Genetic and environmental determinants of use and abuse of alcohol: the Finnish Twin Cohort studies.
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Adult↗
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Asthma: a longitudinal perspective.
In the future, the important longitudinal studies will be those that divide the broad spectrum of asthma into phenotypic groups in order to provide more precise information about mechanisms and outcomes. Asthmatics who present in a clinical setting often have a combination of two or three different phenotypes, and may have more severe illness as a result, but subjects who are tested in epidemiological studies are frequently characterized by only one phenotype. Although the definition of asthma as a combination of symptoms plus either AHR or reduced lung function has greater predictive isolation for assessing the prognosis of respiratory illness that occurs in childhood (27,40,55,66-68), studies that are able to classify subjects according to their different phenotypes are more likely to lead to a better understanding of the factors that influence prognosis. More importantly, by using this approach, future research studies should be better able to separate the mechanisms whereby therapeutic or environmental interventions influence the prognosis of each phenotype. The potential benefits will be a better understanding and evaluation of the factors that make an important contribution to respiratory health.
Asthma↗
Children's self-reported psychotic symptoms and adult schizophreniform disorder: a 15-year longitudinal study.
BACKGROUND: Childhood risk factors for the development of adult schizophrenia have proved to have only modest and nonspecific effects, and most seem unrelated to the adult phenotype. We report the first direct examination of the longitudinal relationship between psychotic symptoms in childhood and adulthood. METHODS: We analyzed prospective data from a birth cohort (N = 761), in which children were asked about delusional beliefs and hallucinatory experiences at age 11 years, and then followed up to age 26 years. Structured diagnostic interviews were employed at both ages and self-report of schizophreniform symptoms was augmented by other data sources at age 26 years. RESULTS: Self-reported psychotic symptoms at age 11 years predicted a very high risk of a schizophreniform diagnosis at age 26 years (odds ratio, 16.4; 95% confidence interval, 3.9-67.8). In terms of attributable risk, 42% of the age-26 schizophreniform cases in the cohort had reported 1 or more psychotic symptoms at age 11 years. Age-11 psychotic symptoms did not predict mania or depression at age 26 years, suggesting specificity of prediction to schizophreniform disorder. The link between child and adult psychotic symptoms was not simply the result of general childhood psychopathology. CONCLUSION: These findings provide the first evidence for continuity of psychotic symptoms from childhood to adulthood.
Adolescent↗
[Controverted existence of anhaptoglobinemia in the tropics].
Anhaptoglobinemia in the tropics has long been considered as a genetic phenomenon (Allison et al 1968; Sulton et al 1959). However, between 1963 and 1968, several other workers found a close relationship between anhaptoglobinemia and hemolytic diseases, thus bringing to question the genetic hypothesis which had earlier existed. The object of our study was to verify the following in a area that was endemic both for malaria and sickle cell disease: if anhaptoglobinemia was present in both populations, if it was proportional to the parasite load or the amount of hemolysis, if anhaptoglobinemia could be used either as a marker for malaria studies or for diagnosis of intravascular hemolysis. Anhaptoglobinemia turned out not to be present in all patients suffering from malaria, but was proportional to the parasite load and hemolysis. In patients with malaria, it was undetected after malarial prophylaxis but reappeared one month after cessation of treatment, while, in sickle cells patients, it disappeared at the end of their crisis. This was evidence of high reticulocyte regeneration. These findings highlight the problem of the existence of the HpO phenotype.
Adolescent↗
Genetics and developmental psychopathology: 1. Phenotypic assessment in the Virginia Twin Study of Adolescent Behavioral Development.
