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At least 1,135 records · Page 63Linked to original sources
PubMed1999

Protease inhibitor-containing regimens compared with nucleoside analogues alone in the suppression of persistent HIV-1 replication in lymphoid tissue.

OBJECTIVE: Lymphoid tissue provides a reservoir where HIV can persist. However, therapies incorporating a protease inhibitor can target this reservoir. This study was designed to investigate the relative long-term effects on lymph-node viral load and cellular architecture of regimens containing multiple nucleosides alone or in combination with protease inhibitors. METHODS: Axillary lymph-node biopsies from 12 patients with undetectable viraemia (viral load < 20 copies/ml: mean CD4 cells 525 x 10(6)/l) for a mean period of 25 months (range, 10-52 months) were investigated for the presence of HIV by in situ hybridization and coculture. Four patients were receiving multiple nucleoside analogues alone or in one case with a suboptimally dosed protease inhibitor (group I). Protease inhibitor was added to the regimen of seven patients at least 6 months prior to lymph-node biopsy (group II). Standard flow cytometry and virological data were obtained from peripheral blood every 3 months. RESULTS: By in situ hybridization, more productively infected CD4+ T cells were found in the lymph nodes of group I patients treated with nucleoside analogues alone. Very low numbers of productively infected lymph node cells were detected in the protease inhibitor-treated group II. No trapping of virions on the follicular dendritic cell (FDC) network was detectable in protease inhibitor-treated patients. In contrast, large deposits of FDC-bound virions were observed in three out of five patients from group I. Virus cultures from lymph node cells were positive in these three group I patients compared with only one out of seven patients from group II. Sequencing reverse transcriptase and protease genes from these isolates revealed typical mutations conferring resistance to the previously administered nucleoside analogue. A more preserved lymph node architecture and less signs of immunopathological change were also observed in protease inhibitor-treated patients. CONCLUSIONS: Undetectable plasma viraemia using the ultrasensitive PCR assay for prolonged periods of time does not always reflect complete HIV-1 suppression within the lymphoid compartment. Our results suggest that protease inhibitor-containing regimens target HIV reservoirs in lymphoid tissue more effectively and preserve or restore lymph node architecture.

Anti-HIV Agents↗
PubMed2000

PMP22 carrying the trembler or trembler-J mutation is intracellularly retained in myelinating Schwann cells.

Missense mutations in the murine peripheral myelin protein-22 gene (Pmp22) underly the neuropathies in the trembler (Tr) and trembler-J (Tr-J) mice and in some humans with Charcot-Marie-Tooth disease. We have generated replication-defective adenoviruses containing epitope-tagged, wild-type-, Tr-, or Tr-J-PMP22 bicistronic with the Lac-Z reporter gene. These viruses were microinjected into the sciatic nerves of 10-day-old Sprague-Dawley rats and, later, analyzed by immunohistochemistry to determine the distribution of mutant protein in infected myelinating Schwann cells. We found that epitope-tagged, wild-type PMP22 is successfully transported to compact myelin, whereas the Tr and the Tr-J mutant proteins are retained in cytoplasmic compartment, colocalizing with the endoplasmic reticulum. These results provide in vivo evidence that the pathogenesis of the Tr and Tr-J mutations are most likely a function of abnormal retention within the endoplasmic reticulum of myelinating Schwann cells.

Adenoviridae↗
PubMedDate not supplied

Telomere biology of human hematopoietic stem cells.

BACKGROUND: Telomeres are protein DNA structures present at the ends of chromosomes and are essential for genetic stability and cell replication. Telomerase is the enzyme complex that maintains telomere integrity. Hematopoietic stem cells express telomerase and contain long telomeres, which become shorter as cells differentiate and mature. The extent of telomere shortening and the level of telomerase activity often correlate with the presence and severity of some hematopoietic diseases. METHODS: The fundamentals of telomeres and telomerase are reviewed, and the telomere biology of human hematopoietic cells is discussed. RESULTS: Telomere length and telomerase activity are important in the self-renewal of hematopoietic stem cells. Changes within these compartments affect both normal hematopoietic cells and the generation of hematopoietic disease. Telomere length provides information pertaining to the proliferative history and potential of a hematopoietic cell. CONCLUSIONS: The role of telomerase and telomeres within the hematopoietic compartment needs further clarification. Advances in our knowledge in this field may improve clinical outcomes for the treatment of hematologic disease.

