Cytoarchitecture and neural afferents of orbitofrontal cortex in the brain of the monkey.

The orbitofrontal cortex of the monkey can be subdivided into a caudal agranular sector, a transitional dysgranular sector, and an anterior granular sector. The neural input into these sectors was investigated with the help of large horseradish peroxidase injections that covered the different sectors of orbitofrontal cortex. The distribution of retrograde labeling showed that the majority of the cortical projections to orbitofrontal cortex arises from a restricted set of telencephalic sources, which include prefrontal cortex, lateral, and inferomedial temporal cortex, the temporal pole, cingulate gyrus, insula, entorhinal cortex, hippocampus, amygdala, and claustrum. The posterior portion of the orbitofrontal cortex receives additional input from the piriform cortex and the anterolateral portion from gustatory, somatosensory, and premotor areas. Thalamic projections to the orbitofrontal cortex arise from midline and intralaminar nuclei, from the anteromedial nucleus, the medial dorsal nucleus, and the pulvinar nucleus. Orbitofrontal cortex also receives projections from the hypothalamus, nucleus basalis, ventral tegmental area, the raphe nuclei, the nucleus locus coeruleus, and scattered neurons of the pontomesencephalic tegmentum. The non-isocortical (agranular-dysgranular) sectors of orbitofrontal cortex receive more intense projections from the non-isocortical sectors of paralimbic areas, the hippocampus, amygdala, and midline thalamic nuclei, whereas the isocortical (granular) sector receives more intense projections from the dorsolateral prefrontal area, the granular insula, granular temporopolar cortex, posterolateral temporal cortex, and from the medial dorsal and pulvinar thalamic nuclei. Retrograde labeling within cingulate, entorhinal, and hippocampal cortices was most pronounced when the injection site extended medially into the dysgranular paraolfactory cortex of the gyrus rectus, an area that can be conceptualized as an orbitofrontal extension of the cingulate complex. These observations demonstrate that the orbitofrontal cortex has cytoarchitectonically organized projections and that it provides a convergence zone for afferents from heteromodal association and limbic areas. The diverse connections of orbitofrontal cortex are in keeping with the participation of this region in visceral, gustatory, and olfactory functions and with its importance in memory, motivation, and epileptogenesis.


Ultrastructural and immunocytochemical study of lamina II islet cells in rat spinal dorsal horn.

In order to compare the ultrastructure of GABA-immunoreactive and nonimmunoreactive islet cells in lamina II of the rat dorsal horn, a combined ultrastructural and immunocytochemical study of nine Golgi-stained neurones was performed. Cell bodies of these neurones were tested with antiserum to GABA, and in most cases with antiserum to glycine, while parts of the cell body and dendritic tree were examined with the electron microscope. Four of the neurones had cell bodies that were immunoreactive with GABA antiserum, and 2 of these were also glycine-immunoreactive, while 2 were not. Cell bodies of the remaining five neurones were not immunoreactive with GABA antiserum, nor, in the 3 cases tested, with glycine antiserum. Three of the GABA-immunoreactive cells possessed vesicle-containing dendrites and were presynaptic at dendrodendritic synapses, whereas no vesicles were observed in the dendrites of any of the neurones that were not GABA-immunoreactive. The axon of one of the nonimmunoreactive cells was found with the electron microscope. It gave rise to boutons that contained round agranular vesicles and a few dense-cored vesicles. Three synapses formed by this axon were identified and all were asymmetric. No obvious differences were detected in the types of profile that were presynaptic to GABA-immunoreactive and nonimmunoreactive cells. These results suggest that GABAergic islet cells are a source of presynaptic dendrites in lamina II of the rat and that some presynaptic dendrites contain GABA and glycine, while others contain GABA without glycine. The nonimmunoreactive islet cells presumably represent a distinct functional class of neurones and some of these may release an excitatory amino acid transmitter, possibly in addition to one or more neuropeptides.


The auditory cortex of the mouse: connections of the ultrasonic field.

The cortical and subcortical connections of the ultrasonic field (UF) of the auditory cortex of the house mouse (Mus musculus) were studied by using retrograde and anterograde transport of horseradish peroxidase (HRP). Small amounts of HRP were locally injected into the electrophysiologically defined UF. Superficial (layer I-IV) and deep (layer IV-VI) injections were prepared. Superficial injections led to labelling of both cells (retrograde) and terminals (anterograde) in areas of the ipsilateral primary and secondary auditory cortex and in its dorsoposterior field, in an ipsilateral dorsal association area (patches of label), probably in ipsilateral secondary somatosensory cortex, in the contralateral homotopic UF, and in the ipsilateral medial geniculate body (MGBv, MGBd, and MGBm) and caudal posterior nucleus complex. Deep injections showed the same connectivities as superficial ones and, in addition, terminals in the very caudal caudatoputamen, in the nucleus limitans and the nucleus reticularis of the thalamus, in the rostral pole, the dorsomedial, and lateral nucleus of the inferior colliculus, in the stratum griseum intermediale of the superior colliculus, and in a pontine nucleus ventromedial of the lateral lemniscus. All these projections occurred only ipsilaterally. The majority of connections, except those with the nucleus limitans, superior colliculus and pontine nucleus, suggest that UF is part of the primary anditory cortex (AI) and/or of the anterior anditory field (AAF) of the auditory cortex. Since UF has no regular tonotopy, this has important implications for the functional role that AI/AAF can have in communication-sound analysis.


Immunohistochemical localization of ryanodine binding proteins in the central nervous system of gymnotiform fish.

The ryanodine receptor, an integral membrane protein of the sarcoplasmic reticulum in muscle, embodies a high conductance channel permeable to calcium ions. Recent studies have identified ryanodine-binding proteins in avian and mammalian central nervous systems. These neuronal ryanodine receptors appear to function as Ca2+ channels which may gate the release of Ca2+ from caffeine-sensitive intracellular pools in neurons. In the present investigation, we employed monoclonal antibodies against ryanodine-binding proteins of avian muscle cells to the brain of weakly electric gymnotiform fish. Immunoprecipitation and Western blot analysis revealed two isoforms in the fish brain, with molecular weights comparable to those of avian and fish muscle ryanodine-binding proteins. By employing immunohistochemical techniques, we mapped these proteins in fish brain. Ryanodine receptor-like immunoreactivity was found in nerve cell bodies as well as dendrites and axonal processes. The ryanodine-binding protein is distributed throughout the neuraxis in specific cell types of the gymnotiform brain. In the telencephalon, immunoreactive cells were found in the glomerular layer of the olfactory bulb, in the supracommissural subdivision of the ventral telencephalon, and in the intermediate rostral subdivision of the ventral telencephalon. In the diencephalon, immunoreactive cells or fibers were observed in the nucleus prethalamicus and the habenula, within the nucleus at the base of the optic tract and the adjacent dorsal tegmental nucleus, the pretectal nuclei A and B, and the nucleus electrosensorius. In addition, immunopositive cells were seen in several nuclei of the hypothalamus, with the inferior and lateral subdivision of the nucleus recessus lateralis displaying the highest concentration of neurons. In the mesencephalon, the optic tectum contained the greatest number of immunopositive cells. In the rhombencephalon, labelling was seen in the nucleus of the lateral valvula, central gray, lateral tegmental nucleus, in boundary cells of the nucleus praeminentialis, efferent octavolateral nucleus, an area adjacent to the medial edge of the lateral reticular nucleus, nucleus medialis, and electrosensory lateral line lobe. As in avian brain, cerebellar Purkinje cells were positive for ryanodine-binding protein, although only subsets of Purkinje cells were labelled.


Synaptic connections of the narrow-field, bistratified rod amacrine cell (AII) in the rabbit retina.

The synaptic connections of the narrow-field, bistratified rod amacrine cell (AII) in the inner plexiform layer (IPL) of the rabbit retina were reconstructed from electron micrographs of continuous series of thin sections. The AII amacrine cell receives a large synaptic input from the axonal endings of rod bipolar cells in the most vitreal region of the IPL (sublamina b, S5) and a smaller input from axonal endings of cone bipolar cells in the scleral region of the IPL (sublamina a, S1-S2). Amacrine input, localized at multiple levels in the IPL, equals the total number of synapses received from bipolar cells. The axonal endings of cone bipolar cells represent the major target for the chemical output of the AII amacrine cell: these synapses are established by the lobular appendages in sublamina a (S1-S2). Ganglion cell dendrites represent only 4% of the output of the AII amacrine and most of them are also postsynaptic to the cone bipolars which receive AII input. The AII amacrine is not presynaptic to other amacrine cells. Finally, the AII amacrine makes gap junctions with the axonal arborizations of cone bipolars that stratify in sublamina b (S3-S4) as well as with other AII amacrine cells in S5. Therefore, in the rabbit retina 1) the rod pathway consists of five neurons arranged in series: rod-->rod bipolar-->AII amacrine-->cone bipolar-->ganglion cell; 2) it seems unlikely that a class of ganglion cells exists that is exclusively devoted to scotopic functions. In ventral, midperipheral retina, about nine rod bipolar cells converge onto a single AII amacrine, but one of them establishes a much higher proportion of synaptic contacts than the rest. Conversely, each rod bipolar cell diverges onto four AII amacrine cells, but one of them receives the largest fraction of synapses. Thus, within the pattern of convergence and divergence suggested by population studies, preferential synaptic pathways are established.


Three-dimensional analysis of the structure and composition of CA3 branched dendritic spines and their synaptic relationships with mossy fiber boutons in the rat hippocampus.

