review in PubMed using the terms 'gastric cancer' and 'colorectal metastasis' was performed. The identified papers were screened for relevance and the reference lists of relevant papers were also reviewed to ensure capture of all relevant reports. Twenty-four papers containing 26 cases of gastric cancer with metastasis to the colon or rectum were found. There was wide variation in presentation and practice in these cases, which tended to be in patients with poor histopathological features. Diagnosis is often challenging owing to the unusual radiological appearance and submucosal nature of the metastatic lesions. Treatment ranges from palliative care to radical resection. Colorectal metastases from gastric primary cancer are rare, but cases are reported and should be part of the index of suspicion during the work-up of patients with lower gastrointestinal symptoms and a history of gastric cancer. Treatment options range from aggressive surgical resection to palliative care and should be centred on the patient's fitness and wishes.

Potential for Anthropogenic Fin Damage to Affect Individual Responses to Prey in Bluegill Sunfish (Lepomis macrochirus): A New Hypothesis for Kinematic Studies.

In fishes, damage to important morphological structures such as fins through natural damage and anthropogenic factors can have cascading effects on prey capture performance and individual fitness. Bluegill sunfish (Lepomis macrochirus) are a common freshwater species in North America, are a model organism for performance studies, and often experience natural injuries. We opportunistically sampled two populations of fish in the lab to generate a hypothesis for the effect of sub-lethal fin damage resulting from the capture technique on kinematic performance during prey capture in bluegill. We found no statistical differences in mean prey capture kinematics or predator accuracy, but damaged fish used more variable kinematics and more readily struck at non-prey items. We suggest that a reduction in stability and individual consistency occurs as a result of fin damage. This difference could have consequences for higher-order ecological interactions such as competitive ability, despite a lack of apparent performance cost at the individual level, and deserves consideration in future studies of prey capture performance in fish.

Whole-fat dairy products do not adversely affect adiposity or cardiometabolic risk factors in children in the Milky Way Study: a double-blind randomized controlled pilot study.

BACKGROUND: Limited evidence supports the common public health guideline that children >2 y of age should consume dairy with reduced fat content. OBJECTIVES: We aimed to investigate the effects of whole-fat compared with reduced-fat dairy intake on measures of adiposity and biomarkers of cardiometabolic risk in healthy 4- to 6-y-old children. METHODS: The Milky Way Study enrolled 49 children (mean ± SD age: 5.2 ± 0.9 y; 47% girls) who were habitual consumers of whole-fat dairy, then randomly assigned them in a double-blind fashion to remain on whole-fat dairy or switch their dairy consumption to reduced-fat products for 3 mo. Primary endpoints included measures of adiposity, body composition, blood pressure, fasting serum lipids, blood glucose, glycated hemoglobin (HbA1c), and C-reactive protein (CRP) and were assessed at baseline and study end. Pre- and postintervention results were compared using linear mixed models, adjusted for growth, age, and sex. RESULTS: Dairy fat intake was reduced by an adjusted (mean ± SEM) 12.9 ± 4.1 g/d in the reduced-fat compared with the whole-fat dairy group (95% CI: -21.2, -4.6 g/d; P = 0.003), whereas dietary energy intakes remained similar (P = 0.936). We found no significant differential changes between dairy groups in any measure of adiposity, body composition, blood pressure, or fasting serum lipids, glucose, HbA1c, and CRP. CONCLUSIONS: Our results suggest that although changing from whole-fat to reduced-fat dairy products does reduce dairy fat intake, it does not result in changes to markers of adiposity or cardiometabolic disease risk in healthy children.This trial was registered at www.anzctr.org.au as ACTRN12616001642471.

A review of the use of biological mesh products in modern UK surgical practice: a religious and cultural perspective.

