Wave intensity analysis and its application to the coronary circulation.

Wave intensity analysis (WIA) is a technique developed from the field of gas dynamics that is now being applied to assess cardiovascular physiology. It allows quantification of the forces acting to alter flow and pressure within a fluid system, and as such it is highly insightful in ascribing cause to dynamic blood pressure or velocity changes. When co-incident waves arrive at the same spatial location they exert either counteracting or summative effects on flow and pressure. WIA however allows waves of different origins to be measured uninfluenced by other simultaneously arriving waves. It therefore has found particular applicability within the coronary circulation where both proximal (aortic) and distal (myocardial) ends of the coronary artery can markedly influence blood flow. Using these concepts, a repeating pattern of 6 waves has been consistently identified within the coronary arteries, 3 originating proximally and 3 distally. Each has been associated with a particular part of the cardiac cycle. The most clinically relevant wave to date is the backward decompression wave, which causes the marked increase in coronary flow velocity observed at the start of the diastole. It has been proposed that this wave is generated by the elastic re-expansion of the intra-myocardial blood vessels that are compressed during systolic contraction. Particularly by quantifying this wave, WIA has been used to provide mechanistic and prognostic insight into a number of conditions including aortic stenosis, left ventricular hypertrophy, coronary artery disease and heart failure. It has proven itself to be highly sensitive and as such a number of novel research directions are encouraged where further insights would be beneficial.

Patient-specific coronary stenoses can be modeled using a combination of OCT and flow velocities to accurately predict hyperemic pressure gradients.

Computational fluid dynamics (CFD) is increasingly being developed for the diagnostics of arterial diseases. Imaging methods such as computed tomography (CT) and angiography are commonly used. However, these have limited spatial resolution and are subject to movement artifact. This study developed a new approach to generate CFD models by combining high-fidelity, patient-specific coronary anatomy models derived from optical coherence tomography (OCT) imaging with patient-specific pressure and velocity phasic data. Additionally, we used a new technique which does not require the catheter to be used to determine the centerline of the vessel. The CFD data were then compared with invasively measured pressure and velocity. Angiography imaging data of 21 vessels collected from 19 patients were fused with OCT visualizations of the same vessels using an algorithm that produces reconstructions inheriting the in-plane (10 µm) and longitudinal (0.2 mm) resolution of OCT. Proximal pressure and distal velocity waveforms ensemble averaged from invasively measured data were used as inlet and outlet boundary conditions, respectively, in CFD simulations. The resulting distal pressure waveform was compared against the measured waveform to test the model. The results followed the shape of the measured waveforms closely (cross-correlation coefficient = 0.898 ± 0.005, ), indicating realistic modeling of flow resistance, the mean of differences between measured and simulated results was -3. 5 mmHg, standard deviation of differences (SDD) = 8.2 mmHg over the cycle and -9.8 mmHg, SDD = 16.4 mmHg at peak flow. Models incorporating phasic velocity in patient-specific models of coronary anatomy derived from high-resolution OCT images show a good correlation with the measured pressure waveforms in all cases, indicating that the model results may be an accurate representation of the measured flow conditions.

Bone healing and the effect of implant surface topography on osteoconduction in hyperglycemia.

Dental implant failures that occur clinically for unknown reasons could be related to undiagnosed hyperglycemia. The exact mechanisms that underlie such failures are not known, but there is a general consensus that bone growth is compromised in hyperglycemia. Nevertheless, contradictory findings exist related to peri-implant bone healing in hyperglycemia. We hypothesized that hyperglycemia delays early bone healing by impeding osteoconduction, and that the compromised implant integration due to hyperglycemia could be abrogated by using nanotopographically complex implants. Thus we undertook two parallel experiments, an osteotomy model and a bone in-growth chamber model. The osteotomy model tracked temporal bone healing in the femora of euglycemic and hyperglycemic rats using micro computed tomography (microCT) analysis and histology. The bone in-growth chamber model used implant surfaces of either micro- or nanotopographical complexity and measured bone-implant contact (BIC) using backscattered electron imaging in both metabolic groups. Quantitative microCT analyses on bone volume, trabeculae number and trabeculae connectivity density provided clear evidence that bone healing, both reparative trabecular bone formation and remodeling, was delayed in hyperglycemia, and the reparative bone volume changed with time between metabolic groups. Furthermore, fluorochrome labeling showed evidently less mineralized bone in hyperglycemic than euglycemic animals. An increased probability of osteoconduction was seen on nano-compared with microtopographically complex surfaces, independent of metabolic group. The nanotopographically complex surfaces in hyperglycemia outperformed microtopographically complex surfaces in euglycemic animals. In conclusion, the compromised implant integration in hyperglycemia is abrogated by the addition of nanotopographical features to an underlying microtopographically complex implant surface.

