The pulmonary absorption of aerosolized and intratracheally instilled rhG-CSF and monoPEGylated rhG-CSF

PURPOSE: The objective of this study was to highlight differences in the pulmonary absorption of a monoPEGylated rhG-CSF and rhG-CSF after intratracheal instillation and aerosol delivery. METHODS: Male Sprague Dawley rats (250 g) were anesthetized and intratracheally instilled (IT) with protein solution or were endotracheally intubated and administered aerosol for 20 min via a Harvard small animal ventilator. A DeVilbiss "Aerosonic" nebulizer containing 5 ml of protein solution at approximately 3 mg/ml was used to generate aerosol. The volume of protein solution deposited in the lung lobes was estimated to be approximately 13 microliters after delivery of Tc-99m HSA solutions. The PEGylated proteins consisted of a 6 kDa (P6) or 12 kDa PEG (P12) linked to the N-terminus of rhG-CSF. rhG-CSF also was administered IT in buffers at pH 4 and pH 7 and in dosing volumes ranging from 100 to 400 microliters. Blood samples were removed at intervals after dosing and the total white blood cell counts (WBC) were determined. Plasma was assayed for proteins by an enzyme immuno assay. RESULTS: The plasma protein concentration v. time profiles were strikingly different for aerosol v. IT delivery. The Cmax values for rhG-CSF and P12 after aerosol delivery were greater than found after IT (Aerosol: 598 +/- 135 (ng/ml) rhG-CSF; 182 +/- 14 P12 v. IT: 105 +/- 12 rhG-CSF; 65.9 +/- 5 P12). Similarly, Tmax was reached much earlier after aerosol administration (Aerosol: 21.7 +/- 4.8 (min) rhG-CSF; 168 +/- 31 P12 v. IT: 100 +/- 17 rhG-CSF; 310 +/- 121 P12). Estimated bioavailabilities (F(lung)%) were significantly greater via aerosol delivery than those obtained after IT (Aerosol: 66 +/- 14 rhG-CSF; 12.3 +/- 1.9 P12 v. IT: 11.9 +/- 1.5 rhG-CSF; 1.6 +/- 0.1 P12). An increase in circulating WBC counts was induced by all proteins delivered to the lungs. The rate and extent of absorption of rhG-CSF was not influenced by the pH employed nor the instilled volume. CONCLUSIONS: Estimates of bioavailability are dependent upon the technique employed to administer drug to the lungs. Aerosol administration provides a better estimate of the systemic absorption of macromolecules.     

Meeting the social service needs of persons with AIDS: hospices' response

A national sample of 148 directors of hospice social service departments (or persons most familiar with the delivery of social services in the hospice) participated in an exploratory study investigating the effects of the acquired immune deficiency syndrome (AIDS) epidemic on the delivery of hospice social services. Findings suggest, as does the literature, that the psychosocial needs of persons dying from AIDS present different challenges than those of traditional hospice patients. Furthermore, the results indicate the need for greater collaborative efforts among community agencies as well as specific and ongoing training for staff and volunteers who work with persons with AIDS (PWAs). Implications for the delivery of hospice social services to this population are discussed.     

Mapping of selective rat chromosome regions using mouse microsatellite markers

Four hundred eighty mouse microsatellite markers distributed in discrete regions on five mouse chromosomes were screened for producing PCR products in the rat. Ninety-eight of these markers or 20% give distinctive PCR products. Among these ninety-eight markers, twenty-three are polymorphic between the inbred hypertensive Dahl salt-sensitive (S) rat strain and several normotensive rat strains of interest. Fourteen of these polymorphic markers have been mapped to the homologous chromosome regions of the rat, and have further been utilized to localize quantitative trait loci (QTL) for blood pressure in the S rat.     

Antiviral cytotoxic activity across a species barrier in mixed xenogeneic chimeras: functional restriction to host MHC

Reconstitution of lethally irradiated mice with a mixture of mouse and rat bone marrow cells (mouse + rat-->mouse) results in mixed xenogeneic chimerism and donor-specific tolerance. The current study demonstrates that mouse and rat T lymphocytes that have developed in xenogeneic chimeras are restricted to Ag presentation by mouse, but not rat, APC. Restriction to host Ags results in functional immunocompetence with generation of antiviral cytotoxic activity in vivo, within and across species barriers. These data demonstrate for the first time that the host thymus is sufficient to support development and positive selection of functional cross-species T lymphocytes. The superior immunocompetence, as compared with fully xenogeneic (rat-->mouse) chimeras, may prove to be of significant benefit in the clinical application of xenotransplantation to solid organ transplantation and immune reconstitution for AIDS.     