INTRODUCTION: The UK is an increasingly multicultural society. This change coincides with an increasing use of animal products in medicine and surgery and a change in the UK law of consent. The refusal of Jehovah's Witnesses to accept blood products is well known, but the use of animal products in surgery is a neglected topic. As society becomes more diverse and medicine becomes ever more advanced, there is increasing potential for a mismatch between what is medically possible and what is acceptable from a religious perspective. METHODS: Surgical products were identified by searching the literature and contacting manufacturing companies. Literature was identified by using PubMed and OVID (MEDLINE). Religious views were established by contacting national bodies for each group. FINDINGS: The views of common UK religious groups and the constituent parts of biological meshes are summarised in tables intended to be used as a reference during clinical practice. On an elective basis, the Islamic, Hindu. Sikh and Jain leaders contacted had strong views on avoiding animal derived products. The Christian and Jewish leaders contacted did not. All religious leaders contacted accepted the use of mesh derived from human tissue. All products, including those of porcine and bovine origin, were acceptable to all leaders contacted if the procedure was performed to save life. The highlighting of this issue should prompt earlier consideration and discussion in the surgical planning and the consenting process with all final decisions taken by both the surgeon and the individual patient.

Characterizing the Composition of the Pediatric Gut Microbiome: A Systematic Review.

The consortium of trillions of microorganisms that live inside the human gut are integral to health. Little has been done to collate and characterize the microbiome of children. A systematic review was undertaken to address this gap (PROSPERO ID: CRD42018109599). MEDLINE and EMBASE were searched using the keywords: "healthy preadolescent children" and "gut microbiome" to 31 August 2018. Of the 815 journal articles, 42 met the inclusion criteria. The primary outcome was the relative abundance of bacteria at the phylum, family, and genus taxonomic ranks. α-diversity, short chain fatty acid concentrations, diet, 16S rRNA sequencing region, and geographical location were documented. The preadolescent gut microbiome is dominated at the phylum level by Firmicutes (weighted overall average relative abundance = 51.1%) and Bacteroidetes (36.0%); genus level by Bacteroides (16.0%), Prevotella (8.69%), Faecalibacterium (7.51%), and Bifidobacterium (5.47%). Geographic location and 16S rRNA sequencing region were independently associated with microbial proportions. There was limited consensus between studies that reported α-diversity and short chain fatty acids. Broadly speaking, participants from non-Western locations, who were less likely to follow a Westernized dietary pattern, had higher α-diversity and SCFA concentrations. Confirmatory studies will increase the understanding of the composition and functional capacity of the preadolescent gut microbiome.

Multifunctional Structures and Multistructural Functions: Integration in the Evolution of Biomechanical Systems.

Integration is an essential feature of complex biomechanical systems, with coordination and covariation occurring among and within structural components at time scales that vary from microseconds to deep evolutionary time. Integration has been suggested to both promote and constrain morphological evolution, and the effects of integration on the evolution of structure likely vary by system, clade, historical contingency, and time scale. In this introduction to the 2019 symposium "Multifunctional Structures and Multistructural Functions," we discuss the role of integration among structures in the context of functional integration and multifunctionality. We highlight articles from this issue of Integrative and Comparative Biology that explore integration within and among kinematics, sensory and motor systems, physiological systems, developmental processes, morphometric dimensions, and biomechanical functions. From these myriad examples it is clear that integration can exist at multiple levels of organization that can interact with adjacent levels to result in complex patterns of structural and functional phenotypes. We conclude with a synthesis of major themes and potential future directions, particularly with respect to using multifunctionality, itself, as a trait in evolutionary analyses.

Low-level cadmium exposure and cardiovascular outcomes in elderly Australian women: A cohort study.

BACKGROUND: Cadmium has been associated with increased risk of cardiovascular disease (CVD) in observational studies, however there has been a limited focus on this relationship in women. OBJECTIVES: This study investigated the association of urinary cadmium (UCd) concentrations with CVD outcomes and all-cause mortality in elderly Western Australian (WA) women. METHODS: UCd excretion was measured at baseline in 1359 women, mean age 75.2 ±â€¯2.7 years and 14.5 years of atherosclerotic vascular disease (ASVD) hospitalisations and deaths, including both the principle cause of death and all associated causes of death. Health outcome data were retrieved from the Western Australian Data Linkage System. Cox regression analysis was used to estimate hazard ratios of ASVD and all-cause mortality. UCd was ln-transformed and models were adjusted for demographic and CVD risk factors. RESULTS: Median (IQR) concentration of UCd was 0.18 (0.09-0.32) µg/L. In multivariable-adjusted analyses per ln unit (equivalent to ∼2.7 fold) increase in UCd, there was a 36% increase in the risk of death from heart failure and 17% increase in the risk of a heart failure event, respectively (HR = 1.36, 95% CI 1.11-1.67; HR = 1.17, 95% CI 1.01-1.35). When analyses were restricted to never smokers the relationship between UCd and death from heart failure remained (HR 1.29, 95% CI 1.01-1.63). CONCLUSIONS: This study suggests that even at low levels of exposure cadmium may be associated with heart failure hospitalisations and deaths in older women, however given the dilute nature of these urine samples, the results must be interpreted with caution.

