Identification of a Sacral, Visceral Sensory Transcriptome in Embryonic and Adult Mice.

Visceral sensory neurons encode distinct sensations from healthy organs and initiate pain states that are resistant to common analgesics. Transcriptome analysis is transforming our understanding of sensory neuron subtypes but has generally focused on somatic sensory neurons or the total population of neurons in which visceral neurons form the minority. Our aim was to define transcripts specifically expressed by sacral visceral sensory neurons, as a step towards understanding the unique biology of these neurons and potentially leading to identification of new analgesic targets for pelvic visceral pain. Our strategy was to identify genes differentially expressed between sacral dorsal root ganglia (DRG) that include somatic neurons and sacral visceral neurons, and adjacent lumbar DRG that comprise exclusively of somatic sensory neurons. This was performed in adult and E18.5 male and female mice. By developing a method to restrict analyses to nociceptive Trpv1 neurons, a larger group of genes were detected as differentially expressed between spinal levels. We identified many novel genes that had not previously been associated with pelvic visceral sensation or nociception. Limited sex differences were detected across the transcriptome of sensory ganglia, but more were revealed in sacral levels and especially in Trpv1 nociceptive neurons. These data will facilitate development of new tools to modify mature and developing sensory neurons and nociceptive pathways.

Four studies of crisis in parents of prematures. 1965.

The responses of 86 families to the birth of a premature baby have been investigated in four linked studies in order to refine the concept and understanding of crisis. Patterns of the grappling behavior during the crisis were identified which enabled accurate predictions of the short-term mental health outcome. Psychological tasks presented by the stress of premature delivery were also identified. The adequacy with which these tasks were accomplished was predictive of the patterns of early maternal care and mother-child relationships. Results indicate that this type of study is relevant to studies of the causation of mental health and mental illness and to preventive intervention. Certain methodologic and research implications are derived from these studies and point to further research effort which is now practical and desirable.

Relapse following clozapine withdrawal: effect of neuroleptic drugs and cyproheptadine.

The objective of this study was to report the effect of the slow withdrawal of clozapine from 19 patients with neuroleptic-responsive schizophrenia at the end of a 2-year clinical trial of clozapine and to compare this with the results of naturalistic discontinuation of clozapine treatment in 64 neuroleptic-resistant schizophrenic patients. Nineteen neuroleptic-responsive schizophrenic patients who received clozapine were withdrawn from clozapine by tapering it over 3-week period with and without the addition of a typical neuroleptic. Fifteen of the 19 neuroleptic-responsive patients experienced the return of psychotic symptoms during or after the clozapine taper, which were most severe in the ten patients in whom the withdrawal of clozapine was carried out without prior addition of neuroleptic treatment. Addition of a neuroleptic prior to clozapine withdrawal prevented the emergence of positive symptoms during clozapine withdrawal in each of eight patients. Nevertheless, psychotic symptoms emerged, usually within a week after discontinuing clozapine, in six of the eight patients. Neuroleptic treatment, with or without an anticholingergic drug, was much less effective in treating positive symptoms in these patients immediately after the clozapine withdrawal than it had been 2 years previously. Cyproheptadine, a non-selective serotonin receptor antagonist, augmented the antipsychotic effect of neuroleptics in each of four patients who relapsed following withdrawal from clozapine and relieved extrapyramidal symptoms in a fifth patient. The frequency of relapse following withdrawal of clozapine in 64 neuroleptic-resistant patients was significantly lower (25/64, 39.1%) than in the neuroleptic-responsive patients.

Rise in maternal serum alpha-fetoprotein concentration after chorionic villus sampling and the possibility of isoimmunization.

Maternal serum alpha-fetoprotein concentrations were determined by radioimmunoassay in 72 patients immediately before and after chorionic villus sampling for prenatal diagnosis. Fifty percent showed a rise of greater than or equal to 5 ng/ml. Assuming such rises represent fetal blood crossing the intervillous space, in 14% of the cases greater than or equal to 60 microliters of fetal blood was transferred at the time of chorionic villus sampling. A positive correlation was found between the magnitude of rise in maternal serum alpha-fetoprotein levels and the amount of villi removed (r = 0.39, p less than 0.001). When cases were examined by number of passes, a greater rise in maternal serum alpha-fetoprotein levels was noted with multiple passes than with single passes for a given sample size. The transfer of greater than or equal to 60 microliters of fetal blood suggests that maternal sensitization to fetal antigens may occur after chorionic villus sampling. During biopsy, as small a sample of villi as necessary for diagnosis should be taken with as few catheter passes as possible.

Statistical-mechanical theory of passive transport through partially sieving or leaky membranes.

The basic equations for multicomponent transport through partially sieving or leaky membranes are discussed from a statistical-mechanical viewpoint. They have the same mathematical form as the corresponding equations for open membranes, but differ in a discontinuous way from the equations for semipermeable membranes (since a "leak" in a semipermeable membrane constitutes a discontinuous or singular perturbation). Partially sieving membranes can be made to mimic semipermeable behavior through the introduction of characteristic time scales. They may approximate semipermeable behavior at short times, but always deviate at longer times.

