Mechanisms of immunotherapeutic intervention by anti-CD154 (CD40L) antibody in high-risk corneal transplantation.

This study aimed to determine the effects of anti-CD154 on T cell cytokine profiles and ocular chemokine gene expression after high-risk corneal transplantation and to specifically determine if CD154 blockade is associated with a switch from a Th1 to a Th2 alloimmune response. Mice were used as recipients of syngeneic or multiple minor H or MHC antigen-mismatched corneal grafts. Recipient beds were neovascularized (high-risk). Hosts were randomized to receive either anti-CD154 antibody or control immunoglobulin (Ig) perioperatively. Two weeks after corneal transplantation, allospecific delayed-type hypersensitivity (DTH) was evaluated. Frequencies of interferon-gamma (IFN-gamma)-, interleukin-2 (IL-2)-, IL-4-, and IL-5-secreting T cells in the hosts were measured by enzyme-linked immunospot (ELISPOT) assay. Ocular chemokine gene expression in anti-CD154-treated and control hamster Ig-treated groups was determined using a multiprobe ribonuclease protection assay (RPA). Leukocyte infiltration of corneal grafts was evaluated microscopically. Anti-CD154-treated mice did not exhibit allospecific DTH. The frequencies of Th1 cytokine-producing but not Th2 cytokine-producing T cells were significantly reduced in anti-CD154-treated hosts. Postoperative mRNA levels of RANTES and macrophage inflammatory protein-1beta (MIP-1beta) in anti-CD154-treated eyes were substantially suppressed compared with hamster Ig-treated controls. Leukocyte infiltration was profoundly suppressed in grafts of anti-CD154-treated hosts. These data demonstrate that blockade of the CD40-CD154 costimulatory pathway after corneal transplantation inhibits Th1-mediated responses but does not induce a switch to a Th2-specific response. In addition, anti-CD154 therapy suppresses ocular chemokine gene expression and leukocytic infiltration into allografts.     

Massive strychnine intoxication: serial blood levels in a fatal case.

A fatal case of strychnine intoxication is reported. The patient expired despite early aggressive management and prevention of metabolic complications. Serial blood levels are reported. In contrast to a previous report describing first order elimination kinetics, our data suggest that strychnine follows Michaelis-Menton elimination kinetics. The case illustrates the rapid, dramatic course of severe strychnine ingestions. A review of the toxicokinetics, mechanism of action and treatment of strychnine intoxication follows.     

Volume Flow Rate of Common Carotid Artery Measured by Doppler Method and Color Velocity Imaging Quantification (CVI-Q)

BACKGROUND: Common carotid artery (CCA) volume flow rate (VFR) is clinically useful for study of cerebrovascular disease. Color Velocity Imaging Quantification (CVI-Q; Philips Ultrasound International, Irvine, CA), previously reported as accurate and reliable, tracks the flow lumen over the cardiac cycle, as well as mean spatial velocity, which is multiplied by vessel area to obtain VFR. VFR can also be obtained by Doppler sampling for mean velocity, and vessel area based on static B-mode lumen diameter. We compared CCA VFR by CVI-Q and Doppler method (DM), since knowledge of how they compare is crucial when both are used clinically. METHOD: We prospectively studied patients having clinical carotid duplex exams and healthy controls. All had CCA VFR measured by both methods in the same exam session. RESULTS: Thirty-four studies were reviewed. CCA VFR by CVI-Q in those without ICA stenosis was 337 +/- 96 mL/m, and by DM 359 +/- 130 mL/m; P = .33. There was no difference between methods for 50-75% or 75-95% ICA stenosis. In 7 patients with ICA occlusion, and 3 with 95-99% stenosis, VFR was higher by DM than by CVI-Q (Occlusion: 125 vs 58 mL/m, P = .007; 95-99%: 152 vs 63 mL/m, P = .038). There was no statistically significant difference between methods for measurement of the ratio of VFR between right and left CCA. CONCLUSION: In patients with 0-95% ICA stenosis, VFR by CVI-Q and DM showed no difference. For 95-100% ICA stenosis the methods differ; with higher VFR by DM. Side-to-side VFR ratios remain constant, irrespective of VFR method, and can still provide clinically useful information.     

Fluid therapy for induced labour under epidural analgesia: biochemical consequences for mother and infant

Two types of fluid regimen were provided for patients having labour induced under epidural analgesia. Reasons for the infusion were to pre-load the circulation before the epidural, and subsequently to sustain maternal hydration. Both fluids were isotonic, one was predominantly saline based (Hartmann's solution) and the other contained both saline and dextrose. Blood glucose and serum sodium, lactate and beta-hydroxybutyrate were measured before the start of induction, at delivery and in the cord sample. Blood glucose and serum sodium were measured in the babies at 12 and 24 h of age. The dextrose-saline fluid caused small but significant changes in blood glucose and serum sodium which did not exceed the normal reference limits for either. The use of Hartmann's solution was associated with considerable rises in maternal serum beta-hydroxybutyrate at delivery. Neither fluid had any significant effect on the blood glucose or serum sodium in infants at 12 and 24 h of age.     