Cigarette smoking and risk of Hodgkin lymphoma and its subtypes: a pooled analysis from the International Lymphoma Epidemiology Consortium (InterLymph).

BACKGROUND: The etiology of Hodgkin lymphoma (HL) remains incompletely characterized. Studies of the association between smoking and HL have yielded ambiguous results, possibly due to differences between HL subtypes. PATIENTS AND METHODS: Through the InterLymph Consortium, 12 case-control studies regarding cigarette smoking and HL were identified. Pooled analyses on the association between smoking and HL stratified by tumor histology and Epstein-Barr virus (EBV) status were conducted using random effects models adjusted for confounders. Analyses included 3335 HL cases and 14 278 controls. RESULTS: Overall, 54.5% of cases and 57.4% of controls were ever cigarette smokers. Compared with never smokers, ever smokers had an odds ratio (OR) of HL of 1.10 [95% confidence interval (CI) 1.01-1.21]. This increased risk reflected associations with mixed cellularity cHL (OR = 1.60, 95% CI 1.29-1.99) and EBV-positive cHL (OR = 1.81, 95% CI 1.27-2.56) among current smokers, whereas risk of nodular sclerosis (OR = 1.09, 95% CI 0.90-1.32) and EBV-negative HL (OR = 1.02, 95% CI 0.72-1.44) was not increased. CONCLUSION: These results support the notion of etiologic heterogeneity between HL subtypes, highlighting the need for HL stratification in future studies. Even if not relevant to all subtypes, our study emphasizes that cigarette smoking should be added to the few modifiable HL risk factors identified.

Postmenopausal hormone therapy and non-Hodgkin lymphoma: a pooled analysis of InterLymph case-control studies.

BACKGROUND: Non-Hodgkin lymphoma (NHL) subtypes, diffuse large B-cell (DLBCL) and follicular lymphoma (FL) have different sex ratios and are diagnosed at ages over 60 years; DLBCL is more common in men and diagnosed at older ages than FL, which occurs more among women. This analysis of postmenopausal women examines the relationship between postmenopausal hormone therapy and NHL. DESIGN: Self-reported use of postmenopausal hormone therapy from 2094 postmenopausal women with NHL and 2731 without were pooled across nine case-control studies (1983-2005) from North America, Europe and Japan. Study-specific odds ratios (OR) and 95% confidence intervals (CI) estimated using logistic regression were pooled using random-effects meta-analyses. RESULTS: Postmenopausal women who used hormone therapy were at decreased risk of NHL (pooled OR = 0.79, 95% CI 0.69-0.90). Risks were reduced when the age of starting was 50 years or older. There was no clear trend with number of years of use. Current users were at decreased risk while those stopping over 2 years before diagnosis were not. Having a hysterectomy or not did not affect the risk. Favourable effects were present for DLBCL (pooled OR = 0.66, 95% CI 0.54-0.80) and FL (pooled OR = 0.82, 95% CI 0.66-1.01). CONCLUSION: Postmenopausal hormone therapy, particularly used close to menopause, is associated with a decreased risk of NHL.

Menstrual and reproductive factors, and hormonal contraception use: associations with non-Hodgkin lymphoma in a pooled analysis of InterLymph case-control studies.