Biomarkers, Tumor↗
PubMed1990

Effect of inhibitors of cytoplasmic structures and functions on rabies virus infection in vitro.

The effect in vitro of some cytoplasmic structure and function inhibitors on the different stages of rabies virus infection was investigated. Treatment of fibroblasts (CER) and human neuroblastoma cells (IMR-32) with substances acting on low pH intracellular compartments (methylamine and monensin) prevented rabies virus genome delivery in the cytosol. An early inhibition of viral infection was also obtained in the presence of B and D cytochalasins and trifluoperazine which interact with microfilament structures. Treatment with colchicine and vinblastine did not affect rabies multiplication, suggesting that microtubules are not involved in this process. However, the multiplication of prebound virions did not take place in the presence of inhibitors of oxidative phosphorylation (sodium azide and CCCP) and of glycolysis (2-deoxy-D-glucose) indicating that rabies virus replication is largely energy-dependent in both host cells examined.

Animals↗
PubMed2000

Relationship between pre-existing viral reservoirs and the re-emergence of plasma viremia after discontinuation of highly active anti-retroviral therapy.

We examined the pathogenic significance of the latent viral reservoir in the resting CD4+ T cell compartment of HIV-1-infected individuals as well as its involvement in the rebound of plasma viremia after discontinuation of highly active anti-retroviral therapy (HAART). Using heteroduplex mobility and tracking assays, we show that the detectable pool of latently infected, resting CD4+ T cells does not account entirely for the early rebounding plasma HIV in infected individuals in whom HAART has been discontinued. In the majority of patients examined, the rebounding plasma virus was genetically distinct from both the cell-associated HIV RNA and the replication-competent virus within the detectable pool of latently infected, resting CD4 + T cells. These results indicate the existence of other persistent HIV reservoirs that could prompt rapid emergence of plasma viremia after cessation of HAART and underscore the necessity to develop therapies directed toward such populations of infected cells.

Adult↗
PubMed2003

Mouse cytomegalovirus immediate-early protein 1 binds with host cell repressors to relieve suppressive effects on viral transcription and replication during lytic infection.

Herpesviruses start their transcriptional cascade at nuclear domain 10 (ND10). The deposition of virus genomes at these nuclear sites occurs due to the binding of the interferon-inducible repressor protein promyelocytic leukemia protein (PML) and/or Daxx to a viral DNA-protein complex. However, the presence of repressive proteins at the nuclear site of virus transcription has remained unexplained. We investigated the mouse cytomegalovirus (MCMV) immediate-early 1 protein (IE1), which is necessary for productive infection at low multiplicities of infection and therefore likely to be involved in overcoming cellular repression. Temporal analysis of IE1 distribution revealed its initial segregation into ND10 by binding to PML and/or Daxx and IE1-dependent recruitment of the transcriptional repressor histone deacetylase-2 (HDAC-2) to this site. However, these protein aggregates are dissociated in cells producing sufficient IE1 through titration of PML, Daxx, and HDAC-2. Importantly, binding of IE1 to HDAC-2 decreased deacetylation activity. Moreover, inhibition of HDAC by trichostatin-A resulted in an increase in viral protein synthesis, an increase in cells starting the formation of prereplication compartments, and an increase in the total infectious viruses produced. Thus, IE1, like trichostatin-A, reverses the repressive effect of HDAC evident in the presence of acetylated histones in the immediate-early promoter region. Since HDAC also binds to the promoter region of IE1, as determined by the chromatin immunoprecipitation assay, these combined results suggest that IE1 inhibits or reverses HDAC-mediated repression of the infecting viral genomes, possibly by a process akin to activation of heterochromatin. We propose that even permissive cells can repress transcription of infecting viral genomes through repressors, including HDAC, Daxx, and PML, and the segregation of IE1 to ND10 that would inactivate those repressors. The virus can counter this repression by overexpressing IE1 when present in sufficient copy number, thus reducing the availability and effectiveness of these repressors.

