Suppression of stimulus frequency otoacoustic emissions

Observations of the suppression of stimulus frequency evoked otoacoustic emissions (SFOAEs) by a second tone were made in human subjects. Measurements were made with the suppressor tone at frequencies and levels at, above, and below the stimulus tone generating the SFOAE. Data were collected with the stimulus tone at a range of levels (20-60 dB SPL), over a range of frequencies and in six different ears, in three subjects. The results were fitted to a phenomenological model, which allowed the data to be expressed as two parameters against the frequency of the suppressor tone. Characteristics of the suppression were examined, in particular the asymmetry between suppression by tones of higher and lower frequency than the tone evoking the SFOAE. At relatively low levels of suppressor tone, suppressors with frequencies higher than the stimulus tone were more effective suppressors than lower frequencies. At higher levels of suppressor tone, the situation was reversed, with lower frequencies being more effective than higher frequencies. These results were discussed in terms of nonlinear interaction between waves in the cochlea. This interpretation was used to estimate the shape of the traveling wave envelope produced by the stimulus tone, from the results of the suppression experiments. It was shown that the estimates of the shapes of the traveling wave envelope were nonlinear, the peak of the envelope becoming sharper at lower levels of stimulus. A simple quantitative model of SFOAE suppression was formulated using concepts of energy flow within the cochlea. This model produced SFOAE suppression results with all the major characteristics of SFOAE suppression from a real, human ear.     

Attenuation of Fos-like immunoreactivity in the trigeminal nucleus caudalis following trigeminovascular activation in the anaesthetised guinea-pig

The present study has examined the involvement of sensory neurotransmitters in activating neurones in the trigeminal nucleus caudalis following stimulation of the trigeminovascular system in anaesthetised guinea-pigs. Electrical stimulation of the right trigeminal ganglion produced a unilateral expression of Fos-like immunoreactivity (Fos-LI) in the trigeminal nucleus caudalis. The tachykinin NK1 receptor antagonist, GR205171 (100 micrograms/kg i.v.) and the N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (1 mg/kg i.v.) each inhibited expression of Fos-LI following electrical stimulation. The calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP8-37 (1.3 mg/kg i.v.), administered following rostral intracarotid infusion of mannitol to disrupt the blood-brain barrier, tended to reduce Fos-LI evoked by electrical stimulation, although this failed to reach statistical significance. Capsaicin (10 nmol in 0.1 ml), administered intracisternally, produced a bilateral expression of Fos-LI in the trigeminal nucleus caudalis. This expression was unaffected by the peripherally acting NK1 receptor antagonist, GR82334 (0.2 mg/kg i.v.) or CGRP8-37 (1.3 mg/kg i.v.). The centrally penetrant NK1 receptor antagonist, GR205171 (100 micrograms/kg i.v.), inhibited significantly Fos-LI evoked by intracisternal capsaicin administration. It is concluded that the sensory neurotransmitters, substance P and glutamate are released centrally following activation of the trigeminovascular system and that each may be involved in activation of cells in the trigeminal nucleus caudalis.     

PMS after 40: persistence of a stress-related symptom pattern

BACKGROUND AND OBJECTIVE: Various yellow light lasers have been used over the past decade in an attempt to eradicate facial telangiectasia. Based on their power output, spot size, and pulsing characteristics, these lasers belong to one of two categories that exist at either end of a spectrum--high power, short pulse, and large spot size, or low power, long exposure, and small spot size. The copper bromide laser clearly belongs in the latter group, but with higher available power than most other lasers in this group, it exists further along the spectrum toward the region in which the laser parameters might be considered closer to theoretical ideals for treating certain cutaneous vascular pathologies. The objective of this study was to ascertain the role and efficacy of the copper bromide laser on treatment of a variety of facial telangiectasia. STUDY DESIGN/MATERIALS AND METHODS: A total of 570 patients with facial telangiectasia of different diameters and on different regions of the face were treated with the copper bromide laser one or more times and followed up over 5 years. RESULTS: More than 75% clearance was achieved in 70% patients, 50-75% clearance in 17.4% patients, and < 50% clearance in 12.6% patients. Poor results were correlated with anatomical location on the nasal alae and nasal tip and also with vessel size. Very small (< 100 microns) and very large (> 300 microns) vessels did not respond as well as vessels in the 100-300-micron diameter group. Very large vessels responded better to a combination of sclerotherapy and laser treatment. There were no reported long-term adverse effects. CONCLUSION: The copper bromide laser is a safe and effective modality for the treatment of the majority of facial telangiectasia. It is less suited to treating very small vessel lesions such as diffuse erythema, and conversely very large vessels as well as those of the nasal alae. These latter two groups respond better and more permanently to combined sclerotherapy and laser treatment.     

