Incident depression in patients diagnosed with multiple sclerosis: a multi-database study.

BACKGROUND AND PURPOSE: Data on rates of newly diagnosed depression after multiple sclerosis (MS) diagnosis are sparse. Here, incident, treated depression in MS patients after diagnosis compared with matched non-MS patients is described. METHODS: A matched cohort study was conducted in two separate electronic medical databases: the US Department of Defense (US-DOD) military healthcare system and the UK's Clinical Practice Research Datalink GOLD (UK-CPRD). The study population included all patients with a first recorded diagnosis of MS and matched non-MS patients. Patients with a history of treated depression were excluded. Incidence rates and incidence rate ratios with 95% confidence intervals for treated depression after MS diagnosis/matched date were estimated. RESULTS: Incidence rate ratios of treated depression amongst MS patients compared with non-MS patients were 3.20 (95% confidence interval 3.05-3.35) in the US-DOD and 1.90 (95% confidence interval 1.74-2.06) in the UK-CPRD. Incidence rate ratios were elevated across age and sex. Rates were higher in females than males but, compared to non-MS patients, males with MS had a higher relative risk than females with MS. CONCLUSIONS: Multiple sclerosis patients in the UK and the USA have a two- to three-fold increased risk of new, treated depression compared to matched non-MS patients.

Gene drive: progress and prospects.

Gene drive is a naturally occurring phenomenon in which selfish genetic elements manipulate gametogenesis and reproduction to increase their own transmission to the next generation. Currently, there is great excitement about the potential of harnessing such systems to control major pest and vector populations. If synthetic gene drive systems can be constructed and applied to key species, they may be able to rapidly spread either modifying or eliminating the targeted populations. This approach has been lauded as a revolutionary and efficient mechanism to control insect-borne diseases and crop pests. Driving endosymbionts have already been deployed to combat the transmission of dengue and Zika virus in mosquitoes. However, there are a variety of barriers to successfully implementing gene drive techniques in wild populations. There is a risk that targeted organisms will rapidly evolve an ability to suppress the synthetic drive system, rendering it ineffective. There are also potential risks of synthetic gene drivers invading non-target species or populations. This Special Feature covers the current state of affairs regarding both natural and synthetic gene drive systems with the aim to identify knowledge gaps. By understanding how natural drive systems spread through populations, we may be able to better predict the outcomes of synthetic drive release.

The copulatory plug delays ejaculation by rival males and affects sperm competition outcome in house mice.

Females of many species mate with multiple males (polyandry), resulting in male-male competition extending to post-copulation (sperm competition). Males adapt to such post-copulatory sexual selection by altering features of their ejaculate that increase its competitiveness and/or by decreasing the risk of sperm competition through female manipulation or interference with rival male behaviour. At ejaculation, males of many species deposit copulatory plugs, which are commonly interpreted as a male adaptation to post-copulatory competition and are thought to reduce or delay female remating. Here, we used a vertebrate model species, the house mouse, to study the consequences of copulatory plugs for post-copulatory competition. We experimentally manipulated plugs after a female's first mating and investigated the consequences for rival male behaviour and paternity outcome. We found that even intact copulatory plugs were ineffective at preventing female remating, but that plugs influenced the rival male copulatory behaviour. Rivals facing intact copulatory plugs performed more but shorter copulations and ejaculated later than when the plug had been fully or partially removed. This suggests that the copulatory plug represents a considerable physical barrier to rival males. The paternity share of first males increased with a longer delay between the first and second males' ejaculations, indicative of fitness consequences of copulatory plugs. However, when males provided little copulatory stimulation, the incidence of pregnancy failure increased, representing a potential benefit of intense and repeated copulation besides plug removal. We discuss the potential mechanisms of how plugs influence sperm competition outcome and consequences for male copulatory behaviour.

Female house mice avoid fertilization by t haplotype incompatible males in a mate choice experiment.

