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PubMed2001

Circadian rhythm of double (rate-pressure) product in healthy normotensive young subjects.

The double product (DP), systolic blood pressure multiplied by heart rate, is a surrogate measure of myocardial oxygen demand and cardiac workload used increasingly today in medicine. The double product is more strongly correlated with left ventricular mass than the daily blood pressure mean. The purpose of this study was to describe the normative circadian pattern of the double product in healthy normotensive young adults. We studied 125 men and 75 women, 23.0+/-3.3 (mean +/- SD) years of age, without medical history of hypertension and 24h ambulatory systolic/diastolic blood pressure mean consistently below 135/85 mm Hg. Subjects underwent ambulatory blood pressure monitoring at 30-minute intervals for 48 consecutive hours once each season of the year, yielding 930 protocol-correct blood pressure and heart rate time series. Subjects maintained their usual routine of diurnal activity and nocturnal sleep and avoided use of over-the-counter and other medication. Circadian rhythmicity in the double product was established by population multiple-component analysis. The double product rose rapidly from the lowest value, attained 3h before awaking from sleep at night, to a markedly elevated level at the commencement of morning activity. The double product was highest in the afternoon, roughly 7h after the commencement of diurnal activity. In both men and women, the shape of the high-amplitude circadian rhythm in the double product was best described by a complex model composed of three cosine curves having periods of 24h, 12h, and 6h. The 24h mean in the double product of 8092.51+/-42.76 (mean +/- SD) in men was significantly lower than that of 8353.17+/-37.48 in women (P < .001). The circadian double amplitude of the rhythm was statistically significantly greater (P < .001) in men (50% of the 24h mean) than women (44% of the 24h mean). The double product did not differ between seasons in women, but it did in men (P = .017) due to reduced heart rate in summer. The circadian pattern of large amplitude in the double product and its gender differences must be taken into account when using this variable to assess cardiac workload, risk of left ventricular hypertrophy, and efficiency of antihypertensive therapy.

Adult↗
PubMed2002

A peptide DNA surrogate accelerates autoimmune manifestations and nephritis in lupus-prone mice.

Lupus-associated anti-DNA Abs display features of Ag selection, yet the triggering Ag in the disease is unknown. We previously demonstrated that the peptide DWEYSVWLSN is bound by a pathogenic anti-DNA Ab, and that immunization of nonautoimmune mice with this peptide induces autoantibodies and renal Ig deposition. To elucidate differences in the induced B cell responses in mice genetically predisposed to autoimmunity, young (NZB x NZW)F(1) mice were immunized with this peptide DNA mimetope. DWEYSVWLSN-immunized mice had significantly increased IgG anti-dsDNA, anti-laminin, and anti-cardiolipin Ab titers compared with controls. In addition, glomerular histopathology in the form of endocapillary disease and crescent formation was markedly more severe in DWEYSVWLSN-immunized mice. Analysis of mAbs from DWEYSVWLSN-immunized mice revealed that anti-peptide Abs were often cross-reactive with DNA. Genetic elements used in the Ab response in immunized mice were homologous to those used in the spontaneous anti-DNA response in (NZB x NZW)F(1) mice, as well as in other, experimentally induced anti-DNA Abs. Our results indicate that peptide immunization can induce a molecular genetic response common to a variety of stimuli that break tolerance to mammalian dsDNA. Based on the similarity between spontaneously arising anti-DNA Abs and several types of induced anti-DNA Abs, we suggest that there may be more than a single Ag that can trigger systemic lupus erythematosus.

Animals↗
PubMed2003

Gastric mucosal-to-end-tidal PCO2 difference during major abdominal surgery: influence of the arterial-to-end-tidal PCO2 difference?

BACKGROUND AND OBJECTIVE: Because gastric mucosal PCO2 must be referenced to arterial values via a gastric-to-arterial PCO2 gap (Pg-aCO2), the gastric-to-end-tidal PCO2 difference (Pg-ETCO2) may be proposed as a surrogate method to monitor Pg-aCO2. However, the influence of arterial-to-end-tidal PCO2 (Pa-ETCO2) on its value remains unknown. Pa-ETCO2 may be enhanced by a low cardiac output and subsequent reduced perfusion of the lungs. This study was designed to compare such gaps observed during abdominal surgery in patients with or without preoperative cardiac dysfunction. METHODS: Haemodynamic, metabolic and tonometric variables were measured in seven patients with Crohn's disease and in five patients with chronic heart failure scheduled for abdominal surgery. Data were collected before skin incision (T0); at extractor placement (T1), 30 (T2) and 60 (T3) min later; at organ extraction (T4), 30 (T5) and 60 (T6) min later, and at the end of surgery (T7). RESULTS: Gradients appeared larger in the cardiac group. The difference was significant for Pg-ETCO2 during the whole study period, while it was only reached at T1-T2 for Pa-ETCO2 and at T5-T6 for Pg-aCO2. Gaps did not change significantly over the peroperative time points in either group. No major haemodynamic variations were registered in either group. CONCLUSIONS: In patients with preoperative chronic heart failure, Pg-ETCO2 remained constant throughout a major general surgical procedure and was only moderately influenced by the Pa-ETCO2 gap. In these patients, Pg-ETCO2 may be used as a reliable index of gastrointestinal perfusion after control of PaCO2.

