Inhibition of mouse peritoneal macrophage DNA synthesis by infection with the arenavirus Pichinde.

Macrophage DNA synthesis and proliferation occur during the development of cell-mediated immunity and in the early nonspecific reaction to infection. Arenaviruses have a predilection for infection of cells of the reticuloendothelial system, and in this study we have examined the effect of the arenavirus Pichinde on macrophage DNA synthesis. We have found that infection of mouse peritoneal macrophages with Pichinde caused a profound dose-dependent inhibition of the DNA synthesis induced by macrophage growth factor-colony stimulating factor. At a multiplicity of inoculum of 5, there is a 75 to 95% inhibition of DNA synthesis. Viable virus is necessary for inhibition since Pichinde inactivated by heat or cobalt irradiation had no effect. Similarly, virus pretreated with an antiserum to Pichinde was without inhibitory effect. Inhibition was demonstrated by measuring DNA synthesis spectrofluorometrically as well as by [3H]thymidine incorporation. The inhibition of DNA synthesis was not associated with any cytopathology. There was no evidence that the inhibition was due to soluble factors, such as prostaglandins or interferon, released by infected cells. These studies demonstrate, for the first time in vitro, a significant alteration in macrophage function caused by infection with an arenavirus. It is possible that inhibition of macrophage proliferation represents a mechanism by which some microorganisms interfere with host resistance.     

Phase I clinical and pharmacokinetic study of cyclophosphamide administered by five-day continuous intravenous infusion

Summary A total of 14 patients, 7 male and 7 female, received in all 21 evaluable courses of cyclophosphamide administered by 5-day continuous infusion. Cyclophosphamide doses were escalated from 300 to 400 mg/m² per day for 5 days and repeated every 21–28 days. The patient population had a median age of 55 years (range 38–76) and a median Karnofsky performance status of 80 (range 60–100). Only 1 patient had not received prior therapy; 5 patients had received only prior chemotherapy, 1 had received only prior radiotherapy, and 7 had received both. Tumor types were gastric (1), lung (2), colon (4), urethral adenocarcinoma (1), cervical (2), chondrosarcoma (1), melanoma (1), uterine leiomyosarcoma (1), and pancreatic (1). The dose-limiting toxicity was granulocytopenia, with median WBC nadir of 1700/l (range 100–4800) in 8 heavily pretreated patients treated at 350 mg/m² per day for 5 days. One patient without heavy prior treatment received two courses at 400 mg/m² and had WBC nadirs of 800/l and 600l. WBC nadirs occurred between days 9 and 21 (median 14). Drug-induced thrombocytopenia occurred in only one patient (350 mg/m² per day, nadir 85000/l). Neither hyponatremia nor symptomatic hypoosmolality was observed. Radiation-induced hemorrhagic cystitis may have been worsened in one patient. Nausea and vomiting were mild. Objective remissions were not observed. The maximum tolerated dose for previously treated patients is 350 mg/m² per day for 5 days. This dose approximates the doses of cyclophosphamide commonly used with bolus administration. Plasma steady-state concentrations (Css) of cyclophosphamide, measured by gas liquid chromatography, were 2.09–6.79 g/ml. Steady state was achieved in 14.5±5.9 h (mean ±SD). After the infusion, cyclophosphamide disappeared from plasma monoexponentially, with a t^1/2 of 5.3±3.6 h. The area under the curve of plasma cyclophosphamide concentrations versus time (AUC) was 543±150 g/ml h and reflected a cyclophosphamide total-body clearance (CL_TB) of 103±31.6 ml/min. Plasma alkylating activity, assessed by p-nitrobenzyl-pyridine, remained steady at 1.6–4.3 g/ml nor-nitrogen mustard equivalents. Urinary excretion of cyclophosphamide and alkylating activity accounted for 9.3%±7.6% and 15.1%±2.0% of the administered daily dose, respectively. The t^1/2 and AUC of cyclophosphamide associated with the 5-day continuous infusion schedule are similar to those reported after administration of cyclophosphamide 1500 mg/m² as an i.v. bolus. The AUC of alkylating activity associated with the 5-day continuous infusion of cyclophosphamide is about three times greater than the AUC of alkylating activity calculated after a 1500-mg/m² bolus dose of cyclophosphamide. Daily urinary excretions of cyclophosphamide and alkylating activity associated with the 5-day continuous infusion schedule are similar to those reported after bolus doses of cyclophosphamide.     