Animals↗
PubMed2007

Relationship between CD38 expression on peripheral blood T-cells and monocytes, and response to antiretroviral therapy: a one-year longitudinal study of a cohort of chronically infected ART-naive HIV-1+ patients.

BACKGROUND: HIV-1 infection has been associated with high expression of CD38 on peripheral blood (PB) CD8+ and CD4+ T-cells, which has been related with poor prognosis in untreated HIV-1+ patients. In turn, CD38 expression on PB monocytes from HIV-1+ individuals and its behavior after starting antiretroviral therapy (ART) have been poorly studied. METHODS: CD38 expression on PB CD8+ and CD4+ T-lymphocytes and monocytes was prospectively analyzed in 30 ART-naive HIV-1+ patients, using a quantitative multiparameter flow cytometry approach. Patients were tested prior to therapy, and at weeks +2, +4, +8, +12, and +52 after ART. RESULTS: Prior to ART, CD38 expression was significantly increased on PB CD8+ and CD4+ T-cells and monocytes; despite a significant decrease after ART, CD38 expression remained abnormally high on PB CD8+ T-cells and monocytes, even after one year of therapy, in the absence of detectable plasma viral load. The ART-induced early changes on CD38 expression by PB T-cells and monocytes differed among the cell subsets analyzed and patient groups, probably reflecting an interaction between the direct effects of therapy and a redistribution of the PB compartments of T-cells and monocytes. Hierarchical clustering analysis showed that the overall pattern of changes in CD38 expression observed early after starting ART was predictive of a better response to therapy, not only for PB CD8+ T-cells, but also for CD4+ T-cells and monocytes. Accordingly, those HIV-1+ patients, who experienced a more pronounced increase in CD38 expression on both PB CD4+ T-cells and monocytes after 2 weeks of ART, showed a more rapid viral clearance, which might reflect decreased HIV-1 replication in lymph nodes and other tissues, and a partial restoration of hematopoiesis. CONCLUSIONS: Combined quantitative measurement of CD38 expression on PB monocytes, and CD8+ and CD4+ T-cells is a more useful tool for monitoring HIV-1+ patients under ART, rather than quantitation of CD38 expression on PB CD8+ T-lymphocytes alone.

ADP-ribosyl Cyclase 1↗
PubMed1998

Ignorability and parameter estimation in longitudinal pharmacokinetic studies.

In the analysis of longitudinal pharmacokinetic data, both balanced (equal number of samples per subject) and unbalanced data are used. It is implicitly assumed that the process that caused the missing data can be ignored. A simulation study was performed to determine the effect of ignoring the missing data (i.e., "ignorability") on the accuracy and precision of parameter estimation in longitudinal pharmacokinetic studies. A two-compartment model with multiple intravenous bolus inputs was assumed. Subjects with balanced data sets had six samples, and those with unbalanced data had 1 to 5 samples missing (i.e., supplied in a decreasing order from 5 to 1 samples). The proportion of subjects with 1 to 5 samples missing varied from 25% to 75% in a fixed sample size of 100. The effect of ignorability was studied at intersubject variability ranging from 15% to 60% for a drug assumed to be dosed at its elimination half-life. One hundred replicate data sets of 100 subjects each were simulated for each missing data scenario. The accuracy of parameter estimation was not significantly affected by the amount of ignorable missing data at any given level of variability. However, the precision of parameter estimation was affected by the degree of "missingness."

