Selective location of acceptors for botulinum neurotoxin A in the central and peripheral nervous systems

The main site of action for botulinum neurotoxin is cholinergic motor nerve terminals where specific acceptors concentrate the toxin on the cell surface, thereby facilitating its internalization and inactivation of a component essential for transmitter release. In this study, the interaction in vitro of [125I]botulinum neurotoxin type A with central and peripheral nerve terminals of different types was investigated using Ultrofilm and electron-microscope autoradiography. It was found that: (i) The neurotoxin binds to synapse-rich areas of rat brain, particularly in the hippocampus and cerebellum; identity of the neuron types labelled is unclear although cholinergic nerves seem to be labelled, perhaps not exclusively, in many areas. (ii) Toxin uptake at central nerve terminals appears to be minimal and its penetration into intact brain slices is restricted; this may account for the toxin's lower central toxicity. (iii) Selective labelling of cholinergic nerves but not purinergic, peptidergic or adrenergic nerve terminals in mouse ileum suggests that the toxin may be a specific marker for cholinergic nerves in the periphery. Based on these localization studies and published pharmacological observations, it is concluded that efficient toxin-induced blockade of neurotransmission depends on the presence of specific acceptors of high affinity for the toxin and of an effective neuronal uptake mechanism. Inhibition of the release of numerous transmitters from different kinds of nerve terminals lacking one of these features can be produced by high toxin concentrations when uptake occurs via low affinity acceptors or by non-specific means. Notably, this widespread action of the toxin indicates the occurrence of a common intracellular target in several, possibly all, nerve types.     

Semi-automated method for the determination of free fatty acids in plasma

A semi-automated method for the determination of free fatty acids in plasma based on Mosinger's manual method (Mosinger, 1965) is described and the results of a comparison with Dole's titrimetric method (Dole, 1956) are presented. There is almost perfect correlation between the two methods, and the automated technique is simple, reliable, and significantly more accurate and precise than the titrimetric method.     

Substance P and somatostatin metabolism in sympathetic and special sensory ganglia in vitro

Mechanisms regulating the content of the putative peptide transmitters, substance P and somatostatin, were examined in several neuronal populations in culture. Substance P levels increased more than 25-fold within 48 h in sympathetic neurons in the explanted rat superior cervical ganglion, and remained elevated for 4 weeks. Identity of the peptide was authenticated by combined high pressure liquid chromatography-radioimmunoassay. Veratridine prevented the increase of substance P in vitro, and tetrodotoxin blocked the veratridine effect, suggesting that sodium ion influx and membrane depolarization prevent peptide elevation. Veratridine (or potassium)-induced membrane depolarization released substance P into the culture medium through a calcium-dependent process. Consequently, at least some veratridine effects are attributable to release and subsequent depletion of ganglion peptide. However, the inhibitory effects of veratridine were far greater than could be accounted for by the quantity of peptide released, suggesting a separate influence on net synthesis (synthesis less catabolism) of substance P. Viewed in conjunction with previous in vivo studies, our observations suggest that trans-synaptic impulses, through the mediation of postsynaptic sodium flux, release substance P from sympathetic neurons and also regulate intracellular peptide metabolism. To determine whether the processes regulating substance P in sympathetic neurons reflect generalized mechanisms, a different peptide, somatostatin, was examined in sympathetic neurons; moreover, substance P was examined in a different neuronal population, special sensory neurons in the nodose ganglion. Substance P levels increased significantly in both sympathetic and sensory neurons after explantation, and somatostatin levels increased in sympathetic neurons. In each instance, the increase was dependent upon the presence of the calcium ions. Moreover, these increases were all prevented by veratridine, in a tetrodotoxin-sensitive manner. Our observations suggest that common regulatory mechanisms govern peptide transmitter metabolism in diverse neuronal populations.     