The t haplotype in house mice is a well-known selfish genetic element with detrimental, nonadditive fitness consequences to its carriers: recessive lethal mutations cause t/t homozygotes to perish in utero. Given the severe genetic incompatibility imposed by the t haplotype, we predict females to avoid fertilization by t haplotype incompatible males. Indeed, some of the strongest evidence for compatibility mate choice is related to the t haplotype in house mice. However, all previous evidence for compatibility mate choice in this system is based on olfactory preference. It is so far unknown how general these preferences are and whether they are relevant in an actual mating context. Here, we assess female compatibility mate choice related to t haplotypes in a setting that--for the first time--allowed females to directly interact and mate with males. This approach enabled us to analyse female behaviour during the testing period, and the resulting paternity success and fitness consequences of a given choice. We show that genetic incompatibilities arising from the t haplotype had severe indirect fitness consequences and t females avoided fertilization by t incompatible males. The results are inconclusive whether this avoidance of t fertilization by t females was caused by pre- or post-copulatory processes.

Causes of male sexual trait divergence in introduced populations of guppies.

Males from different populations of the same species often differ in their sexually selected traits. Variation in sexually selected traits can be attributed to sexual selection if phenotypic divergence matches the direction of sexual selection gradients among populations. However, phenotypic divergence of sexually selected traits may also be influenced by other factors, such as natural selection and genetic constraints. Here, we document differences in male sexual traits among six introduced Australian populations of guppies and untangle the forces driving divergence in these sexually selected traits. Using an experimental approach, we found that male size, area of orange coloration, number of sperm per ejaculate and linear sexual selection gradients for male traits differed among populations. Within populations, a large mismatch between the direction of selection and male traits suggests that constraints may be important in preventing male traits from evolving in the direction of selection. Among populations, however, variation in sexual selection explained more than half of the differences in trait variation, suggesting that, despite within-population constraints, sexual selection has contributed to population divergence of male traits. Differences in sexual traits were also associated with predation risk and neutral genetic distance. Our study highlights the importance of sexual selection in trait divergence in introduced populations, despite the presence of constraining factors such as predation risk and evolutionary history.

Genes or culture: are mitochondrial genes associated with tool use in bottlenose dolphins (Tursiops sp.)?

Some bottlenose dolphins use marine sponges as foraging tools ('sponging'), which appears to be socially transmitted from mothers mainly to their female offspring. Yet, explanations alternative to social transmission have been proposed. Firstly, the propensity to engage in sponging might be due to differences in diving ability caused by variation of mitochondrial genes coding for proteins of the respiratory chain. Secondly, the cultural technique of sponging may have selected for changes in these same genes (or other autosomal ones) among its possessors. We tested whether sponging can be predicted by mitochondrial coding genes and whether these genes are under selection. In 29 spongers and 54 non-spongers from two study sites, the non-coding haplotype at the HVRI locus was a significant predictor of sponging, whereas the coding mitochondrial genes were not. There was no evidence of selection in the investigated genes. Our study shows that mitochondrial gene variation is unlikely to be a viable alternative to cultural transmission as a primary driver of tool use in dolphins.

Infections in patients diagnosed with multiple sclerosis: A multi-database study.

BACKGROUND: Recent data on the rates of infections among patients with multiple sclerosis (MS) are sparse. The objective of this study was to quantify incidence of infections in patients with MS compared with a matched sample of patients without MS (non-MS). METHODS: This study was conducted in two separate electronic medical databases: the United States Department of Defense (US-DOD) military health care system and the United Kingdom's Clinical Practice Research Datalink GOLD (UK-CPRD). We identified patients with a first recorded diagnosis of MS between 2001 and 2016 (UK-CPRD) or 2004 and 2017 (US-DOD) and matched non-MS patients. We identified infections recorded after the MS diagnosis date (or the matched date in non-MS patients) and calculated incidence rates (IRs) and incidence rate ratios (IRRs) with 95% confidence intervals (CIs) by infection site and type. RESULTS: Relative to non-MS patients, MS patients had higher rates of any infection (US-DOD IRR 1.76; 95% CI 1.72-1.80 and UK-CPRD IRR 1.25; 95% CI 1.21-1.29) and a two-fold higher rate of hospitalized infections (US-DOD IRR 2.43; 95% CI 2.23-2.63 and UK-CPRD IRR 2.00; 95% CI 1.84-2.17). IRs of any infection were higher in females compared with males in both MS and non-MS patients, while IRs of hospitalized infections were similar between sexes in both MS and non-MS patients. The IR of first urinary tract or kidney infection was nearly two-fold higher in MS compared with non-MS patients (US-DOD IRR 1.88; 95% CI 1.81-1.95 and UK-CPRD IRR 1.97; 95% CI 1.86-2.09) with higher rates in females compared with males. IRs for any opportunistic infection, candidiasis and any herpes virus were increased between 20 and 52% among MS patients compared with non-MS patients. IRs of meningitis, tuberculosis, hepatitis B and C were all low. CONCLUSION: MS patients have an increased risk of infection, notably infections of the renal tract, and a two-fold increased risk of hospitalized infections compared with non-MS patients.