We introduce an overlapping cohort sequential longitudinal study of behavioral development and psychopathology in a representative sample of 1412 pairs of twins aged 8 through 16 years. Multiple phenotypic assessments involve a full psychiatric interview with each child and each parent, and supplementary parental, teacher, and child interview material and questionnaires. For the first wave of assessments, the numbers of reported DSM-III-R symptoms of Major Depressive Disorder (MDD), Separation Anxiety Disorder (SAD), Overanxious Disorder (OAD), Oppositional Defiant Disorder (ODD), Conduct Disorder (CD), and Attention Deficit Hyperactivity Disorder (ADHD), assessed through interviews, confirm patterns of age and sex trends found in other epidemiological samples, but underscore their dependence on whether the child or the parent is the informant. Correlations across domains for symptoms reported by the same informant are often as large as correlations across informants for the same domain of symptoms. Factor analyses of these symptom counts, taking account of informant view and unreliability of assessment, show the high degree of correlation between SAD and OAD, between MDD and OAD, and between CD and ODD. ADHD symptoms are relatively independent of the other domains, but show moderate correlations with CD, ODD, and MDD. Factorially derived dimensional questionnaire scales, based on child, parental, and teacher reports, show patterns of relationship to symptom counts consistent with both convergent and discriminant validity as indices of liability to clinical symptoms. Across informants, questionnaire scales provide as good a prediction of symptoms as do clinical interviews. Multitrait-multimethod confirmatory factor analysis reveals the patterns of relationship between symptoms of psychiatric disorder in children taking due account of informant and unique sources of variance. Gender differences are consistent within the correlated clusters of ODD/CD and MDD/SAD/OAD, although there are disorder-specific age trends. There are large informant-specific influences on the reporting of symptoms in clinical interviews. Dimensional questionnaire scales provide a useful source of additional information. In subsequent analyses of genetic and environmental etiology of childhood psychopathology we must expect that results may differ by informant and method of assessment. Multivariate and developmental analyses that explore the sources of these differences will shed new light on the relationship between genetic and environmentally influenced vulnerability and the manifestation of psychopathology in specific circumstances.
Adolescent↗
Haptoglobin phenotype is an independent risk factor for cardiovascular disease in individuals with diabetes: The Strong Heart Study.
OBJECTIVES: The goal of this study was to determine if the haptoglobin phenotype was predictive of cardiovascular disease (CVD) in diabetic mellitus (DM). BACKGROUND: Cardiovascular disease is the most frequent, severe, and costly complication of type 2 DM. There are clear geographic and ethnic differences in the risk of CVD among diabetic patients that cannot be fully explained by differences in conventional CVD risk factors. We have demonstrated that a functional allelic polymorphism in the haptoglobin gene acts as a major determinant of susceptibility for the development of diabetic microvascular complications. METHODS: We sought to determine if this paradigm concerning the haptoglobin gene could be extended to CVD in DM. We tested this hypothesis in a case-control sample from the Strong Heart study, a population-based longitudinal study of CVD in American Indians. Haptoglobin phenotype was determined by polyacrylamide gel electrophoresis in 206 CVD cases and 206 matched controls age 45 to 74 years. Median follow-up was six years. RESULTS: In multivariate analyses controlling for conventional CVD risk factors, haptoglobin phenotype was a highly statistically significant, independent predictor of CVD in DM. The odds ratio of having CVD in DM with the haptoglobin 2-2 phenotype was 5.0 times greater than in DM with the haptoglobin 1-1 phenotype (p = 0.002). An intermediate risk of CVD was associated with the haptoglobin 2-1 phenotype. CONCLUSIONS: This study suggests that determination of haptoglobin phenotype may contribute to the algorithm used in CVD risk stratification, and in evaluation of new therapies to prevent CVD in the diabetic patient.
Aged↗
Flow cytometric lymphocyte immunophenotyping in homosexual men with the persistent generalized lymphadenopathy syndrome: a longitudinal study of lymph nodes and blood.