This paper is the third in a series to quantify differences in the composition of subcellular organelles and three-dimensional structure of dendritic spines that could contribute to their specific biological properties. Proximal apical dendritic spines of the CA3 pyramidal cells receiving synaptic input from mossy fiber (MF) boutons in the adult rat hippocampus were evaluated in three sets of serial electron micrographs. These CA3 spines are unusual in that they have from 1 to 16 branches emerging from a single dendritic origin. The branched spines usually contain subcellular organelles that are rarely found in adult spines of other brain regions including ribosomes, multivesicular bodies (MVB), mitochondria, and microtubules. MVBs occur most often in the spine heads that also contain smooth endoplasmic reticulum, and ribosomes occur most often in spines that have spinules, which are small nonsynaptic protuberances emerging from the spine head. Most of the branched spines are surrounded by a single MF bouton, which establishes synapses with multiple spine heads. The postsynaptic densities (PSDs) occupy about 10-15% of the spine head membrane, a value that is consistent with spines from other brain regions, with spines of different geometries, and with immature spines. Individual MF boutons usually synapse with several different branched spines, all of which originate from the same parent dendrite. Larger branched spines and MF boutons are more likely to synapse with multiple MF boutons and spines, respectively, than smaller spines and boutons. Complete three-dimensional reconstructions of representative spines with 1, 6, or 12 heads were measured to obtain the volumes, total surface areas, and PSD surface areas. Overall, these dimensions were larger for the complete branched spines than for unbranched or branched spines in other brain regions. However, individual branches were of comparable size to the large mushroom spines in hippocampal area CA1 and in the visual cortex, though the CA3 branches were more irregular in shape. The diameters of each spine branch were measured along the cytoplasmic path from the PSD to the origin with the dendrite, and the lengths of branch segments over which the diameters remained approximately uniform were computed for subsequent use in biophysical models. No constrictions in the segments of the branched spines were thin enough to reduce charge transfer along their lengths.(ABSTRACT TRUNCATED AT 400 WORDS)


GAD- and GABA-immunoreactivity in the ascending auditory pathway of horseshoe and mustached bats.

A comparative study of the immunostain to antibodies directed against glutamic acid decarboxylase (GAD) and gamma-aminobutyric acid (GABA) in the ascending auditory pathway was carried out in horseshoe bats (Rhinolophus rouxi) and mustached bats (Pteronotus parnellii). In both species GAD/GABA-positive puncta (presumed axonal boutons) and GAD/GABA-positive cells were found in the cochlear nucleus, the superior olivary complex, the nuclei of the lateral lemniscus the inferior colliculus, and the medial geniculate body. General features of the immunostaining pattern in the auditory pathway agree with observations in other mammals. Quantitative analysis of puncta distribution shows that many auditory centers are characterized by subregional differences in puncta density and distribution. This indicates local differences in putatively inhibitory input related to connectivity and tonotopic organization. The following species characteristic features were found: 1) The dorsal non-laminated portion of the dorsal cochlear nucleus in horseshoe bats lacks the GAD/GABA-immunoreactive cells typical for the ventral laminated portion and the dorsal cochlear nucleus of other species. Clearly, a cytoarchitectonic specialization is accompanied by a loss of putatively GABAergic local inhibitory circuits. 2) The ventral division of the medial geniculate body of the mustached bat lacks GAD/GABA-immunopositive cells. Such cells are present in the horseshoe bat and other mammals. This finding implies functional differences in the organization of the medial geniculate body within the same mammalian order.


Fine structure of rat septohippocampal neurons: II. A time course analysis following axotomy.

Previous light microscopic immunocytochemical studies with antibodies against transmitter-synthesizing enzymes have suggested that septohippocampal neurons undergo retrograde degeneration following transection of their axons by cutting the fimbria-fornix. However, a fine-structural analysis of the degeneration process in these cells is lacking so far. Here we have identified septohippocampal neurons by retrograde tracing with Fluoro-Gold. Thereafter, the fimbria-fornix was transected bilaterally. Fine-structural changes in prelabeled septohippocampal neurons were then studied after varying survival times up to 10 weeks. Examination under the fluorescence microscope of Vibratome sections through the septal region revealed numerous retrogradely labeled cells after all survival times following axotomy. These neurons were then intracellularly injected with the fluorescent dye Lucifer Yellow in order to stain their dendritic arbor. Many cells were found after each survival time that displayed characteristics of septohippocampal neurons in control rats (see Naumann et al., J Comp Neurol 325:207-218, 1992). In addition, increasing with survival time, there were many shrunken neurons with a reduced dendritic arbor. Representative examples of both normal appearing and shrunken neurons were photoconverted for subsequent electron microscopic analysis. Relatively few signs of neuronal degeneration were found at each survival time analyzed. The majority of cells, including the heavily shrunken ones, displayed fine-structural characteristics of normal neurons. However, a few degenerating neurons and reactive glial cells were present in all survival stages. We conclude that axotomized septohippocampal projection neurons cease the expression of transmitter-synthesizing enzymes and shrink, but many more cells survive for extended periods of time without target-derived neurotrophic factor than was assumed in previous light microscopic studies.


Neuroepithelial cells in the rat spinal cord express glutamate decarboxylase immunoreactivity in vivo and in vitro.

It is unknown whether neuroepithelial cells in the mammalian central nervous system express neurotransmitter-synthesizing enzymes. In this study, expression of glutamate decarboxylase (GAD), the gamma-aminobutyric acid (GABA)-synthesizing enzyme, was examined in proliferative cells and postmitotic neuroblasts in embryonic rat spinal cord. Immunostaining coronal sections of the embryonic spinal cord with K2 antiserum, which recognizes GAD proteins encoded by the GAD67 gene, revealed intensely stained neuroepithelial cells in the basal plate at embryonic day (E) 13, in the intermediate plate between E 13-16, and last seen in the alar plate at E 16. Nissl counterstaining demonstrated that a small number of these GAD-immunoreactive cells adjacent to the neural tube lumen were mitotic. The ventral-to-dorsal gradient of GAD expression in precursor cells and postmitotic neuroblasts correlates anatomically and temporally with the sequential generation of motoneurons, commissural neurons, and interneurons in the dorsal horn. Some of these GAD-immunoreactive neuroepithelial cells may re-enter the mitotic cycle, while others are postmitotic neuroblasts presumably migrating to the intermediate zone to differentiate into young neurons. Double-immunostaining cells acutely dissociated from E 11-18 spinal cords with K2 and anti-bromodeoxyuridine antisera, following a bromodeoxyuridine pulse in vivo, revealed considerable numbers of DNA-synthesizing cells immunoreactive for GAD. The absolute number of double-stained cells peaked during E 12-15, coinciding with terminal cell division in most spinal neurons. These observations suggest that spinal neuronal precursors can synthesize GAD-related proteins prior to, or during, the terminal cell cycle. Although GAD immunoreactivity revealed by K2 antiserum was detected in proliferative cells and in migrating postmitotic neuroblasts, GABA immunoreactivity was never detectable in these cells. These early embryonic GAD-immunoreactive neuroepithelial cells may either synthesize levels of GABA that cannot be detected immunocytochemically, and/or express enzymatically inactive GAD-related proteins.


Transient expression of GABA immunoreactivity in the developing rat spinal cord.

The development of GABAergic neurons in the spinal cord of the rat has been investigated by immunocytochemical staining of frozen sections with anti-gamma-aminobutyric acid (GABA) antiserum. In the cervical cord, GABA-immunoreactive fibers first appeared at embryonic day (E) 13 in the presumptive white matter within the ventral commissure, ventral funiculus, and dorsal root entrance zone, and in the ventral roots. There were no GABA-immunoreactive cell bodies detected at this age. By E14, motoneurons, the earliest generated spinal cells, were the first cell population to become GABA-immunoreactive at the cell body level. Thereafter, GABA-immunoreactive neurons increased progressively in number and extended from ventral to dorsal regions. GABA-immunoreactive relay neurons within lamina I of the dorsal horn were initially detected at E17. Interneurons in the substantia gelatinosa, the latest generated cells in the spinal cord, were also the last to express the GABA immunoreactivity at E18. Immunoreactive neurons peaked in intensity and extent at E18 and 19. GABA immunoreactivity was only detectable in neurons within the intermediate and marginal zones 1-3 days after they withdrew from the cell cycle. This contrasts to glutamate decarboxylase immunoreactivity, which is detected in precursor cells in the ventricular zone prior to, or during, withdrawal from the cell cycle. Toward the end of gestation, GABA immunoreactivity declined in intensity and extent. This regression began in the ventral horn of the cervical region and ended in the dorsal horn of the lumbosacral region. During the first week after birth, immunoreactivity in motoneurons and in many other neurons within the ventral horn, intermediate gray, and deeper layers of the dorsal horn disappeared, and only in those neurons predominantly within the superficial layers of the dorsal horn did it persist into adulthood. Thus, the expression and regression of GABA immunoreactivity in the spinal cord followed ventral-to-dorsal, rostral-to-caudal, and medial-to-lateral gradients. These observations indicate that the majority of embryonic spinal neurons pass through a stage of transient expression of GABA immunoreactivity. The functional significance of this transient expression is unknown, but it coincides with the period of intense neurite growth of motoneurons, sensory neurons, and interneurons, and of neuromuscular junction formation, suggesting that the transient presence of GABA may play an important role in the differentiation of sensorimotor neuronal circuits.


Sexual dimorphism in the vasotocin system of the bullfrog (Rana catesbeiana).

Arginine vasotocin (AVT) is widespread in amphibian brains, where its levels have been correlated with reproductive behaviors. To better understand which neural systems are involved in central actions of AVT, we used immunocytochemistry to compare the distribution of AVT in the brains of male and female bullfrogs (Rana catesbeiana). AVT-immunoreactive cells were observed in the septal nucleus, amygdala pars lateralis, magnocellular preoptic area, suprachiasmatic nucleus, and hypothalamus. AVT-immunoreactive cells were also found in the pretrigeminal nucleus, but only in animals killed in the fall. Immunoreactive fibers were broadly distributed in hypothalamic and extrahypothalamic areas. The most obvious sex differences were found in the amygdala pars lateralis, where the density of immunoreactive cells and fibers was significantly greater in male than in female bullfrogs. In addition, in the habenular nucleus, males had a denser distribution of AVT-immunoreactive fibers than females. In the suprachiasmatic nucleus, AVT-immunoreactive cells were larger in females than in males but did not differ in number. Since the areas that showed sex differences in AVT distribution have also been implicated in control of reproductive behaviors, they may form the neural substrates for the effects of AVT on sexually dimorphic behaviors in amphibians.


Topical isotretinoin for photodamaged skin.