Abdomen↗
PubMed2006

Leaf and wood carbon isotope ratios, specific leaf areas and wood growth of Eucalyptus species across a rainfall gradient in Australia.

Leaves and samples of recent wood of Eucalyptus species were collected along a rainfall gradient parallel to the coast of Western Australia between Perth in the north and Walpole in the south and along a southwest to northeast transect from Walpole in southwestern Australia, to near Mount Olga in central Australia. The collection included 65 species of Eucalyptus sampled at 73 sites and many of the species were collected at several sites along the rainfall gradient. Specific leaf area (SLA) and isotopic ratio of 13C to 12C (delta 13C) of leaves that grew in 2002, and tree ring growth and delta 13C of individual cell layers of the wood were measured. Rainfall data were obtained from the Australian Bureau of Meteorology for 29 locations that represented one or a few closely located collection sites. Site-averaged data and species-specific values of delta 13C decreased with decreasing annual rainfall between 1200 and 300 mm at a rate of 1.63 per thousand per 1000 mm decrease in rainfall. Responses became variable in the low rainfall region (< 300 mm), with some species showing decreasing delta 13C with rainfall, whereas delta 13C increased or remained constant in other species. The range of delta 13C values in the low rainfall region was as large as the range observed at sites receiving > 300 mm of annual rainfall. Specific leaf area varied between 2 and 6 m2 kg(-1) and tended to increase with decreasing annual rainfall in some species, but not all, whereas delta 13C decreased with SLA. The relationship between delta 13C and SLA was highly species and soil-type specific. Leaf-area-based nitrogen (N) content varied between 2 and almost 6 g m(-2) and decreased with rainfall. Thus, thicker leaves were associated with higher N content and this compensated for the effect of drought on delta 13C. Nitrogen content was also related to soil type and species identity. Based on a linear mixed model, statistical analysis of the whole data set showed that 27% of the variation in delta 13C was associated with changes in SLA, 16% with soil type and only 1% with rainfall. Additionally, 21% was associated with species identity. For a subset of sites with > 300 mm rainfall, 43% of the variation was explained by SLA, 13% by soil type and only 3% by rainfall. The species effect decreased to 9% because there were fewer species in the subset of sites. The small effect of rainfall on delta 13C was further supported by a path analysis that yielded a standardized path coefficient of 0.38 for the effect of rainfall on SLA and -0.50 for the effect of SLA on delta 13C, but an insignificantly low standardized path coefficient of -0.05 for the direct effect of rainfall on delta 13C. Thus, in contrast to our hypothesis that delta 13C decreases with rainfall independent of soil type and species, we detected no statistically significant relationship between rainfall and delta 13C in leaves of trees growing at sites receiving < 300 mm of rainfall annually. Rainfall affected delta 13C indirectly through soil type (a surrogate for water-holding capacity) across the rainfall gradient. Annual tree rings are not clearly visible in evergreen Eucalyptus species, even in the seasonally cool climate of SW Australia. Generally, visible density transitions in the wood are related not to a strict annual cycle but to periods of growth associated mainly with rainfall. The relationship between delta 13C of leaves and the width of these stem increments was not statistically significant. Analysis of stem growth periods showed that delta 13C in wood responded to rainfall events, but carbohydrate storage and reallocation also affected the isotopic signature. Although delta 13C in wood of any one species varied over a range of 2 to 4 per thousand, there was a general relationship between delta 13C of the leaves and the annual range of delta 13C in wood. We conclude that species-specific traits are important in understanding the response of Eucalyptus to rainfall and that the diversity of the genus may reflect its response to the large climatic gradient in Australia and to the large annual and interannual variations in rainfall at any one location.

Australia↗
PubMed2001

Evaluation of blink reflex results obtained from workers previously diagnosed with solvent-induced toxic encephalopathy.