Experimental evidence that high levels of inbreeding depress sperm competitiveness.

The effects of inbreeding on sperm quantity and quality are among the most dramatic examples of inbreeding depression. The extent to which inbreeding depression results in decreased fertilization success of a male's sperm, however, remains largely unknown. This task is made more difficult by the fact that other factors, such as cryptic female choice, male sperm allocation and mating order, can also drive patterns of paternity. Here, we use artificial insemination to eliminate these extraneous sources of variation and to measure the effects of inbreeding on the competitiveness of a male's sperm. We simultaneously inseminated female guppies (Poecilia reticulata) with equal amounts of sperm from an outbred (f = 0) male and either a highly (f = 0.59) or a moderately inbred (f = 0.25) male. Highly inbred males sired significantly fewer offspring than outbred males, but share of paternity did not differ between moderately inbred and outbred males. These findings therefore confirm that severe inbreeding can impair the competitiveness of sperm, but suggest that in the focal population inbreeding at order of a brother-sister mating does not reduce a male's sperm competitiveness.

A 2.5 year study on health and locomotion symmetry in young Standardbred horses subjected to two levels of high intensity training distance.

The aim of this study was to document effects of two high-intensity training regimes on horse health. Sixteen Standardbred horses in training from September as 1-year-olds with the goal to race as 3-year-olds were used in a 2.5 year study. Horses were trained in either a control training program (C-group) or in a program with 30% reduced high intensity distance compared to the C-group (R-group). Clinical examinations were performed nine times. Locomotion asymmetry was registered with a sensor-based system 17 times. There was no difference in health scores, locomotion asymmetry or veterinary treatments between groups. Subjective lameness score and objective front limb locomotion asymmetry increased during the spring both as 2- and 3-year-olds after introduction of speed- and uphill interval training but decreased during winter. Hind limb locomotion asymmetry increased during spring as 2-year-olds and was still above initial level in December as 3-year-olds. Horses that qualified for races early had less asymmetric front limb locomotion and were less lame in clinical examinations (0.7 ± 0.3 vs. 1.6 ± 0.2 degrees [AAEP scale], P = 0.04) than late qualifiers. Days lost to training were higher in C-group than in R-group (27 ± 3% and 17 ± 3%, P = 0.029). It is concluded that (1) less days may be lost to training by reducing the high intensity training distance and (2) the introduction of new training may alter locomotion asymmetry and this can be detected with objective locomotion analysis.

Improved postprandial glycemic control with insulin aspart. A randomized double-blind cross-over trial in type 1 diabetes.