Plasma C-terminal proEndothelin-1 (CTproET-1) is affected by age, renal function, left atrial size and diastolic blood pressure in healthy subjects.

Endothelin-1 (ET-1) is a short chained peptide primarily of endothelial origin. Concentrations of this peptide are increased in subjects with hypertension, primary pulmonary hypertension and myocardial infarction, however its short half-life makes quantification difficult. The C-terminal of proET-1 (CTproET-1) is stoichiometrically secreted with its bioactive peptide and would be a valid method of measuring the active peptide as it has a stable half-life and is less resistant to proteolytic cleavage. The objective of this study was to understand the factors (clinical, echocardiographic and biochemical) that specifically influence plasma CTproET-1 in healthy subjects. 518 healthy volunteers were recruited from a screening study. Plasma CTproET-1 concentrations were quantified using a novel immunoluminometric sandwich assay. In multivariate analyses, age (P<0.001), diastolic BP (P=0.007), LA size (P=0.001) and eGFR (P<0.001) were independently predictive of plasma CTproET-1 levels in the healthy subjects. Therefore the interpretation of plasma CTproET-1 levels in such individuals should take into account these variables to avoid potential confounding.

Location of side branch access critically affects results in bifurcation stenting: Insights from bench modeling and computational flow simulation.

BACKGROUND: The aim of this study was to evaluate the impact of stent design and side branch access on final strut apposition during bifurcation stenting. METHODS AND RESULTS: A series of 6 different commercially available Drug Eluting Stents (DES) (n=42) were deployed in an identical model of a coronary bifurcation. Kissing Balloon (KB) optimization was performed after either proximal or distal recrossing of the guidewire and results were analyzed by micro-Computed-Tomography. Stent design only had a minor impact on side branch lumen area free of stent struts. Similar rate of strut malapposition was observed within the bifurcation when a consistent KB optimization protocol and an optimal distal recrossing of the wire to reaccess the side branch (SB) are followed. Conversely, proximal instead of distal cell recrossing toward the side branch produced a significant lower area of the side branch lumen free of struts than an optimal distal recrossing (60.3±7.1% versus 81.1±8.0%, p<0.0001), as well as a higher rate of strut malapposed toward the SB ostium (40.6±6.0% versus 26.0±5.7%, p=0.0005). CONCLUSIONS: Optimal cell recrossing of the guidewire may be critical to ensure successful stent optimization in bifurcation PCI.

Recent developments in renal denervation.

Renal denervation is a novel catheter based approach that has been shown to effectively lower blood pressure in patients with resistant hypertension. Small studies have shown additional benefits in patients being treated for hypertension, such as improvements in insulin sensitivity, sleep apnoea and arrhythmias. More recently, it has been used for the first time for the treatment of sympathetic overactivation in patients with chronic systolic heart failure. Currently renal denervation therapy uses electrode-tipped catheters which deliver radio frequency energy to sympathetic afferent and efferent nerves running close to the lumen of the renal arteries. Further trials are on-going to assess the utility of this novel therapy in disease states beyond resistant hypertension.

Stent flexibility versus concertina effect: mechanism of an unpleasant trade-off in stent design and its implications for stent selection in the cath-lab.

The "concertina effect", longitudinal deformation of the proximal segments of a deployed stent when force is applied from a guide catheter or other equipment, is a recently recognised problem which seems to particularly affect more recent stent designs. Until now, flexibility and deliverability have been paramount aims in stent design. Developments have focussed on optimising these features which are commonly evaluated by clinicians and demanded by regulatory bodies. Contemporary stent designs now provide high flexibility by reducing the number of connecting links between stent segments and by allowing the connecting links to easily change their length. These design evolutions may, however, simultaneously reduce longitudinal strength and have the unintended effect of inducing some risk of longitudinal compression of the stent (the "concertina effect") during difficult clinical cases. Progress in stent design and elimination of restenosis by drug coating has improved PCI outcome and enabled new applications. Here we discuss design trade-offs that shaped evolution and improvement in stent design, from early bare metal designs to the latest generation of drug eluting stent (DES) platforms. Longitudinal strength was not recognised as a critical parameter by clinicians or regulators until recently. Measurements, only now becoming publically available, seem to confirm vulnerability of some modern designs to longitudinal deformation. Clinicians could be more guarded in their assumption that changes in technology are beneficial in all clinical situations. Sometimes a silent trade-off may have taken place, adopting choices that are favourable for the vast majority of patients but exposing a few patients to unintended hazard.

