Administration of transforming growth factor-alpha enhances anatomical and behavioral recovery following olfactory nerve transection

Although replacement of olfactory receptor neurons (ORNs) and subsequent reinnervation of the olfactory bulb occur following ORN injury, the intrinsic and extrinsic factors that contribute to the regulation of this dynamic process have not yet been fully identified. Recent research indicates that several growth factors have neurogenic effects on ORNs in vitro, and that chronic in vivo administration of either basic fibroblast growth factor, epidermal growth factor, or transforming growth factor-alpha (TGF-alpha) following chemical lesion can enhance the normal rate of ORN reinnervation of the olfactory bulb. The primary goal of the present experiments was to further assess the extent to which growth factor-related enhancements in the rate of anatomical recovery during ORN reconstitution and subsequent reinnervation of olfactory bulb are accompanied by enhancements in the rate of recovery of odor-guided behavior.A series of experiments in rats was conducted to initially characterize the time course of the anatomical and behavioral recovery normally observed following ORN reconstitution as a consequence of olfactory nerve transection, and to subsequently characterize the anatomical and behavioral effects of TGF-alpha administration on this normal rate of recovery. Consistent with a host of prior studies, olfactory nerve transection produced consistent and substantial deafferentation of olfactory bulb followed by a time-dependent anatomical recovery which was significantly enhanced by administration of TGF-alpha. The effect of TGF-alpha on functional recovery following olfactory nerve transection was also assessed using an odor-guided fear conditioning task. ORN lesioned animals receiving injections of TGF-alpha during recovery were found to display enhanced conditioned responding to an olfactory stimulus compared to untreated subjects. Further behavioral analyses suggested that this enhanced functional recovery was likely not due to non-specific effects of TGF-alpha on cognition or motor activity, but rather to enhanced olfactory input to the CNS.Future studies will likely reveal the exact mechanism of action mediating the anatomical and concomitant behavioral effects of this growth factor. Since ORNs are one of only a few populations of neurons capable of regeneration or replacement, the continued study of the cellular and molecular factors that coordinate this regenerative process may ultimately lead to the development of therapeutic strategies to promote an enhanced functional recovery following injury to other neuronal populations.     

Histological and cytological criteria in the diagnosis of malignant melanomas by cryostat sections

Summary Although cryostat sections in general allow a distinction to be made between malignant melanomas and other pigmented lesions in clinically doubtful cases, the differential diagnosis may be difficult. The histological and cytological criteria taken into account can be classified as major, minor, and insufficient. Knowing the diagnostic value of each makes a conventionally established diagnosis safer. Variance analysis does not contribute to the problem but it can nevertheless be shown that the evaluation of six major criteria makes a quick and reliable cryostat section diagnosis possible. If these results are confirmed in a prospective study it would be a decisive step on the way to a quicker and safer cryostat section diagnosis of malignant melanoma, even for the less experienced histopathologist.The results published here were presented in part at the DDG meeting 1980 at Westerland/SyltWe are grateful to Miss Schubert, Institute of Biomathematics of the University of Munich, for the statistical evaluations     

Psychoeducational and cognitive-behavioral strategies in the management of bipolar disorder

Despite advances in the pharmacologic treatment of bipolar disorder, it is clear that additional strategies are needed to provide patients with longer-term mood stability. Recent years have witnessed the development of a number of psychosocial strategies for bipolar disorder that are design as adjuncts to ongoing pharmacotherapy. In this article we describe psychoeducational and cognitive-behavioral approaches to the management of bipolar disorder, with emphasis on broader treatment packages that can be offered by cognitive-behavior therapists working in specialty bipolar clinics, as well as specific strategies that can be integrated into standard pharmacotherapy for the disorder. A growing body of evidence documents the potential value of these interventions, and large-scale studies are underway, including the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), which will provide outcome on these interventions from the perspective of large, multicenter trials.     

Afterpotentials following penicillin-induced paroxysmal depolarizations in rat hippocampal CA1 pyramidal cells in vitro

Epileptic discharges were induced by superfusion of rat hippocampal slices with penicillin. Under these conditions the neurons generated paroxysmal depolarization shifts (PDS) after electrical stimulation of Schaffer collaterals. The PDS were followed by large afterhyperpolarizations lasting about 2 s. The mechanisms causing these afterhyperpolarizations were studied in CA1 pyramidal cells. A late component of the after hyperpolarizations, which determined their overall duration, was blocked by intracellular application of EGTA and reduced by superfusion with 8-Br-cAMP. In the same neurons these drugs had a comparable effect on after hyperpolarizations following depolarizing current injections; it was therefore concluded that the late component of the PDS afterhyperpolarizations was caused by a slow Ca²⁺-activated K⁺ current. An initial fast component of PDS afterhyperpolarizations, which peaked about 60 ms after PDS onset, was reduced by EGTA but not affected by 8-Br-cAMP suggesting that the fast Ca²⁺-activated K⁺ current also contributed to the PDS afterhyperpolarizations. Superfusion of the slice with the -aminobutyric acid B receptor (GABA_B) antagonists phaclofen or 5-aminovalerate reduced the amplitude of the afterhyperpolarizations during the first 1000 ms but did not affect the late Ca²⁺-dependent component, indicating that a GABA_B-mediated K⁺ inhibitory postsynaptic potential (IPSP) contributed to the PDS afterhyperpolarization. Intracellular injection of Cl^– revealed that an early part of the afterhyperpolarizations lasting about 500 ms was Cl^–-dependent. This component was blocked by superfusion of the slices with bicuculline, suggesting that a GABA_A-mediated Cl^– IPSP contributed to the PDS afterhyperpolarization. The experiments show that different synaptic and intrinsic components with different time courses participate in the generation of PDS afterpotentials.     

