A minimal physiologically based pharmacokinetic model that predicts anti-PEG IgG-mediated clearance of PEGylated drugs in human and mouse.

Circulating antibodies that specifically bind polyethylene glycol (PEG), a polymer routinely used in protein and nanoparticle therapeutics, have been associated with reduced efficacy and increased adverse reactions to some PEGylated therapeutics. In addition to acute induction of anti-PEG antibodies (APA) by PEGylated drugs, typically low but detectable levels of APA are also found in up to 70% of the general population. Despite the broad implications of APA, the dynamics of APA-mediated clearance of PEGylated drugs, and why many patients continue to respond to PEGylated drugs despite the presence of pre-existing APA, remains not well understood. Here, we developed a minimal physiologically based pharmacokinetic (mPBPK) model that incorporates various properties of APA and PEGylated drugs. Our mPBPK model reproduced clinical PK data of APA-mediated accelerated blood clearance of pegloticase, as well as APA-dependent elimination of PEGyated liposomes in mice. Our model predicts that the prolonged circulation of PEGylated drugs will be compromised only at APA concentrations greater than ~500 ng/mL, providing a quantitative explanation to why the effects of APA on PEGylated treatments appear to be limited in most patients. This mPBPK model is readily adaptable to other PEGylated drugs and particles to predict the precise levels of APA that could render them ineffective, providing a powerful tool to support the development and interpretation of preclinical and clinical studies of various PEGylated therapeutics.

Desmoplastic small round cell tumor masquerading as advanced ovarian cancer.

Desmoplastic small round cell tumor (DSRCT) is a rare abdominal malignancy usually diagnosed in young adult males. Most patients have widespread disease at presentation, with an organ of origin difficult to ascertain. A 33-year-old female presented to her gynecologist with complaints of suprapubic pressure, abdominal pain, and increased abdominal girth. She had a large intraabdominal tumor on ultrasound, thought to be ovarian cancer. She underwent surgical exploration, which confirmed a malignancy, but the exact etiology was uncertain. Final pathology was consistent with DSRCT. DSRCT is a rare malignancy that can mimic other more commonly seen tumors such as lymphoma and ovarian cancer. When encountering an extensive intraabdominal malignancy of uncertain etiology, DSRCT should be in the differential diagnosis.

A cysteine protease inhibitor protects dogs from cardiac damage during infection by Trypanosoma cruzi.

Cruzain is an essential cysteine protease of Trypanosoma cruzi and a therapeutic target for Chagas' disease. Eight dogs were infected with T. cruzi; three were treated with an inhibitor of cruzain, K777, for 14 days. Treatment with K777 abrogated myocardial damage by T. cruzi, as documented by histopathological lesion scores and serum troponin I levels.

Effects of vitamin E supplementation during erythropoietin treatment of the anaemia of prematurity.

AIMS: To evaluate the effects of vitamin E supplementation on haemoglobin concentration and the requirement for transfusion in premature infants treated with erythropoietin and iron. METHODS: Randomised, double blind, placebo controlled trial. Thirty infants

Correlation among markers of renal osteodystrophy in pediatric hemodialysis patients.

Serum levels of parathyroid hormone (PTH), alkaline phosphatase (AP), and calcium (Ca2+) have been used to evaluate renal osteodystrophy (RO) in adult patients undergoing dialysis. Osteocalcin (BGP) is a bone protein which also serves as a marker for bone turnover. Serum BGP levels correlate positively with rates of bone turnover and serum concentrations of PTH, AP, and Ca2+ in various studies of adult end-stage renal disease (ESRD) patients, whereas other studies reveal BGP to be a poor indicator of bone turnover in ESRD. RO is a significant problem in pediatric ESRD patients; however, there have been few studies evaluating the correlation of markers for RO in children with ESRD. We measured serum PTH, AP, Ca2+, and BGP levels in a group (n=23) of pediatric patients with ESRD and assessed the correlation among the markers. There was a positive correlation between serum PTH and AP (r=0.658, p<0.001). In contrast, there was no correlation between either serum Ca2+ or BGP, and either PTH or AP. The correlation between Ca2+, BGP and either PTH or AP was unaffected by growth in our patient population. Finally, neither age nor pubertal stage improved the correlation between either Ca2+ or BGP, and either PTH or AP. We conclude that serum PTH and AP are useful markers for RO, whereas calcium and BGP levels should not be used to evaluate RO in pediatric ESRD patients.

Serum beta2-microglobulin and immunoglobulin levels in young hemodialysis patients.