Physical punishment and signs of mental distress in normal adolescents

Adolescents (375 males and 496 females) were administered the Brief Symptom Inventory (BSI), the General Well-Being Scale (GWB), the Parental Bonding Instrument (PBI), and two questions about each parent, supplementing the PBI, tapping violent punitive behavior. Signs of mental distress in adolescents and reported physical punishment from parents were analyzed. Results indicated that greater physical punishment was associated with higher levels of psychiatric symptoms and lower general well-being. These results persisted after controlling for parental attitudes, as quantified by the PBI, and socioeconomic status. The findings of this study can contribute to efforts to raise public awareness of the negative consequences of physical punishment on the mental health of children.     

Serum LDH and ALP isozyme activities in mice bearing solid Ehrlich carcinoma and/or treated with the maximum tolerated dose (MTD) of aloin

After a large-scale contamination of an urban area with gamma-ray emitting radionuclides (e.g. caesium isotopes) decision makers will need guidance as to its potential radiological consequences and to optimum means of mitigation. To provide such information, a dynamic radioecological model PARATI has been developed and used to simulate the contamination of realistic urban environments in a computer model and to estimate the various radiation fields in such environments. In this study, the computer-simulated realistic behaviour and movements of individuals and populations in such radiation fields are described, and the resulting radiation exposures and their variabilities are estimated. For the scenarios considered, the doses of individuals in the same contaminated environment may vary by more than one order of magnitude. Studies on population habits and on the behaviour of radionuclides on important urban surfaces even a long time after the contamination might reduce the uncertainty considerably.     

Therapeutic motor training increases parallel fiber synapse number per Purkinje neuron in cerebellar cortex of rats given postnatal binge alcohol exposure: preliminary report

Because therapeutic approaches to fetal alcohol effects in humans have been rare, this study explored the rehabilitative effect of complex motor training on an animal model of binge drinking in the third trimester of human pregnancy. Neonatal alcohol exposure induces significant and permanent reductions in Purkinje and granule cell number accompanied by impaired motor behavior in rats. The purpose of this study was to determine: (1) whether the motor skill impairment caused by exposure to alcohol in the early postnatal period could be ameliorated by the learning of a set of complex motor tasks that had been demonstrated to cause synaptogenesis in the cerebellar cortex; and (2) the extent to which cerebellar neurons in alcohol-exposed (AE) rats exhibit synaptic plasticity. The AE group was given 4.5 g/kg/day of ethanol from postnatal days 4 to 9 via an artificial rearing procedure producing a mean peak blood alcohol level of 257 mg/dl. Control groups consisted of a gastrostomy control (GC) group, that received an isocaloric mixture of maltose/dextrin instead of ethanol, and a suckle control (SC) group, that was reared normally by dams. At approximately 6 months of age, animals from the three groups were assigned either to a rehabilitation condition (RC; that received 10 days of training on the motor tasks) or to an inactive condition (IC; where rats stayed in isolation in their cages). Although SC rats were significantly faster to complete the course in the first 5 days of training, there were no differences in ability to perform among animals from all three groups-SC, GC, and AE--at the end of the training period. Unbiased stereological techniques were used to obtain estimates of the number of parallel fiber synapses/Purkinje cell within the cerebellar paramedian lobule. Results showed that the RC rats from the SC and AE groups had significantly more synapses/Purkinje cell than corresponding IC animals. These data demonstrate that rehabilitative intervention (complex motor training) can improve motor performance impaired by postnatal alcohol exposure and that surviving Purkinje neurons retain the capacity for synaptic plasticity.     

Primary low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) arising in dura

The study was designed to clarify the difference in pharmacokinetics of monoclonal antibodies (mAb) in animal models and humans, and to elucidate the applicability of animal models. 99mTc-labeled murine mAb -- against carcinoembryonic antigen (designated BW431/26), and neural cell adhesion molecule (NE150) -- and one chimeric mouse/human mAb against nonspecific cross-reacting antigen (chNCA) were administered i.v. to normal mice and athymic mice (370 kBq, 400 ng) xenografted with human cancer cells expressing antigens, and into patients with tumor (925 MBq, 1 mg). The biodistribution of two of the three mAb (not 99mTc-BW431/26) differed clearly in mice and patients. 99mTc-NE150 showed specific uptake in xenografted tumor and otherwise a normal biodistribution; however, clinical examination showed increased uptake in the liver with rapid blood clearance (mean alpha half-life = 31.1 min) compared with 99mTc-BW431/26 (28.4 h). 99mTc-chNCA demonstrated increased blood clearance and renal excretion in both normal and athymic mice, with accumulation in tumors. Clinical examination showed rapid blood clearance (mean alpha half-life = 6.4 min) and increased uptake in the liver. High-performance liquid chromatographic analysis of 99mTc-chNCA revealed the immune complex in blood, suggesting uptake of the complex by the reticuloendothelial cells. The biodistribution of radiolabeled mAb in animal and human models was variable and specific for each of the three mAb. The results of animal studies with mAb should be evaluated carefully before being extrapolated to humans, on the basis of the nature of the mAb and interacting substances.