We reviewed blink reflexes recorded from 51 railroad workers with long-term occupational exposure to solvents who were diagnosed by others with solvent-induced toxic encephalopathy. No worker fulfilled conventional clinical criteria for dementia or trigeminal mononeuropathy. All workers had normal R1 and R2 blink reflex latencies. R1 latencies correlated significantly with several nerve conduction measures, including F wave latencies, suggesting that some intersubject variability reflected intrinsic conduction properties, not isolated brain-stem function. Although normal, the workers' R1 latencies were significantly prolonged compared with historical control groups, including gender-matched control subjects of similar mean age (11.2 ms vs 9.9 ms; P < 0.0001). Stepwise multiple regression models demonstrated significant associations of R1 latency with age and use of CNS-active prescription medications (P = 0.003), but duration of occupational solvent exposure did not enter into the models. Paradoxically, workers using CNS-active medications had significantly shorter R1 latencies compared with workers not using such medications (10.9 vs 11.7 ms; P = 0.01). Job title, another potential surrogate measure of exposure, was not significantly related to reflex latencies. The geographical site of predominant solvent exposure did influence R1 latency, and workers from one site had longer exposure duration and longer R1 latencies than remaining workers. However, an interaction between age and exposure duration (r = 0.39; P = 0.003) confounded interpretation of this observation. Disability or work status, mental status findings, or classification of encephalopathy did not influence blink reflex latencies. The overall results do not support, but do not entirely exclude, a possible relationship between subclinical blink reflex abnormalities and occupational exposure to solvents. Nevertheless, it is clear from these results that the small group differences in R1 latency between exposed workers and control subjects are of no diagnostic importance and of uncertain physiologic importance, and they may reflect unrecognized confounders and technical factors.

Adult↗
PubMed2006

Evaluation of surrogate markers for passive transfer of immunity in kittens.

OBJECTIVE: To identify surrogate markers of passive transfer of immunity in kittens. DESIGN: Prospective clinical trial. ANIMALS: 55 kittens from 12 specific-pathogen-free queens. PROCEDURE: Kittens were allocated at birth into colostrum-fed (n = 27) and colostrum-deprived (28) groups. Blood was collected at birth and on days 1, 2, 4, 7, 14, 28, and 56. Serum samples were analyzed for activities of alkaline phosphatase (ALP), alanine aminotransferase, aspartate aminotransferase, creatine kinase, lactate dehydrogenase, gamma-glutamyltransferase, amylase, and lipase and for concentrations of albumin, total protein, bilirubin, urea nitrogen, creatinine, cholesterol, glucose, calcium, phosphorus, and triglycerides by use of an automated analyzer. Total serum solids concentrations were estimated by use of refractometry. Serum IgG concentrations were quantified by use of radial immunodiffusion. RESULTS: All kittens were agammaglobulinemic at birth. Colostrum-fed kittens had significantly higher IgG concentrations than did colostrum-deprived kittens from 1 though 28 days of age. Transient significant differences in serum biochemical variables between the colostrum-deprived and colostrum-fed groups were substantially resolved by day 4. Passive transfer of immunity could be reliably determined at 1 day of age and to a lesser extent at 2 days of age only by measurement of serum activity of ALP. CONCLUSIONS AND CLINICAL RELEVANCE: Adequacy of passive transfer in kittens initially correlated with serum activity of ALP, but quantification of serum IgG concentration was necessary after 2 days of age.

Aging↗
PubMed1995

Kinetic analysis of the interactions of recombinant human VpreB and Ig V domains.

The surrogate light chain, composed of VpreB and lambda 5/14.1 proteins, is selectively expressed on B cell precursors, and is important for B cell development. The surrogate light chain associates with cell surface mu-chains on preB cells, but little is known about the ligand specificity and affinity of VpreB binding. To analyze its interactions with Igs, we made recombinant human VpreB protein and measured its affinity for H and L chain V domains using surface plasmon resonance. The recombinant VpreB protein existed as a homodimer in solution. VpreB chains associated with each other with an apparent Kd = 5 x 10(-7) M, and bound to a human VH domain, a mouse VH domain, and a human VL domain with a similar affinity. VpreB protein also bound to human Fab fragments of IgG with an apparent Kd = 6 x 10(-7) M, but showed a very low affinity for human Fc fragments of IgG. VpreB-Fab complex formation was reproduced by the formation of a trimolecular VpreB-VH-VL complex. Thus, VpreB proteins can associate with each other and also form complexes with Ig at sites different from those involved in VH-VL interaction. By flow cytometry, biotinylated VpreB protein bound to surface Ig-positive B cells but not T cells. Receptors that contain VpreB could be cross-linked by either Ig or by self-association.