Retrograde tracing studies of subdivisions of the orbicularis oculi muscle in the rhesus monkey

Functionally and anatomically, the orbicularis oculi (OO) muscle can be subdivided in a pretarsal, a preseptal, and an orbital portion. In the rhesus monkey, fluorescent and neuronal retrograde tracing experiments were performed in the pretarsal or the orbital portion of the OO muscle, or both, using fast blue, diamidino yellow, and wheat germ agglutinin-horseradish peroxidase as tracers. The preseptal portion was not investigated because of close anatomical relationships to the other portions. It was found that motoneurons innervating the OO muscle are located exclusively within the intermediate subnucleus of the motor facial nucleus. The upper pretarsal motoneurons show a specific distribution in the dorso-rostral border area of the intermediate subnucleus, representing a dome-like organization, while lower pretarsal motoneurons are situated more ventrally in the adjacent area. The pretarsal motoneurons are all located dorsally in the rostral half and the upper part of the caudal half of the intermediate subnucleus. The upper pretarsal portion is subserved by about one third of the total intermediate motoneuron population. The size of the upper pretarsal motoneurons is similar to that of the motoneurons of the lower pretarsal portion of the OO muscle and falls, for the vast majority, into the large motoneuronal range. Motoneurons belonging to the upper and lower orbital portions are located ventrally and are more randomly distributed in the rostral half of the intermediate subnucleus. The size of orbital motoneurons varies from small to large. The large fraction of pretarsal motoneurons may reflect the specific function of the upper pretarsal portion during rapid and highly coordinated movements of the eyelids in different types of blinking. Received: 18 September 1997 / Accepted: 13 March 1998     

Anxiety psychopathology predictive of outcome in patients with panic disorder and depression treated with imipramine, alprazolam and placebo

This study examines clinical predictors of outcome for patients with panic disorder and depression in a 16 week, placebo-controlled trial of alprazolam and imipramine (n = 126). Baseline global severity of illness and phobic avoidance were differentially predictive of acute response to treatment. Patients in the mild to moderate range of global distress experienced smaller degrees of improvement on alprazolam than on imipramine at week 4. At endpoint, the relative effectiveness of the active medication versus placebo was diminished in patients with higher levels of phobic avoidance. This relationship was not evident for completers, suggesting that the adverse effects of avoidance on outcome after sustained treatment was reduced.     

Helicobacter pylori gastric infection in gnotobiotic beagle dogs.

Establishment of infection with Helicobacter pylori and gastritis in nonhuman species is currently only successful in gnotobiotic piglets. This study was designed to determine whether H. pylori will colonize the gastrointestinal tract of gnotobiotic dogs. Gnotobiotic beagle pups were derived by standard methods. Group A (five dogs) was orally challenged with 3 x 10(8) H. pylori at 7 days of age. Group B (two dogs) received only peptone water but was contact-exposed beginning on day 23 postinfection (p.i.). Necropsy was performed on dogs on day 30 p.i. H. pylori colonized the stomach of all dogs (groups A and B). Urease map analysis correlated with the microbiologic findings and indicated that the density of colonization was less than that observed in human tissue. Organisms were also recovered from the pharynx, esophagus, duodenum, and rectum of 1, 2, 2, and 1 dog, respectively. All group A and one group B dog developed serum immunoglobulin G specific for H. pylori by day 30 p.i. Gross lesions were restricted to the stomach and consisted of small (less than 1 mm) lymphoid follicles. Microscopically, there were focal to diffuse lymphoplasmacytic infiltrates with follicle formation and mild to moderate infiltration of neutrophils and eosinophils in the gastric lamina propria. With the Warthin-Starry silver stain, organisms were seen on the surface of the gastric epithelial cells, beneath the mucus layer. We conclude that H. pylori colonizes the stomachs of gnotobiotic dogs for at least 1 month and the lesions resemble those seen in humans. H. pylori is transmissible by contact from infected to noninfected dogs.     

Diffusion in gel-enzyme-linked immunosorbent assay—a new serological test for leptospirosis

A new serological test, diffusion in gel-enzyme-linked immunosorbent assay (DIG-ELISA) was developed and compared with the microscopic agglutination test (MAT) for the serological diagnosis of leptospirosis. The results suggest that DIG-ELISA is a viable alternative to the MAT because of its simplicity, sensitivity, versatility and potential for standardisation.     

Inhibitory interaction in the cat's lateral geniculate nucleus

Summary Spike activities of optic tract fibers and corresponding relay cells were recorded simultaneously in layers A and A₁ of the dorsal lateral geniculate nucleus of the cat. Light stimuli of various diameters were shone into the receptive field center of these unit pairs and their input/output ratios were determined. An increase of the stimulus size leads to an impairment of the input/output ratio in on-center and off-center relay cells. This suppressive effect has approximately the same latency as the excitatory response.Intracellular recordings suggest that the inhibitory effect of the surround is due to a postsynaptic process. Inhibitory postsynaptic potentials occur during and — under certain stimulus conditions —before the excitatory response. The short latency of these IPSPs suggests that they result from the activity of adjacent units with the same RF characteristics as the recorded neuron. This inhibitory input is not restricted to the RF periphery but may also be activated by stimulation within the RF center. Most neurons are also inhibited by units with antagonistic center responses.During the period of this research Ernst Pöppel held a training grant of the Stiftung Volkswagenwerk, Az. 11 1015.