Photodamaged skin is characterized clinically by coarseness, telangiectasia, wrinkling, discrete hyperpigmented and hypopigmented macules, atrophy, and ultimately the development of neoplasms. Studies on the UVB-irradiated hairless mouse indicate that topical application of tretinoin or isotretinoin induces structural modifications at the dermal level. Clinical trials indicate that tretinoin improves skin appearance in patients who have photodamage. This double-blind, vehicle-controlled clinical trial was conducted to determine whether 36 weeks of treatment with topical isotretinoin improves mildly to moderately photodamaged facial skin. After they gave written informed consent 776 patients were randomly assigned to 36 weeks of treatment with either vehicle cream or isotretinoin cream, applied once nightly. Efficacy was evaluated by means of physician and patient assessment and a blinded analysis of standardized photographs taken before and after treatment. When compared with vehicle, treatment with isotretinoin resulted in statistically significant improvement in overall appearance, fine wrinkling, discrete pigmentation, sallowness, and texture. Isotretinoin cream was well tolerated.


Pharmacokinetics and drug interactions of etretinate and acitretin.

Acitretin, the metabolite of etretinate, is eliminated far more rapidly from the human body than is etretinate. It had therefore been suggested that only a short period of contraception would be required after the cessation of long-term therapy with acitretin. However, recent studies have demonstrated the presence of etretinate in the plasma of patients who were treated with acitretin. In this article we provide results from a study in our center and discuss earlier data in light of the recently discovered metabolic pathways for acitretin. Reesterification of acitretin to etretinate, however, results in a loss of the metabolic advantages of acitretin. Because of this situation the recommended contraception period after acitretin therapy has been lengthened to 2 years.


Guidelines for optimal use of isotretinoin in acne.

Isotretinoin is most effective for patients with acne who fail to respond to other forms of treatment; virtually all patients respond to isotretinoin, 0.5 to 1.0 mg/kg/day. As many as 61% of patients are cured after one course, but 39% require further isotretinoin (16%) or oral antibiotics (23%). The relapse rate can be reduced by the administration of the higher dose of 1 mg/kg/day (thus achieving a significant cumulative dose of > 120 mg/kg), especially to young patients and men with truncal acne and more severe disease. About 85% require a 4-month course, but 15% require longer treatment, with some up to 10 months. There are several reasons for a slow response to treatment, including the presence of macrocomedones, ovarian dysfunction, and as-yet unknown factors. Macrocomedones can be treated with light cautery, ovarian dysfunction with hormonal therapies, and in those persons who have no obvious explanation for slow response, persistence with isotretinoin alone is required. Repeat courses of isotretinoin can also be given. Six years ago most patients treated with isotretinoin had severe acne (60%), but today most patients (60%) have therapy-resistant moderate acne. Isotretinoin is a consideration in such patients to reduce the physical and psychological effects of acne, particularly because there is no simple method to treat acne scars.


Side effects of systemic retinoids and their clinical management.

The safety profile of oral retinoids appears to be well established, although rare new side effects are occasionally reported. Appropriate patient selection, use of the lowest required dose, and adequate follow-up are significant factors in the prevention of these toxicities. Teratogenicity, which can be avoided by following recommended precautions, is the main adverse effect.


Long-term safety of retinoid therapy.

The concern about long-term toxicity of oral synthetic retinoids has developed because many patients, especially those with genodermatoses, require lifelong therapy. Several organ systems are at risk, especially the hepatic, skeletal, and cardiovascular systems. Although acute hepatotoxicity is a rare side effect of etretinate and acitretin therapy, prospective studies have not demonstrated chronic liver toxicity. The frequency of bone changes induced by retinoids is difficult to estimate, because this adverse effect is usually asymptomatic and requires x-ray or scintigraphic examination for detection. Atherosclerosis develops in many patients who receive long-term retinoid therapy, but the extent to which the process is aggravated by drug-induced hyperlipidemia is not known. Many patients have now been treated with either etretinate or isotretinoin continuously for as many as 15 years and have not developed any signs of severe chronic toxicity. However, continued intense surveillance is recommended for patients expected to require lifelong therapy.


Retinoids for the future: oncology.

A major incentive for the development of the synthetic retinoids has been their potential for the treatment and prevention of cancer. Early studies demonstrated that treatment with isotretinoin or etretinate alone could result in the regression of some existing skin cancers. However, even at high doses the response rates were poor. Greater efficacy has been observed with retinoids used in the prevention of cancer of the skin and oral cavity in high-risk patients. The potential for retinoids as chemopreventive agents is being further explored as selected retinoids are being targeted to specific malignancies, such as fenretinide for breast cancer chemoprevention. The effectiveness of tretinoin as a treatment for promyelocytic leukemia has raised enthusiasm for retinoids as cancer therapeutic agents. Furthermore, evidence of synergy between the retinoids and a variety of cytokines as enhances of differentiation chart a bright future for retinoids in oncology.


Retinoids in psoriasis and disorders of keratinization.

Synthetic retinoids, particularly the aromatic retinoid etretinate (Tigason, Europe; Tegison, United States), have had an established role in the treatment of psoriasis and a variety of ichthyosiform disorders for more than a decade. Isotretinoin (Accutane), which was released at approximately the same time, plays a less important role in these disorders. The mechanism of action of etretinate is still incompletely understood although, like retinoic acid, it is thought to interfere with the terminal differentiation of keratinocytes. The recent detection of nuclear retinoic acid receptors may lead to a unifying theory of retinoid effects and provide the means for more targeted use of this class of compounds. The substantial amount of data on the clinical effectiveness of etretinate was obtained empirically from numerous multicenter trials and individual reports; its indications, dosimetry, pharmacokinetics, and side effects are well established. The main adverse effect associated with etretinate is its teratogenicity (common to all retinoids), which is of particular concern because the lipophilic compound is stored in fat tissue, resulting in an elimination half-life of as many as 120 days. To avoid this problem the much less lipophilic unesterified acid of etretinate, acitretin, has been made available and has now replaced etretinate in many countries. Acitretin represents the active principle of etretinate and has an elimination half-life of 2 days. No significant clinical differences have been observed between these two compounds. Partial in vivo conversion of acitretin into etretinate, however, has been described in some patients. Both compounds are standard treatment for pustular and erythrodermic psoriasis.(ABSTRACT TRUNCATED AT 250 WORDS)


Interaction properties of doubly phosphorylated beta-casein, a major component of the human milk caseins.

Doubly phosphorylated beta-casein constitutes nearly 30% of the total human beta-caseins and is thus one of the major components of that fraction. The properties and mode of association of doubly phosphorylated beta-casein are therefore important determinants of the structure and function of the human casein micelle. Doubly phosphorylated beta-casein has an absorbency of 6.2 and a partial specific volume of .74. The protein precipitated at room temperature when 10 mM Ca2+ was added but produced a clear solution in 1 M NaCl. Equilibrium dialysis produced an average of 2.06 major Ca(2+)-binding sites at 37 degrees C with a dissociation constant of 12.1 x 10(-4) M. The monomer at 20 degrees C was calculated to have a solvation of 2.1 g of H2O/g of protein and an axial ratio of 6.8, suggesting a prolate ellipsoid of about 11 by 2 nm. At high ionic strength, evidence exists for a spherical structure with a molecular weight of 2.25 x 10(6). This structure would represent a polymer of about 90 monomers with a radius of 14.8 nm and a solvation of 1.93 g of H2O/g of protein. This association behavior is similar to that of other phosphorylated human beta-caseins but differs from the nonphosphorylated form. It changes when both Ca2+ and inorganic orthophosphate are present.


B-cell mitogenic activity of slime products produced from slime-forming, encapsulated Lactococcus lactis ssp. cremoris.

The mitogenic activities of whole cell lyophylized preparations, cell-wall components, and slime products obtained from Lactococcus lactis ssp. cremoris KVS20 were examined on murine spleen cells. Whole cell lyophylized preparations and slime products significantly (P < .05) stimulated mitogenic responses of the cells. The highest activity was induced by slime products in which the optimal concentration was 116 microg/ml. The significant (P < .05) increase of mitogenic activity induced by slime products occurred at 24 h, and the peak response was obtained 48 h after the stimulation. The activity was much higher in the fraction enriched with B cells than in the fraction enriched with T cells. In addition, slime products induced mitogenic activity to spleen cells of athymic nu/nu mice. The chemical analysis of lipopolysaccharide and the minimal concentration for mitogenic response eliminated the possibility that the activity of slime products may be due to the contamination of lipopolysaccharide. The data demonstrate that slime products are a potent B-cell-dependent mitogen.


Effect of high doses of a sustained-release bovine somatotropin on antibody formation in dairy cows.

Eighty-two lactating Holstein cows received either one, three, or five concurrent, intramuscular injections of a unit dose (.6 g) of zinc methionyl bST (some-tribove) or five doses of the vehicle. Injections were administered at 14-d intervals from 60 d postpartum until the end of lactation or necropsy. Thirty-eight cows continued on the same treatment for a 2nd yr. Blood bST antibodies developed within the first 7 wk of treatment, and the number of cows with anti-bST binding generally declined with time. Thirteen out of 59 cows receiving bST developed binding activity > 25% (positives) during the 1st yr. At the .6-g dose level, no binding was detected after wk 15. Seven of the 13 positive cows were among the group randomly selected to continue on study during yr 2. In the 2nd yr, only 2 out of 24 bST-treated cows were positive. Binding activity was associated with the IgG fraction in serum. Binding capacities of antibodies ranged from .625 to 3.04 mg of bST/L, and affinities ranged from 1.14 x 10(8) to 3.14 x 10(8) L/mol. Cows considered to be clinically positive had performance similar to those of their herdmates having binding < 25%. No evidence of a pathologic effect of antibodies existed in treated cows, their calves, or fetuses. The presence of anti-bST antibodies did not affect milk production of the cow or growth of the calves conceived during bST treatment.


Estrous cyclicity in nonlactating and lactating Holsteins and Jerseys during a Pakistani summer.