Animals↗
PubMed2005

Genetic composition of human immunodeficiency virus type 1 in cerebrospinal fluid and blood without treatment and during failing antiretroviral therapy.

Human immunodeficiency virus (HIV) infection of the central nervous system (CNS) is a significant cause of morbidity. The requirements for HIV adaptation to the CNS for neuropathogenesis and the value of CSF virus as a surrogate for virus activity in brain parenchyma are not well established. We studied 18 HIV-infected subjects, most with advanced immunodeficiency and some neurocognitive impairment but none with evidence of opportunistic infection or malignancy of the CNS. Clonal sequences of C2-V3 env and population sequences of pol from HIV RNA in cerebrospinal fluid (CSF) and plasma were correlated with clinical and virologic variables. Most (14 of 18) subjects had partitioning of C2-V3 sequences according to compartment, and 9 of 13 subjects with drug resistance exhibited discordant resistance patterns between the two compartments. Regression analyses identified three to seven positions in C2-V3 that discriminated CSF from plasma HIV. The presence of compartmental differences at one or more of the identified positions in C2-V3 was highly associated with the presence of discordant resistance (P = 0.007), reflecting the autonomous replication of HIV and the independent evolution of drug resistance in the CNS. Discordance of resistance was associated with severity of neurocognitive deficits (P = 0.07), while low nadir CD4 counts were linked both to the severity of neurocognitive deficits and to discordant resistance patterns (P = 0.05 and 0.09, respectively). These observations support the study of CSF HIV as an accessible surrogate for HIV virions in the brain, confirm the high frequency of discordant resistance in subjects with advanced disease in the absence of opportunistic infection or malignancy of the CNS, and begin to identify genetic patterns in HIV env associated with adaptation to the CNS.

AIDS Dementia Complex↗
PubMed2003

Inverse relationship between bioconcentration factor and exposure concentration for metals: implications for hazard assessment of metals in the aquatic environment.

The bioconcentration factor (BCF) and bioaccumulation factor (BAF) are used as the criteria for bioaccumulation in the context of identifying and classifying substances that are hazardous to the aquatic environment. The BCF/BAF criteria, while developed as surrogates for chronic toxicity and/or biomagnification of anthropogenic organic substances, are applied to all substances including metals. This work examines the theoretical and experimental basis for the use of BCF/BAF in the hazard assessment of Zn, Cd, Cu, Pb, Ni, and Ag. As well, BCF/BAFs for Hg (methyl and inorganic forms) and hexachlorobenzene (HCB) were evaluated. The BCF/BAF data for Zn, Cd, Cu, Pb, Ni, and Ag were characterized by extreme variability in mean BCF/BAF values and a clear inverse relationship between BCF/BAF and aqueous exposure. The high variability persisted when even when data were limited to an exposure range where chronic toxicity would be expected. Mean BCF/BAF values for Hg were also variable, but the inverse relationship was equivocal, in contrast with HCB, which conformed to the BCF model. This study illustrates that the BCF/BAF criteria, as currently applied, are inappropriate for the hazard identification and classification of metals. Furthermore, using BCF and BAF data leads to conclusions that are inconsistent with the toxicological data, as values are highest (indicating hazard) at low exposure concentrations and are lowest (indicating no hazard) at high exposure concentrations, where impacts are likely. Bioconcentration and bioaccumulation factors do not distinguish between essential mineral nutrient, normal background metal bioaccumulation, the adaptive capabilities of animals to vary uptake and elimination within the spectrum of exposure regimes, nor the specific ability to sequester, detoxify, and store internalized metal from metal uptake that results in adverse effect. An alternative to BCF, the accumulation factor (ACF), for metals was assessed and, while providing an improvement, it did not provide a complete solution. A bioaccumulation criterion for the hazard identification of metals is required, and work directed at linking chronic toxicity and bioaccumulation may provide some solutions.

Analysis of Variance↗
PubMed2000

Relationships of age, menopause and central obesity on cardiovascular disease risk factors in Chinese women.