OBJECTIVE: Insulin aspart is a novel rapid-acting insulin analog. This study was performed to compare the postprandial serum glucose control after administration of insulin aspart with that of unmodified human insulin. RESEARCH DESIGN AND METHODS: The trial was a double-blind double-dummy injection three-way cross-over study in 22 subjects with type 1 diabetes. Insulin aspart was injected subcutaneously immediately before the meal, and human insulin was injected subcutaneously 30 min before the meal or immediately before the meal. RESULTS: The postprandial glucose control as assessed by the excursion of serum glucose was superior with insulin aspart as compared with that with human insulin injected immediately before or 30 min before a meal (891 +/- 521 vs. 1,311 +/- 512 vs. 1,106 +/- 571 mmol.l-1.min-1, P < 0.0001 and P < 0.02). This was accompanied by a significantly lower glucose maximum concentration [Cmax(SG)] for insulin aspart than for human insulin injected immediately before the meal (13.5 +/- 3.5 vs. 16.4 +/- 3.4 mmol/l, P < 0.001). Insulin aspart was, on average, absorbed twice as fast as human insulin, with median time to insulin aspart Cmax(ins) on the order of 40 min, and the maximum concentration was approximately twice as high for insulin aspart. The relative bioavailability of the insulins indicated a similar extent of absorption. Insulin aspart was well tolerated. CONCLUSIONS: This study demonstrates the ability of insulin aspart to improve postprandial glucose control when compared with human insulin.

Improved glycemic control with insulin aspart: a multicenter randomized double-blind crossover trial in type 1 diabetic patients. UK Insulin Aspart Study Group.

OBJECTIVE: To compare glycemic control obtained with the new rapid-acting insulin analog insulin aspart with that obtained with unmodified human insulin using algorithm-driven dosage adjustment. RESEARCH DESIGN AND METHODS: This was a multicenter randomized double-blind crossover study of 90 male subjects with type 1 diabetes. Insulin aspart or soluble human insulin was administered before meals, and NPH insulin was administered at bedtime as basal therapy. Each 4-week study period ended with a 24-h inpatient serum insulin and plasma glucose profile. RESULTS: The 24-h plasma glucose control obtained with insulin aspart, as assessed by excursions of blood glucose outside a predefined normal range (4.0-7.0 mmo/l), was superior (22% reduction in excursion, P < 0.01). Fructosamine levels remained unchanged with insulin aspart, with daytime glycemic control superior but nighttime glycemic control inferior. Eight-point home blood glucose profiles confirmed that insulin aspart significantly improved postprandial blood glucose control after lunch and dinner (P < 0.05) without deterioration of preprandial blood glucose control. Hypoglycemic episodes requiring third-party intervention were significantly fewer with insulin aspart than with human insulin (20 vs. 44 events, P < 0.002). Insulin aspart was well tolerated. CONCLUSIONS: In comparison with human insulin, insulin aspart can improve postprandial glycemic control as assessed by a reduction in hyper- and hypoglycemic excursions in people with type 1 diabetes. For its full potential to be realized, it will need to provide better control of nighttime hyperglycemia.

Human chorionic gonadotropin-beta gene expression in first trimester placenta.

The hCGbeta gene family contains six genes linked in tandem on chromosome 19 and labeled beta genes 7, 8, 5, 1, 2, and 3. Previous studies on a small number of placentas have indicated that beta gene 5 was the most highly expressed gene during the first trimester of pregnancy, followed by genes 3 and 8. Beta genes 7, 1, and 2 were expressed at very low levels. The purpose of this study was to determine 1) whether this pattern of expression was typical during normal pregnancy by sampling a large number of first trimester placentas, and 2) whether there was a correlation between gestational age and the pattern of hCGbeta gene expression. Total RNA from 27 first trimester placentas varying in age from 6-16 weeks was reverse transcribed into complementary DNA. The complementary DNA was amplified by PCR, and the amount of DNA representative of each hCGbeta gene was quantified by Genescan analysis. In 14 of the 27 placentas, hCGbeta gene 5 accounted for 50% or more of the total beta messenger RNA expressed. Beta gene 3 was expressed at levels ranging from 1-42% of the total, and beta gene 8 expression ranged from 12-32% of the total. Gene 7 expression was less than 3% of the total beta expression in all 27 placentas. Although there appeared to be a trend toward lower expression of beta gene 3 in placentas beyond 10 weeks gestational age, there was no correlation of the pattern of beta expression with placental age. Beta gene expression was also examined in two blighted ova, a spontaneous abortion sample, and a hydatidiform mole as well as in cultured JAR choriocarcinoma cells. With the exception of JAR cells, these abnormal tissues had low levels of gene 3 expression, but these levels were within the range of the patterns observed in normal placentas. These data suggest that it is the total amount of hCGbeta gene expression rather than the expression of individual beta genes that is important for the maintenance of normal pregnancy.