Data from 36 cows were used in a 2 x 2 factorial arrangement to determine the effects of breed and lactation status on estrous cyclicity during a Pakistani summer (June through October). Cows were selected from a herd of Holsteins and Jerseys imported from the United States 5 yr earlier. Ambient temperatures were highest in June and declined in the ensuing months with the onset of the rainy season. Relative humidity increased in July and August and them remained stable until the end of the study. Although early morning rectal temperatures gradually declined from June through October, late afternoon rectal temperatures were highest in August. Average early morning rectal temperatures were higher in Holsteins than in Jerseys (38.5 vs. 38.3 degrees C). Even though all cows were cyclic throughout the study, as indicated by patterns of progesterone secretion, observed expression of estrus was low (36.8%) and unaffected by breed or lactation status. Average serum progesterone concentrations were lower (2.4 vs. 3.1 ng/ml), and cortisol concentrations were higher (4.1 vs. 3.9 ng/ml), in Holsteins than in Jerseys. Breed by lactation status interactions were significant for lengths of the luteal phase and estrous cycle. Lengths for lactating Holsteins were longer than those of other groups.


Season and lactation number effects on milk production and reproduction of dairy cattle in Arizona.

Records representing 19,266 Holstein cows from Arizona DHIA data over a 5-yr period were analyzed to determine the effects of season and lactation number on milk production and reproduction. Seasons were winter (December, January, and February), spring (March, April, and May), summer (June, July, and August), and fall (September, October, and November). Traits analyzed by least squares ANOVA were 305-d FCM, complete lactation milk, calving interval, and services per conception. All sources of variation were significant except the interaction between lactation number and season of calving for complete lactation milk. Milk production was depressed for cows calving in summer and fall. First lactation cows had lowest milk production, and highest production occurred in either lactation 4 or 5. Cows calving in spring and summer had reduced reproductive performance, as measured by calving interval and services per conception. First lactation cows had lowest values for both reproductive traits. Previous days dry was negatively related to milk production for spring calvings but was positively related for all other seasons. Cows with higher milk production had reduced reproductive performance. Partial regression coefficients for calving interval and services per conception were 12 d and .25 services per conception per 1000 kg of 305-d FCM, respectively. Despite the negative effects of thermal stress, milk production and fertility in this study were not depressed as severely as in previous research reported from Arizona. Calving schedules may be adjusted to minimize the adverse effect of heat stress.


Lactation curve estimation for use in economic optimization models in the dairy industry.

Monthly data on completed lactations were employed to estimate a three-stage least squares lactation curve model for milk production, milk fat content, milk protein content, and body weight change in lactating Holstein cattle. In comparison with previous work on the lactation curve, our study employed an augmented incomplete gamma model of the lactation curve, a simultaneous rather than single equation estimation technique, monthly rather than daily or weekly observations, and a pragmatic treatment of the genetic background of individual cows using sire proof data. In addition to considering genetic and dietary effects on the lactation curve, the model isolates the seasonal effect of calving date and current production month as well as the age of the cow. By allowing for the simultaneous explanation of various measures of cow performance, the model accommodates formulation of diets tailored for individual cows or groups of cows and can be used in profit-maximizing mathematical programming models. Diet, production, and body weight changes are determined simultaneously and are not independent of one another.


Effects of feeding diets containing calcium salts of long-chain fatty acids to lactating dairy cows.

Four cows were utilized in a 4 x 4 Latin square design to investigate the effects of feeding Ca salts of long-chain fatty acids. Treatments were control diet with 1) no added fat, 2) 3% Ca salts of long-chain fatty acids, 3) 6% Ca salts of long-chain fatty acids, and 4) 9% Ca salts of long-chain fatty acids. Cows were fed chopped alfalfa hay, alfalfa haylage, corn silage, and concentrate (15:22:13:50) on a DM basis. Dry matter intake, energy intake, and ruminal fermentation were not altered greatly until Ca salts of long-chain fatty acids constituted 9% of DMI. Digestibilities of DM, OM, ADF, NDF, and hemicellulose were not affected by treatment. Digestibilities of cellulose, soluble residue, total C18 fatty acids, and total fatty acids followed quadratic patterns. Absorption of N was increased linearly when fat was fed, but digestibility of Ca was decreased linearly. Milk production, CP, and SNF were not altered greatly by inclusion of 3 or 6% Ca salts of long-chain fatty acids in the diet, but inclusion of 9% Ca salts of long-chain fatty acids decreased their production. Calcium salts of long-chain fatty acids increased milk fat percentage and production of fat and FCM when fed as 3 or 6% of the dietary DM but decreased yields of milk fat and FCM when fed as 9%. Calcium salts of fatty acids can be fed to provide up to 6% of the dietary DM without deleterious effects on ruminal fermentation and digestibilities of most nutrients.


Effects of feeding lactating dairy cows diets containing extruded soybeans and calcium salts of long-chain fatty acids.

Four multiparous Holstein cows averaging 36 DIM and fitted with ruminal cannulas were utilized in a 4 x 4 Latin square design to investigate the effects of feeding extruded whole soybeans and Ca salts of long-chain fatty acids. Treatments were diets containing 1) no added fat, 2) 16% extruded whole soybeans, 3) 16% extruded whole soybeans and 3% Ca salts of long-chain fatty acids, and 4) 16% extruded whole soybeans and 6% Ca salts of long-chain fatty acids. Cows were fed for ad libitum intake a diet of alfalfa haylage, corn silage, and concentrate (35:15:50, DM basis). Intakes of DM and energy and production of milk, 4% FCM, fat, CP, and SNF were decreased by feeding extruded whole soybeans and 6% Ca salts of long-chain fatty acids, but differences were small among the other treatments. The weight percentages and yields of C18:0, C18:1, and C18:2 in milk were increased, and most shorter chain fatty acids were decreased, by feeding supplemental fat. Digestibilities of DM, OM, ADF, soluble residue, total C18 fatty acids, and total fatty acids were decreased, but digestibility of hemicellulose was increased by feeding supplemental fat. The largest decrease in digestibilities of most dietary constituents and in energy and N utilization occurred when 16% extruded whole soybeans plus 6% Ca salts of long-chain fatty acids were fed to the cows. Calcium salts of long-chain fatty acids can supply up to 3% of the dietary DM in diets containing 16% extruded whole soybeans without having deleterious effects on most variables measured in this experiment.


Influence of method of administration of rapeseed oil in dairy cows. 1. Digestion of nonlipid components.

The effects of rapeseed oil supplements on ruminal digestion and total tract digestibility of nutrients were studied in four cows in midlactation, fitted with ruminal cannulas and used in a Latin square design (three periods x three diets). Treatments were basal diet only (control) or 1 kg of rapeseed oil added to a basal diet by continuous infusion or by a single administration via the ruminal cannula. The ratio of forage: concentrate of the basal diet was 68:32 on a DM basis. Total lipid contents were 3.9, 9.4, and 9.4% of DM in control diets and in diets with continuous and single supplementation, respectively. Fat supply decreased total tract OM digestibility (77.0, 72.0, and 74.0% in control diet and in diets with continuous and single supplementation, respectively) because of a depressive effect on fiber digestion. With both oil administration methods, the relative proportion of propionic acid increased and acetic and butyric acids in ruminal fluid decreased. Moreover, continuous infusion of oil increased the proportion of propionate and decreased the proportion of butyrate. When oil was added as a single administration, ammonia N concentration before feeding was lower than when oil was infused continuously.


Effects of concentration of dietary phosphorus on amount and route of excretion.

Objectives were to determine the effect of dietary concentration of P in DM on routes of excretion of P and to evaluate direct and indirect measures of calculating DM digestibility and P excretion. Twelve lactating Holstein cows were fed 20 kg of DM containing .41% P daily for 4 wk and then were assigned randomly to one of three diets: low (.30%), medium (.41%), or high (.56%) in P for 9 wk. Total collections of excreta (feces and urine) and milk were made during wk 4, 7, 10, and 13. At wk 4, cows excreted 88.2% of P consumed daily: 68.6% of excreted P in feces, 1.0% in urine, and 30.3% secreted in milk. Cows assigned to the low P diet decreased intake by 26.8% and excretion of P in feces by 22.7% in wk 13 compared with wk 4, whereas cows fed the high P diet increased intake by 36.5% and excretion of P in feces by 48.6%. Digestibility of DM was 62.6% when calculated from total collection of feces but only 55.7 or 56.5% when estimated indirectly using Cr or acid detergent lignin as indigestible markers. Apparent excretion of P was less than that estimated using either of the marker techniques (49.7 vs. 59.1 and 58.1 +/- .7 g/d of P) because digestibility of DM was underestimated. A prediction equation was developed for P excretion based on P intake and milk production.


Comparison of trace elements in milk of four species.

The objective of this study was to compare trace elements in milks of four species. Milk samples of 4 ml or more were obtained from guinea pigs, dairy cattle, horses, and humans. The milks were analyzed for the trace elements Al, B, Ba, Cu, Fe, Li, Mn, Mo, Si, Sr, Ti, and Zn by inductively coupled argon plasma spectroscopy. Zinc ranged from more than 4 ppm in guinea pig milk to less than 2 ppm in mare milk. Strontium was over 1 ppm in the milk of guinea pigs and less than .1 ppm for the human. Iron ranged from over .7 ppm for the guinea pig to less than .2 ppm for the cow. Copper was over .5 ppm in guinea pig milk and only .05 ppm for cow milk. Boron ranged from .59 to .10 ppm, Si from .58 to .16 ppm, Al from .45 to .10 ppm; and Ba from .22 to .08 ppm in milks of the four species studied. Titanium ranged from a trace to .11 ppm. Lithium, Mn, and Mo all were less than .04 ppm. Milk Mn was surprisingly low relative to bodily needs.


Effect of yeast culture supplement on production, rumen fermentation, and duodenal nitrogen flow in dairy cows.

Six lactating Holstein cows fitted with rumen and T-type duodenal cannulas were used in a crossover design to examine effects of yeast culture supplement on production parameters, rumen fermentation, and flow of N to the duodenum. Treatments were control and control plus 10 g/d of yeast culture. Dry matter intake was greater, and milk production tended to be higher, for cows supplemented with yeast culture, but milk composition was not affected. Rumen pH was not affected by yeast culture, but peak lactic acid concentration decreased from 1.93 to 1.73 mM. Rumen fluid acetate:propionate ratio, dilution rate (percentage per hour), and ammonia N concentration (milligrams per deciliter) were 2.28, .12, and 10.7 and 2.04, .13, and 9.6 for control cows and for cows supplemented with yeast culture, respectively. Although numbers of fiber-digesting bacteria were not affected by yeast culture, DM disappearance of wheat straw tended to be higher at 12 and 24 h, and CP and ADF digestibilities were greater. Duodenal NAN flow tended to be higher in cows supplemented with yeast culture because of higher bacterial N flow. Duodenal AA profile and flow of Met were significantly affected by yeast culture supplementation. The results suggest that yeast culture may alter the AA profile of bacterial protein.