We have performed lymphocyte phenotypic analysis on serial lymph node biopsies and peripheral blood samples from 11 patients with the persistent generalized lymphadenopathy (PGL) syndrome and correlated the findings with histologic and clinical findings (median follow-up 18 months) in a search for factors that may predict evolution to acquired immunodeficiency syndrome (AIDS). Follow-up lymph node biopsies showed higher percentages of T-cells, both OKT4+ and OKT8+ phenotypes, and lower percentages of Slg+ B-cells and OKla+ cells. The lymph node changes were relatively minor in degree compared to the progressive peripheral blood OKT4+ lymphocytopenia observed over a similar time interval. The one patient who developed a malignant lymphoma had a high percentage of nodal T-cells and low peripheral blood T-cell counts. We conclude that serial lymph node studies contribute to an understanding of the natural history of PGL, but that peripheral blood counts are a more sensitive indicator of immune status in individual patients.
AIDS-Related Complex↗
Relation between variations in the phenotypic expression of an unstable hemoglobin disorder (hemoglobin Zürich) and carboxyhemoglobin levels.
Longitudinal studies in a group of 15 asymptomatic subjects with hemoglobin Zürich from two unrelated families indicated marked variation in the clinical and hematologic expression of the hemoglobinopathy, even within the same family. Carbon monoxide bound to normal hemoglobin stabilized the molecule when exposed to a variety of denaturing procedures. The marked increase in the affinity of hemoglobin Zürich for carbon monoxide, approximately 65 times that of normal hemoglobin, led to a study of carboxyhemoglobin levels in smoking and nonsmoking subjects with hemoglobin Zürich and their relation to the phenotypic expression of the hemoglobinopathy. The carboxyhemoglobin content in whole blood from persons with hemoglobin Zürich ranged from 3.9 to 6.7 percent in nine nonsmokers and from 9.8 to 19.7 percent in six smokers. Rates of hemolysis as determined by values for hematocrit, reticulocyte count, and haptoglobin and hemopexin levels were less in smokers than in nonsmokers. Also, rates of Heinz body formation in intact red cells and isopropanol-induced precipitation of the abnormal hemoglobin in hemolysates were less in smokers than in non-smokers. These observations suggest that variability in the phenotypic expression of hemoglobin Zürich is a post-translation event secondary to stabilization of the abnormal hemoglobin by carbon monoxide.
Adolescent↗
Coordinate changes in Myosin heavy chain isoform gene expression are selectively associated with alterations in dilated cardiomyopathy phenotype.
BACKGROUND: The most common cause of chronic heart failure in the US is secondary or primary dilated cardiomyopathy (DCM). The DCM phenotype exhibits changes in the expression of genes that regulate contractile function and pathologic hypertrophy. However, it is unclear if any of these alterations in gene expression are disease producing or modifying. MATERIALS AND METHODS: One approach to providing evidence for cause-effect of a disease-influencing gene is to quantitatively compare changes in phenotype to changes in gene expression by employing serial measurements in a longitudinal experimental design. We investigated the quantitative relationships between changes in gene expression and phenotype n 47 patients with idiopathic DCM. In endomyocardial biopsies at baseline and 6 months later, we measured mRNA expression of genes regulating contractile function (beta-adrenergic receptors, sarcoplasmic reticulum Ca(2) + ATPase, and alpha- and beta-myosin heavy chain isoforms) or associated with pathologic hypertrophy (beta-myosin heavy chain and atrial natriuretic peptide), plus beta-adrenergic receptor protein expression. Left ventricular phenotype was assessed by radionuclide ejection fraction. RESULTS: Improvement in DCM phenotype was directly related to a coordinate increase in alpha- and a decrease in beta-myosin heavy chain mRNA expression. In contrast, modification of phenotype was unrelated to changes in the expression of beta(1)- or beta(2)-adrenergic receptor mRNA or protein, or to the mRNA expression of sarcoplasmic reticulum Ca(2) + ATPase and atrial natriuretic peptide. CONCLUSION: We conclude that in human DCM, phenotypic modification is selectively associated with myosin heavy chain isoform changes. These data support the hypothesis that myosin heavy chain isoform changes contribute to disease progression in human DCM.
Antihypertensive Agents↗
Six-month stability and outcome of a prepubertal and early adolescent bipolar disorder phenotype.