Safety and efficacy of the cystic fibrosis transmembrane conductance regulator potentiator icenticaftor (QBW251)

BackgroundThis is the first-in-human study of icenticaftor, an oral potentiator of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) channel. Restoration of CFTR activity has shown significant clinical benefits, but more studies are needed to address all CFTR mutations.MethodsSafety, pharmacodynamics/pharmacokinetics of icenticaftor were evaluated in a randomized, double-blind, placebo-controlled study in healthy volunteers. Efficacy was assessed in adult CF patients with ≥1 pre-specified CFTR Class III or IV mutation (150 and 450 mg bid), or homozygous for F508del mutation (450 mg bid). Primary efficacy endpoint was change from baseline in lung clearance index (LCI_2.5). Secondary endpoints included %predicted FEV₁ and sweat chloride level.ResultsClass IV mutations were present in 22 patients, Class III in 2 (both S549N), and 25 were homozygous for F508del. Icenticaftor was well-tolerated in healthy and CF subjects with no unexpected events or discontinuations in the CF groups. The most frequent study-drug related adverse events in CF patients were nausea (12.2%), headache (10.2%), and fatigue (6.1%). Icenticaftor 450 mg bid for 14 days showed significant improvements in all endpoints versus placebo in patients with Class III and IV mutations; mean %predicted FEV₁ increased by 6.46%, LCI_2.5 decreased by 1.13 points and sweat chloride decreased by 8.36 mmol/L. No significant efficacy was observed in patients homozygous for a single F508del.ConclusionsIcenticaftor was safe and well-tolerated in healthy volunteers and CF patients, and demonstrated clinically meaningful changes in lung function and sweat chloride level in CF patients with Class III and IV CFTR mutations.ClinicalTrials.gov: NCT02190604     

Epidermal growth factor receptors on ependymomas and other brain tumors

Epidermal growth factor receptor (EGFR) and transferrin receptor levels were determined in 14 intracranial neoplasms (four glioblastomas multiforme, four medulloblastomas, four ependymomas, one cerebellar astrocytoma, and one acoustic neurinoma) and in four samples of "normal" brain tissue. A competitive radioreceptor assay with 125I-epidermal growth factor and 125I-transferrin was performed using the primitive neuroectodermal tumor-derived TE-671 tissue-culture cell line as a standard. Epidermal growth factor receptors were present on TE-671 cells, all four ependymomas, and two of the four glioblastomas multiforme. The number of EGFR's per cell for ependymomas were estimated to range from 1000 to 6000. Transferrin receptors were detected on TE-671 cells, two of the four medulloblastomas, and one of the four glioblastomas multiforme. A cell surface binding assay, performed directly on the rat ependymal cell monolayer, was also analyzed. The identification of EGFR's on ependymomas and TR's on medulloblastomas suggests that malignant central nervous system tumors that spread by cerebrospinal fluid pathways may be treatable by intrathecal antibody-toxin conjugates. The presence of EGFR's on all of the ependymomas may reflect a role of the receptor in the malignant phenotype of this tumor.     

Influence of renal nerves on renal function during development

The present review summarizes recent studies describing the role of renal sympathetic innervation in the regulation of renal function during development. The afferent renal innervation appears early during fetal life and probably precedes the development of efferent renal nerves. There is suggestive evidence that renal nerves are required for the proper development of the kidney and that neurotrophic growth factors play an important role in renal embryogenesis and in renal tubular differentiation. Renal sympathetic innervation modulates renal hemodynamics early during development. Renal nerve stimulation during -adrenoceptor blockade produces renal vasodilation in fetal and newborn animals but not in adults. Unlike the effect of renal nerves on fetal renal hemodynamics which is observed in the young fetus, the role of renal sympathetic nerves in modulating fluid and electrolyte homeostasis seems to develop during late gestation. Recent studies have also shown that renal nerves play an important role in regulating renin secretion during the transition from fetal to newborn life. For example, renal denervation during fetal life suppressed the physiological rise in plasma renin activity associated with delivery and decreased renal renin mRNA levels after birth. Taken together, these studies suggest that renal nerves influence fetal renal development and that the influence of renal sympathetic innervation on renal hemodynamics and function changes with maturation.     