Developing and paying for medicines for orphan indications in oncology: utilitarian regulation vs equitable care?

Despite 'orphan drug' legislation, bringing new medicines for rare diseases to market and securing funding for their provision is sometimes both costly and problematic, even in the case of medicines for very rare 'ultra orphan' oncological indications. In this paper difficulties surrounding the introduction of a new treatment for osteosarcoma exemplify the challenges that innovators can face. The implications of current policy debate on 'value-based' medicines pricing in Europe, North America and elsewhere are also explored in the context of sustaining research into and facilitating cancer patient access to medicines for low-prevalence indications. Tensions exist between utilitarian strategies aimed at optimising the welfare of the majority in the society and minority-interest-focused approaches to equitable care provision. Current regulatory and pricing strategies should be revisited with the objective of facilitating fair and timely drug supply to patients without sacrificing safety or overall affordability. Failures effectively to tackle the problems considered here could undermine public interests in developing better therapies for cancer patients.

The diagnostic performance of mid-regional portion of pro-atrial natriuretic peptide for the detection of left ventricular hypertrophy in Caucasian hypertensive patients.

Left ventricular hypertrophy (LVH) is predictive of cardiovascular disease. The vasodilator, natriuretic and diuretic actions of atrial natriuretic peptide (ANP) support a role in the pathophysiology of hypertension. Measuring the redundant precursor fragment mid-regional portion of pro-atrial natriuretic peptide (MRproANP) overcomes the technical difficulties of quantifying the bioactive ANP. This study sought to investigate the diagnostic and prognostic utility of MRproANP in a hypertensive Caucasian patient population. A total of 194 hypertensive patients (39 patients with LVH, 69±7.82 years of age, 74% female vs 155 patients without LVH, 68±6.51 years of age, 71% female) were derived from a screening study. Plasma MRproANP concentrations were quantified using immunoluminometric assays. Hypertensive patients with LVH had higher MRproANP concentrations than those without LVH (103.04 (50.58) vs 84.11 pmol l(-1) (44.82); P=0.014). Independent predictors of left ventricular mass index were LogMRproANP (P=0.022), male gender (P<0.001), body mass index (P=0.001) and history of angina or myocardial infarction (P=0.009). The receiver operating curve for MRproANP for the detection of LVH was limited, yielding an area under the curve of only 0.628 (confidence interval 0.523-0.733; P=0.014). Therefore, the role of MRproANP may not lie in the diagnosis of LVH but in monitoring the response to therapy. A nonsignificant trend towards greater mortality in patients with above-median MRproANP levels compared with below-median levels (P=0.167) was observed. Larger studies are required to assess its prognostic utility further.

Influence of confounding factors on plasma mid-regional pro-adrenomedullin and mid-regional pro-A-type natriuretic peptide concentrations in healthy individuals.

BACKGROUND: MRproADM and MRproANP can be used as diagnostic and prognostic markers in heart failure. AIM: The objective was to identify confounding factors for the interpretation of plasma MRproADM and MRproANP concentrations. METHODS: A total of 518 healthy volunteers with a mean age of 60.84 ± 7.41 years were analyzed. We evaluated the influence of demographic factors, renal function and echocardiographic indices on the candidate peptides. RESULTS: Multivariate analysis revealed that age (P < 0.001), BMI (P < 0.001) and eGFR (P < 0.001) were independent predictors for MRproADM concentrations in healthy subjects. The independent predictors for MRproANP were age (P < 0.001), female gender (P < 0.001), heart rate (P < 0.001) and eGFR (P = 0.039). CONCLUSION: The interpretation of both peptides is multifaceted due to confounders. Knowledge of these factors will further our understanding of how these peptides behave in health and in disease.

Low-temperature particulate calcium phosphates for bone regeneration.

