Studies of the human oropharyngeal airspaces using magnetic resonance imaging IV--the oropharyngeal retention effect for four inhalation delivery systems.

Magnetic resonance imaging (MRI) of the oropharyngeal region from 20 adult volunteers using four model inhalation devices (varying mouthpiece diameters, airflow resistances) and tidal breathing was carried out. Statistical analysis (convex hull method) selected 12 scans from 80 data sets representing the extremes of all dimensions in the population. Twelve physical mouth-throat models were made by stereolithography using the exact scan data. The aim was to produce models with varying dimensions to span the adult population, and to investigate if oropharyngeal dimensions affected throat retention for different delivery systems. In an in vitro analysis, the models were used to determine the retention effect of the oropharyngeal airspaces when drug aerosols were administered from four inhalation delivery systems: a pressurised metered dose inhaler (pMDI), two different dry powder inhalers (DPIs A and B), and a nebulizer. The aims of this work were to determine the key parameters governing mouth-throat retention and whether retention was dependent on the delivery system used. Characterizing the throat models by measuring 51 different dimensional variables enabled determination of the most influential variables for dose retention for each inhalation delivery system. Throat model retention was found to be dependent on the delivery system (pMDI approximately DPI(A) > DPI(B) > Neb.). The most influential variable was the total throat model volume. Throat models representing high, median, and low oropharyngeal filtration in healthy adults have been identified.     

Behavioral, biochemical and neurotoxicological actions of the alpha-ethyl homologue of p-chloroamphetamine

The present set of experiments was designed to examine the effects of extension of the alpha-methyl of p-chloroamphetamine (PCA) to an alpha-ethyl. Therefore, the alpha-ethyl homologue of PCA, 1-(4-chlorophenyl)-2-aminobutane (CAB), was compared to PCA in a number of pharmacological assays. CAB was 2-fold less potent than PCA at inhibiting synaptosomal uptake of [3H]5-hydroxytryptamine ([3H]5-HT), and 5-fold less potent at inhibiting uptake of [3H]dopamine ([3H]DA). In drug discrimination assays, CAB was approximately 3-fold less potent than PCA in animals trained to discriminate 3,4-methylenedioxymethamphetamine (MDMA) or its alpha-ethyl homologue, S-(+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (S-(+)-MBDB), from saline. Monitoring with in vivo microdialysis, 10 mg/kg of PCA caused a large increase in extracellular DA and a significant decrease in 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum. In contrast, 11 mg/kg CAB caused no increase and 22 mg/kg CAB caused only a slight increase in extracellular DA. Both doses of CAB caused a decrease in extracellular DOPAC. The potential 5-HT neurotoxicity of CAB was examined by measuring monoamine and metabolite levels and [3H]paroxetine binding at one week following acute doses. A 10 mg/kg dose of PCA caused an 80% decrease in cortical and hippocampal serotonergic markers, while an equimolar dose of CAB decreased only hippocampal 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels. However, 22 mg/kg of CAB produced a 20-40% decrease in all serotonergic markers. Thus, extension of the alpha-alkyl significantly decreases the dopaminergic effects of PCA. The similar decrease in relative 5-HT neurotoxicity and the decreased ability to alter dopaminergic systems in vivo and in vitro supports the involvement of DA in the neurotoxicity of PCA.     

Case Study of Institution-Building by Nurse Bertha Wright and Colleagues

Purpose: To illuminate the history of nurses' participation in institution-building in the early 1900s, using the Baby Hospital in Oakland, California (now called Children's Hospital Oakland) as a case.
Design: Historical research using a framework of women's history theory focused on the women who founded Oakland's Baby Hospital, 1910–1930.
Method: Data collection included studying original sources, archival material, and interviews. Data evaluation included external criticism for authenticity and genuineness, and internal criticism for accuracy and bias.
Findings: In 1912, nurse Bertha Wright and social worker Mabel Weed, with a circle of community women, including Jessica Peixotto and Jean Howard McDuffie, established the Baby Hospital. Their activism included home visits, education, research, publications, political lobbying, and state policy and program development. At the center of this activity, was the lifelong commitment of Wright and Weed, who created new definitions of family. With social changes in the late 1920s, the male Board of Directors seized control of the hospital, and relegated women to auxiliary roles.
Conclusions: Health and social issues of the United States at the turn of the century are still problematic as a new century approaches and pertain to maternal-child health, foster care, and immigration. Feminists, including nurses, have played a central role in creating solutions. Knowledge of some of their incredible effort has been lost, particularly nursing's history in the western United States.     

