A Comparison Between Recipients Receiving Matched Kidney and Those Receiving Mismatched Kidney from the Same Cadaver Donor

The optimal allocation of cadaveric kidneys for transplantation with reference to human leukocyte antigen (HLA) match and sharing these organs to a distant center remains controversial. The current analysis was performed using the United Network for Organ Sharing (UNOS) database for cadaveric kidney transplants (Tx) between 1988 and 1997. The graft survivals of zero-mismatch (matched) kidneys with the mate (mismatched) kidneys were compared. There were 2385 donors and 4770 Tx. Significant differences in recipient demographics between matched and mismatched Tx were: fewer African-American race (AA) in the matched group (9.0% vs. 21.9%), higher number of previous Tx (25.5% vs. 14.8%) and elevated mean cold ischemia time (24.0 vs. 22.2 h). Post-Tx dialysis requirements were similar (22.8% vs. 24.1%, p = 0.62) and matched kidneys had to travel more distance (920 vs. 232 miles). Using a Cox model, the matched group had a decreased relative hazard of graft failure of 23.0% (p = 0.0002) or 35% (p < 0.0001) with and without censoring for death. There was significantly better graft survival in the matched recipients in all pairs except AA (matched) and non-AA (mismatched). For older donors (> or = 50 years, n = 1508), the matched grafts survival was marginally significant (p =0.05). Matched kidneys have improved survival compared with the mismatched kidneys despite the longer distance traveled. The benefit of mismatched transplants was predominantly seen in non-AA.     

BK Virus-Specific Antibodies and BKV DNA in Renal Transplant Recipients with BKV Nephritis

We evaluated twenty renal transplant subjects at various stages of BKV nephritis (BKVN) for BKV-specific IgG and IgM antibodies using ELISA technique and BKV-DNA using PCR. They were divided as early onset (n = 7), stabilizing (n = 3), resolved (n = 8) and late onset (n = 2) BKVN. BKV-specific antibodies and BKV-DNA were simultaneously determined. The mean BKV-specific IgG level in early onset and stabilizing BKVN were 64 and 39 EIA units, and were significantly lower than 138 EIA units seen in resolved BKVN, P = 0.007, P = 0.008. The mean BKV-specific IgM levels in stabilizing BKVN was higher than resolved BKVN (130 vs 51 EIA units), P = 0.006. Mean plasma BKV loads for each group were 955,925, 5642 and 42 copies/mL of plasma, respectively. Prospective study in six BKVN cases revealed mean IgG, IgM levels and BKV-DNA at the time of diagnosis of BKVN as 39, 110 EIA units and 586,758 copies/mL of plasma, respectively. After a mean period of 5.2 months, IgG level increased to 120 EIA units (p = 0.0058) and had no detectable viral copies in circulation. Recovery from BKVN and elimination of BKV is associated with the development of BKV-specific IgG antibodies and this provides insight into the role of humoral immunity to BKV in the pathogenesis of BKVN.     

Antimurine antibody formation following OKT3 therapy

OKT3 is an IgG2a murine monoclonal antibody directed against the CD3 antigen receptor of human T lymphocytes. A major concern with OKT3 treatment in solid organ transplant recipients is the development of antimouse antibody, which may preclude retreatment with this agent. We have administered OKT3 on 215 occasions (150 renal, 34 hepatic, 26 cardiac, 5 pancreatic) in 179 patients between April 1982 and December 1988. The mean duration of treatment was 10.5 days (range, 2-22 days). Antimouse antibody data were analyzed on the most recent 133 treatment courses where the antibody status was available pretreatment. Determination of antimouse antibody production was elicited by ELISA technology at days 0, 7, 14, and 28 of OKT3 treatment. Patients were categorized according to the antibody response as follows: (a) absence of antibody; (b) low titer (1:100); or (c) high titer (greater than or equal to 1:1000). Our earlier experience has demonstrated that retreatment with OKT3 is successful in groups a and b. The development of antimurine antibodies was analyzed with regard to the following parameters: (1) The duration of OKT3 treatment; (2) treatment type (prophylactic, primary, or secondary); (3) primary treatment or retreatment; (4) concomitant immunosuppressive regimen (double or triple therapy); (5) dosage of concomitant immunosuppressive drugs; and (6) transplant organ type. The following results were obtained. (1) Duration of treatment had no effect on antibody production (11.0 days in antibody negative and 10.0 days in antibody positive). (2) There was no difference in antibody formation rates for the first treatment of OKT3 when it was used as prophylaxis (26%), primary (19%), or secondary (27%) therapy. (3) Antibody formation rate with first treatment was 29%; with retreatment, patients who were antibody negative following first treatment became positive in 28% of cases, and retreated patients who were low titer positive following first treatment converted to high titer in 57% of cases. (4) Antibody formation was higher in patients receiving double immunosuppressive therapy (36%) than in those receiving triple immunosuppressive therapy (21%) during OKT3 treatment. (5) Concomitant immunosuppression was lower in the antibody-positive group during OKT3 therapy: steroids, 61 mg/day vs. 52 mg/day; azathioprine, 89 mg/day vs. 66 mg/day; CsA, 317 mg/day vs. 186 mg/day. (6) Antibody formation rates were lower in non-renal transplants following first treatment with OKT3 (liver 17%, heart 17%, kidney 28%); this reflects the higher doses of concomitant immunosuppressive therapy used in nonrenal transplants.(ABSTRACT TRUNCATED AT 400 WORDS)     