Chronotherapeutic oral drug absorption system verapamil is effective in reducing morning blood pressure in African Americans: a post hoc analysis of the chrono trial

Results of several clinical trials have shown that verapamil is effective in reducing blood pressure (BP) in African Americans, a population at high risk for hypertension and target-organ damage. Nonetheless, adequate control of BP is perceived as difficult to achieve in this population. A post hoc analysis of data from the community-based CHRONO trial (Controlling Hypertension in the moRning with a ChrONO medication) was undertaken to assess racial/ethnic differences in the safety and efficacy of the Chronotherapeutic Oral Drug Absorption System (CODAS) formulation of verapamil in a real-world setting. Once-daily administration of the CODAS formulation of verapamil significantly reduced morning BP (P<0.0001) regardless of race or ethnicity. In the African-American population (N=466), the response rate for systolic BP (<140 mmHg or > or =10% reduction from baseline) and diastolic BP (<90 mmHg or reduction > or =10 mmHg from baseline) combined was 70.8%, and 60% of those individuals responded at the lowest (200 mg) dose. Of the 59.7% of African Americans who reached the target BP of <140/90 mmHg, 64% did so at the 200-mg dose. Response rates were not affected by gender, age or treatment history, and CODAS-verapamil was well tolerated in all ethnic/racial treatment groups. In a trial conducted in actual clinical practices, the CODAS formulation of verapamil was shown to be safe and effective in African Americans, Caucasians, Hispanics and Asians.     

Proteins induced in BHK cells by infection with foot-and-mouth desease virus.

Although the infection of BHK cells with foot-and-mouth disease virus did not cause a marked inhibition of cellular protein synthesis, the proteins synthesized gradually changed from host-specific to virus-specific. The synthesis of at least thirteen virus-induced proteins was demonstrated by polyacrylamide electrophoretic analysis of the infected cells. Only a small proportion of the virus-induced proteins was incorporated into the mature virus particles. The addition of amino acid analogues caused an accumulation of the larger mol. wt. proteins, suggesting that in infected cells, some cleavages occurred, giving rise to the smaller mol. wt. proteins. The operation of the precursor-cleavage mechanism was more clearly shown in pulse-chase experiments, in which it was found that the proteins were degraded from larger to smaller mol. wt.     

Gonocytes in fetal guinea pig testes: Phagocytosis of degenerating gonocytes by Sertoli cells

In fetal testes of non-inbred guinea pigs, virus-like particles were seen in the primordial germ cells, but not in the somatic cells. Using the particles as a marker for the gonocytes it was possible to trace the phagocytosis of degenerating gonocytes by the Sertoli cells in the fetal testis.     

The MMPI and chronic pain: The diagnosis of psychogenic pain

This study investigates the capacity of the MMPI to discriminate among groups of patients with different types of pain. When multivariate analysis of variance is used, the standard set of MMPI scales discriminates between acute pain and chronic pain but not between chronic pain of two different etiologies (surgicaliatrogenic vs. unknown). The three scales that discriminate acute from chronic pain patients are those in the neurotic triad, Hs, D, and Hy. The possibility that the unknown pain etiology group could be broken down into psychogenic pain and undetected somatogenic pathology subgroups was explored using cluster analysis. This procedure did not yield any group of patients who could be identified as having chronic pain of psychogenic origin. These results suggest that the MMPI is not a reliable tool for the differential diagnosis of chronic pain. It appears, however, that patterns of findings are partly contingent on population characteristics. Researchers should be cautious about generalizing to populations other than those from which samples are drawn.This research was supported in part by a grant from Roche Laboratories, Nutley, New Jersey, and the Anesthesiology Research Center, Grant No. GM1599-1-06, University of Washington, Seattle, Washington.     

The libidinal cocoon: a nurturing retreat for the families of plane crash victims

In 1985 the families of 137 passengers killed when a Delta Airlines jet crashed at Dallas-Fort Worth International Airport stayed in a secluded hotel while waiting for the victims' bodies to be retrieved and identified. In this protected environment, which the author calls the "libidinal cocoon," the families received intensive nurturing from the author, a Dallas psychiatrist; a team of Red Cross nurses; hotel staff; airline representatives; clergy; and each other. The supportive environment allowed the families to regress safely and to satisfy the basic yearning, intensified in times of personal loss, for an idealized caretaker who will meet all one's needs. The author believes this kind of intervention may be useful in future disasters with massive casualties.