A naturally occurring genetic variant in the human chorionic gonadotropin-beta gene 5 is assembly inefficient.

The hCGbeta gene family is composed of six homologous genes linked in tandem repeat on chromosome 19; the order of the genes is 7, 8, 5, 1, 2, and 3. Previous studies have shown that hCGbeta gene 5 is highly expressed during the first trimester of pregnancy. The purpose of our study was to identify naturally occurring polymorphisms in hCGbeta gene 5 and determine whether these alterations affected hCG function. The data presented here show that hCGbeta gene 5 was highly conserved in the 334 asymptomatic individuals and 41 infertile patients examined for polymorphisms using PCR followed by single stranded conformational polymorphism analysis. Most of the polymorphisms detected were either silent or located in intron regions. However, one genetic variant identified in beta gene 5 exon 3 was a G to A transition that changed the naturally occurring valine residue to methionine in codon 79 (V79M) in 4.2% of the random population studied. The V79M polymorphism was always linked to a silent C to T transition in codon 82 (tyrosine). To determine whether betaV79M hCG had biological properties that differed from those of wild-type hCG, a beta-subunit containing the V79M substitution was created by site-directed mutagenesis and was coexpressed with the glycoprotein hormone alpha-subunit in Chinese hamster ovary cells and 293T cells. When we examined betaV79M hCG biosynthesis, we detected atypical betaV79M hCG folding intermediates, including a betaV79M conformational variant that resulted in a beta-subunit with impaired ability to assemble with the alpha-subunit. The inefficient assembly of betaV79M hCG appeared to be independent of beta-subunit glycosylation or of the cell type studied, but, rather, was due to the inability of the betaV79M subunit to fold correctly. The majority of the V79M beta-subunit synthesized was secreted as unassembled free beta. Although the amount of alphabeta hCG heterodimer formed and secreted by betaV79M-producing cells was less than that by wild-type beta-producing cells, the hCG that was secreted as alphabeta V79M heterodimer exhibited biological activity indistinguishable from that of wild-type hCG.

Influence of cyclosporine pharmacokinetics, trough concentrations, and AUC monitoring on outcome after kidney transplantation.

To assess the importance of cyclosporine pharmacokinetics on graft outcome and acute rejection episodes, pretransplant and a total of 1868 posttransplant whole-blood cyclosporine pharmacokinetic profiles were performed in 160 consecutive kidney transplant recipients. The following posttransplant pharmacokinetic risk factors were associated with a poorer graft survival and a higher incidence of acute rejection: F, < 25%; clearance, > 325 ml/min; steady-state cyclosporine concentrations, < 350 ng/ml during intravenous infusion; or average cyclosporine concentrations, < 400 ng/ml during the first oral study. Although the discrimination between rejecting and nonrejecting patients was greatest for cyclosporine concentrations obtained at 24 hours after drug administration, measurements at 6 and 14 hours, as well as average concentrations, were all highly predictive. Because of the strong association between the cyclosporine concentrations and outcome, an equation is described to provide initial oral dose prediction. Furthermore, this association suggests that improved cyclosporine pharmacokinetic monitoring may aid in improving outcome after kidney transplantation.

Demographic factors influencing cyclosporine pharmacokinetic parameters in patients with uremia: racial differences in bioavailability.