Amyloidosis is a complication of long-term hemodialysis treatment. The major histological feature of hemodialysis-associated amyloidosis (HAA) is the deposition of amyloid fibrils in the affected lesions, due, in part, to elevated serum beta2-microglobulin (beta2M) levels. In vitro studies reveal that serum immunoglobulin light and heavy chains co-deposit with beta2M in tissues affected by HAA. Only one study of HAA has been performed in young dialysis patients. We therefore assessed risk factors for HAA in a group (n=30) of young (18.7+/-0.9 years) patients receiving chronic, uninterrupted hemodialysis using cellulose acetate membranes. All patients initiated dialysis before reaching 18 years of age. The pre-dialysis serum beta2M level was 49.7+/-3.9 mg/l (normal 0-2.4 mg/l). Since serum albumin was normal (4.3+/-0.1 mg/dl) and serum protein/albumin was elevated (1.7+/-0.0, normal 1.2-1.5), indicating increased circulating protein, we assayed immunoglobulins in the same patients. The serum immunoglobulin levels (expressed as a percentage of the total level of serum proteins) were elevated (21.3+/-0.9%, normal 11.1%-21.0%). The Kt/v was 1.37+/-0.03, suggesting that the high levels of serum beta2M and immunoglobulins were not due to inadequate dialysis in these patients. Patients with residual renal function (Kr) did display significantly lower serum levels of beta2M (33.2+/-2.3, P=0.03). Furthermore, improved clearance of beta2M correlated with higher values of Kr (r=0.914). In contrast, serum levels of immunoglobulin (22.6+/-3.7, P=0.5) were unaffected by Kr. In addition, there was no correlation between older age at onset of dialysis and serum levels of either beta2M (r=0.107) or immunoglobulins (r=0.321). Finally, the length of time on dialysis had no effect on serum levels of either beta2M (r=0.105) or immunoglobulins (r=0.092). Taken together, these results indicate that young hemodialysis patients may be at risk for HAA.

Is this patient pregnant? Can you reliably rule in or rule out early pregnancy by clinical examination? .

This review addresses a common problem facing the clinician: "When treating or evaluating a woman of childbearing years, what is the value of historical or physical examination features in determining the probability of early pregnancy?" We focus on the clinical examination findings that may help the clinician rule in or rule out early pregnancy. Generally accepted indicators of pregnancy include amenorrhea, morning sickness, tender or tingling breasts, and, after 8 weeks' gestational age, an enlarged uterus with a soft cervix. We reviewed the value (ie, sensitivity and specificity) of these indicators, as well as home pregnancy test results, as predictors of the diagnosis of early pregnancy. The available evidence suggests that some historical features, when absent, are fair but not reliable for ruling out pregnancy. When diagnosing early pregnancy, the clinician should not rely on the clinical examination or a home pregnancy test-a laboratory test should be requested.

Cytologic screening after hysterectomy for benign disease.

OBJECTIVE: Our purpose was to determine the effectiveness of vaginal cytology tests after hysterectomy for benign disease. STUDY DESIGN: We studied a 10-year retrospective cohort of patients after hysterectomy (n = 697 women, 9074 woman years). Patients were excluded if they had any type of invasive gynecologic malignancy. The main outcome variable was development of a vaginal cytologic abnormality, evaluated with Kaplan-Meier estimates and proportional hazards regression. RESULTS: We found 33 abnormal cytology results; most were of little clinical significance except for two biopsy-proven dysplasia cases. When we controlled for age, the risk was 4.67 for patients with a history of a cervical cytologic abnormality (95% confidence interval 2.1 to 10.6). We needed 633 tests to detect one true positive case of vaginal dysplasia. CONCLUSIONS: The low incidence of vaginal dysplasia and carcinoma, combined with the high false-positive rate, supports decreasing the number of screening tests performed for these low-risk patients.

Routine intravenous pyelograms before hysterectomy in cases of benign disease: possibly effective, definitely expensive.

Intraoperative ureteral injuries are potentially serious iatrogenic complications. Routine preoperative intravenous pyelograms might decrease the risk of such injuries during hysterectomy in cases of nonmalignant disease, but no prospective studies have been conducted to determine their effectiveness. Since gynecologists must frequently decide whether to obtain pyelograms, we used decision analysis to determine how costly routine pyelograms would be and under what circumstance pyelograms might be especially justifiable. Our cost-effectiveness study was based on decision analysis techniques, with the best available estimates from the literature, and on expert opinion. These estimates were varied over a broad range during a sensitivity analysis so as not to bias the results. At a baseline ureteral incidence injury rate of 0.5%, the marginal cost-effectiveness ratio indicates 833 pyelograms would be obtained to prevent a single injury and approximately $3.33 million would be spent to prevent a single death. As the probability of an injury increases, the marginal cost-effectiveness ratio is less dependent on the test efficacy and is more modest. Since abnormal ureteral anatomy probably predicts ureteral injury, we suggest selectively obtaining preoperative pyelograms only when the probability of an abnormality is high.

Leiomyoma in a müllerian remnant. A case report.

Leiomyomas are a rather common occurrence in the normal uterus. Müllerian dysgenesis, however, occurs in only approximately 1 in 5,000 female births. We found no case reports of leiomyoma arising from a müllerian remnant, as in the case reported here. Surgical management considerations include identification of the blood supply, separation of the mass from the broad ligament and care in identifying the entire length of the ureter. Due to the extreme rarity of leiomyoma in müllerian remnants, it should be considered low on the list of differential diagnoses of pelvic masses in women with müllerian dysgenesis.

Does maternal platelet-associated or platelet-bindable IgG correlate with levels in umbilical cord blood or colostrum during normal pregnancy?