OBJECTIVE: Six-month follow-up data are provided on a prepubertal and early adolescent bipolar disorder phenotype (PEA-BP). Stabilities were defined as continuous presence of PEA-BP and of individual mania criteria between baseline and 6 months. METHOD: Baseline and 6-month assessments of consecutively ascertained PEA-BP outpatients (n = 91) included comprehensive instruments given to mothers and children, separately, by research nurses; consensus conferences; and offsite blind best estimates of both diagnoses and mania items. To fit the study phenotype, subjects needed to have current DSM-IV mania or hypomania with elated mood and/or grandiosity as one mania criterion and to be definite cases by severity ratings. RESULTS: Of the 93 baseline subjects, 91 completed the 6-month assessment, for a retention rate of 97.8%. Baseline age was 10.9 +/- 2.7 years, and age of onset of current episode was 7.3 +/- 3.5 years. At 6 months, 85.7% still had full criteria and severity for mania or hypomania, and only 14.3% had recovered. Six-month stabilities of elated mood and grandiosity were high. Cox modeling and logistic regression did not show any significant effect of multiple covariates (e.g., gender, puberty, psychosis, mixed mania, rapid cycling, or naturalistic treatment). CONCLUSIONS: These longitudinal stability findings provide validation of a PEA-BP phenotype. Poor outcome was consistent with similarity of PEA-BP baseline characteristics to those of treatment-resistant adult-onset mania.
Adolescent↗
High IL-7 plasma levels may induce and predict the emergence of HIV-1 virulent strains in pediatric infection.
BACKGROUND: HIV-1 infection results in severe immunodeficiency when T-cell loss cannot be compensated. IL-7 is one of the main cytokines involved in the maintenance of T-cell homeostasis. However, IL-7 can also enhance HIV-1 replication in vivo and lead to an accelerated progression of AIDS. OBJECTIVE: The aim of our study was to evaluate if the increase of IL-7 levels in response to CD4+ T cell depletion could favor the emergence of HIV-1 strains with more aggressive phenotypes in pediatric infection. STUDY DESIGN: Plasma IL-7 levels were measured in 42 HIV-1 vertically infected infants at different times of infection, and HIV-1 isolates were obtained from primary cell cultures to determine replication rate and syncytium-inducing (SI) capability on MT-2 cell line. RESULTS: IL-7 levels were significantly higher in infants harboring HIV-1 SI strains compared to those with non-syncytium-inducing (NSI) viruses (p<0.0001). Likewise, IL-7 levels were higher in infants with rapid replicating viral strains versus those with slow replicating viruses (p=0.0006). Despite the strong negative correlation between IL-7 levels and CD4+ T lymphocyte counts (r=-0.55, p=0.0001), covariance analysis demonstrated that the high levels of IL-7 were associated with more virulent phenotype features (SI and rapid replicating strains) independently of CD4+ T cell depletion. In 19 of the 42 infants, longitudinal follow-up studies showed that SI to NSI phenotype switch can occur after HAART administration, with a reduction in IL-7 levels and an increase in CD4+ T cell counts. CONCLUSIONS: IL-7 response to T-cell depletion may enhance T-cell production, but at the same time may foster HIV-1 disease progression favoring the emergence of more virulent HIV-1 strains characterized by SI capability and rapid replication rate.
CD4 Lymphocyte Count↗
Effect of the HIV-1 syncytium-inducing phenotype on disease stage in vertically-infected children.