Humans↗
PubMed1992

Impaired S-phase transit of Werner syndrome cells expressed in lymphoblastoid cell lines.

The clinical phenotype of Werner's syndrome (WS) includes short stature, premature cataracts, skin atrophy, osteoporosis, graying and loss of hair, neoplasia, diabetes mellitus, and arteriosclerosis. Cultured cells from patients with this autosomal recessive disorder exhibit chromosomal instability and a markedly reduced replicative lifespan and growth rate. To elucidate the cell cycle alterations associated with the growth deficit, we continuously labeled lymphoid cell lines from five WS patients and from four healthy adult controls with 5-bromodeoxyuridine. Bivariate Hoechst 33258/ethidium bromide flow cytometry revealed a 2.4-h prolongation in the minimal duration of the S phase of WS cells (P less than 0.005). Moreover, the fraction of proliferating cells irreversibly arrested in the S phase (5.4% vs 1.4% in controls) was significantly elevated in WS (P less than 0.001). Other cell cycle compartments were not significantly affected in WS cell lines. As a partial test of the hypothesis that the WS phenotype is due to a defect in DNA topoisomerase I (topo I) or DNA topoisomerase II (topo II) we exposed lymphoid cells from a healthy control to the topo I inhibitor camptothecin or to the topo II inhibitor 4'-(9-acridinylamino)methanesulfon-m-anisidine. The cell kinetic alterations elicited by these compounds differed from that exhibited by untreated WS patients. Thus, a primary defect in topo I or II is unlikely in WS. Our cell cycle results, however, provide important evidence that the biochemical genetic lesion is in fact expressed in lymphoblastoid cell lines, the most readily available cells from such subjects.

Adult↗
PubMed1999

Limitation of Tat-associated transcriptional processivity in HIV-infected PBMC.

The ability of HIV to match levels of viral mRNA to the activation state of the host cell may play a role in its ability to persist as well as to replicate. This linkage depends on the function of the viral transcriptional regulatory protein, Tat, which increases the efficiency of RNA elongation (transcriptional processivity) in response to cellular activation. To quantify levels of Tat function in vivo, a quantitative competitive RT-PCR assay was developed that reflects levels of TAR leader fragments (nonprocessive transcripts) and viral mRNA (processive transcripts), indicating low or high levels of Tat function, respectively. The abundance of these RNA species was measured in peripheral blood mononuclear cells (PBMC) of 22 HIV-1-positive individuals (CD4(+) T cell counts 63-934/mm3) and in established cell line models of HIV constitutive replication (H9IIIB) and reversible latency (U1 and ACH-2). In PBMC, the level of total viral transcripts ranged over four orders of magnitude; however, nonprocessive transcription predominated: 70% of PBMC samples had a ratio of processive to total transcripts of <0.3 and none of the samples had 100% processivity. The cell line studies revealed that, even in activated H9IIIB cells, nonprocessive transcription dominates and that latently infected cells can have different transcriptional responses to activation. This is the first study that enumerates degrees of transcriptional processivity in the circulating mononuclear cell compartment and the results suggest that limitation of Tat function may be a common phenotype throughout the course of the disease.

Cell Line↗
PubMed1997

Mechanism of adenovirus improvement of cationic liposome-mediated gene transfer.

Substantial effort has been focused on the development of highly efficient gene transfer strategies. Although viral and non-viral methods have been elaborated, mechanisms of gene delivery are still poorly understood. We exploited our recent observation that replication-deficient type 5 adenovirus dramatically enhances lipofectAMINE-mediated gene transfer (lipoadenofection) in differentiated cells to elucidate the mechanism of adenovirus action in this process. Heat-induced denaturation of viral capsid abolishes adenovirus action whereas inactivation of viral genome by short treatment with UV has no effect. Electron microscopic observations reveal the formation of a complex containing adenovirus and lipofectAMINE which probably carries DNA into cells via endocytosis. Anti-adenovirus antiserum or monoclonal anti-alpha(v)beta3 integrin antibody inhibits lipoadenofection, at least partially. Neutralization of endosomal compartments with chloroquine, ammonium chloride or monensin does not prevent adenovirus improvement of gene transfer. Hence, adenovirus-lipofectAMINE-DNA complexes in which viral particles are each encompassed by three lipid layers, penetrate cells via an endocytic pathway involving probably the adenovirus receptor and alpha(v)beta3 integrin. The resulting efficient transfer and expression of plasmid DNA proceeds from a mechanism in which adenoviral endosomolytic activity appears to be required while viral genome is not essential.