3,3',5'-Tri-O-methylpiceatannol and 4,3',5'-tri-O-methylpiceatannol: improvements over piceatannol in bioactivity

Piceatannol (3,4,3',5'-tetrahydroxy-trans-stilbene) (NSC 365798) has recently been isolated and was subsequently synthesized for NCI tumor panel testing as a new antileukemic natural product from the seeds of Euphorbia lagascae. During the synthesis, a bioactive reaction mixture of several partially O-methylated piceatannol analogues was obtained. This mixture has now been maximized and subjected to bioactivity-directed fractionation, using brine shrimp lethality, to yield 3,3',5'-tri-O-methylpiceatannol (NSC 381281); this new compound has improved stability and better bioactivity in several systems than piceatannol itself. To confirm the structure, 5 was synthesized from vanillin. In addition, the isovanillin analogue, 4,3',5'-tri-O-methylpiceatannol (NSC 381864), another new compound, was synthesized and found to be bioactive.     

Genetic differentiation between and within strains of the saw-toothed grain beetle, Oryzaephilus surinamensis (Coleoptera: Silvanidae) at RAPD loci

Nine strains of Oryzaephilus surinamensis have been kept in laboratory culture for periods ranging from 5 to 30 years (30–180 generations). Two RAPD primers provided sufficient information to separate the strains reliably and unambiguously. The strains are maintained at a population size of 200 breeding adults. The marked divergence between strains is consistent with the small population size, which for the older strains, according to population genetics theory, implies that roughly half the original genetic variation should now be lost from within strains. However, there is no indication that the older strains have less inter-strain variation. The results demonstrate RAPD loci can reliably detect population subdivision, which in field populations of pest species is of fundamental importance in understanding the population genetics of insecticide resistance.     

High dose carboplatin/VP-16 plus ifosfamide with autologous bone marrow support in the treatment of refractory germ cell tumors.

We report seven patients with germ cell tumors which either recurred following a minimum of two regimens of platinum-based chemotherapy or were refractory to cisplatin. The patients were treated with one or two courses of high dose carboplatin (CBDCA) and etoposide (VP-16) plus ifosfamide (IFX) with mesna uroprotection and autologous bone marrow support. The doses given were CBDCA 500 mg/m2 every other day x 3 and VP-16 400 mg/m2 every other day x 3. IFX was given in a dose of 2 g/m2 daily x 5 days with mesna. The original intent of the protocol was to explore escalating doses of IFX, but excessive renal toxicity at the first dose level prevented escalation. Of the seven patients treated, four developed a marked decline in their renal function and three of the four required hemodialysis or hemofiltration. Six of seven patients treated had a decline in their serum markers indicating a response to therapy, but all have relapsed. Our conclusion is that while the combination of CBDCA/VP-16/IFX with ABMT is active in this group of patients, it is associated with excessive renal toxicity which is probably due to underlying renal dysfunction secondary to extensive prior cisplatin-based chemotherapy.     

Mechanical analysis of heterogenic inhibition between soleus muscle and the pretibial flexors in the cat.

1. The role of proprioceptive pathways linking the direct antagonists soleus (S) and tibialis anterior (TA) muscles in governing the mechanical properties of the ankle joint were studied in the decerebrate cat. Actions of these heterogenic pathways were compared with those between S and extensor digitorum longus (EDL), a muscle that also acts at the metatarsophalangeal joint. These neurally mediated interactions between S and either TA or EDL were studied by applying controlled length changes to the isolated tendons of pairs of these muscles and recording the resulting changes in force. The muscles were activated with the use of electrically evoked crossed-extension reflexes, flexion reflexes, and brain stem stimulation. 2. Heterogenic inhibition from TA or EDL onto S was well developed whether S was initially quiescent or activated by a crossed-extension reflex. The inhibition persisted for the duration of the stretch of TA or EDL. During a crossed-extension reflex, TA did not generate background force, but brief stretch reflexes could be obtained. During flexion reflexes, stretch reflexes in S were usually abolished, and heterogenic inhibition from S to TA was weak or absent. 3. The strength of the heterogenic inhibition onto S was dependent on the initial length and activation level of TA and EDL. Changes in flexor length or activation level per se did not alter the background force or strength of the stretch reflex in S. Even taking into account the variation of strength of inhibition with the initial state of the muscle of origin, the strength of the inhibition was stronger from TA to S than the other way around. 4. The contributions of heterogenic inhibition from TA and EDL to S were independent in the sense that these components summed linearly with each other and with the autogenic reflex in S. In addition, the magnitude of the inhibition from TA to S was proportional to the amplitude of stretch for low to intermediate levels of initial force in S. The inhibition appeared to affect the mechanical responses of S essentially as rapidly as the stretch reflex in this muscle. 5. The heterogenic inhibition from TA to S was reduced or abolished by intravenous injections of strychnine but unaffected by injections of picrotoxin or bicuculline. These results, together with the observation that the inhibition sums linearly with the stretch reflex, suggest that the mechanism of this heterogenic inhibition is glycinergic and postsynaptic and, therefore, may include Ia-disynaptic reciprocal inhibition.(ABSTRACT TRUNCATED AT 400 WORDS)