Use of tissue plasminogen activator (rt-PA) in young children with cancer and dysfunctional central venous catheters

PURPOSE: To determine the efficacy and safety of low, nonescalating dose tissue plasminogen activator (rt-PA) in restoring the patency of occluded central venous access devices (CVCs) in children with cancer who weigh less than 30 kg. PATIENTS AND METHODS: A single-center review of the use of rt-PA (0.5 mg indwelling for 30 minutes in the CVC) was conducted in 42 cancer patients with large bore central venous access devices implanted over a 2-year period. All patients weighed less than 30 kg. None had been previously treated with a thrombolytic agent. The efficacy for restoring function to CVCs was measured and correlated with patient age, weight and CVC lumen size. Propensity to rethrombose following an initial occlusion and treatment was also determined. RESULTS: Of 235 doses of rt-PA administered in a 2-year period, 55 doses administered to 42 patients met the eligibility criteria as outlined. Twenty-nine patients (69%) had function restored with a single dose; 8 patients (19%) required 2 doses, and 5 patients (12%) failed 2 doses; for an overall success rate of 88%. No significant adverse events occurred. Of the 37 cleared CVCs, 14 (38%) reoccluded within 1 month. A higher proportion of patients initially treated with one rt-PA (71%) experienced another CVC dysfunction within 1 month, compared with 29% CVC dysfunction in those requiring >1 dose. CONCLUSIONS: This article describes the use of rt-PA (0.5 mg, without dose escalation) to lyse CVC-associated thrombi specifically in small children with cancer, a patient population in which it is particularly desirable to minimize the degree of fibrinolysis. One dose of 0.5 mg rt-PA, with an additional dose if necessary, is as safe and effective as previously reported escalating dose regimens for CVC clot lysis. There is no statistically significant correlation of treatment failure with patient age, weight, or catheter lumen size, and no significant propensity for rapid rethrombosis following a single dysfunction and treatment. Patients initially treated with a single dose of rt-PA appear to have more subsequent dysfunctions in the month after treatment, an observation that warrants further study.     

Transient hyperphosphatasemia after organ transplantation in children

Transient, isolated hyperphosphatasemia is a rare, benign condition of childhood. Few cases have been described in transplant patients. We report six cases: three after liver transplantation and three after kidney transplantation. Such a phenomenon was found to be as benign after organ transplantation as it is in healthy children. Hence, an isolated increase in the serum alkaline phosphatase level following transplantation should not be of concern in this population of patients.     

Providing research and research training infrastructures for clinical research in the reproductive sciences

The Reproductive Sciences Branch of the National Institutes of Child Health and Human Development has created pioneering new research and research training programs that address the impending shortage of physician-scientists in obstetrics, gynecology, and women's health and the need to bolster translational and clinical research. This article provides a brief overview of the Specialized Cooperative Centers Program in Reproduction Research, the National Cooperative Program for Infertility Research, the Reproductive Medicine Network, the Reproductive Scientist Development Program, the Women's Reproductive Health Research Career Development Program, and the Contraception and Infertility Research Loan Repayment Program and describes how these programs collectively create an infrastructure to promote the next generation of physician-scientists and to provide an information exchange between basic and clinical investigators. A key component in increasing the number of clinical investigators is the Contraception and Infertility Research Loan Repayment Program. This program has enabled clinicians to be involved in research without having to be concerned about educational loan debt. Other component programs provide basic/translational, clinical hypothesis-oriented research and clinical trials research infrastructure. The programs created are individually strong and collectively poised to support translational and clinical research efforts and to build a well-trained cadre of physician-scientists. The collective use of these types of programs is proposed as a model for the National Institutes of Health.     

Intermittent human immunodeficiency type 1 virus (HIV-1) shedding in semen and efficiency of sperm processing despite high seminal HIV-1 RNA levels

To study seminal excretion of human immunodeficiency virus type 1 (HIV-1) during 4 years of follow-up in an HIV-1-infected patient, the relationship between high viral excretion and inflammatory status of semen, and the efficiency of sperm processing methods in obtaining spermatozoa with undetectable RNA and proviral DNA levels.Case report.University hospital and research group on human fertility.One HIV-1-infected patient.Paired blood and semen samples were obtained during 4 years of follow-up.CD4 cell count; blood and seminal plasma viral load; and HIV-1 RNA and proviral DNA in different cell fractions obtained during sperm processing, as measured by the density gradient method and the swim-up method; sperm parameters; and polymorphonuclear granulocyte count.Shedding of HIV-1 in semen was intermittent. The highest seminal viral loads were associated with a markedly increased polymorphonuclear granulocyte count, which reflects inflammation of the genital tract. Spermatozoa with undetectable levels of HIV-1 RNA or DNA were obtained regardless of the viral load in semen.In an HIV-1-infected man with intermittent seminal viral excretion, sperm processing was effective in obtaining spermatozoa without detectable HIV-1 genomes.     

Anti-inflammatory effects of the macrolides

Since their introduction into clinical practice, the macrolides have played an important role in the treatment of both upper and lower respiratory tract disease. In addition to their antibacterial effects, increased evidence is mounting to suggest that the macrolides possess other clinically relevant properties, such as anti-inflammatory and immunomodulatory activities. Several in vitro and clinical trials have been published supporting this hypothesis. This article reviews some of the evidence.     

