Changes in the fine structure of venous endothelium in the rabbit following adrenaline infusion

Summary The fine structure of the endothelium lining the femoral and mesenteric veins in the rabbit was examined following the infusion of concentrations of adrenaline varying from 0.5 to 5.0 g/kg. Control animals were infused with saline.Vesiculation of the endothelial cells was observed following each infusion of adrenaline, the effect being most marked with the highest dose used. It is suggested that this vesiculation may be associated with the release of antihaemophilic globulin and/or plasminogen activator from the endothelial cells.The authors wish to express their gratitude to Mrs. M. Woodford, Miss. G. Moore and Mr. R. Ellis for their skilful technical assistance     

The Optimum Dosage Regimen of Intravenous Infusion for Drugs Obeying Parallel First-order and Michaelis-Menten Elimination Kinetics

IntravenousInfusionIsoneofthewarwidelyu。dIntheclinlcaltherapy．Within时slon,drugcandirectlyenterthecirculationofthebody,andplasmaconcentrationcanmain－tainastableStateafteraPer止dOfcontinuousInfusion．ItIsposslbktoletpbteauconcentra－tlonequaltothemosteffectivetherapeuticconcentrationbyadjustingtherateofInfusion．ButtheweaknessofintravenousInfusionIsthattheplasmaconcentralonkvelIstoolowtomeettheneedofclinicaltherapyduringtheInitialadmlnlstratlonperiod．Asimpleandpractlcafmethdtooverco…     

Preparation of nanoliposomes linked to HER2/neu-derived (P5) peptide containing MPL adjuvant as vaccine against breast cancer

The study was aimed at evaluating antitumor and immunomodulatory effects of liposomal vaccine composed of P5 human epidermal growth factor receptor 2 (HER2)/neu-derived peptide coupled to the surface of high-temperature nanoliposomes containing distearoylphosphocholine:distearoylphosphoglycerol:Chol:dioleoylphosphatidylethanolamine (DOPE) comprising monophosphoryl lipid A (MPL) adjuvant in HER2/neu overexpressing the breast cancer model. BALB/c mice bearing TUBO carcinoma were subcutaneously immunized with formulations containing 10 µg P5 peptide and 25 µg MPL three times with 2-week intervals. To determine immuno responses in immunized mice, the amount of released interferon-γ and IL-4 were measured by the enzyme-linked immunospot method and the flow cytometric analysis on the isolated splenocytes. The results demonstrated that tumor-bearing mice immunized with Lip/DOPE/MPL/P5 formulation had the most released interferon-γ and the highest cytotoxic T lymphocyte responses that led to the lowest tumor size and the longest survival time than those of other formulations. The results achieved by Lip/DOPE/MPL/P5 formulation could make it a suitable candidate to induce effective antigen-specific tumor immunity against breast cancer.     

IGF‐I deficient mice show reduced peripheral nerve conduction velocities and decreased axonal diameters and respond to exogenous IGF‐I treatment

Although insulin‐like growth factor‐I (IGF‐I) can act as a neurotrophic factor for peripheral neurons in vitro and in vivo following injury, the role IGF‐I plays during normal development and functioning of the peripheral nervous system is unclear. Here, we report that transgenic mice with reduced levels (two genotypes: heterozygous Igf1^+/− or homozygous insertional mutant Igf1^m/m) or totally lacking IGF‐I (homozygous Igf1^−/−) show a decrease in motor and sensory nerve conduction velocities in vivo. In addition, A‐fiber responses in isolated peroneal nerves from Igf1^+/− and Igf1^−/− mice are impaired. The nerve function impairment is most profound in Igf1^−/− mice. Histopathology of the peroneal nerves in Igf1^−/− mice demonstrates a shift to smaller axonal diameters but maintains the same total number of myelinated fibers as Igf1^+/+ mice. Comparisons of myelin thickness with axonal diameter indicate that there is no significant reduction in peripheral nerve myelination in IGF‐I–deficient mice. In addition, in Igf1^m/m mice with very low serum levels of IGF‐I, replacement therapy with exogenous recombinant hIGF‐I restores both motor and sensory nerve conduction velocities. These findings demonstrate not only that IGF‐I serves an important role in the growth and development of the peripheral nervous system, but also that systemic IGF‐I treatment can enhance nerve function in IGF‐I–deficient adult mice. © 1999 John Wiley & Sons, Inc. J Neurobiol 39: 142–152, 1999     

Genetic transformation of a Corynebacterial symbiont from the Chagas disease vector Triatoma infestans

Insect-borne diseases have experienced a troubling resurgence in recent years. Emergence of resistance to pesticides greatly hampers control efforts. Paratransgenesis, or the genetic transformation of bacterial symbionts of disease vectors, is an alternative to traditional approaches. Previously, we developed paratransgenic lines of Rhodnius prolixus, a vector of Chagas disease in Central America. Here, we report identification of a Corynebacterial species as a symbiont of Triatoma infestans, a leading vector of Chagas disease in South America. We have modified this bacterium to produce an immunologically active single chain antibody fragment, termed rDB3. This study establishes the basis for generating paratransgenic T. infestans as a strategy for control of Chagas disease.     