Biological characterization of Drosophila Rapgap1, a GTPase activating protein for Rap1

The activity of Ras family proteins is modulated in vivo by the function of GTPase activating proteins, which increase their intrinsic rate of GTP hydrolysis. We have isolated cDNAs encoding a GAP for the Drosophila Rap1 GTPase. Drosophila Rapgap1 encodes an 850-amino acid protein with a central region that displays substantial sequence similarity to human RapGAP. This domain, when expressed in Escherichia coli, potently stimulates Rap1 GTPase activity in vitro. Unlike Rap1, which is ubiquitously expressed, Rapgap1 expression is highly restricted. Rapgap1 is expressed at high levels in the developing photoreceptor cells and in the optic lobe. Rapgap1 mRNA is also localized in the pole plasm in an oskar-dependent manner. Although mutations that completely abolish Rapgap1 function display no obvious phenotypic abnormalities, overexpression of Rapgap1 induces a rough eye phenotype that is exacerbated by reducing Rap1 gene dosage. Thus, Rapgap1 can function as a negative regulator of Rap1-mediated signaling in vivo.     

The significance of adult hematuria: 1,000 hematuria evaluations including a risk-benefit and cost-effectiveness analysis

Between March 1976 and June 1985, 1,000 consecutive adults with asymptomatic gross or microscopic hematuria in the absence of proteinuria were evaluated urologically. Lesions that could account for the hematuria were detected in 88.3 per cent of the patients. Life-threatening lesions were diagnosed in 9.1 per cent of the patients, while lesions requiring at least observation were present in 22.8 per cent. The incidence of life-threatening lesions increased with age, with a sharp increase after age 50 years. Life-threatening lesions were more common in men (13.6 per cent) than in women (4.9 per cent). In general, as the degree of hematuria increased so did the yield of life-threatening lesions; however, there was no "safe" lower limit of hematuria. Of the patients with life-threatening lesions 18.6 per cent had at least 1 urinalysis with less than 3 red blood cells per high power field within 6 months of the diagnosis. The direct medical cost of a hematuria evaluation was $777. The difference in direct medical costs to diagnose and treat localized versus metastatic genitourinary cancer was $48,070 in 3 matched pairs of patients. In this study group 77 of 84 patients (92 per cent) diagnosed with genitourinary cancer had localized disease. A hematuria evaluation was cost-effective for all groups studied. A literature-based estimate of the life-threatening risks of diagnostic studies applied to the study data resulted in a 1.1 per cent life-threatening risk per hematuria evaluation. For all categories studied, except for women less than 40 years old with microscopic hematuria, the risk of a hematuria evaluation was less than the incidence of life-threatening lesions discovered as a result of the evaluation. Asymptomatic hematuria, whether gross or microscopic, is a significant finding and warrants evaluation from a risk-benefit and cost-effectiveness standpoint.     

Patience is a virtue: Multiple preoperative visits are associated with decreased recurrence in pediatric pilonidal disease

Background/PurposeThis study aimed to compare preoperative management strategies for patients undergoing trephination for pilonidal disease and evaluate risk factors for recurrence.MethodsA retrospective review was performed of children undergoing index surgical treatment with trephination for pilonidal disease between September 2017 and April 2019. Intraoperative and postoperative management were standardized. Demographic and perioperative data were collected and analyzed.ResultsOne-hundred twenty patients were identified with a median follow-up time of 7.5 months (interquartile range 4.1–13.2 months). Overall, 24 (20%) patients had a postoperative recurrence of pilonidal disease. Patients with multiple preoperative surgery clinic visits were less likely to have recurrent disease compared to those seen only once preoperatively (11% vs 26%, p = 0.040). Compared to patients without recurrence, those who recurred went to the operating room sooner from the time of initial surgical consultation (32 days vs 54 days, p < 0.001). Perioperative antibiotics, history of acute infection, and prior drainage procedures were not risk factors for recurrence.ConclusionsMultiple preoperative clinic visits are associated with a lower recurrence rate in children undergoing trephination for pilonidal disease. An increased duration of preoperative medical management may be responsible for this finding. Prospective study is needed to confirm these findings and identify additional factors that influence recurrence.Type of StudyTreatment Study.Level of EvidenceIII (Retrospective Comparative).     

Yohimbine bioavailability in humans

Summary Pharmacokinetic profiles were determined in seven healthy young male subjects following single oral and intravenous doses of 10 mg of yohimbine hydrochloride.The drug was rapidly eliminated (t_1/2 0.58 h orally and t_1/2 0.68 h intravenously). Following intravenous administration the data fit a two-compartment pharmacokinetic model, with a very rapid distribution phase (t_1/2a was approximately 6 min). Both the oral and the intravenous yohimbine clearance values were high but oral clearance values were much higher (mean 9.77 ml·min^–1·kg^–1 intravenous versus 55.9 ml·min^–1·kg^–1 oral). The oral bioavailability showed great variability, ranging from 7% to 87% (mean value was 33%).The imcomplete oral bioavailability of yohimbine may reflect either incomplete absorption from the gastrointestinal tract or an hepatic first pass effect. Although yohimbine is rapidly absorbed when given orally, the bioavailability is quite variable and considerable individualization of dosing may be necessary when the drug is used orally for clinical indications.Supported in part by NIH grant # MOIRR 0042