The impact of several demographic and blood biochemistry factors on the pharmacokinetics of the immunosuppressive drug cyclosporine were studied in 187 patients with uremia. All patients underwent a pharmacokinetic evaluation including a 3 mg/kg intravenous dose of cyclosporine and a 14 mg/kg oral dose of cyclosporine. Cyclosporine was analyzed by specific monoclonal radioimmunoassay on whole blood samples. Statistical analysis included univariate analyses and stepwise multiple regression analysis. Major findings were as follows: The bioavailability (F) of cyclosporine was significantly lower in black patients than in white patients (mean values of 30.9% +/- 12.3% and 39.5% +/- 16.5%, respectively; p < 0.001). This difference was noted both before transplant and at 1 week after kidney transplantation, at which time the corresponding mean values were 28.6% +/- 15.5% and 36.1% +/- 15.5%, respectively (p < 0.01). Other factors that correlated with F were serum triglyceride (positively) and blood hemoglobin concentrations (inversely). Patients with diabetes displayed a longer mean absorption time than other patients and a larger volume of distribution of cyclosporine at steady state (VSS). Other factors that correlated with VSS were serum albumin concentration and patient height. Cyclosporine clearance (CL) decreased with patient age and also with increasing concentrations of serum triglycerides and blood hemoglobin. It was lower in patients with the pretransplant diagnosis of nephrosclerosis than in patients with other diseases. Several pharmacokinetic parameters correlated with the level of substances that can potentially bind cyclosporine in the blood. Serum triglycerides correlated with maximum concentration, time to maximum concentration, F, and CL. Blood hemoglobin concentration and blood hematocrit correlated with F, CL, and intravenous mean residence time. Although several relationships were observed between demographic factors and cyclosporine pharmacokinetics, the racial difference in F is of great clinical significance and may contribute to the poorer outcome observed after kidney transplantation in black patients.

Increased nonrenal clearance and increased diuretic efficiency of furosemide in cystic fibrosis.

The pharmacokinetics of furosemide and its diuretic effect were studied in six patients with cystic fibrosis (CF) and in six age-matched healthy volunteers. Furosemide was given intravenously at a dose of approximately 0.5 mg/kg. Renal excretion of furosemide was decreased in CF because nonrenal clearance was more than twice as high as in controls (p = 0.03). Nonrenal clearance correlated with the volume of distribution (r2 = 0.52, p = 0.01), which makes a difference in the distribution and binding determinants for clearance. Another reason for increased nonrenal clearance could be induction of drug metabolism in CF, but the excretion of furosemide conjugate did not differ significantly between the groups. Although 26% less furosemide was excreted in CF than in controls (p = 0.03), the diuretic response (calculated as excretion of water and electrolytes) did not differ. Thus the diuretic efficiency was higher in CF for Na+ (p = 0.02), Cl- (p = 0.01), K+ (p = 0.07), and volume (p = 0.005). This difference is probably secondary to the different rates of delivery of furosemide into urine.

The role of cyclosporine dosage and plasma levels in efficacy and toxicity in bone marrow transplant recipients.

The efficacy and toxicity of cyclosporine (CsA) treatment for graft-versus-host disease (GVHD) was studied in 53 bone marrow transplant recipients. No correlation was found between acute or chronic GVHD and CsA dosage (daily or cumulative) or CsA plasma levels. Acute nephrotoxicity developed in 63% of the patients. Patients with nephrotoxicity had significantly higher CsA plasma levels during the first month after transplantation compared with patients without nephrotoxicity (P less than 0.05) although the cumulative CsA doses did not differ. Children had significantly fewer episodes of nephrotoxicity compared with adults (P less than 0.01). In spite of this, children received a significantly higher cumulative CsA dose (P less than 0.001). However, CsA plasma levels did not differ between children and adults, suggesting a difference in availability or elimination of the drug. Hypertension developed in 28% of the patients. Hypertensive patients tended to be younger compared with normotensive patients (P = 0.07). Nephrotoxicity tended to be less common in patients with hypertension (P = 0.06). No correlation existed between hypertension and CsA dose or CsA plasma levels. In conclusion, no correlation was found between CsA dose and GVHD or CsA toxicity, and in the single patient CsA plasma levels were of no value in predicting side effects of CsA treatment.

Fewer acute rejection episodes and improved outcome in kidney-transplanted patients with selection criteria based on crossmatching.