BACKGROUND: The two most common forms of non-Hodgkin lymphoma (NHL) exhibit different sex ratios: diffuse large B-cell lymphoma (DLBCL) occurs more frequently in men and follicular lymphoma (FL) more frequently in women. Looking among women alone, this pooled analysis explores the relationship between reproductive histories and these cancers. MATERIALS AND METHODS: Self-reported reproductive histories from 4263 women with NHL and 5971 women without NHL were pooled across 18 case-control studies (1983-2005) from North America, Europe and Japan. Study-specific odd ratios (ORs) and confidence intervals (CIs) were estimated using logistic regression and pooled using random-effects meta-analyses. RESULTS: Associations with reproductive factors were found for FL rather than NHL overall and DLBCL. In particular, the risk of FL decreased with increasing number of pregnancies (pooled OR(trend) = 0.88, 95% CI 0.81-0.96). FL was associated with hormonal contraception (pooled OR = 1.30, 95% CI 1.04-1.63), and risks were increased when use started after the age of 21, was used for <5 years or stopped for >20 years before diagnosis. DLBCL, on the other hand, was not associated with hormonal contraception (pooled OR = 0.87, 95% CI 0.65-1.16). CONCLUSIONS: Hormonal contraception is associated with an increased risk of FL but not of DLBCL or NHL overall.

Effects of diet source and vaccination for porcine circovirustype 2 and Mycoplasma hyopneumoniae on nursery pig performance.

Two experiments were conducted to evaluate the effect of nursery diet sources, porcine circovirustype 2 (PCV2) and Mycoplasma hyopneumoniae (M. hyo) vaccines, and vaccination timing on pig (Sus scrofa) performance. In Exp. 1, a total of 400 pigs (5.6 BW, 1.03 kg SD) were used in a 20-d study. Treatments were arranged in a 4 × 2 factorial in a blocked design (5 pigs/pen and10 pens/treatment), with main effects of diet manufacturing source (A, B, C, or D) and vaccination timing (d 0 or 8). On either d 0 (weaning) or 8, pigs received 2 vaccines (Circumvent PCV, Intervet/Schering-Plough Animal Health, Millsboro, DE; and RespiSure One, Pfizer Animal Health, New York, NY). A pre-determined amount of segregated early weaning (SEW) diet (0.45 kg/pig) was fed followed by a transition diet until d 8, and a common diet from d 8 to 20. Diet source affected (P < 0.001) ADG during the first 4 d and affected (P ≤ 0.02) ADG and ADFI from d 4 to 8. There were no differences (P ≥ 0.18) among diet sources once pigs were fed a common diet (d 8 to 20). Overall, diet source did not affect ADG; but ADFI tended (P = 0.06) to be decreased for pigs fed Diet C compared with those fed Diets A, B, and D. Pigs vaccinated on d 0 had decreased (P ≤ 0.01) ADG and ADFI (d 4 to 8 and d 0 to 8), resulting in lighter (P = 0.003) BW on d 8 than those of pigs not yet vaccinated (d 8). However, overall ADG was not affected by vaccination timing. In Exp. 2, 360 pigs (5.9 SD, 0.91 kg BW) were used in a 35-d trial to evaluate the effects of different vaccines. Treatments were arranged in a 3 by 2 factorial in a blocked design (5 pigs/pen and 12 pens/treatment). Main effects included PCV2 vaccine (none; CircoFLEX, Boehringer Ingelheim Vetmedica Inc., St. Joseph, MO; or Circumvent PCV); with or without M. hyo vaccine (RespiSure, Pfizer Animal Health, New York, NY). Overall, pigs vaccinated with Circumvent PCV had decreased (P < 0.02) ADG and ADFI compared with CircoFLEX-vaccinated or control pigs. On d 35, pigs vaccinated with Circumvent PCV weighed less (P < 0.01) than CircoFLEX-vaccinated or control pigs. RespiSure-vaccinated pigs had decreased (P ≤ 0.05) ADG compared with control pigs from d 14 to 21 and d 21 to 29. On d 35, RespiSure-vaccinated pigs tended (P = 0.06) to weigh and consume less than control pigs. These data indicate diet source and vaccination timing affects pig performance after weaning. Vaccination for PCV2 and M. hyo independently reduced ADG and ADFI, but the effect was product-dependent.