First phase release coefficient of insulin in subjects with normal glucose tolerance on glucose infusion analyzed by computer simulation

We report here a mathematical model using computer simulation to solve the phase fractionation coefficient (f) of instantaneous insulin release on glucose infusion. By extensive model testing with the cited parameters obtained from the literature, the values of the factor f were shown to lie in range of 0.93+/-0.02 (mean+/-2S.D., n=15), indicating that the high pulsatile bolus of glucose by i.v. infusion may trigger acute insulin release (AIR) corresponding to a fraction of more than 90% of the stored insulin release in the first phase from the secretory granules of pancreatic beta cells. In addition, the value of the factor f was shown to be independent of both the glucose infusion method and the non-insulin-dependent uptake of glucose.     

Chronomodulated chemotherapy: clinical value and possibilities for dissemination in the United States

Modern medicine has been relatively slow to apply chronotherapeutic principles to standard oncologic practice. Despite the impressive body of evidence supporting the use of chronochemotherapy, with only a rare exception most oncology clinics in the United States lack the expertise and capability to implement it. At the same time, American medicine has increasingly come to recognize the importance of toxicity mitigation, cytoprotection, and quality of life for patients undergoing cancer treatment. However, toxicity mitigation strategies such as chronomodulated infusional chemotherapy and novel cytoprotective agents are not widely embraced by U.S. physicians. This article explores some reasons why this situation exists, including the influence of non-medical biases that may affect management decisions on the application of chemotherapy. The author conducted a survey of U.S. companies representing the three private insurance payers available (HMO, PPO, Indemnity) as well as representatives of Medicare and Medicaid. Responses to the survey confirmed that U.S. insurers do not at present officially reimburse for chronotherapy; however, changes will come about through educational efforts aimed at increasing awareness among insurers as to the clinical benefits and cost-effectiveness of this mode of treatment. At this juncture, the outlook for cancer chronotherapy as a first-line approach to the treatment of metastatic cancer in the United States remains uncertain. Under the current method of insurance reimbursement, the advancement of chronotherapy in the United States is threatened despite evidence that such treatment is both therapeutically sound and cost-effective.     

Examining costs of induced and constitutive immune investment in Tenebrio molitor

Central to the conceptual basis of ecological immunity is the notion that immune effector systems are costly to produce, run, and/or maintain. Using the mealworm beetle, Tenebrio molitor, as a model we investigated two aspects of the costs of innate immunity. We conducted an experiment designed to identify the cost of an induced immune response, and the cost of constitutive investment in immunity, as well as potential interactions. The immune traits under consideration were the encapsulation response and prophylactic cuticular melanization, which are mechanistically linked by the melanin-producing phenoloxidase cascade. If immunity is costly, we predicted reduced longevity and/or fecundity as a consequence of investment in either immune trait. We found a measurable longevity cost associated with producing an inducible immune response (encapsulation). In contrast to other studies, this cost was expressed under ad libitum feeding conditions. We found no measurable costs for constitutive investment in immunity (prophylactic investment in cuticular colour).     

Adaptive decision making in a lymphocyte infusion trial

We describe an adaptive Bayesian design for a clinical trial of an experimental treatment for patients with hematologic malignancies who initially received an allogeneic bone marrow transplant but subsequently suffered a disease recurrence. Treatment consists of up to two courses of targeted immunotherapy followed by allogeneic donor lymphocyte infusion. The immunotherapy is a necessary precursor to the lymphocyte infusion, but it may cause severe liver toxicity and is certain to cause a low white blood cell count and low platelets. The primary scientific goal is to determine the infusion time that has the highest probability of treatment success, defined as the event that the patient does not suffer severe toxicity and is alive with recovered white blood cell count 50 days from the start of therapy. The method is based on a parametric model accounting for toxicity, time to white blood cell recovery, and survival time. The design includes an algorithm for between-patient immunotherapy dose de-escalation based on the toxicity data and an adaptive randomization among five possible infusion times according to their most recent posterior success probabilities. A simulation study shows that the design reliably selects the best infusion time while randomizing greater proportions of patients to superior infusion times.     

Vanadium-contaminated perioperatively administered infusion solutions and drugs

Vanadium was determined in 51 solutions and drugs for intravenous administration and in 6 salt components of a multitrace element solution using electrothermal atomic absorption spectrometry. The highest V contaminations were found in albumin solutions showing values of more than 600 μg/L V. Two heparines contained 14.3 and 122 μg/L V, respectively. In the ultratrace element solution, 14.8 μg/L vanadium were determined. The most contaminated salt of this solution was Mn(II)-dl-aspartate (12.8 μg V/g). The concentrations of unbound V (V _f ) in the albumin solutions were between 0.31 and 299 μg/L. The manufacturing process is the reason for V contamination. The biological half-life of V administered intravenously by albumin solutions in man was about 125 h.