The syncytium-inducing (SI) capability of HIV-1 isolates from 48 HIV-infected children was determined in order to examine the association of the SI phenotype with an AIDS diagnosis and/or with other clinical parameters in HIV-infected children. In a retrospective cross-sectional analysis, phenotypic data were linked to clinical and immunologic data from each patient. Multiple longitudinal samples were analyzed from 14 patients. Children with SI viruses were older than children with nonsyncytium-inducing (NSI) strains. Twelve of 13 children less than 2 years old carried NSI viruses, seven of the 12 already had a diagnosis of AIDS. Two children under 2 years of age died within 1 month of NSI virus isolation. Although plasma p24 antigen levels tended to be higher in the NSI group, the difference appeared to reflect high p24 levels in children under 2 years old with AIDS. When children under 2 were omitted, differences in age, CD4+ cell counts, p24 antigenemia, and clinical parameters were not significant. The SI phenotype of HIV-1 did not occur more frequently in children with an AIDS diagnosis. Four children remained stable with SI isolates overtime periods of 16 to 31 months. Three children's isolates converted from NSI to SI and 2 converted from SI to NSI. These data indicate that SI viruses do not play a significant role in progression to AIDS during the first 2 years of life. Furthermore, for children above the age of 2, the association between advanced disease stage and the SI phenotype in adults may not apply.
Acquired Immunodeficiency Syndrome↗
Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly.
The age-associated decrease in functionality of the human immune system is thought to have a negative impact on the capacity to provide protection against infection, in turn leading to increased incidence of mortality. In a previous longitudinal study of octogenarians, we identified an immune risk phenotype (IRP) in the very elderly defined by an inverted CD4/CD8 ratio, which was associated with increased mortality and persistent CMV infection. In this study, we analyzed the CD8 clonal composition of nonagenarians and middle-aged individuals. An increased number of CD8 T cell clones was observed in the nonagenarians, and was associated with CMV-seropositivity. Surprisingly, CMV-seropositive nonagenarians with the IRP had a significantly lower number of clones compared with non-IRP individuals. The decrease in clone numbers in IRP individuals was associated with shorter survival time. MHC/peptide multimer staining indicated that the frequency of CMV-specific T cells was higher in nonagenarians than in the middle-aged, but the ratio of functionally intact cells was significantly lower. The lowest ratio of functional CMV-specific T cells was found in an IRP individual. A thorough longitudinal analysis of the CMV-specific T cells in nonagenarians showed a stable pattern with respect to frequency, phenotype, and clonal composition. We hypothesize that the number of different CD8 T cell clonal expansions increases as the individual ages, possibly, as a compensatory mechanism to control latent infections, e.g., CMV, but eventually a point is reached where clonal exhaustion leads to shrinkage of the CD8 clonal repertoire, associated with decreased survival.
Aged, 80 and over↗
Ultradian rapid cycling in prepubertal and early adolescent bipolarity is not in transmission disequilibrium with val/met COMT alleles.
BACKGROUND: Prepubertal children and early adolescents with bipolar disorders (PEA-BP) who participate in the ongoing study "Phenomenology and Course of Pediatric Bipolar Disorders" have a high prevalence of ultradian (within 24-hour periods) rapid cycling. Based on a case-control finding reported in bipolar (BP) adults of an association between rapid and ultradian rapid cycling with the low-activity allele of catechol-O-methyltransferase (l-COMT), study of linkage and linkage disequilibrium of l-COMT in the PEA-BP population seemed warranted. METHODS: Genotypes on a subset of the larger PEA-BP sample, for whom trio blood collection was complete (i. e., probands and both of their biological parents), were used to perform transmission disequilibrium tests (TDTs). Diagnoses were established from a comprehensive battery that included WASH-U-KSADS (Washington University Kiddie Schedule for Affective Disorders and Schizophrenia) given to both mothers and children and from consensus conferences. Probands with PEA-BP (N = 52) were 10.9 +/- 2.8 years old at index episode; had a mean age of BP onset at 8.0 +/- 3.8 years; were severely impaired, with a mean Children's Global Assessment Scale score of 44.5 +/- 8.9; and manifested the cardinal features of BP (84.6% had euphoric mood, 76.9% had grandiosity, and 57.7% had psychosis). Ultradian rapid cycling occurred in 75%. Genotyping of the single nucleotide polymorphism at COMT was performed using automated capillary electrophoresis single-strand conformational polymorphism with detection by laser-induced fluorescence. RESULTS: Transmission disequilibrium tests were not significant for preferential transmission of l-COMT for the ultradian rapid-cycling subgroup or for the entire PEA-BP sample. CONCLUSIONS: The lack of linkage disequilibrium between l-COMT and ultradian rapid cycling in the PEA-BP sample compared to reported findings of an association in case-control studies of adults is discussed in terms of age-specific developmentally relevant phenotypes, anticipatory mechanisms, and heterogeneity. Repeat TDT analyses after these PEA-BP probands reach their adult phenotypes will be informative.