Comparison of gaseous microemboli counts in arterial, simultaneous and venous heat exchange with a hollow fiber membrane oxygenator

Potential sources of gaseous microemboli during cardiopulmonary bypass are varied. However, it is known that membrane oxygenators generate fewer gaseous microemboli than bubble oxygenators and that bubblers cannot utilize arterial heat exchange without generating significant gaseous microemboli during rewarming. A membrane oxygenator utilizing simultaneous gas and heat exchange raises the concern that concurrent gas and heat exchange would result in a higher production of gaseous microemboli compared to conventional venous heat exchange devices. This in vitro study compared venous, simultaneous, arterial and control (venous) heat exchanger gaseous microemboli counts during rewarming. No significant difference was found between the four heat exchangers when comparing inlet and outlet gaseous microemboli counts. This in vitro study suggests that there is no difference in gaseous microemboli generation when varying the position of the heat exchanger in the extracorporeal circuit incorporating a microporous membrane oxygenator.     

Phase II study of intravenous melphalan (NSC-8806) in the treatment of patients with advanced squamous carcinoma of the head and neck

The Illinois Cancer Center entered 25 patients on a phase II trial of intravenous melphalan treating patients with recurrent, metastatic or locally advanced and inoperable squamous cell carcinoma of the head and neck. All patients had bi-dimensionally measurable disease, at least a sixty day life expectancy, and adequate performance status (ECOG scale 2). All patients except one had received prior radiotherapy, chemotherapy or both. Melphalan dosage was 30 mg/m² every three weeks. Twenty-four patients were evaluable for response. One patient with laryngeal carcinoma had a clinical complete response of a nodal metastasis. Four patients had stabilization of disease for one to three months. There was formidable toxicity, including neutropenia (ANC < 1000/l 36%), and thrombocytopenia (< 50,000/l 32%). There were no drug-related deaths. Melphalan administered intravenously does not appear to be efficacious therapy in patients with previously treated advanced head and neck squamous carcinomas.     

Comparison of risk estimates for selected diseases and causes of death

BACKGROUND: Lifetime risk estimates of disease are limited by long-term data extrapolations and are less relevant to individuals who have already lived a period of time without the disease, but are approaching the age at which the disease risk becomes common. In contrast, short-term age-conditional risk estimates, such as the risk of developing a disease in the next 10 years among those alive and free of the disease at a given age, are less restricted by long-term extrapolation of current rates and can present patients with risk information tailored to their age. This study focuses on short-term age-conditional risk estimates for a broad set of important chronic diseases and nondisease causes of death among white and black men and women. METHODS: The Feuer et al. (1993, Journal of the National Cancer Institute) [15] method was applied to data from a variety of sources to obtain risk estimates for select cancers, myocardial infarction, diabetes mellitus, multiple sclerosis, Alzheimer's, and death from motor vehicle accidents, homicide or legal intervention, and suicide. RESULTS: Acute deaths from suicide, homicide or legal intervention, and fatal motor vehicle accidents dominate the risk picture for persons in their 20s, with only diabetes mellitus and end-stage renal disease therapy (for blacks only) having similar levels of risk in this age range. Late in life, cancer, acute myocardial infarction, Alzheimer's, and stroke become most common. The chronic diseases affecting the population later in life present the most likely diseases someone will face. Several interesting differences in disease and death risks were derived and reported among age-specific race and gender subgroups of the population. CONCLUSION: Presentation of risk estimates for a broad set of chronic diseases and nondisease causes of death within short-term age ranges among population subgroups provides tailored information that may lead to better educated prevention, screening, and control behaviors and more efficient allocation of health resources.