Adenoviridae↗
PubMed1998

Comparison of serum and liver hepatitis C virus quasispecies in HCV-related hepatocellular carcinoma.

BACKGROUND/AIMS: The hepatitis C virus (HCV) genome consists of quasispecies populations of heterogeneous variants, especially in the hypervariable region. To assess the profiles of viral quasispecies in HCV-related hepatocellular carcinoma, we studied the viral population patterns in serum and liver tissues of 13 HCV-positive patients with hepatocellular carcinoma developed on cirrhotic and non-cirrhotic livers (5 and 8 cases, respectively). METHODS: HCV genome heterogeneity was analyzed by polymerase chain reaction-mediated single-strand conformation polymorphism analysis, which showed multiple DNA bands representing different hypervariable region sequences. RESULTS: The HCV populations were different between tumorous and nontumorous tissues in 3/5 hepatocellular carcinomas with cirrhosis and in 6/8 without cirrhosis. At least one or more than one common band was detected in both compartments in all but one case. No significant differences in the complexity of HCV quasispecies were found in hepatocellular carcinoma with or without underlying cirrhosis. Comparison of the HCV quasispecies profiles in serum and liver tissues showed a different distribution of HCV variants between these two compartments in 6/7 patients. In four cases, both common and compartmentalized sequences were detected, whereas in two cases, both without cirrhosis, the HCV population in serum was completely different from that found in the liver. CONCLUSIONS: These results suggest that the complexity of HCV populations is influenced by the presence of hepatocellular carcinoma rather than by the severity of the underlying chronic liver disease. The different quasispecies patterns found in serum and liver may reflect different biological properties of circulating and intrahepatic HCV particles or the existence of extrahepatic sites of replication.

Aged↗
PubMed2002

The significance of telomerase activation and cellular immortalization in human cancer.

Repression of telomerase in the somatic tissues of humans, and probably other long-lived mammals, appears to have evolved as a powerful protective barrier against cancer. Immortalization in vitro of normal human cells that lack telomerase involves the reactivation of telomerase or, rarely, an alternative (ALT) mechanism for maintaining telomeres. Inactivation of the effectors of replicative senescence, i.e. genes encoding one or more elements of the p16/pRB and/or ARF/p53/p21 anti-proliferative pathways, is required for telomerase depression leading to immortalization. Regulation of telomerase in normal human cells is mediated primarily by transcriptional repression of hTERT, the gene encoding the catalytic subunit of telomerase. Rodent cells do not possess stringent controls on telomerase activity in the soma and this explains why they are so readily immortalized and transformed in culture compared with their human counterparts. Because active telomerase has been found to exist in the proliferative compartments of self-renewing tissues, it is not yet clear whether the telomerase present in 90% of human cancers exists as a consequence of selection of pre-existing telomerase-positive cells during carcinogenesis or through induction of hTERT expression in cells in which it is normally tightly repressed. In support of the latter, chromosome transfer techniques have revealed the presence of genes on normal human chromosomes that are able to extinguish hTERT transcription in cancer cells and induce them to undergo senescence. It is clear that telomerase is obligatory for continuous tumour cell proliferation, clonal evolution and malignant progression. Telomerase therefore represents an attractive target at which to aim new anti-cancer drugs. Results with a variety of telomerase inhibitory strategies in human cancer cells have confirmed that its functional inactivation results in progressive telomere shortening, leading to growth arrest and/or cell death through apoptosis. Promising candidate small molecule inhibitors are beginning to emerge that will form the basis for anti-telomerase drug development.