OBJECTIVE: To evaluate the inter-relationships of age- and menopause- related changes of general obesity and body fat distribution and their independent effects on cardiovascular risk factors. DESIGN: Cross-sectional study. SUBJECTS: One-hundred and thirty-six premenopausal and 193 postmenopausal Chinese women with body mass index (BMI) < 30 kg/m2. MEASUREMENTS: Anthropometric surrogates of general obesity (BMI, total body fat percentage) and central obesity (waist-to-hip ratio, centrality index) were measured. Blood pressure, 75 g oral glucose tolerance test, glycosylated hemoglobin A1c and lipid profiles were also measured. RESULTS: Significant correlation coefficients between age, general obesity, central obesity and cardiovascular disease risk factors were noted. Through the menopausal transition, the BMI and total body fat percentage were increased significantly. After adjustments for age and BMI, the postmenopausal women showed higher android fat percentage, centrality index, glycosylated hemoglobin A1c, serum concentrations of total cholesterol, low-density lipoprotein (LDL) cholesterol and atherogenic indices than the premenopausal women. In multiple stepwise regression models, age exerted independent effects on oral glucose tolerance test 2 h plasma glucose level, systolic and diastolic blood pressure, total cholesterol level, and LDL cholesterol. Menopause was an independent variable in relation to the changes of glycosylated hemoglobin A1c, total and LDL cholesterol levels, triglyceride levels and atherogenic indices. The centrality index was the major independent variable of all the cardiovascular disease risk factors, except total and LDL cholesterol level. However, the variation of total body fat percentage had no independent effect on any cardiovascular disease risk factors. CONCLUSION: Through the aging and menopausal effects, women will increase total body fat content, favoring the central body fat distribution. Age, menopause and central obesity were all independent and significant factors to the cardiovascular disease risk factors in Chinese women.

Adipose Tissue↗
PubMed1999

Intraoperative electromyographic assessment of recurrent laryngeal nerve stress and pharyngeal injury during anterior cervical spine surgery with Caspar instrumentation.

OBJECT: Recurrent laryngeal nerve (RLN) injury occurs after anterior cervical spine procedures. In this study the authors used intraoperative electromyographic (EMG) monitoring of the posterior pharynx as a surrogate for RLN function and monitored endotracheal tube (ET) cuff pressure to determine if there was an association between these variables and clinical outcome. METHODS: Sixty patients in whom anterior cervical spine procedures were to be performed comprised the study population. After intubation, the ET cuff was adjusted to a just-seal volume and attached to a pressure monitor. A laryngeal surface electrode was placed in the posterior pharynx, and spontaneous EMG activity was monitored throughout the procedure. Cuff pressures and EMG activity were recorded during neck retraction and when EMG activity increased 20% above baseline. Patients were divided into two groups: those with sore throat/dysphonia and those without symptoms. Cuff pressures and EMG values were compared between groups, and the differences were correlated with clinical outcome. CONCLUSIONS: Hoarseness immediately after surgery was reported in 38% of patients whereas 15% exhibited severe symptoms. In symptomatic patients the period of intubation had been longer, and the ET cuff pressures had been elevated. In most patients EMG activity increased during insertion of the retractor and decreased after its removal. In these patients a greater number of episodes of elevated EMG activity during surgery were also noted. Two patients experienced prolonged hoarseness, and one required teflon injections of the vocal fold. This patient's EMG activity increased (15-18 times baseline) during surgery. In the few patients who were symptomatic with increased EMG activity, neither the timing nor direction of change could be associated with symptoms. Intubation time and elevated ET cuff pressure were the most important contributors to dysphonia and sore throat after anterior cervical spine surgery.

Analysis of Variance↗
PubMed2005

Immunotherapy for advanced renal cell cancer.