Hypermobility and musculoskeletal pain in children: a systematic review.

OBJECTIVE: To examine the evidence of an association between hypermobility and musculoskeletal pain in children. METHODS: A systematic review of the literature was performed using the databases PubMed, EMBASE, NHS Evidence, and Medline. Inclusion criteria were observational studies investigating hypermobility and musculoskeletal pain in children. Exclusion criteria were studies conducted on specialist groups (i.e. dancers) or hospital referrals. Pooled odds ratios (ORs) were calculated using random effects models and heterogeneity was tested using χ(2)-tests. Study quality was assessed using the Newcastle-Ottawa Scale for case-control studies. RESULTS: Of the 80 studies identified, 15 met the inclusion criteria and were included in the review. Of these, 13 were included in the statistical analyses. Analysing the data showed that the heterogeneity was too high to allow for interpretation of the meta-analysis (I(2) = 72%). Heterogeneity was much lower when the studies were divided into European (I(2) = 8%) and Afro-Asian subgroups (I(2) = 65%). Sensitivity analysis based on data from studies reporting from European and Afro-Asian regions showed no association in the European studies [OR 1.00, 95% confidence interval (CI) 0.79-1.26] but a marked relationship between hypermobility and joint pain in the Afro-Asian group (OR 2.01, 95% CI 1.45-2.77). Meta-regression showed a highly significant difference between subgroups in both meta-analyses (p < 0.001). CONCLUSION: There seems to be no association between hypermobility and joint pain in Europeans. There does seem to be an association in Afro-Asians; however, there was a high heterogeneity. It is unclear whether this is due to differences in ethnicity, nourishment, climate or study design.

Comparative feeding kinematics and performance of odontocetes: belugas, Pacific white-sided dolphins and long-finned pilot whales.

Cetaceans are thought to display a diversity of feeding modes that are often described as convergent with other more basal aquatic vertebrates (i.e. actinopterygians). However, the biomechanics of feeding in cetaceans has been relatively ignored by functional biologists. This study investigated the feeding behavior, kinematics and pressure generation of three odontocetes with varying feeding modes (belugas, Delphinapterus leucas; Pacific white-sided dolphins, Lagenorhynchus obliquidens; and long-finned pilot whales, Globicephala melas). Four feeding phases were recognized in all odontocetes: (I) preparatory, (II) jaw opening, (III) gular depression, and (IV) jaw closing. Belugas relied on a feeding mode that was composed of discrete ram and suction components. Pacific white-sided dolphins fed using ram, with some suction for compensation or manipulation of prey. Pilot whales were kinematically similar to belugas but relied on a combination of ram and suction that was less discrete than belugas. Belugas were able to purse the anterior lips to occlude lateral gape and form a small, circular anterior aperture that is convergent with feeding behaviors observed in more basal vertebrates. Suction generation in odontocetes is a function of hyolingual displacement and rapid jaw opening, and is likely to be significantly enhanced by lip pursing behaviors. Some degree of subambient pressure was measured in all species, with belugas reaching 126 kPa. Functional variations of suction generation during feeding demonstrate a wider diversity of feeding behaviors in odontocetes than previously thought. However, odontocete suction generation is convergent with that of more basal aquatic vertebrates.

SNPs in dopamine D2 receptor gene (DRD2) and norepinephrine transporter gene (NET) are associated with continuous performance task (CPT) phenotypes in ADHD children and their families.

Haplotype-tagging SNP analyses were conducted to identify molecular genetic substrates of quantitative phenotypes derived from performance on a Continuous Performance Task (CPT). Three hundred sixty-four individuals were sampled from 152 families ascertained on the basis of at least one child having ADHD. Probands, their affected and unaffected siblings, and parents were administered a CPT. Four different components of performance were analyzed and tested for association with SNPs from 10 candidate genes involved in monoaminergic function. After correcting for multiple comparisons and controlling for multiple individuals from the same family, significant associations were identified between commission errors and SNPs in the DRD2 gene (rs2075654, rs1079596), and between reaction time variability and a SNP in the NET gene (rs3785155). These findings suggest that commission errors and reaction time variability are excellent candidates as ADHD endophenotypes based on previously published criteria. Results also shed light on the molecular genetic basis of specific processes that may underlie the disorder.