Animals↗
PubMed1976

Automatic quantitative radiometric assay of bacterial metabolism.

In a two-compartment scintillation vial, suspensions of bacteria were cultured with 1 muCi of [U-14C] glucose and the released 14C02 was measured continuously, cumulatively, and automatically in a liquid-scintillation counter modified to maintain sample temperature at 37 degrees C. We could follow the metabolism of bacterial populations through their early phase of exponential growth with good precision. The data were obtained conveniently, with use of conventional reagents, glassware, and counting equipment. From analysis of the exponential portion of the curves for cumulative activity vs. time, we could measure cell replication rate precisely in units of time. The resulting values were demonstrably independent of some common experimental variables, including the number of bacteria in the inoculum and counting system sensitivity. Sensitivity of the bacteria to antibiotics was measured to within a few percent by noting the relative prolongation of replication time in the presence of those inhibitors. The digital data from the scintillation counter are susceptible to on- or off-line computer analysis, thus providing the prospect for a totally-automated analytical system. The method shows promise for the mechanized quantitative analysis of bacterial growth, and its inhibition.

Anti-Bacterial Agents↗
PubMed1975

A study of the kinetics of microsporogenesis in Campelia zanonia (L.) H.B.K.

During maturation, microspores pass through a series of morphologically distinguishable stages or compartments. A study has been made of the systematic fluctuations in the frequency of microspores in these compartments, when plants are grown under rigidly controlled conditions. A new approach to the construction of cumulative flux rate curves is described; these give the number of cells passing the compartment boundaries per unit time. The curves obtained indicate that simple models, which assume constant flux rates and compartment transit times, will not explain the observations. It is evident that not only do microspores mature at different rates, but that the maturation rate of individual microspores varies during the developmental sequence. The overall process may be controlled by the intimate relationship which exists between the microspores and the tapetal periplasmodium in the Tradescantiae.

Autoradiography↗
PubMed2003

Adenoviral-expressed GP5 of porcine respiratory and reproductive syndrome virus differs in its cellular maturation from the authentic viral protein but maintains known biological functions.

The ORFs 5, 6 and 7, encoding for the three major structural proteins, GP(5), M and N, of the IAF-Klop strain of PRRSV were cloned and expressed in 293 cells using replication-defective human type 5 adenoviral vectors (hAdVs). Although the M protein gene could be cloned into hAdVs and expressed constituvely in 293 cells under the control of the hCMV immediate early promotor/enhancer, hAdVs expressing N and GP(5) proteins, which appeared to be toxic or interfered with adenovirus replication, could only be generated by inclusion of a tetracycline-regulatable promotor in the transfer vector pAdTR5. The recombinant (rec) proteins appeared similar to the authentic viral proteins in regards to their M(r)s and antigenicities. However, the recGP(5) apparently possesses different N-linked oligosaccharides residues. Its sensitivity to endo-beta-galactosidase digestion indicates that poly-N-acetyllactosamine is present on the individually-expressed protein, but not on the authentic GP(5) anchored into the virion envelope. The recGP(5) apparently accumulates within the ER compartment as a glycoprotein that possesses high-mannose N-linked oligosaccharide side chains sensitive to endo-beta-N-acetylglucosaminidase H treatment, by contrast to its viral counterpart for which N-linked oligosaccharide side chains are of both high-mannose and complex types. Coinfection of 293 cells with hAdVs expressing the M and GP(5) did not lead to M-GP(5) heterodimer formation, as demonstrated in PRRSV-infected cells. Moreover, cells infected with inducible hAdV/ORF5 showed that GP(5) of the North American strain is proapoptotic. Indeed, when the expression cassette was turned-on, caspase 3 activity in hAdV/ORF5 infected cells was enhanced and DNA fragmentation could be detected by TUNEL assays. Pigs intradermally injected twice with hAdV/ORF5 developed antibody titers to the authentic viral GP(5) as soon as 10 days following challenge with the homologous virulent PRRSV strain, as revealed by Western blot and virus neutralization tests, suggesting the establishment of a specific immune memory.