Triplet pregnancies and their aftermaths. Part I: Basic considerations

Until recently, triplets were an infrequent occurrence. With the development of ovulation-inducing medications and then assisted reproductive technology (ART), the triplet birth rate in maternal age ranges over 24 years has multiplied three- to fiftyfold. The first review of the clinical aspects of triplet pregnancies was published in 1988. Since then, more data reported on such births have revealed a consistent triad of preterm delivery, low birth weight, and very low birth weight, plus increased maternal risks. This article details comparative risks to mothers and children using population-based data comparing differential outcomes in singletons, twins, and triplets; an extensive review of recent triplet publications is provided in the references.     

A dynamic model for simulating a trip and fall during gait

The purpose of this study was to develop an analytical model to simulate a trip and fall during gait. The human body was modeled as a 12 degree-of-freedom linkage system. The kinematics of the lower extremity for one cycle of gait were obtained for a healthy subject using an optoelectronic three-dimensional data acquisition system. Inverse dynamics was used to compute the moments about the hip, knee and ankle joints of the lower extremity. These moments were then used as input actuators to the joints in to a forward dynamics model to simulate the swing phase of gait from toe-off to heel-strike. An optimization procedure to minimize errors associated with the computed experimental torque was applied to correct for mathematical instability. An experiment was performed to measure the three-dimensional foot--obstacle contact force for a healthy subject tripping on an obstacle during gait. The contact force was applied to the swing limb of the forward dynamics model for 0.09 s beginning at 0.04 s after toe-off. Tripping on an obstacle followed by a muscle-relaxed fall was simulated. The simulation results were visualized with animation software.     

Using a geographical information system to map the distribution of dentists in Ohio

BACKGROUND: Studies have reported that dental care is the highest unmet health care need in the United States and have evaluated this in terms of individual determinants of access and utilization. None of these studies took into consideration the provider issues of availability and accessibility or of spatial relations. The aim of this study was to analyze issues of provider availability and accessibility in Ohio using a geographical information system, or GIS. METHODS: Three Ohio databases were geocoded using GIS software. The databases included all 6,132 dentists licensed to practice in Ohio, 1,898 dentists who had billed the state Medicaid program in 1998 and safety-net clinics that provided free or low-cost care. Each practitioner was mapped at the county and ZIP code levels. RESULTS: Results are reported using maps at the county and ZIP code levels. The maps showed that 69.4 percent of dentists practiced in 12 metropolitan counties, 14 percent in 17 suburban counties and 16.6 percent in 59 rural counties (rural non-Appalachian counties plus Appalachian counties). In Appalachia, the dentist-to-population ratio was about one-half that of the metropolitan counties. CONCLUSION: Obvious disparities exist in the distribution of dentists in Ohio, particularly in rural and Appalachian counties. The need to increase the availability of dentists in these counties is evident. PRACTICE IMPLICATIONS: GIS is a useful tool for evaluating provider distribution and availability and planning programs to attract dentists to areas with small numbers of dentists.     

Identification of a novel route of extraction of sirolimus in human small intestine: roles of metabolism and secretion

Using Caco-2 cell monolayers expressing CYP3A4, we investigated the interplay between metabolism and transport on the first-pass intestinal extraction of the immunosuppressant sirolimus, a CYP3A4/P-glycoprotein (P-gp) substrate. Modified Caco-2 cells metabolized [(14)C]sirolimus to the predicted amounts of CYP3A4-mediated products based on CYP3A4 content, which was approximately 20% of that measured in human small intestinal mucosal homogenate. [(14)C]Sirolimus also degraded to the known ring-opened product, seco-rapamycin. Unexpectedly, a ring-opened dihydro metabolite (M2) was the major product detected in cells at all sirolimus concentrations examined (2-100 microM). Greater M2 formation after apical versus basolateral dosing (1.6-fold) was explained by higher intracellular content of sirolimus after apical dosing. M2 was not detected in incubations with human liver and intestinal microsomes but was readily detected with corresponding homogenates. M2 formation was NADPH-dependent but unaffected by the CYP3A4 inhibitors ketoconazole and troleandomycin. Although M2 was formed from purified seco-rapamycin (20 microM) in the homogenates, it was not detected in cells when seco-rapamycin was added to the apical compartment, because seco-rapamycin was essentially impermeable to the apical membrane. Sirolimus, seco-rapamycin (basolaterally dosed), and M2 were all actively secreted across the apical membrane, and secretion of each was inhibited by the P-gp inhibitor LY335979 [(2R)-anti-5-[3-[4-(10,11-difluoromethanodibenzo-suber-5-yl)piperazin-1-yl]-2-hydroxypropoxy]quinoline trihydrochloride]. Along with CYP3A4-mediated metabolism and P-gp-mediated secretion, we conclude that the following novel pathway, which occurs at least in the intestine, may contribute significantly to the first-pass extraction of sirolimus in humans: intracellular degradation of sirolimus to seco-rapamycin, metabolism of seco-rapamycin to M2 by an unidentified non-microsomal enzyme, and P-gp-mediated secretion of M2 and seco-rapamycin.