Adolescent↗
Lack of Epstein-Barr virus- and HIV-specific CD27- CD8+ T cells is associated with progression to viral disease in HIV-infection.
OBJECTIVE: Despite readily detectable virus-specific CD8+ T cells in most HIV-infected patients, immune surveillance is eventually lost, leading to progression to AIDS. To investigate the underlying mechanism of this loss of immune control phenotypic analysis of HIV- and Epstein-Barr virus (EBV)-specific CD8+ T cells was performed. DESIGN: In three clinically distinct groups, long-term asymptomatics, progressors to opportunistic infections and progressors to EBV-associated non-Hodgkin lymphoma's (NHL), both number and phenotype of virus-specific CD8+ T cells was studied longitudinally. METHODS: The number of HIV- and EBV-specific T cells were determined using HLA-peptide tetrameric complexes. The phenotype of these virus-specific T cells was investigated by costaining with CD27 and CD45RO and thereby identifying specific subsets of CD8+ T cells. RESULTS: Individuals co-infected with HIV and EBV persistently had low numbers of HIV-specific CD27- T cells, in contrast to rising numbers of EBV-specific CD27- CD8+ T cells. However, HIV-infected individuals developing EBV-associated AIDS-related NHL had very low numbers of EBV-specific CD27- CD8+ T cells. Higher numbers of HIV-specific CD27- CD8+ T cells were associated with delayed disease progression. Virus-specific CD27- T cells, compared with CD27+ T cells showed elevated interferon-gamma production in response to viral peptides in vitro, indicative for strong effector function. CONCLUSIONS: Taken together, our data indicate that virus-specific CD27- T cells may be important effector T cells in controlling chronic viral infections in humans and that lack of differentiation into CD27- effector T cells may lead to progression of viral disease.
Adult↗
Deficient expression of NCR in NK cells from acute myeloid leukemia: Evolution during leukemia treatment and impact of leukemia cells in NCRdull phenotype induction.
Natural killer (NK) cells play an important role in tumor-cell clearance, particularly against leukemia, as shown by killer cell inhibitory receptor (KIR)-mismatched allogeneic stem cell transplantation. Analysis of in vitro IL-2-expanded NK cells from patients with myelocytic/monocytic acute myeloid leukemia (AML-NK cells) has revealed poor cytolytic functions because of deficient expression of pivotal activation molecules-the natural cytotoxicity receptors (NCRs) NKp30, NKp44, and NKp46. To exclude the possibility that this observation was caused by the in vitro amplification of a small NCR(dull) population, we analyzed the AML-NK phenotype directly, without any in vitro expansion. We first confirmed that the NCR(dull) phenotype was not an in vitro artifact. Moreover, analysis of a large population of AML patients allowed us to demonstrate that phenotype was not restricted to a French-American-British (FAB) subtype and was not associated with a particular cytogenetic abnormality. Our longitudinal study of AML patients showed that the NCR(dull) phenotype was acquired during leukemia development because we observed its complete (for NKp46) or partial (for NKp30) reversibility in patients achieving complete remission (CR). Reversibility of the NCR(dull) phenotype after CR suggested that leukemia cells might be involved in NCR down-regulation. In agreement with this hypothesis, direct contact between leukemic blasts and NK cells (but not leukemia-cell supernatants) induced loss or decrease in NKp30 and NKp46 expression while impeding NKp44 induction by IL-2. We excluded the major implication of TGF-beta in NCR down-regulation. Although the clinical antitumor value of NK cells is clearly demonstrated in allogeneic stem cell transplantation, the role of NK cells in autologous transplantation is not proved. Interestingly, we observed a correlation between the NCR(dull) phenotype and poor survival in AML patients, suggesting that NK-deficient activation caused by NCR down-regulation could play a role in patient outcome. The prognostic value of NCR expression is discussed, and pathophysiologic implication of the NCR phenotype will be further investigated in a larger study.