Effect of microbial inoculant on quality of alfalfa hay baled at high moisture and lamb performance.

The effectiveness of a microbial hay inoculant in high moisture alfalfa hay was evaluated. Alfalfa (third cutting) was baled at 72% DM without or with inoculant and at 82% DM without inoculant during yr 1. In yr 2, alfalfa (second cutting) was baled at 75% DM without or with inoculant and at 82% DM without inoculant. Application rate of inoculant was 3.8 L/.98 tonne each year. At this application rate, 90 billion cfu were applied per .98 tonne of forage. Hays were core sampled at 0, 14, 30, and 60 d after baling to determine chemical composition. By d 30, all hays had DM content of 89%. In yr 2, 12 wether lambs were assigned to three treatments in a replicated 3 x 3 Latin square. Treatments were chopped, low moisture hay plus corn; chopped, inoculated high moisture hay plus corn; and chopped, high moisture hay plus corn. All diets contained 63% alfalfa hay, 35% ground corn, and 2% minerals and vitamins. In yr 1, inoculated and low moisture hays were not different in chemical composition but were higher in CP and lower in NDF than high moisture hay. Neither NDF nor CP were different among the three hays in yr 2. Average daily gain was not different on the three diets. The feed to gain ratio was lowest for the inoculated hay, intermediate for the low moisture hay, and highest for the high moisture hay diet. Daily gain and feed to gain ratio were not different for lambs fed the inoculated hay baled at 75% DM compared with lambs fed untreated hay baled at 82% DM.


Feeding sequence and strategy effects on ruminal environment and production performance in first lactation cows.

Three primiparous cows were assigned randomly to a 4 x 4 incomplete Latin square to evaluate ruminal characteristics (Experiment 1) with the following feeding strategies: strategy A, supplement (protein), forage plus high moisture ear corn (energy), protein; strategy B, energy plus protein, forage, energy plus protein; strategy C, forage plus energy, protein, forage plus energy, protein; and strategy D, forage, energy plus protein, forage, energy plus protein. In Experiment 2, 36 cows were fed diets similar to those in Experiment 1 from wk 4 through 19 postpartum. Cows fed diets according to strategy A had the highest and strategy D the lowest mean ruminal pH. Diurnal variation in ruminal pH was less with cows fed diets using strategies A and B than C and D. Other ruminal parameters were not significantly different. In Experiment 2, cows fed according to strategy B had higher DMI than those fed according to other strategies. Energy and protein fed together and separately from forage, regardless of sequence, increased milk fat percentage compared with protein fed separately. Milk production and protein yield tended to be highest when protein was fed separately, regardless of sequence to forage. Strategic feeding of protein and energy sources in relation to forage influenced some ruminal and production measurements in primiparous cows.


Lactation, health, and reproduction of dairy cows receiving daily injectable or sustained-release somatotropin.

Seventy-four Holstein cows (26 primiparous) were utilized to compare the efficacy and safety of sustained-release versus daily injectable formulations of recombinant bST. Twenty-four control cows were injected biweekly with oil microsphere; 25 cows were injected biweekly with 350 mg of bST microsphere; and 25 cows were injected daily with 10.3 mg of bST. Injections were initiated between wk 4 and 5 of lactation and continued for 280 d. Administration of bST caused a moderate increase in milk and FCM production and improved the efficiency of feed and energy conversions. Most health-related and reproduction-related variables did not differ among treatment groups. However, incidence of teat and udder disorders and feet and leg problems tended to be higher during the 40-wk injection period for the bST-treated cows than for the control cows. Incidence of GnRH therapy and number of days to first service were higher for daily bST-treated cows than for controls. No differences existed between sustained-release and daily bST-treated cows for any parameters monitored.


Specific gravity of bovine colostrum immunoglobulins as affected by temperature and colostrum components.

The effects of temperature and colostrum components on specific gravity in bovine colostrum were investigated. Thirty-nine first milking colostrum samples were collected from Holstein cows. The samples were assayed for alpha-tocopherol, fat, protein, total solids, and IgG. The concentrations of total solids, total protein, total IgG, and fat in colostrum were 26.6, 12.5, 3.7, and 9.4 g/100 g, respectively. A range of 1.8 to 24.7 micrograms/ml for alpha-tocopherol was measured in the colostrum samples. Specific gravity of the colostrum was measured using a hydrometer in increments of 5 degrees C from 0 to 40 degrees C. Specific gravity explained 76% of the variation in colostral total IgG at a colostrum temperature of 20 degrees C. The regression model was improved only slightly with the addition of protein, fat, and total solids. The model for samples at 20 degrees C was IgG (milligrams per milliliter) = 958 x (specific gravity) - 969. Measurement of specific gravity at variable temperatures necessitated inclusion of temperature in the model for estimation of IgG. Inclusion of the other components of colostrum into the model slightly improved the fit. The regression model for samples at variable temperatures was as follows: IgG (milligrams per milliliter) = 853 x (specific gravity) + .4 x temperature (Celsius degrees) - 866.


Genetics of growth, feed intake, and milk yield in Holstein cattle.

Heritabilities, genetic and phenotypic correlations among growth, forage consumption, and BW changes of heifers and feed consumption, BW changes, and yields of first lactation cows were estimated. Data were from 1266 Holstein progeny of 74 sires born from 1972 to 1985 at three Agriculture Canada research herds. Heavier heifers at 26 wk consumed more feed from 26 to 34 wk than smaller heifers but gained the same BW. The BW gain and feed consumption heritabilities were .17 and .23, respectively; genetic correlation was .44, and phenotypic correlation was .27. During first lactation, feed intake from 8 to 16 wk and measures of milk yield are very tightly intercorrelated both phenotypically and genetically (.78 to .98). Precalving BW gain and BW at calving were genetically uncorrelated with measures of milk yield (-.09 to +.05). Loss of BW during the first 8 wk of first lactation was moderately heritable (.29) and correlated genetically and phenotypically with measures of milk yield in early lactation (.32 to .39) and feed consumption (.26). From 8 to 16 wk, average BW changes were small and had low heritability and weak phenotypic correlations with measures of milk yield or feed intake. The BW at 26 wk and BW gain from 26 to 34 wk were very poor indicators of early first lactation milk yield. Heifer feed intake was weakly correlated phenotypically (-.07 to .16) but moderately genetically correlated (.17 to .23) with early first lactation milk yield and feed consumption.


Milk composition of Majaheim camels.

To determine composition, milk samples were obtained at random from camels at two camel rearing areas near Riyadh, Saudi Arabia. Proximate analyses indicated 3.15% fat, 2.81% protein, 4.16% lactose, 10.95% total solids, .15% acidity, .83% ash, and 88.33% water. Mineral composition was (milligrams per gram) 30.03, Ca; 72.48, K; 43.10, Na; .28, Fe; .18, Pb; and 4.50, Mg. Results should contribute to the overall knowledge of camels as a food source, but much still needs to be learned if efficient improvement programs are to be initiated.


Evaluation of a nisin-based germicidal formulation on teat skin of live cows.

A purified preparation of the nontoxic antimicrobial peptide, nisin (AMBICIN N), was used in the formulation of a germicidal sanitizer suitable for use on cow teats. The germicidal activity of the formulation against mastitis pathogens was measured on teat skin of live cows. The nisin-based formulation gave a mean log reduction of 3.90 against Staphylococcus aureus and 4.22 log reduction against Escherichia coli after exposure for 1 min to the germicide. This activity was comparable with that exhibited by a 1% iodophor teat dip but was significantly greater than that exhibited by the .1 and .5% iodophors and by the .5% chlorhexidine digluconate teat dips. The nisin-based formulation showed little or no potential for skin irritation after multiple application to skin, but iodophor and chlorhexidine digluconate teat dips showed significant potential for skin irritation in comparable studies.


Nonprotein nitrogen and protein distribution in the milk of cows.

The NPN content of milk represents only 5 to 6% of the total N in milk. However, the significance of this milk N fraction to energy and N metabolism in the dairy cow has not been well characterized. The single largest contributor to the NPN fraction of milk NPN is urea. Urea equilibrates in body water, and blood urea is the primary source of milk urea. The urea in milk can be derived from at least two sources: the end product of digestion and amino acid catabolism. Blood urea N was positively associated with intakes of ruminally degradable and undegradable protein and negatively associated with intake of net energy. Consequently, it might be possible to develop a system to evaluate the dietary protein and energy status of the lactating dairy cow employing milk urea in conjunction with milk true protein.


Introduction to special section: comorbidity and treatment implications.

This article initiates the special section on comorbidity and treatment implications. The presence of comorbidity is recognized, the multiple meanings of comorbidity are mentioned, and an invitation for much-needed research on comorbidity and related treatment is extended.


Comorbidity among anxiety disorders: implications for treatment and DSM-IV.

Research on comorbidity among psychological disorders is relatively new. Yet, comorbidity data have fundamental significance for classification and treatment. This significance is particularly apparent in the anxiety disorders, which, prior to DSM-III-R, were subsumed under disorders considered more significant (e.g., psychotic and depressive disorders). After considering definitional, methodological, and theoretical issues of comorbidity, data on comorbidity among the anxiety disorders are reviewed as well as data on comorbidity of anxiety disorders with the depressive, personality, and substance use disorders. Treatment implications are presented with preliminary data on the effects of psychosocial treatment of panic disorder on co-morbid generalized anxiety disorder. Implications of comorbidity for research on the nature of psychopathology and the ultimate integration of dimensional and categorical features in our nosology are considered.


Comorbidity of schizophrenia and substance abuse: implications for treatment.

The problem of substance abuse disorders in schizophrenia patients is reviewed, including the prevalence of co-morbid disorders, assessment, hypothesized mechanisms underlying abuse, and the clinical effects of abuse on the course of illness and cognitive functioning. The principles of treatment for dual-diagnosis schizophrenia patients are outlined, and the limitations of existing interventions are noted. Gaps in current knowledge about the impact of substance abuse on schizophrenia and its treatment are identified, and suggestions are made regarding promising avenues of research in this area.