Statistical-mechanical theory of passive transport through semipermeable membranes.

The first general multicomponent equations for transport through semipermeable membranes are derived from basic statistical-mechanical principles. The procedure follows that used earlier for open membranes, but semipermeability is modelled mathematically by the introduction of external forces on the impermeant species. Gases are treated first in order to clarify the problems involved, but the final results apply to general nonideal solutions of any concentration. The mixed-solvent effect is treated rigorously, and a mixed-solvent osmotic pressure is defined. A useful specific identification of so-called osmotic flow is given, along with a demonstration that such an identification cannot be unique. Results are obtained both for discontinuous membrane models, and for a continuous model.

Energy-barrier models for membrane transport.

Energy-barrier models are analyzed to find hidden assumptions and establish ranges of validity. The analysis proceeds by comparison with integrated results for model continuum membranes. The main conclusions are that a simple energy-barrier model has a wide range of validity, is remarkably accurate even when its conditions of validity are not strictly met, and is almost always superior to the analogous equations of irreversible thermodynamics. Its major limitations are a possible nonphysical divergence at high electric fields or volume flows caused by breakdown of the transition-state approximation, and the inability to treat multicomponent mixtures except in a pseudobinary (Nernst-Planck) approximation.

Hospital and family cooperating to reduce psychological trauma.

In spite of the advantages of increased parent participation in the hospitalization of children, institutions resist change to facilitate family care. The development of one-day surgical units provides increased flexibility and reduces many psychological stresses. A film was made of one child's experience with outpatient herniorraphy after being held by her mother during induction of anesthesia. The film documents one hospital's effort to meet the psychological needs of parents and children; it also helped change inpatient procedures.

Appraisal of equations for neutral solute flux across porous sieving membranes.

General transport equations, based on irreversible thermodynamics applied to membranes without regard to their structures, are compared with results based upon specific membrane models. It is pointed out that the range of validity of the general linear transport equations of irreversible thermodynamics may be extremely small, and that attempts to extend the range by thermodynamic considerations have always involved subtle assumptions of a nonthermodynamic nature. Simple membrane models are used as diagnostic tools to pinpoint such assumptions, with particular reference to the often-concealed assumption of membrane homoporosity. It is shown that it is not possible to write an exact equation for solute flux across an inert porous membrane only in terms of the three customary membrane parameters sigma (reflection coefficient), Ps (permeability coefficient), and Lp (hydraulic conductivity), unless the membrane is strictly homoporous. Even in the linear range heteroporosity imposes a hidden condition of delta p greater than delta pi for such a three-parameter description to be valid. Useful results in the nonlinear regime require more detailed information on membrane structure than is contained in just three parameters.

Effect of heteroporosity on flux equations for membranes.

An investigation is made of the possible errors in simple integrated equations for solute flux across both non-sieving and sieving porous membranes that can result from variations in the membrane structure. Detailed structural models are used, beginning with a membrane consisting of a parallel array of pores and progressing to series--parallel combinations of pore segments of various lengths and cross-sectional areas, with internal cross connections among pore segments allowed. It is shown that there are both upper and lower mathematical bounds on the possible variations that can be produced in a curve of solute flux versus volume flow by arbitrary variation in the membrane structure, subject only to certain general conditions. In particular, the flux equation for a homoporous membrane is a lower bound. The maximum deviations from this lower bound for a membrane of arbitrary structure are only moderately large, and require rather extreme pore size distributions; most distributions introduce only small errors. Implications of these results in studies of real membrane structure and in the design of experiments are discussed.

Equations for membrane transport. Experimental and theoretical tests of the frictional model.

Frictional models for membrane transport are tested experimentally and theoretically for the simple case of a solution consisting of a mixture of two perfect gases and a membrane consisting of a porous graphite septum. Serious disagreement is found, which is traced to a missing viscous term. Kinetic theory is then used as a guide in formulating a corrected set of transport equations, and in giving a physical interpretation to the frictional coefficients. Sieving effects are found to be attributable to entrance effects rather than to true frictional effects within the body of the membrane. The results are shown to be compatible with nonequilibrium thermodynamics. Some correlations and predictions are made of the behavior of various transport coefficients for general solutions.

Corrections to Paper Entitled "Third Virial Coefficient for Air-Water Vapor Mixtures".

This note points out errors in the values of the third virial coefficients for pure water vapor which appeared in a 1967 paper by Hyland and Mason. The errors arose while converting from the units of Goff and of Keyes to the desired units of (liter/mole)2. The consequences of the errors are outlined, and it is shown that there is no effect on the primary results of the paper, namely, in the preferred values of the third interaction virial coefficient for air-water vapor mixtures, C aww .

Steady-state sieving across membranes.

The constraint of steady-state operation for sieving or ultrafiltration across membranes greatly restricts possible theoretical mechanisms. Effective sieving in the steady state requires the coexistence of a removal mechanism with the rejection mechanism. These points are illustrated without elaborate mathematics by a model of membranes in a series array with intervening compartments. This model also shows that in certain regimes the structure of the first membrane alone determines the overall sieving characteristics of the array.