Acute Disease↗
High concordance for essential tremor in monozygotic twins of old age.
OBJECTIVE: To assess the relative contribution of genetic and environmental factors for the etiology of essential tremor (ET) and to explore the effect of different diagnostic criteria. METHODS: A total of 2,448 twins of the Danish twin registry aged 70 years or more were screened for ET by an interview and an Archimedes spiral test. All twin pairs (n = 162) with a positive screening test of at least one of the twins were recontacted and 218 individuals (109 pairs) were interviewed and examined by a movement disorder specialist. The consensus criteria of the Tremor Investigation Group were applied to diagnose ET. RESULTS: Twenty-nine twins fulfilled the criteria of definite, 7 of probable, and 56 of possible ET. The probandwise concordance rate for the broadest definition of ET was 77% for monozygotic twins (MZ) and 59% for dizygotic twins (DZ). However, in an analysis restricted to cases of probable and definite ET, the concordance rates were 93% and 29%. The heritability for the liability to ET ranged from 93% to 99% using a general population prevalence of 1.2% for white 70+-year-olds. The inclusion of probable and exclusion of possible cases in the diagnosis of ET produced the highest concordance rates. CONCLUSION: The high concordance among MZ twins of very old age in this first population-based twin study of ET suggests that a disease phenotype consisting of definite and probable ET has a high heritability and hence is a good candidate for a phenotype to be used in linkage studies.
Age Factors↗
In vitro characteristics of cultured posterior longitudinal ligament tissue.
STUDY DESIGN: To determine the osteogenicity of posterior longitudinal ligament ossification, the posterior longitudinal ligament obtained during anterior cervical surgery from patients with the disorder was analyzed with in vitro cultures. OBJECTIVES: To determine the osteogenicity of the posterior longitudinal ligament. SUMMARY OF BACKGROUND DATA: The osteogenicity of posterior longitudinal ligament ossification in North America requires better documentation. METHODS: The posterior longitudinal ligament obtained during anterior cervical corpectomy with fusion from seven patients, three with ossification of the posterior longitudinal ligament documented by magnetic resonance imaging and computed tomography and four with spondylosis, was blindly submitted for in vitro culture. Explants of the posterior longitudinal ligament were placed in Dulbecco modified Eagle medium with 10% fetal calf serum, antibiotics, 4 mmol/L x L-proline, and 50 mg/L ascorbic acid. After reaching confluency, cells were trypsinized, and first-passage cells were used for all osteocalcin measurements to establish their osteoblastic phenotype. Periosteal cells, previously shown to synthesize osteocalcin, were used as a positive control. The cells were incubated with 1,25(OH)2 vitamin D3 at 10E-8 M for 72 hours in serum-free medium. The supernatants were collected and frozen, after which the quantity of osteocalcin induced by exposure to 1,25(OH)2 vitamin D3 was determined using enzyme-linked immunoassay. Control replicate cultures were measured without incubation using vitamin D3. RESULTS: Ossification of the posterior longitudinal ligament cell lines responded positively with osteocalcin synthesis in the 0.1 to 0.4 ng/M range. The cell line of the patient with spondylosis alone did not respond to vitamin D3 priming. CONCLUSIONS: Posterior longitudinal ligament cells from the three North American white patients with ossification of the posterior longitudinal ligament, when cultured in vitro, synthesized osteocalcin on vitamin D3 priming, confirming their osteoblastic phenotype, whereas posterior longitudinal ligament cells from four white patients with isolated spondylosis did not.
Calcitriol↗