BACKGROUND: The course of advanced renal cell carcinoma is extremely variable, ranging from spontaneous remission to disease progression refractory to chemotherapy. Immunotherapy has held promise of improved outcomes based on uncontrolled studies and randomized controlled trials generally limited by small size and low power. OBJECTIVES: To evaluate immunotherapy for advanced renal cell carcinoma by comparing: (1) high dose interleukin-2 to other options and (2) interferon-alfa to other options. The primary outcome of interest was overall survival at one year, with remission as the main secondary outcome of interest. SEARCH STRATEGY: A systematic search of the CENTRAL, MEDLINE, and EMBASE databases was conducted for the period 1966 through end of December 2003. Handsearches were made of the proceedings of the periodic meetings of the American Urologic Association, the American Society of Clinical Oncology, ECCO - the European Cancer Conference, and the European Society of Medical Oncology for the period 1995 to June 2004. SELECTION CRITERIA: Randomized controlled trials that selected (or stratified) patients with advanced renal cell carcinoma, utilized an immunotherapeutic agent in at least one study arm, and reported remission or survival by allocation. Fifty-three identified studies involving 6117 patients were eligible and all but one reported remission; 32 of these studies reported the one-year survival outcome. DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted each article by following a prospectively designed protocol. Dichotomous outcomes for treatment remission (partial plus complete) and for deaths at one year were used for the main comparisons. Survival hazard ratios were also used for studies of interferon-alfa versus controls, and for two randomized studies of the value of initial nephrectomy prior to interferon-alfa in fit patients with metastases detected at the time of diagnosis. MAIN RESULTS: Combined data for a variety of immunotherapies gave an overall chance of partial or complete remission of only 12.9% (99 study arms), compared to 2.5% in 10 non-immunotherapy control arms, and 4.3% in two placebo arms. Twenty-eight percent of these remissions were designated as complete (data from 45 studies). Median survival averaged 13.3 months (range by arm, 6 to 27+ months). The difference in remission rate between arms was poorly correlated with the difference in median survival so that remission rate is not a good surrogate or intermediate outcome for survival for advanced renal cancer. We were unable to identify any published randomized study of high-dose interleukin-2 versus a non-immunotherapy control, or of high-dose interleukin-2 versus interferon-alfa reporting survival. It has been established that reduced dose interleukin-2 given by intravenous bolus or by subcutaneous injection provides equivalent survival to high dose interleukin-2 with less toxicity. Results from four studies (644 patients) indicate that interferon-alfa is superior to controls (OR for death at one year = 0.56, 95% confidence interval 0.40 to 0.77). Using the method of Parmar 1998, the pooled overall hazard ratio for death was 0.74 (95% confidence interval 0.63 to 0.88). The weighted average median improvement in survival was 3.8 months. T he optimal dose and duration of interferon-alfa remains to be elucidated. The addition of a variety of enhancers, including lower dose intravenous or subcutaneous interleukin-2, has failed to improve survival compared to interferon-alfa alone. Two recent randomized studies have examined the role of initial nephrectomy prior to interferon-alfa therapy in highly selected fit patients with metastases at diagnosis and minimal symptoms: despite minimal improvement in the chance of remission, both studies of up-front nephrectomy improved median survival by 4.8 months over interferon-alfa alone. Recent studies have been examining anti-angiogenesis agents. A landmark study of bevacizumab, an anti-vascular endothelial growth factor antibody, was associated with significant prolongation of the time to progression of disease when given at high dose compared to low-dose or placebo therapy though frequency of remissions or survival were not improved. AUTHORS' CONCLUSIONS: interferon-alfa provides a modest survival benefit compared to other commonly used treatments and should be considered for the control arm of future studies of systemic agents. In fit patients with metastases at diagnosis and minimal symptoms, nephrectomy followed by interferon-alfa gives the best survival strategy for fully validated therapies. The need for more effective specific therapy for this condition is apparent.

Antibodies, Monoclonal↗
PubMed2004

Changes in total lymphocyte count as a surrogate for changes in CD4 count following initiation of HAART: implications for monitoring in resource-limited settings.

BACKGROUND: A major obstacle to the administration of highly active antiretroviral therapy (HAART) in resource-limited settings is the high cost of CD4 count testing. The total lymphocyte count (TLC) has been proposed as a surrogate marker to monitor immune response to therapy. OBJECTIVE: To assess, in a developed country setting, the capability and clinical utility of TLC change as a surrogate marker for CD4 count change in monitoring patients on HAART. METHODS: Longitudinal co-variation between changes in TLC and concomitant changes in CD4 count following the initiation of HAART was examined using a retrospective cohort study of 126 HIV-positive patients attending The Miriam Hospital, Brown University, Providence, RI. Analyses included evaluation of the direction of TLC change as a marker for direction of CD4 change, using sensitivity and specificity; evaluation of absolute change in TLC as a marker for benchmark changes in CD4 (> or =50 over 6 months, > or =100 over 12 months), using receiver-operator characteristic (ROC) curves; and a regression model of change in TLC as a function of change in CD4, to understand within-individual variation of longitudinal TLC measures. RESULTS: In the first 24 months of HAART, the sensitivity of a TLC increase as a marker for CD4 count increase over the same time period ranged from 86-94%, and the specificity ranged from 80-85%. The median change in TLC among patients with a CD4 count rise of > or =100 cells/mm at 1 year of HAART was +766 cells/mm while that of patients with a CD4 count rise of <100 cells/m was +100 cells/mm. The area under the corresponding ROC curve was 0.89, suggesting that change in TLC discriminates well between those with 1-year CD4 change of > or =100 vs. those with change <+100. From a regression analysis, we found that mean change in TLC per 1 cell/mm change in CD4 count was 7.3 (SE 1.2, P < 0.001). The degree of this association varied from individual to individual but was positive for all individuals. CONCLUSIONS: Within the first 2 years of HAART, the direction of change in TLC appears to be a strong marker for direction of concomitant change in CD4 count (sensitivity 86-94% and specificity 80-85%, depending on length of interval). Positive and negative predictive values depend on the proportion of CD4 changes that are positive. In this cohort, that proportion is 87.9%, which yields high positive predictive value (96-98%) but lower negative predictive value (43-63%). Findings from the regression model suggest that taking multiple measurements of TLC at more frequent intervals may reduce variability and potentially improve predictive accuracy.