Comorbidity of personality disorders and depression: implications for treatment.

This article reviews naturalistic and controlled studies of the impact of comorbidity of personality disorders and depression on response to various forms of treatment. The findings support the common belief that personality disorders are associated with a poorer response to treatment for depression. In contrast, the limited data available suggest that the presence of depression may be a positive prognostic indicator for patients with borderline and antisocial personality disorder. There are insufficient data to draw conclusions regarding the influence of specific types of personality disorders on outcome with specific forms of treatment for depression. More specific assessment of personality disorders, particularly of possible underlying dimensions, is likely to be a more fruitful approach than the currently used categorical approach in identifying effective treatments for patients with personality disorders and depression.


Academic underachievement, attention deficits, and aggression: comorbidity and implications for intervention.

Although comorbidity with specific learning disabilities is less frequent than commonly reported, externalizing behavior disorders--particularly attention-deficit hyperactivity disorder (ADHD)--often overlap with various indices of academic underachievement during childhood. Furthermore, by adolescence, delinquency is clearly associated with school failure. Because the link between behavioral and learning problems often appears before formal schooling, and because the co-morbid problems predict a negative course, early intervention is a necessity. Controlled treatment investigations with youngsters who show these combined problems are rare, and such studies present a host of methodologic and practical problems. I discuss issues surrounding multimodality treatment programs and the potential for long-term interventions to break cycles of school failure and externalizing behavior.


Comorbidity and treatment planning: summary and future directions.

This summary blends the commentaries from the 6 articles in the special section on comorbidity. Included is a discussion of various definitions of comorbidity, the merits and demerits of a hierarchical diagnostic system, and consideration of the extent, patterning, and nature of comorbidity. Directive comments with reference to future intervention planning mention both assessment (distinguishing overlapping constructs) and treatment (sequencing and treatment manuals) issues.


Parenting in context: systemic thinking about parental conflict and its influence on children.

Fauber and Long's (1991) overview of research on family therapy with children is a valuable integration of the literatures on the family correlates of and treatments for childhood disorders. Several concerns apply to some of the inferences they draw from risk research, however. Their assertion that various sources of family distress have effects that are mediated primarily through parenting is questionable, as is their suggestion that parenting therefore is the appropriate focus of family treatment. The conceptual issues of reductionism, linearity, holism, and change in defining causality are discussed in questioning these conclusions about etiology and treatment. Other empirical and methodological issues are raised briefly, particularly as they relate to statistical models of direct and indirect influences and to the body of correlational and analogue research on how parental conflict influences children.


Problems in families of male Vietnam veterans with posttraumatic stress disorder.

Interviews were conducted with a nationally representative sample of 1,200 male Vietnam veterans and the spouses or co-resident partners of 376 of these veterans. The veteran interview contained questions to determine the presence of posttraumatic stress disorder (PTSD) and items tapping family and marital adjustment, parenting problems, and violence. The spouse or partner (S/P) interview assessed the S/P's view of these items, as well as her view of her own mental health, drug, and alcohol problems and behavioral problems of school-aged children living at home. Compared with families of male veterans without current PTSD, families of male veterans with current PTSD showed markedly elevated levels of severe and diffuse problems in marital and family adjustment, in parenting skills, and in violent behavior. Clinical implications of these findings are discussed.


Contingent take-home incentive: effects on drug use of methadone maintenance patients.

This study examined contingent methadone take-home privileges for effectiveness in reducing on-going supplemental drug use of methadone maintenance patients. Fifty-three new intakes were randomly assigned to begin receiving take-home privileges after 2 consecutive weeks of drug-free urines or to a noncontingent procedure in which take-homes were delivered independently of urine test results. The contingent procedure produced more individuals with at least 4 consecutive weeks of abstinence (32% vs. 8%); 28% of noncontingent subjects also achieved abstinence after shifting to the contingent procedure. Lower baseline rate of drug-free urines was strongly associated with successful outcome, whereas the type of drug abused (cocaine vs. benzodiazepines) did not influence outcomes. Findings support a recommendation for using contingent take-home incentives to motivate abstinence during methadone maintenance treatment.


How loss affects anger and alienates potential supporters.

The effects of loss of resources and illness symptoms on experienced anger, anger expression, and supporter's anger was studied among patients with severe chronic breathing disorder. Both illness symptoms and resource loss were related to greater anger. Angry feelings, in turn, led to more angry behavior. This angry behavior, in turn, resulted in increased anger of supporters. This process illustrates how chronic stress depletes both personal resources and social resources, making the individual increasingly vulnerable to further stressful experiences, inevitably to be confronted in chronic stress sequences.


Measures of affect and nicotine dependence predict differential response to smoking cessation treatments.

Smokers (N = 126) were randomly assigned to 6-session smoking cessation treatments consisting of 1 of 2 counseling strategies (skills training or support) and 1 of 2 nicotine exposure strategies (nicotine gum or rapid smoking). Counseling and nicotine strategies were completely crossed; all four combinations resulted in equivalent 1-year abstinence rates. Skills training produced higher initial cessation and more coping responses posttreatment than did support. Rapid smoking, but not nicotine gum, produced tachycardia to the taste of cigarettes posttreatment, consistent with cigarette aversion. The treatments were differentially effective among subpopulations of smokers: Subjects high in pretreatment negative affect responded best to support counseling; those low in pretreatment negative affect responded best to skills training. Self-reports of pretreatment craving predicted response to the nicotine exposure treatments.


Family preservation using multisystemic therapy: an effective alternative to incarcerating serious juvenile offenders.

Multisystemic therapy (MST) delivered through a community mental health center was compared with usual services delivered by a Department of Youth Services in the treatment of 84 serious juvenile offenders and their multiproblem families. Offenders were assigned randomly to treatment conditions. Pretreatment and posttreatment assessment batteries evaluating family relations, peer relations, symptomatology, social competence, and self-reported delinquency were completed by the youth and a parent, and archival records were searched at 59 weeks postreferral to obtain data on rearrest and incarceration. In comparison with youths who received usual services, youths who received MST had fewer arrests and self-reported offenses and spent an average of 10 fewer weeks incarcerated. In addition, families in the MST condition reported increased family cohesion and decreased youth aggression in peer relations. The relative effectiveness of MST was neither moderated by demographic characteristics nor mediated by psychosocial variables.


Comparison of integrated systemic and emotionally focused approaches to couples therapy.

This study compared couples receiving two marital therapy approaches and a control group over a 10-week treatment period. Integrated systemic therapy (IST) and an emotionally focused approach (EFT) were both found to be superior to the control and to be equally effective in alleviating marital distress, facilitating conflict resolution and goal attainment, and reducing target complaints at termination. IST couples, however, showed greater maintenance of gains from termination to 4-month follow-up on marital satisfaction and goal attainment. Clients' perceptions of how change occurred and issues related to the use of a team of observers in IST are discussed.


Problem solving and suicidality among prison inmates: another look at state versus trait.

This research examines the relationships between means-ends problem solving and suicidality among adult male prison inmates in light of new evidence based on inpatient and college student populations suggesting that state, rather than trait, vulnerabilities may be responsible for problem-solving deficits and differences. Using the Means-Ends Problem-Solving Procedure (MEPS) with 93 state prison inmates, we found that among inmates with a history of parasuicide, current suicidality did not affect problem-solving performance. We further found that among nonsuicidal inmates, parasuicide history had no effect on problem solving or affect-suicidality measures. Although these results support new research suggesting that trait problem-solving deficits are not causally linked to suicidality, they raise questions about the potentially unique relationships among suicidality, problem solving, depression, and hopelessness in incarcerated populations.


An experimental test of three methods of alcohol risk reduction with young adults.

This study tested 3 forms of alcohol risk reduction programming for young adults. Volunteers were randomly assigned to receive a 6-week class and discussion group, a 6-unit self-help manual, or a single 1-hr feedback and advice session with professional staff. Results reveal significant reductions in self-reported drinking at the end of the intervention phase and maintenance of drinking changes throughout a 2-year follow-up period. Comparable drinking reductions were rated across treatments; however, noncompliance with the self-help reading program suggested limited utility. Treatment response was related to subject age, as subjects showed increased drinking during the year they reached legal drinking status. The efficacy of brief motivational interventions and client matching in prevention programs is discussed.


Effects of videotaped preparatory information on expectations, anxiety, and psychotherapy outcome.

This study examined whether preparation decreases clients' state anxiety and improves therapy outcome and clarified the relations among preparation, expectations, and state anxiety. Ss were 138 adults referred for outpatient psychotherapy. Half of the Ss viewed an 11-min preparatory videotape, while the control group waited an equivalent period before their 1st appointment. Pre-post measures confirmed that Ss who viewed the videotape had more accurate expectations about psychotherapy and lower levels of state anxiety than the control Ss. However, at 2-month follow-up, the prepared group had significantly better outcomes on only 1 of 10 outcome measures. It is suggested that more powerful designs may be necessary to detect long-term effects of preparation and that the short-term benefits demonstrated warrant further study.


Increased saliva cotinine concentrations in smokers during rapid weight loss.

Although the effect of smoking cessation on weight gain is well-documented, little is known about the effect of weight loss on smoking. We examined the association between saliva cotinine levels and weight loss in a group of 9 obese female smokers during participation in a protein-sparing modified fast (Optifast). For the first 3 months of treatment, subjects consumed only the protein-sparing supplement; for the next 3 months, food was gradually reintroduced. Body mass index and saliva cotinine concentration were assessed at study entry and at 3 and 6 months. A significant weight loss was noted at 3 and 6 months, yet the cotinine level increased significantly over this time. It is unclear whether the cotinine increase is due to metabolic changes or an actual increase in nicotine intake. The results suggest that smoking-related health risks may increase during periods of significant weight loss.


D-fenfluramine-induced prolactin and cortisol release in major depression: response to treatment.