Adenoviridae↗
PubMed1993

Biogenesis of rhoptry organelles in Plasmodium falciparum.

Biogenesis of the rhoptry organelle of Plasmodium falciparum was studied by examining the synthesis and assembly of rhoptry proteins at different stages of intraerythrocytic development. Rhoptry proteins examined in this study were those of the high molecular weight complex of 140/130/110 kDa and referred to as Rhop-H1,2,3 and the low molecular weight complex of 80 and 42 kDa referred to as Rhop-L1,2. Co-ordinate, stage-specific expression of three proteins, Rhop-H3, Rhop-L1 and Rhop-L2, was observed; maximum levels of mRNA at the 8 nucleus stage correlated with the onset of protein synthesis. In contrast, mRNA levels for DNA polymerase-alpha, a marker for DNA replication during schizogony, was maximum just prior to the onset of the first nuclear division, indicating that rhoptry biogenesis is not co-ordinate with nuclear division. The assembly of newly synthesized rhoptry proteins was followed by subcellular fractionation of schizonts at different stages of development. At the four-nucleus stage a vesicle could be isolated by sucrose gradient fractionation which had a peak density of 1.12 g ml-1 and contained only Rhop-H2 and Rhop-H3 proteins. This vesicle could represent an intermediate or pre-rhoptry compartment. At the 8-nucleus stage, the Rhop-L1 protein was also detected in a vesicle of low density. At the 16-nucleus stage, the proteins were present in vesicles having a significantly greater density in sucrose, 1.16 g ml-1, similar to that of the mature organelle. The study suggested that the rhoptry proteins first accumulate in a low density vesicle and that assembly into this compartment is staggered. Immunoelectronmicroscopy studies indicated that the Rhop-H3 protein is first present in small granular compartments that becomes more electron dense and enlarges due to the stage-dependent incorporation of proteins.

Animals↗
PubMed2001

Association among neuromuscular and anatomic measures for patients with knee osteoarthritis.

OBJECTIVE: To investigate neuromuscular and anatomic factors involved in varus gonarthrosis by identifying measures associated with degenerative changes. DESIGN: Descriptive study. Individual measures that explained substantial portions of the variability in ratings of knee joint-degenerative changes in patients with knee medial compartment osteoarthritis. SETTING: Outpatient orthopedic clinic and biomechanics and muscular assessment laboratory. PATIENTS: Volunteer sample of 20 subjects (age range, 59 +/- 9 yr) with no history of neurologic disease. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: We assessed degenerative changes, varus alignment, standing balance, and knee proprioception. Weight-bearing radiographs were used to assess the extent of degenerative changes and the degree of varus alignment. Single-limb standing balance control was assessed through tests performed on a force platform. Knee proprioception was assessed with an isokinetic dynamometer, using a joint angle replication test. RESULTS: Forward-stepwise multiple linear regression indicated that the extent of degenerative changes could be best predicted from a linear combination of the independent variables, varus alignment, and standing balance (R =.80, F(2,17) = 14.81, p =.0002). Sixty-four percent of the variability in ratings of degenerative changes was explained by alignment and standing balance measures (37% by varus alignment, 27% by standing balance). Alignment and balance measures were poorly correlated (r =.12, p =.63), further suggesting that they provided different information about gonarthrosis. CONCLUSIONS: Although varus alignment is widely accepted as a clinically important factor in gonarthrosis, and is the focus of many treatment efforts, our results suggest that objective measures of standing balance are also important. As a result, the potential impact of rehabilitation to improve the control of standing balance should be further evaluated in this patient population.

Biomechanical Phenomena↗