Sampling Patients Within and Across Health Care Providers: Multi-Stage Non-Nested Samples in Health Services Research

In order to better inform study design decisions when sampling patients within and across health care providers we develop a simulation-based approach for designing complex multi-stage samples. The approach explores the tradeoff between competing design goals such as precision of estimates, coverage of the target population and cost.We elicit a number of sensible candidate designs, evaluate these designs with respect to multiple sampling goals, investigate their tradeoffs, and identify the design that is the best compromise among all goals. This approach recognizes that, in the practice of sampling, precision of the estimates is not the only important goal, and that there are tradeoffs with coverage and cost that should be explicitly considered. One can easily add other goals. We construct a sample frame with all phase III clinical cancer treatment trials that are conducted by cooperative oncology groups of the National Cancer Institute from October 1, 1998 through December 31, 1999. Simulation results for our study suggest sampling a different number of trials and institutions than initially considered.Simulations of different study designs can uncover efficiency gains both in terms of improved precision of the estimates and in terms of improved coverage of the target population. Simulations enable us to explore the tradeoffs between competing sampling goals and to quantify these efficiency gains. This is true even for complex designs where the stages are not strictly nested in one another.     

Tardive dyskinesia in children treated with atypical antipsychotic medications.

Recent years have witnessed increased antipsychotic treatment of children despite limited long‐term safety data in children. In this study, motor side effects associated with the use of antipsychotic drugs in children were examined in a sample of pediatric psychiatric patients. Child and adolescent psychiatric patients receiving antipsychotics (most were on atypicals) for 6 months or longer (n = 118) were compared with antipsychotic‐naïve patients (n = 80) with similar age, sex ratio, and diagnoses. Only 19% of patients on antipsychotics had ever experienced psychotic symptoms. Eleven children (9%) on antipsychotics exhibited dyskinesia, when compared with 0 in the naïve group (P = 0.003, Fisher's exact test). Nine of 62 African–American children (15%) on antipsychotics exhibited dyskinesia, when compared with only 4% (2 of 52) of European–American children (P = 0.003, Fisher's exact test). Children treated with antipsychotic drugs might experience a significant risk of dyskinesia even when treated only with atypical antipsychotics. Ethnicity might also be a risk factor for dyskinesia in children. Side‐effect profile of the atypical antipsychotic drugs in children may be much different than that in adults. © 2007 Movement Disorder Society     

Malignant Peripheral Nerve Sheath Tumor: An Unusual Cause of Intussusception

Malignant peripheral nerve sheath tumors (MPNST) are defined as any tumor arising from a peripheral nerve or showing nerve sheath differentiation. The majority of these tumors arise on the trunk, extremities, or head and neck region. The literature to date has fewer than 14 cases of MPNST arising in the gastrointestinal tract, and only two cases were ever reported in the small intestine, one of which was a recurrent disease. In this paper, we report the first US case of an MPNST arising in the small intestine and presenting as intussusception.     

Ifosfamide and mesna

The chemistry, pharmacology, pharmacokinetics, and adverse effects of ifosfamide and mesna are described separately, followed by a discussion of the adverse effects of concurrent ifosfamide and mesna, the clinical spectrum of ifosfamide, and the dosage and administration of the two drugs. Ifosfamide, an active analogue of cyclophosphamide, differs from other direct alkylating substances in that it requires biotransformation in the liver before it can exert its alkylating effects. The bioavailability of ifosfamide after oral administration exceeds 95%. The adverse effects of ifosfamide include hematologic, urinary tract, GI tract, and CNS toxicity. Mesna is a thiol compound designed to function as a regional detoxificant of urotoxic oxazaphosphorine cytostatics such as ifosfamide. The drug is rapidly oxidized in the plasma to its dimeric form, dimesna, one third of which is converted back to mesna by glutathione reductase. The mean total urinary availability of mesna administered orally is 76%. Mesna may produce gastrointestinal and allergic reactions. The adverse effects of concurrent ifosfamide and mesna include urinary tract and renal toxicity. Although current FDA-approved labeling is limited to refractory germ cell testicular cancer, ifosfamide has also shown efficacy in the treatment of lymphoma, lung cancer, and sarcomas. Optimum dosage and scheduling remain to be determined; studies suggest that a fractionated dosage schedule provides antineoplastic activity with tolerable toxicity. Ifosfamide, used in combination with mesna for uroprotection, provides a useful therapeutic option for the management of patients with testicular cancer, soft tissue sarcomas, or high-grade malignant lymphomas.