Cross-matches performed on sera from presensitized patients have so far failed to differentiate clinically "relevant" from clinically "irrelevant" antibodies due to insufficient specificity characterization. In order to find a basis for such a possibility, 72 consecutive kidney transplanted patients were selected and studied retrospectively. Our policy has been to accept weakly positive (less than 50%) cytotoxicity on donor B splenic lymphocytes in the crossmatch test. Forty-six patients who had early acute rejections and 26 who had no acute rejections were selected for the study. Antibodies in current sera were characterized according to their target cell reactivity, immunoglobulin class, and HLA/non-HLA specificities. Crossmatches were performed using both the cytotoxicity and the flow cytometric method. We found that the factor that differentiates clinically "relevant" from clinically "irrelevant" antibodies is the HLA specificity of the lymphocyte-reactive antibodies. A high proportion of patients with posttransplant complications such as acute rejections had antibodies with specificities for HLA (particularly class I) antigens, while patients without rejections had either no detectable antibodies or antibodies reactive with non-HLA antigens only. In the present study, after elimination of false-positive reactions by ultracentrifugation of current sera, we found that flow cytometric crossmatches may not necessarily be more specific than the ordinary cytotoxicity crossmatch, since a positive flow cytometric crossmatch is often, but not always, associated with a weakly positive B cell cytotoxic crossmatch (10-25% reactivity). Antibodies causing a positive flow cytometric crossmatch could constitute low-titerd complement-fixing antibodies, non-complement-fixing antibodies, or both. Thus our study shows that it is possible to identify, prior to transplantation, patients with a risk of early posttransplant immunological complications such as acute rejection and to differentiate these from those who are more likely to have an uncomplicated posttransplant clinical course. A more careful patient selection based on adequate crossmatch testing, including specificity determination, might reduce the frequency of acute rejections and improve the outcome of transplantation.

Characterization and significance of donor-reactive B cell antibodies in current sera of kidney transplant patients.

The specificity and class of antibodies resulting in a positive B cell crossmatch were studied in 47 kidney-transplanted patients. The study was performed to determine instances where a positive B cell crossmatch would not be deleterious to the survival of the graft. In order to determine the specificity and class of the antibodies, we used monoclonal antibodies to HLA-A,B,C and DR antigens to block cytotoxicity of sera, and the reagent DTT to characterize the immunoglobulin class. We found that graft survival in patients with DR antibodies was significantly better than in patients with class I antibodies (P less than 0.02). No difference in graft survival in patients with IgM antibodies versus patients with IgG antibodies was observed. The presence of weak HLA class I antibodies in patient's sera only detected as reactivity on B lymphoid cells should be considered a contraindication to transplantation. Thus our study shows that a fraction of patients who have cytotoxic B cell reactive antibodies at the time of transplantation can be successfully transplanted, provided the specificity of each serum is defined prior to transplantation.

The adverse impact of high cyclosporine. Clearance rates on the incidences of acute rejection and graft loss.

The influence of cyclosporine pharmacokinetic parameters on clinical events and outcome after transplantation was studied in 100 renal transplant recipients who underwent a pre- as well as posttransplant CsA pharmacokinetic evaluation. Among the patients, 30 were black and 50 were white. Black recipients had significantly lower bioavailability (F) pre- as well as posttransplantation than white recipients, the posttransplant mean F values being 25.8 +/- 9.0% and 38.1 +/- 16.7%, respectively (P < 0.002). The posttransplant CsA clearance rate (CL) and oral clearance (clearance/bioavailability; CLoral) were significantly higher in patients who had acute rejection than in those who did not, with CL mean values of 425 +/- 141 ml/min and 359 +/- 131 ml/min, respectively (P < 0.02). The initial posttransplant F was significantly lower, and the CLoral higher in patients who eventually lost their grafts than in those who did not, the mean F values being 26.5 +/- 12.8% and 38.7 +/- 17.5%, respectively (P < 0.002). Thus, several important relationships between CsA pharmacokinetic parameters and clinical events following renal transplantation were documented. The CLoral decreased during the first 3 months after transplantation (P < 0.0001), but it was stable thereafter. Neither the bioavailability nor the clearance of CsA showed a correlation with administered dose. These results indicate that certain recipient groups, such as black patients, and individuals with rapid CL, may benefit from larger CsA doses and/or shorter dosage intervals, in order to compensate for these interpatient variabilities.