Existing data regarding the ability to predict neonatal thrombocytopenia during maternal immune thrombocytopenia are confusing. We studied normal pregnancies (n = 20) to define normal values and the correlation between maternal and umbilical cord platelet counts, platelet-associated immunoglobulin G (IgG), and platelet-bindable IgG. The postpartum serum platelet-bindable IgG level was measured to evaluate peripartum changes and the correlation with colostrum platelet-bindable IgG (n = 6). The mean maternal platelet count was 181,500 cells/cm3 mm and the mean umbilical cord platelet count was 293,500 cells/mm3. The median maternal platelet-associated IgG was 803 molecules per platelet, umbilical cord platelet-associated IgG was 791 molecules per platelet, maternal platelet-bindable IgG was 92 molecules per platelet, and umbilical cord platelet-bindable IgG was 256 molecules per platelet. The postpartum median maternal platelet-bindable IgG was 333 molecules per platelet and for colostrum it was 297 molecules per platelet. No clinically useful correlations for predicting the neonatal platelet count during normal pregnancy were found. Normal pregnancies may have high levels of maternal- or umbilical cord platelet-associated IgG, perhaps due to nonspecific binding.

Quantitation of human interleukin-1 beta with polyclonal antibodies.

Polyclonal antisera to human recombinant interleukin-1 beta have been developed in rabbits and mice. When measured by indirect enzyme-linked immunoassays, the antisera bound rIL-1 beta in a dose-dependent manner but did not bind to rIL-1 alpha or murine rIL-1. Both antisera specifically neutralized thymocyte activation induced by rIL-1 beta or normal monocyte IL-1 and growth inhibition induced by rIL-1 beta. The antiserum specificities led us to examine a double antibody ELISA for quantitating IL-1 beta. The linear portion of the standard curve from an ELISA against rIL-1 beta ranged from 0.5 to 10.0 half-maximal units of [3H]thymidine incorporation in mouse thymocyte cultures. A similar correlation was observed using monocyte derived IL-1 from two sources. The major result of this work was the observation that polyclonal antibodies made against a recombinant molecule also recognized natural IL-1. We suggest that these antisera recognize epitopes unique to IL-1 beta which reside at or near regions of the molecule responsible for biological activity.

Who should have intravenous pyelograms before hysterectomy for benign disease?

A review of 493 cases was undertaken to identify which patients undergoing hysterectomy for benign disease had received a preoperative intravenous pyelogram (IVP), an abnormality identified by IVP, and intraoperative ureteral injuries. Intravenous pyelograms were performed on 299 patients (60.6%). Factors significantly associated with obtaining a preoperative IVP included an abdominal approach, uterine size of 12 weeks or greater, and uterine prolapse. Seventy-seven patients (27%) had an abnormal IVP; factors likely to be associated with abnormality included uterine size of 12 weeks or larger or an adnexal mass of 4 cm or larger. Endometriosis, pelvic inflammatory disease, pelvic relaxation, and previous intra-abdominal surgery were not associated with an increased prevalence of abnormal IVP findings. Two ureteral injuries were documented, one in the IVP group (0.3%) and one in the non-IVP group (0.5%). Clinical findings may be used to select for a preoperative IVP those patients who are likely to have abnormalities of importance to the pelvic surgeon.

Family history of diabetes mellitus and oral glucose tolerance testing criteria.

A review of 185 obstetrical patients, having a family history of diabetes mellitus without medical history of glucose intolerance in the non-pregnant state was conducted. A 3-hour 100-g oral glucose tolerance test was performed on all patients between 20 and 34 weeks of gestation. According to O'Sullivan's criteria for glucose tolerance testing, normal glucose tolerance occurred in 89.7%, while Class A diabetes was identified in 10.3% of patients tested. 3.8% of the study population fulfilled the O'Sullivan criteria for abnormal glucose intolerance and required insulin treatment during pregnancy. The Division of Perinatal Medicine at Duke University has traditionally defined the abnormal glucose tolerance test at glucose values lower than O'Sullivan's internationally accepted criteria. An intermediate group, having abnormal glucose values according to the Duke criteria, was classified as "Carbohydrate Intolerance", comprised 32.4% of the patients tested and were managed identically to O'Sullivan Class A Diabetes. Analysis or perinatal outcome, including macrosomia, birth trauma and neonatal morbidity, revealed that Carbohydrate Intolerance patients fulfilling O'Sullivan criteria, being similar to patients with 'normal' GTT test results. Patients having a family history of diabetes mellitus, appeared as a group to be at increased risk for macrosomia, fetal distress and cesarean delivery, compared with the general population.

Primary care in the postmenopausal woman.

For the obstetrician/gynecologist to function as a primary care physician he or she must be aware of all aspects of the patient's health care needs. Nutrition, weight control, exercise programs, and immunization are essential components of health maintenance. One must be alert to the development of chronic disease and disability, and utilize available screening techniques wisely and effectively. Education can increase compliance and sometimes modify harmful behavior. Informing the patient regarding common changes at menopause and beyond may smooth the transition. A sympathetic and supportive approach, along with judicious use of pharmacologic agents, should help each woman maintain the level of performance to which she is accustomed.