Adolescent↗
PubMed1999

Mu-surrogate light chain physicochemical interactions of the human preB cell receptor: implications for VH repertoire selection and cell signaling at the preB cell stage.

The surrogate light chain (SL) composed of the A-like and VpreB polypeptides is organized as two Ig domains and an extra-loop structure. It associates to the mu-chain in preB cells. We have produced human VpreB, SL, two Fdmu (VH-CH1), and the two corresponding Fab-like (Fdmu-SL) recombinant proteins in baculovirus. The correctness of the general conformation of the proteins was assessed by epitope mapping and affinity measurements using a new batch of anti-VpreB mAbs. Plasmon resonance analysis showed that both VpreB and the entire SL associated with the Fdmu fragments, with Kd values of 3x10(-8) M for VpreB-Fdmu and of 10(-9) to 10(-10) M, depending upon the V(H), for SL-Fdmu. These results indicate that the A-like chain, in addition to be covalently bound to the Cmu1 domain, also interacts with the VH domain. Therefore, a dual role of the SL emerges: 1) interaction of the C-domain of A-like would release the mu-chain from its interaction with binding protein in the endoplasmic reticulum, and 2) interaction of a part of A-like and most of VpreB would bind to VH, ensuring a "quality control" of the native heavy chain that represents the first step of selection of the B cell repertoire. We also demonstrated that two Fab-like fragments did not interact with each other, suggesting that activation of the cell surface preB receptor does not involve aggregation neither in cis nor in trans of the Fab-like structures.

Antibodies, Monoclonal↗
PubMed1999

Proinsulin in pregnant women with normal glucose tolerance or mild gestational diabetes mellitus.

Pregnancy is characterized by peripheral insulin resistance, which is physiologically compensated by an increase in insulin secretion. Type 2 diabetes and impaired glucose tolerance (IGT) have been associated with an inappropriate increase in insulin precursors, namely proinsulin. The aim of this study was to determine levels of proinsulin (PI), specific insulin (SI) and the proinsulin-to-specific insulin (PI/SI) ratio in consecutive pregnant women (n = 209) with normal glucose tolerance (NGT), as assessed by a 2h oral glucose tolerance test, and with mild gestational diabetes (GDM), in comparison to 32 healthy, non-pregnant women. Furthermore, we related these variables to surrogate markers of insulin resistance and insulin secretion. We found no significant differences in the levels of PI and the PI/ SI ratio between pregnant and non-pregnant women (PI: 5.0 +/- 3.6 vs. 4.8 +/- 3.5 pmol/L, p = NS), and between pregnant women with mild GDM and NGT (PI: 5.4 +/- 2.4 vs. 4.9 +/- 3.9 pmol/L, p = NS). SI was elevated in women with mild GDM (112.2 +/- 47.3 vs. 94.8 +/- 43.0 pmol/L in NGT, p=0.02). PI was related to fasting glucose (r = 0.17, p < 0.02), but not post-load glucose levels, and to fasting insulin [specific insulin: r = 0.67, p = 0.0001; total immunoreactive insulin (IRI): r = 0.69, p = 0.0001], as well as post-load insulin levels (IRI at 120 min: r = 0.18, p < 0.03). The PI/SI ratio showed no association with fasting or post-load glucose or insulin levels. Pregnant women presented with a metabolic pattern suggestive of enhanced insulin resistance, namely increased fasting and post-load insulin levels. In women with mild GDM, fasting and post-load hyperglycemia, as well as an additional increase in insulin resistance was found. Group differences weakened when accounting for differences in body weight. The data of the present study suggest that in normal pregnancy as well as mild GDM metabolic alterations including enhanced insulin resistance and hyperglycemia do not result in an increase in circulating levels of proinsulin, both in absolute terms and relative to levels of specific insulin, as indicated by the proinsulin-to-specific insulin ratio.

Adult↗
PubMed2004

Butterbur, a herbal remedy, confers complementary anti-inflammatory activity in asthmatic patients receiving inhaled corticosteroids.