Regulation of myosin light chain phosphorylation by RhoB in neuronal cells.

The phosphorylation of myosin light chain (MLC) is a key regulatory point in the control of cellular morphology. Evidence suggests that RhoA-a member of the Rho GTPase family-regulates MLC phosphorylation via Rho kinase (ROK). Neurones display subtle alterations in their cytoarchitecture during the synaptic plasticity following high-frequency stimulation. We have recently demonstrated that RhoB, and not RhoA, is activated in neurones by high-frequency stimulation. However, the downstream consequences of RhoB activation in cells are unclear. In this study, we tested the hypothesis that RhoB might stimulate neuronal MLC phosphorylation. Transfection of PC12 cells with constitutively active RhoB increased MLC phosphorylation. Conversely, dominant-negative RhoB vectors reduced MLC phosphorylation. The effect of RhoB was attenuated by pretreatment with a selective ROK inhibitor. This confirms that Rho GTPases are important regulators of MLC phosphorylation, but suggests that, in neuronal cells, the control is exerted via RhoB rather than RhoA.

Evaluation of the virological and metabolic effects of switching protease inhibitor combination antiretroviral therapy to nevirapine-based therapy for the treatment of HIV infection.

In spite of indisputable benefits, the use of antiretroviral therapy is associated with multiple metabolic complications. Switching to simpler regimens might maintain viral suppression, improve metabolic side effects, and provide insight into the pathogenesis of these complications. Our objective was to carefully characterize the virological and metabolic effects of switching from a successful protease inhibitor (PI)-based antiretroviral regimen to a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen with nevirapine (NVP). Forty patients, taking their first successful (less than 40 HIV RNA copies/ml) PI-based regimen, switched their PI to NVP. If patients did not tolerate NVP, substitution with efavirenz was allowed. The duration of the study was 48 weeks. At 12 weeks intervals subjects had multiple virological and metabolic parameters including glucose, insulin, C-peptide, glucagon, proinsulin, blood lipids, and lipoproteins. A subgroup of 18 patients also had body composition evaluations with DEXA scans and MRIs of the abdomen and the thighs as well as insulin tolerance tests. Ninety-five percent of the patients maintained viral suppression (95% CI 88-100%); only one patient failed and another developed hepatitis. There were improvements in glucose (decreased fasting glucose, insulin, and improved insulin tolerance) and lipid metabolism (decreased triglycerides and increased HDL), but no changes in body composition and bone mineral density. Our study supports a pathogenic role for PIs in the development of hypertriglyceridemia and insulin resistance, but a more limited role in the fat redistribution syndrome.

Increased long-term potentiation in the CA1 region of rat hippocampus via modulation of GTPase signalling or inhibition of Rho kinase.

There is accumulating evidence that Ras, and Ras-related GTPases of the Rho family, such as RhoA, RhoB and Rac1, are involved in synaptic plasticity in brain regions such as the hippocampus. We have recently shown that Rho family GTPases are activated by synaptic transmission in the CA1 region of the hippocampus. Since the function of these GTPases is dependent on post-translational isoprenylation by either farnesyl or geranylgeranyl transferases, we tested the hypothesis that inhibition of isoprenylation would modify long-term potentiation (LTP). Farnesyl transferase inhibition, which suppressed activation of RhoB and Ras but not RhoA or Rac1, reduced the magnitude of LTP, while geranylgeranyl transferase inhibition, which inhibited RhoA and Rac1 but not RhoB, increased the magnitude of LTP. In addition, Y-27632, a specific inhibitor of a downstream effector of Rho GTPases-Rho-kinase-also increased the magnitude of LTP. This provides strong evidence that GTPases are important mediators of synaptic plasticity, and demonstrates that Rho-kinase acts to reduce the degree of plasticity at hippocampal synapses during LTP. Rho-kinase inhibitors have the unusual property of increasing the magnitude of LTP, and so may be potential cognitive enhancers.