BACKGROUND: Low-temperature synthesized calcium phosphates are produced by mixing calcium phosphate powders in an aqueous solution resulting in a precipitated phase. These compounds can be formulated in several forms (e.g. injectable cements and implantable blocks), and are commonly used as bone substitutes and drug delivery systems for the treatment of bone defects. As bone substitutes, calcium phosphates in general offer the advantages of being biocompatible and osteoconductive. AIMS: The present work employed a machine-based process to derive a reproducible preparation method for low-temperature calcium phosphate particulate (LTCP). The in vivo outcomes of LTCP were compared with those of three commercially available bone substitutes by histomorphometric measurements of bone formation and material degradation in a rat femur implantation model. MATERIALS & METHODS: Specifically, LTCP, anorganic bovine bone (AB), bioactive glass (BG), and demineralized bone matrix (DBM) were implanted in defects created in the distal aspect of rat femora. Reparative bone and particulate volumes of these biomaterials were evaluated post-operatively using micro-computed tomography and histological analyses at 3, 6, 12, and 16 weeks. RESULTS & DISCUSSION: Results showed that, despite invoking bone formation, AB, BG, and DBM were found un-resorbed in situ at 16 weeks. Conversely, LTCP showed an early increase in bone formation as well as clear evidence of complete degradation and reparative bone remodelling, resulting in the total reconstitution of the marrow cavity and marrow tissue. CONCLUSION: LTCP promoted increased early bone formation, associated with an improved degradation rate, compared with the other three bone-substitute biomaterials tested.

Use of gastrointestinal proton pump inhibitors to regulate osteoclast-mediated resorption of calcium phosphate cements in vivo.

Osteoclasts degrade bone through the creation of an enclosed, acidic extracellular microenvironment adjacent to the bone surface. Membrane bound proton pumps in the osteoclast cell membrane function to create this acidified environment. Accordingly, this H(+) ion transport mechanism provides a potential target for a specific class of drugs, proton pump inhibitors (PPI), with a view to controlling osteoclast mediated bone resorption. Self setting calcium phosphate cements are common bone graft materials that are degraded by osteoclastic activity. We have already shown that incorporation of bafilomycin, a non-regulated PPI, within these cements prevents or delays osteoclast mediated resorption of the cement. We demonstrate here that two regulated proton pump inhibitors, Pantaprazole and Omeprazole, currently used clinically to treat gastroesophageal reflux disorders, are effective in inhibiting osteoclast mediated resorption in-vivo when delivered to a bony defect in self setting calcium phosphate cements. As determined by qualitative histology, Pantaprazole at a dose of 0.5mg/ml produced a delay in osteoclast resorption whilst this effect was not as evident using Omeprazole at an equivalent dose, but higher doses of Omeprazole (40mg/ml) did delay cement resorption. These data demonstrate, for the first time, the functional effect of blocking the H(+)/K(+) ATPase pump in-vivo on the capacity of osteoclasts to resorb bone and the potential of this strategy to modulate osteoclast mediated resorption of calcium phosphate biomaterials.

Quantifying the paradoxical effect of higher systolic blood pressure on mortality in chronic heart failure.

BACKGROUND: Although higher blood pressures are generally recognised to be an adverse prognostic marker in risk assessment of cardiology patients, its relationship to risk in chronic heart failure (CHF) may be different. OBJECTIVE: To examine systematically published reports on the relationship between blood pressure and mortality in CHF. METHODS: Medline and Embase were used to identify studies that gave a hazard or relative risk ratio for systolic blood pressure in a stable population with CHF. Included studies were analysed to obtain a unified hazard ratio and quantify the degree of confidence. RESULTS: 10 studies met the inclusion criteria, giving a total population of 8088, with 29 222 person-years of follow-up. All studies showed that a higher systolic blood pressure (SBP) was a favourable prognostic marker in CHF, in contrast to the general population where it is an indicator of poorer prognosis. The decrease in mortality rates associated with a 10 mm Hg higher SBP was 13.0% (95% CI 10.6% to 15.4%) in the heart failure population. This was not related to aetiology, ACE inhibitor or beta blocker use. CONCLUSION: SBP is an easily measured, continuous variable that has a remarkably consistent relationship with mortality within the CHF population. The potential of this simple variable in outpatient assessment of patients with CHF should not be neglected. One possible application of this information is in the optimisation of cardiac resynchronisation devices.

In vitro immunologic properties of human umbilical cord perivascular cells.