BACKGROUND: The effects of butterbur (BB), a herbal remedy, as add-on therapy to inhaled corticosteroids in patients with atopic asthma is currently unknown. OBJECTIVE: We evaluated the effects of BB, given as add-on therapy to asthmatic patients maintained on inhaled corticosteroids, assessing adenosine monophosphate (AMP) bronchoprovocation (primary outcome variable) along with other surrogate inflammatory markers such as exhaled nitric oxide, serum eosinophil cationic protein and peripheral blood eosinophil count. METHODS: Sixteen atopic asthmatic patients with mean (standard error of mean) forced expiratory volume in 1 s (FEV1) of 78 (4)% predicted, maintained on their constant dose of inhaled corticosteroids throughout the study, received twice daily for 1 week either BB 25 mg or placebo (PL), in a double-blind, cross-over fashion, with a 1-week washout period prior to each randomized treatment. Measurements were made at baselines prior to each randomized treatment and following the randomized treatment period. RESULTS: Baseline values for the primary and secondary outcomes were not significantly different prior to BB and PL. AMP provocative concentration causing a 20% reduction from baseline FEV1 (PC20) as doubling dilution change from baseline, significantly improved (P<0.05) with BB, 0.6 (0.2), compared with PL, -0.1 (0.3); a 0.7 doubling dilution difference. Exhaled nitric oxide as change from baseline was significantly reduced (P<0.05) with BB, -1.2 (0.8) p.p.b., compared with PL, 0.5 (0.4) p.p.b. Both serum eosinophil cationic protein and peripheral blood eosinophil count as change from baseline were also significantly suppressed (P<0.05) with BB, -3.9 (3.3) microg/L, -31 (28)x106/L compared with PL, 3.3 (2.5) microg/L, 38 (16)x106/L, respectively. CONCLUSION: Chronic dosing with BB conferred complementary anti-inflammatory activity in atopic asthmatic patients maintained on inhaled corticosteroids. Further studies are now required to assess the potential role for BB as either monotherapy in milder patients or add-on therapy in more severe asthmatics.

Adenosine Monophosphate↗
PubMed2001

Circulating human B cells that express surrogate light chains display a unique antibody repertoire.

Circulating human B cells that coexpress V-preB and conventional L chains (V-preB+L+ B cells) are a recently described subset of B cells that express Abs with features of self-reactivity. Initial analysis of V-preB+L+ B cells was limited to Ig-kappa and to the small, underused VH5 family. To determine whether Abs commonly expressed by V-preB+L+ B cells show similar features, we analyzed Ig H chains from three highly expressed VH families, VH1, VH3, and VH4, and Ig-lambda. We find that VH1 and VH3 Abs expressed by V-preB+L+ B cells resemble VH5 in that they display increased JH6 use, long CDR3s, and an increased frequency of D-D fusions. Abs in all three of these VH families also show skewed D reading frame use resulting in predominance of hydrophobic amino acids, which are counterselected in conventional B cells. Like Ig-kappa genes, the Ig-lambda genes in V-preB+L+ B cells show long CDR3s, but they differ from Ig-kappa genes in that they display no evidence of receptor editing. We conclude that a large number of H and L chain Abs expressed by V-preB+L+ B cells display features associated with self-reactive Abs.

Antibody Diversity↗
PubMed2006

Incidence, time course, and determinants of menstrual bleeding after breast cancer treatment: a prospective study.

PURPOSE: To assess ovarian function using the surrogate of monthly bleeding after breast cancer treatment in premenopausal women. PATIENTS AND METHODS: Five hundred ninety-five US women age 20 to 45 years were accrued from January 1998 to July 2002 within 8 months of diagnosis with stages I to III breast cancer (median follow-up 45 months). Daily bleeding records were obtained prospectively, as well as extensive clinical, demographic, quality of life, and treatment data. Repeated measures logistic regression was used to assess which variables were predictive of monthly bleeding. RESULTS: Significantly different proportions of women had monthly bleeding depending on their age (P < .001), chemotherapy program (P < .001), and time since treatment regimen. In the month after the standard course of doxorubicin and cyclophosphamide (AC), whether or not followed by paclitaxel or docetaxel, approximately 16% had monthly bleeding compared with the cyclophosphamide, methotrexate, fluorouracil (CMF) group, in which 48% bled (P < .001). Following any AC regimen, there was a slow recovery phase of about 9 months followed by a plateau, during which almost half continued monthly bleeding for the remainder of the follow-up period compared with after CMF in which there was no recovery phase and a continual decline in monthly bleeding to approximately 18% of women at study end (P < .001). Tamoxifen use decreased bleeding between months 12 and 24 after chemotherapy with 15% fewer women having bleeding. CONCLUSION: Using daily menstrual bleeding records, it is demonstrated that age, the specific chemotherapy regimen received, and tamoxifen use impact ovarian function.

Adult↗