In order to test the effects of various biological treatments on serotonergic function in depression, twenty-one patients with a diagnosis of major depression underwent neuroendocrine challenge tests before and after treatment with either ECT, fluoxetine or amitriptyline. The serotonin (5-HT) releasing agent d-fenfluramine was used as a challenge drug and cortisol (CORT) and prolactin (PRL) plasma levels were monitored over a 5-h period. Overall PRL responses were significantly enhanced following pharmacotherapy irrespective of therapeutic outcome. Effective treatment in each case lowered baseline CORT levels but CORT response to d-fenfluramine remained blunted. Hypercortisolaemia may be involved in the impaired pretreatment PRL response as a strong inverse relationship was established, for the combined studies, between basal CORT plasma concentrations and PRL responses.


The familial relation of personality disorders (DSM-II-R) to unipolar major depression.

Four hundred and fifty directly interviewed relatives of probands with non-psychotic unipolar major depression and 320 directly interviewed relatives of controls were compared by the prevalences of personality disorders (P.D.) as defined by DSM-III-R, in relation to presence or absence of the relatives' affective disorder. Overall, there was only a trend for an increased risk for P.D. in relatives of depressed patients. However, P.D. and unipolar major depression co-occurred more frequently in relatives than expected by chance. It is suggested that this association is mainly due to non-familial factors. Compared with other P.D., the relationship of borderline P.D. to major depression was not substantially stronger.


Help-seeking patterns of community residents with depressive symptoms.

From a community sample, fifty-five individuals identified as having three or more symptoms of depression were asked if and where they had sought help and how they found or would find treatment. Only 20 subjects (33.9%) reported having sought professional help. No demographic differences were found between help-seekers and non-help-seekers. Eighty percent of the help-seekers had seen a mental health professional while 20% had seen a non-psychiatric physician. However, non-psychiatric physicians and friends or personal acquaintances were most frequently cited as the first point of contact for locating treatment. Results suggest that most individuals with a moderate number of depressive symptoms do not seek professional assistance but that, among those who do, a majority is eventually seen by a mental health professional. Virtually all utilize intermediaries other than mental health professionals, however, to locate assistance. The non-psychiatric physician plays a prominent role in locating help for depressed individuals, which suggests the need to educate physicians about appropriate treatment referral.


Brofaromine in major depressed patients: a controlled clinical trial versus imipramine and open follow-up of up to one year.

In an 8-week controlled double-blind clinical trial with a total of 216 patients Brofaromine was found to be superior to Imipramine with regard to efficacy (Hamilton Depression Scale, von Zerssen self-rating scale, global evaluation) and tolerability (adverse experiences, global evaluation). Mean daily dosages were 93.1 mg/day in the Brofaromine group and 92 mg/day in the Imipramine Group. No tyramine reduced diet had to be observed. Long-term efficacy and tolerability also proved to be good in an open follow-up in the Brofaromine group.


Thyroid abnormalities during chronic lithium treatment in Hong Kong Chinese: a controlled study.

Fifty Chinese psychiatric patients on chronic lithium treatment and the same number of sex- and age-matched control outpatients were assessed by a thyroidologist and underwent laboratory investigations. Lithium patients had a higher rate of goitres (50% vs 10%, P < 0.0001) and a higher mean TSH level (P < 0.005) than controls. Thyroid antibodies were detected in 7 older manic-depressive patients as opposed to 1 control, but not in patients with recurrent unipolar mania. Five patients, but no controls, had single or multiple episodes of hyperthyroidism, which was followed in 2 of them by biochemical hypothyroidism. It is suggested that variations in iodine status, dietary goitrogens, immunogenetic makeup and their complex interactions with chronic lithium treatment may contribute to ethnically different patterns of thyroid abnormalities.


The sleep structure of patients with anxiety disorders in comparison to that of healthy controls and depressive patients under baseline conditions and after cholinergic stimulation.

This study investigated sleep EEG during placebo and after cholinergic stimulation with RS 86 in 36 healthy subjects, 34 patients with major depression and 20 patients with anxiety disorders. Cholinergic stimulation with RS 86 led to a decrease of slow wave sleep and REM latency. RS 86 had a more profound impact on REM latency in patients with major depression than in healthy controls and patients with anxiety disorders. Six out of 36 healthy controls, three out of 20 patients with anxiety disorders and 24 of 34 patients with depression displayed sleep onset REM periods after cholinergic stimulation. Also effects on REM density and duration of the first REM period were more pronounced in major depression. Even in those patients with anxiety disorders and a secondary major depression no depression-like sleep abnormalities could be provoked. The results underline the usefulness of the cholinergic REM induction test to differentiate patients with major depression from those with other psychiatric disorders. The results can be interpreted as further evidence for the cholinergic-aminergic imbalance model of depression and for the reciprocal interaction model of nonREM-REM regulation.


Circadian rhythm abnormalities of deep body temperature in depressive disorders.

We investigated circadian rhythms of body temperature in 62 inpatients with major depressive episodes, by monitoring the deep body temperature through the abdominal skin every two hours for a consecutive 48-h period. The data were analyzed by both the least-squares method and the maximum entropy spectral analysis (MEM) and were compared with those in 29 normal volunteers who apparently had a regular 24-h sleep-wake schedule. Circadian rhythm phase disturbances in the depressed patients were likely to be manifested in a phase normal or a phase delay pattern rather than in a phase advance pattern. The amplitude of body temperature was significantly smaller and the mesor was higher in the depressed patients than in the normal subjects. Analysis by MEM revealed that the periods of circadian rhythm of body temperature tended to be longer in the depressed patients than in the normal subjects, though there was no significant difference. The power spectral density by MEM was significantly lower, and there were significantly more ultradian rhythm components in the depressed patients than in the normal subjects. These findings suggest that the fundamental rhythm disturbance in depression may be a weakening of the coupling processes between internal pacemakers and an abnormal sensitivity to environmental information.


Diurnal variation: reliability of measurement and relationship to typical and atypical symptoms of depression.

We used three rating scales to study diurnal variation of mood in 37 patients with major depressive disorder (17 drug-free patients and 20 treatment refractory patients on stable regimens of antidepressant medication). The three rating scales included global self-ratings administered twice a day; an itemized, prospective, observer-rated scale administered twice a day; and the retrospective item on the Hamilton Depression Rating Scale. Z scores and Intraclass Correlation Coefficients demonstrated a poor level of agreement between the itemized, prospective scale and the self-ratings. In addition, stepwise multiple regression analysis and point bi-serial correlation showed no systematic relationship between atypical diurnal variation (i.e., mood worsening in the evening) and atypical depressive symptoms (weight gain, hypersomnia, etc.), or between typical diurnal variation (i.e., mood worsening in the morning) and typical depressive symptoms (weight loss, insomnia, etc.). This lack of relationship was observed in both drug-free and medicated patients using each of the three rating scales. We discuss possible explanations for these negative findings.


Severe disturbance occurring during treatment for depression of a bulimic patient with fluoxetine.

We report on a 32-year old woman with bulimia nervosa treated with fluoxetine for depression. Fluoxetine is the only drug currently recommended for the treatment of bulimia. The patient became severely disturbed with tension, irritability, self-damage by cutting and violent, intense, suicidal and paranoid ideation qualitatively different to previous symptoms in the course of her illness. Clinical impression was of a striking association between fluoxetine and these symptoms. We suggest caution when using fluoxetine in bulimic patients with depression who have additional impulsive behaviours such as self-cutting, alcohol and/or drug abuse and shop-lifting.


Living arrangements, knowledge of health risks, and stress as determinants of health-risk behavior among college students.

The association of knowledge of health risks, living arrangements, and perceived stress with health-risk behaviors was examined in a sample of college students included in the Health Promotion and Disease Prevention Supplement of the National Health Interview Survey. Regressions of each health-risk behavior (dependent variable) were performed on the predicted correlates. Although knowledge was not associated with participation in physical activity or smoking, the study found that students who knew more about the harmful effects of alcohol drank less, and those with greater knowledge of health risks practiced fewer risky behaviors. Students living independently were more likely to smoke, and those living in residence halls were less like to do so. Drinking, however, was more common among students living in residence halls or independently than among those living at home. Hall residents engaged in more group physical activity than other students did, but their physical activity was unrelated to health-risk behaviors. Stress was associated with smoking but not with other health practices. The findings suggest that smoking may be less influenced by health knowledge and more associated than drinking is with a response to stress. Drinking appears to be a social activity associated with living among peers and is potentially modifiable by increased knowledge about the effects of alcohol on health.


Assessing alcohol problems in college students.

Alcohol abuse among college students is prevalent, yet few instruments with sound reliability and validity are available to assess these problems in this population. As part of a large, baseline assessment battery for a prospective study of offspring of alcoholics, the 27-item Young Adult Alcohol Problems Screening Test (YAAPST) was given to 490 freshmen at a large midwestern university; approximately 9 months later, 482 subjects completed the scale again. In addition to asking about such traditional problems as experiencing blackouts and driving while intoxicated, the YAAPST included specific items relating to college experiences (eg, getting into sexual situations that were later regretted, missing classes, and receiving lower grades than usual). The YAAPST was designed to assess these drinking consequences over two different time frames, lifetime and past year, and also to indicate the frequency of occurrence during the past year. Results indicated that the YAAPST is a unidimensional scale with good psychometric properties (good internal consistency and test-retest reliability). Three different approaches were used to demonstrate the validity of the YAAPST. Findings supported criterion validity (with interview-based alcohol abuse/dependence diagnoses as the criterion), concurrent validity (comparing the YAAPST with other drinking measures), and construct validity (correlating the YAAPST with etiologically relevant personality, motivational, and peer influence variables). The YAAPST is a promising screening instrument for alcohol problems in college students. It has excellent psychometric properties and the potential to provide a range of useful information to the clinician or researcher.


Fitness profiles and activity patterns of entering college students.

Fitness levels of American youth have shown a marked decline in the last decade, according to recent studies. To determine whether such a tendency persists for entering college students, the authors evaluated 115 male and 143 female students for performance on the following fitness-related variables: (1) maximal oxygen consumption (estimated from Astrand cycling protocol), (2) body composition (skin-fold techniques), (3) muscle endurance (sit-up protocol), (4) muscle strength (bench-press protocol), and (5) joint flexibility (upper and lower body protocols). Although neither men nor women exhibited high levels of cardiorespiratory fitness, the women in the study showed higher relative levels than their male counterparts. Both groups showed excellent levels of muscle strength (compared with normative standards), but they achieved only an average standard for muscle endurance. Findings of relatively low levels of cardiovascular fitness compared with levels of muscle strength, particularly in men, seem to be a reflection of an inappropriate concentration of physical activity.