BACKGROUND: It has been shown recently that human umbilical cord perivascular cells (HUCPVC) are bio-equivalent to bone marrow-derived mesenchymal stromal cells (BM-MSC) in their mesenchymal differentiation and marker expression. HUCPVC populations provide high yields of rapidly proliferating mesenchymal progenitor cells. The question we wished to address, in two independent laboratory studies, was whether HUCPVC exhibit a similar in vitro immunologic phenotype to that of BM-MSC. METHODS: HUCPVC were isolated by physical extraction of umbilical vessels followed by enzymatic digestion of the perivascular cells, and lymphocytes were obtained from heparinized human peripheral blood. Experimental evaluations were lymphocyte proliferation in HUPCVC or BM-MSC co-cultures with peripheral blood lymphocytes (PBL), mixed lymphocyte cultures (MLC) containing BM-MSC or HUCPVC, CD25 and CD45 expression in co-cultures containing HUCPVC, and finally lymphocyte proliferation in TransWell MLC with HUCPVC. RESULTS: Both HUCPVC and BM-MSC showed no significant increase in proliferation of lymphocytes when co-cultured. The addition of 10% HUCPVC or BM-MSC significantly reduced proliferation of PBL in one-way MLC. Upon inclusion of HUCPVC with activated T-cell lines, the expression of both CD25 and CD45 showed a significant decrease. HUCPVC were able to reduce lymphocyte cell numbers significantly when separated with a membrane insert. DISCUSSION: HUCPVC are not alloreactive and exhibit immunosuppression in vitro. Lymphocyte activation is significantly reduced in the presence of HUCPVC, and the immunosuppressive effect of HUCPVC is due, in part, to a soluble factor. Thus HUCPVC shows a similar immunologic phenotype to BM-MSC.

N-terminal pro-B-type natriuretic peptide is better than TIMI risk score at predicting death after acute myocardial infarction.

BACKGROUND: The TIMI risk score is a well-validated scoring system used to predict mortality in patients following an ST-segment elevation myocardial infarction (STEMI). N-terminal pro-B-type natriuretic peptide (NTproBNP) has also been found to be useful in predicting mortality following STEMI. OBJECTIVE: To investigate the utility of the TIMI score and NTproBNP levels at predicting risk of death in patients with acute myocardial infarction (AMI). METHODS: 473 patients (352 men, mean (SD) age 63.7 (12.3) years) with AMI were studied. Blood was drawn within 24 hours after the onset of chest pain and the plasma concentration of NTproBNP was determined using an in-house non-competitive immunoassay. Patients' TIMI risk score was measured and patients stratified into low- (0 to 2), intermediate- (3-7) and high-risk (>8) groups. RESULTS: Mortality was 8.9% and was related to higher TIMI risk scores (p = 0.029 for trend). Higher NTproBNP levels were also related to increased mortality (median (range) fmol/ml, survivors 700.2 (0.3-11485.3) vs dead 5781.3 (1.4-10835.9), p<0.001). In a multivariate binary logistic regression model, independent predictors of mortality were NTproBNP levels in the first 24 hours (odds ratio (OR) = 4.21, 95% CI 1.96 to 9.07, p<0.001) together with drug treatments. The receiver operating curve for NTproBNP in the first 24 hours yielded an area under the curve (AUC) of 0.79 (95% CI 0.70 to 0.88), p<0.001, for TIMI risk score the AUC was 0.67 (95% CI 0.58 to 0.76), p = 0.001. CONCLUSION: In the first 24 hours following an AMI, NTproBNP is better than the TIMI risk score at predicting mortality. A simple NTproBNP blood test is more easily applicable and is more accurate than a clinical risk score.

Changes in the conformational structure, microscopic and macroscopic pK(a)s of meloxicam on complexation with natural and modified cyclodextrins.

Spectroscopic and phase solubility techniques have been used to study the complexation of neutral meloxicam (Mel) with alpha-, beta-, gamma- and HP-beta-cyclodextrins (CDs). The results indicate that neutral Mel has two conformational structures, enol and zwitterions, with the latter more dominant in water. The two pK(a)s of Mel were found to change in the presence of beta-CD, where a blue shift in lambdamax was observed but not in the presence of alpha, HP-beta- and gamma-CD. Rigorous analysis of phase solubility diagrams indicate that beta- and HP-beta-CD form 1:2 Mel/beta-CD type complexes with Mel while alpha- and gamma-CD form only 1:1 complexes. The fact that the overall 1:2 Mel/CD complex formation constant (beta12) was found significantly higher for beta-CD than for HP-beta-CD, combined with further spectroscopic studies, indicate that beta-CD favors inclusion of the neutral enol form over the zwitterion. Unlike alpha-, HP-beta- and gamma-CDs, the hydrophobic microenvironment of a tight 1:2 Mel/beta-CD complex was found to mimic those of organic solvents, thus favoring inclusion of the enol rather than the zwitterion, and hence shifting the tautomerization equilibrium towards the enol conformer.

A three-phase, fully resorbable, polyester/calcium phosphate scaffold for bone tissue engineering: Evolution of scaffold design.

Bone tissue engineering strategies are fundamentally based upon porous scaffold materials that serve as a support for ingrowth of host cells and/or provide a substrate for exogenously delivered cells. Here we report the application of a surface calcium phosphate (CaP) mineral layer to a macroporous polymeric/CaP composite biomaterial, with a macroporous interconnectivity, and its subsequent in vivo evaluation in a rodent femoral defect. The application of the mineral layer eliminates the fibrous tissue encapsulation and foreign body giant cell response commonly seen at the interface of polymeric materials, yet retains the unique characteristics of the parent material as being macroporous, completely biodegradable and possessing a high degree of interconnectivity. This represents the third generation of this scaffold material, incorporating iterative changes to the scaffold design in response to both materials and biological design criteria to produce a material with enhanced in vitro and in vivo performance.

In vivo response to starch-based scaffolds designed for bone tissue engineering applications.

Our purpose was to evaluate the in vivo endosseous response to three starch-based scaffolds implanted in rats (n = 54). We implanted the three scaffold groups; a 50/50 (wt %) blend of corn starch and ethylene-vinyl alcohol (SEVA-C), the same composition coated with a biomimetic calcium phosphate (Ca-P) layer (SEVA-C/CaP), and a 50/50 (wt %) blend of corn starch and cellulose acetate (SCA), all produced by extrusion with blowing agents, into distal femurs proximal to the epiphyseal plate, for 1, 3, or 6 weeks. Our results showed that at 1 week considerable reparative bone formed around all scaffold groups, although the bone was separated from the scaffold by an intervening soft tissue interfacial zone that comprised two distinct compartments: the surface of the scaffold was occupied by multinucleate giant cells and the compartment between these cells and the surrounding bone was occupied by a streaming fibrous-like tissue. The extracellular matrix of the latter was continuous with the extracellular bone matrix itself, labeled positively for osteocalcin and appeared mineralized by back-scattered electron imaging. All three scaffolds showed a similar tissue response, with the soft tissue interface diminishing with time. No bone contact was observed with SEVA-C at any time point, only transitory bone contact was observed with SEVA-C/CaP at 3 weeks, but SCA exhibited direct bone contact at 6 weeks where 56.23 +/- 6.46% of the scaffold surface was occupied by bone. We conclude that all materials exhibited a favorable bony response and that the rapidly forming initial "connective tissue" seen around all scaffolds was a very early form of bone formation.

Polyalanine and polyserine frameshift products in Huntington's disease.

Codon reiteration disorders are caused by abnormal expansions of either polyglutamine or polyalanine tracts within the coding region of a protein. These mutations impair normal protein folding, resulting in aggregate formation in the affected tissues. Huntington's disease is the most common of the nine disorders caused by polyglutamine expansion mutations. The most extensively studied polyalanine expansion disorder is oculopharyngeal muscular dystrophy. There may be a link between diseases caused by polyglutamine and polyalanine expansion mutations as it has been shown that the expanded CAG/polyglutamine tract within the SCA3 gene can shift to the GCA[corrected]/polyalanine frame. Here, we show that this frameshifting phenomenon is more widespread and occurs in Huntington's disease. We have shown both +1 frameshift and +2 frameshift products (which may contain polyalanine or polyserine tracts, respectively) in human postmortem Huntington's disease brains and in a transgenic mouse model of Huntington's disease. Our data suggest that +1 and +2 frameshift products are generated at low levels. This may be relevant to the pathogenesis of human Huntington's disease, as we have previously shown that both polyserine and polyalanine-containing proteins are modifiers of mutant huntingtin toxicity, with low expression levels of polyalanine-containing proteins having a protective effect.