Recurrent pain in college students.

The authors investigated the prevalence of recurrent pain in a college student sample. Of the 1,564 students surveyed, 467 (29%) indicated that they had experienced recurrent pain at an intensity that was mostly in the mild-to-moderate range. Students who reported having recurrent pain were significantly older and more depressed than students who did not indicate they suffered from recurrent pain. Pain intensity was positively correlated (r = .14) with depression among the students who reported having recurrent pain. Implications of the findings for future research, treatment, and health promotion efforts are discussed.


A liberal arts health promotion course.

With a grant from the W. K. Kellogg Foundation, the University of North Carolina at Asheville and the Mountain Area Health Education Center established a campus health promotion program that also trained family practice residents in health promotion skills. The heart of the program was a 3-credit course that emphasized stress management, aerobic conditioning, interpersonal relationship skills, and nutrition. Follow-ups after 2 years revealed that 90% of the students who responded said the course had had some lasting effect on their lives.


Surveying University of Arizona students' health.

The authors sampled more than 600 University of Arizona students to determine how student attitudes, beliefs, and practices should be considered by healthcare personnel in planning campus health education programs. The survey found that students worried more about diet, exercise, and weight than they did about more serious health problems and that, although generally positive and optimistic, the students frequently felt anxious and overwhelmed. Two thirds of the students were sexually active, 74% of those who were active used various contraceptive methods. More than three quarters of those surveyed indicated they currently drank alcoholic beverages; one quarter of the drinkers said they frequently downed three or more drinks on one occasion, and 44% of the drinkers reported driving while under the influence of alcohol.


Aging in humans: a continuous 20-year study of physiologic and dietary parameters.

The old adage, "You are what you eat," is not always reliable, as demonstrated in this mixed-longitudinal study of men that began in 1969. Mean values of percent body fat, total body potassium (TBK), and total serum cholesterol (SCHOL) did not show changes that correlated with any studied nutrient from repeated 4-day diet records. Mean blood pressure increased with increased body weight as age increased. High-density lipoprotein cholesterol decreased when polyunsaturated fat intake increased. The men had decreased mean height, TBK and increase in percent body fat as age increased. Food energy intake decreased equally from carbohydrates, protein and fat as age increased. Large standard deviations of mean values of measured parameters document heterogeneity of these subjects. A subset of 144 male cohorts was studied serially for 20 years in time-age, cross-sectional and longitudinal series. As they aged, height and TBK decreased (p < or = 0.05), percent body fat and blood pressure increased (p < or = 0.04) and SCHOL had no significant change. Intake of all nutrients decreased significantly (p < or = 0.03) longitudinally and with time, showing a time effect.


Marginal nutritional status among institutionalized elderly women as compared to those living more independently (Dutch Nutrition Surveillance System).

The nutritional status (assessed by anthropometric indices, and biochemical and hematological variables in blood) of three groups of elderly women (aged > or = 65 years) was evaluated within the framework of the Dutch Nutrition Surveillance System. The groups were composed of women living in a nursing home (n = 51), women living in service flats and receiving their dinners from the nursing home kitchen (n = 29), and women living independently (n = 52). Mean blood levels of folate, pyridoxal 5'-phosphate, 25-hydroxyvitamin D, alpha-tocopherol, vitamin C, albumin, selenium and total cholesterol were significantly (p < 0.05) lower among nursing home women. Among these women a biochemical deficiency was frequently found for 25-hydroxyvitamin D (73%), pyridoxal 5'-phosphate (57%), vitamin C (38%), selenium (30%) and folate (28%). These nutritional risks were largely independent of each other. Since folate and pyridoxal 5'-phosphate were associated with several clinicochemical indicators, health status may be an important determining factor for this unfavorable situation. Low 25-hydroxyvitamin D concentrations were associated with limited exposure to ultraviolet radiation and nonusage of vitamin D supplements. We conclude that dietary intake variables are not the only determinants of a marginal nutritional status among nursing home women. Use of foods with a high nutrient density should be encouraged, whereas other preventive measures are needed to improve vitamin D status.


Lack of an effect of multivitamins containing vitamin A on serum retinyl esters and liver function tests in healthy women.

Two hundred eighty-four female adults (aged 40-70 years) were longitudinally studied to investigate the relationship between dietary supplemental vitamin A and serum biochemical markers of vitamin A toxicity. Serum retinol, retinyl esters, and retinol-binding protein (RBP), alkaline phosphatase and aspartate aminotransferase activities and bile acids were measured at baseline, 1 and 2 years. Fasting serum retinol and retinyl ester concentrations were determined by high-performance liquid chromatography, and dietary and supplemental intake of vitamin A were assessed by 3-day food records. There was no difference in dietary vitamin A intake between supplement users and nonusers. In supplemental users, the mean +/- SEM supplemental vitamin A intake was 952 +/- 81 IU/day (range 250-5000 retinol equivalents/day). Serum retinol, retinyl esters, and RBP concentrations were not different between the two groups during the 2-year period. For each group, serum retinyl esters significantly increased over time (p < 0.03), but the magnitude of the increase was not different between the groups. Serum levels of retinol, retinyl esters, and RBP were not correlated with vitamin A intake or age in either group. Biochemical measures of liver damage (serum alkaline phosphatase and aspartate aminotransferase activities and serum bile acids) were not related to serum retinol, retinyl esters or RBP concentrations, nor were they different between nonusers and users of supplemental vitamin A. This study provides evidence that long-term supplemental vitamin A in doses commonly found in multivitamin supplements does not present a risk for hypervitaminosis A.


Effects of dietary magnesium and nickel on growth and bone characteristics in rats.

We examined the interaction of dietary magnesium (Mg) and nickel (Ni) on growth and, in particular, the size, composition and mechanical properties of bones in weanling rats. Male rats were fed a diet with 0.3, 1.0 or 2.0 times the recommended concentration of Mg and adequate amounts of other nutrients. After a week, groups fed the low- and high-Mg diets were subdivided and fed the same concentration of Mg plus 0 or 500 mg Ni/kg diet (from Ni chloride) for the remaining 7 weeks. Rats fed low Mg with added Ni grew slowly and had smaller femurs and vertebrae that contained less ash and withstood less force before breaking or compression than did bones of rats fed the low-Mg diet without Ni. However, the breaking stress calculated for femurs from Mg-depleted, Ni-supplemented animals was increased. Ni did not produce these effects when added to a diet high in Mg. Compared with high dietary concentrations, the low-Mg intake had little effect unless Ni was added.


Zinc status before and after zinc supplementation of eating disorder patients.

Reduced food consumption is a major manifestation of zinc (Zn) deficiency. Many manifestations of Zn deficiency are complications of anorexia nervosa and bulimia nervosa. We evaluated serum and 24-hour urinary Zn values in 12 healthy volunteers and 33 eating disorder patients before and after hospitalization which included either Zn supplementation (75 mg Zn/day) or placebo. Bulimics had depressed serum Zn concentrations (p < 0.025). Admission urinary Zn was lower in bulimics (258 +/- 44 micrograms/day), and significantly depressed in anorexics (196 +/- 36 micrograms/day, p < 0.005) vs controls (376 +/- 45 micrograms/day). During hospitalization, serum Zn concentrations increased in all supplemented patients vs no change with placebo. Urinary Zn excretion increased in supplemented bulimics (p < 0.001) and placebo (p < 0.05). Urinary Zn excretion markedly increased in supplemented anorexics (179 +/- 65 to 1052 +/- 242 micrograms/day); however, placebo values fell or remained unacceptably low (admission 208 +/- 48 micrograms/day; discharge 160 +/- 17 micrograms/day). By dietary history, controls consumed the Recommended Dietary Allowance (RDA) for Zn (11.95 +/- 1.25 mg/day); anorexics 6.46 +/- 1.14 mg/day; and bulimics 8.93 +/- 1.29 mg/day. We suggest that Zn deficiency may act as a "sustaining" factor for abnormal eating behavior in certain eating disorder patients.


Glucose appearance rate following protein ingestion in normal subjects.

The fate of amino acids deaminated following protein ingestion is uncertain. Presumably, the majority of the carbon skeletons of the amino acids are converted into glucose in the liver. In the present study, tritiated glucose dilution tracer studies have been used to determine the effect of a protein meal on the glucose appearance rate in plasma. Five normal male subjects ingested 50 g of protein in the form of cottage cheese. The glucose appearance rate was determined using a constant infusion of 3H-glucose, and compared to the glucose appearance rate following the ingestion of just water in the same subjects over an 8-hour period. The total amount of protein deaminated and converted to urea also was quantitated. Urea production could account for the metabolism of 29.3 g of protein ingested, or 58.5%. Glucose appearing in the circulation as a result of amino acid metabolism determined by tracer methodology was 9.68 +/- 5.7 g. Based on the gluconeogenic potential of cottage cheese (42.3 g of glucose from 50 g of cottage cheese protein), this could only account for at most 43% of protein metabolized, or 23% of the total amount of protein ingested. The fate of the remaining amino acids metabolized remains to be determined.


Weight loss, body composition and risk factors for cardiovascular disease in obese children: long-term effects of two treatment strategies.

Two treatment strategies were compared to determine their effects on weight loss, body composition and risk factors for cardiovascular disease (CVD) in 32 obese children (relative weight > 120%) aged 6-15 years. Modes of therapy included individual (Group I) or group treatment (Group II). The children were treated for 1 year and observed during the second year. Relative body weight decreased by 16.6% in Group I (p < 0.001) and by 15.8% (p < 0.01) in Group II during the first year; in both groups the lower relative body weight was maintained during the year of observation. No changes were observed in linear growth or lean body mass. Weight reduction was accompanied by increased high-density lipoprotein cholesterol (HDL-C) levels, increased ratio of HDL-C to total cholesterol, and reduced triglyceride concentrations in both groups. Fasting plasma insulin concentrations decreased significantly in Group I. In conclusion, intensive treatment produced significant weight loss, improved serum lipid profile and reduced hyperinsulinemia. These changes, if sustained, may reduce the risk of CVD later in life.