Regulated expression of the cell adhesion glycoprotein F3 in adult hypothalamic magnocellular neurons

F3, a glycoprotein of the immunoglobulin superfamily implicated in axonal growth, occurs in oxytocin (OT)-secreting and vasopressin (AVP)-secreting neurons of the adult hypothalamo-neurohypophysial system (HNS) whose axons undergo morphological changes in response to stimulation. Immunocytochemistry and immunoblot analysis showed that during basal conditions of HNS secretion, there are higher levels of this glycosylphosphatidyl inositol-anchored protein in the neurohypophysis, where their axons terminate, than in the hypothalamic nuclei containing their somata. Physiological stimulation (lactation, osmotic challenge) reversed this pattern and resulted in upregulation of F3 expression, paralleling that of OT and AVP under these conditions. In situ hybridization revealed that F3 expression in the hypothalamus is restricted to its magnocellular neurons and demonstrated a more than threefold increase in F3 mRNA levels in response to stimulation. Confocal and electron microscopy localized F3 in secretory granules in all neuronal compartments, a localization confirmed by detection of F3 immunoreactivity in granule-enriched fractions obtained by sucrose density gradient fractionation of rat neurohypophyses. F3 was not visible on any cell surface in the magnocellular nuclei. In contrast, in the neurohypophysis, it was present not only in secretory granules but also on the surface of axon terminals and glia and in extracellular spaces. Taken together, our observations reveal that the cell adhesion glycoprotein F3 is colocalized with neurohypophysial peptides in secretory granules. It follows, therefore, the regulated pathway of secretion in HNS neurons to be released by exocytosis at their axon terminals in the neurohypophysis, where it may intervene in activity-dependent structural axonal plasticity.     

Substrate specificity of the mammary tissue anionic amino acid carrier operating in the cotransport and exchange modes

Endogenous opioid peptides serve as growth factors in developing, renewing, and neoplastic cells and tissues. This study examined the hypothesis that opioids serve to modulate the homeostatic renewal of ocular surface epithelium in the rat. DNA synthesis in the epithelium of the central (CC) and peripheral (PC) cornea, limbus (LM), and conjunctiva (CN) was investigated using adult male rats. Animals received an injection of opioid growth factor (OGF), [Met5]-enkephalin, OGF and naloxone (NAL), NAL alone, naltrexone (NTX), or an equivalent volume of sterile water (CO) and sacrificed 4 h later (i.e. 16:00 h). [3H]thymidine was administered 1 h before sacrifice. With the exception of NTX (20 mg/kg), all compounds were given at 10 mg/kg. Examination of 5 time points over an 18-h period revealed no variation in DNA synthesis within a region of ocular surface basal epithelium (BE). OGF depressed DNA synthesis of the BE by 25, 48, and 50% in the PC, LM, and CN, respectively; little labeling was recorded in the BE of the CC. Exposure to OGF-NAL or NAL alone did not alter DNA synthesis of the BE. Complete blockade of OGF-zeta receptor interaction by administration of the potent opioid antagonist, NTX, increased the number of epithelial cells in the PC, LM, and CN undergoing DNA synthesis by 30 to 72%. The effects of OGF and NTX on DNA synthesis of BE also were observed in an organ culture setting. Utilizing immunocytochemistry, OGF and its receptor zeta were associated with both the basal and the suprabasal cells of the ocular surface epithelium. These results indicate that an endogenous opioid peptide, OGF, and its receptor are present and govern homeostatic cellular renewal processes in ocular surface epithelium. OGF regulates DNA synthesis in a direct manner, and does so by a tonic, inhibitory, and receptor-mediated mechanism.     

DNA vaccination with cytokine fusion constructs biases the immune response to ovalbumin

DNA vaccination may work through direct transfection of antigen presenting cells (APC), or by secretion of the encoded protein by muscle or skin cells for uptake by APC. If cytokines are attached to the antigen, they may influence APC or responding T cells to drive the response toward a Th1 or Th2 direction, and/or potentiate it in an antigen-specific manner. To test this concept, expression vectors were constructed containing the ovalbumin (OVA) gene either alone, or linked to cytokine genes including GM-CSF, IFN-gamma, IL-2, IL-4, IL-12, or a sequence encoding nine amino acids of IL-1 beta. These constructs expressed OVA-cytokine fusion proteins in vitro which retained cytokine bioactivity. C57BL/6 mice were injected intramuscularly with the DNA constructs. Little if any OVA-specific antibody was produced in response to any of the DNA constructs, except for OVA-IL-4. However, lymphocytes from BALB/c mice vaccinated with OVA-IL-12 and OVA-IL-1 beta constructs produced more IFN-gamma and less IL-4 during in vitro restimulation assays than did other groups. All constructs elicited OVA-specific cytotoxic responses which were maintained or even increased over 16 weeks. The OVA-IL-12 and OVA-IL-1 beta peptide constructs elicited the strongest cytotoxic responses at 2 weeks postinjection. Cytotoxic responses were seen in all animals, even those lacking OVA-specific Ab, and were not related to Ab level. These studies indicate that the humoral, cytokine, and cytotoxic responses to DNA vaccination can be effectively altered by certain cytokine fusion constructs.     

Triazolam-induced changes in alcoholic thought processes

This study was designed to examine and contrast cognitive effects (explicit memory and access to semantic knowledge) of the benzodiazepine Halcion (triazolam) in ten normal volunteers and ten cognitively un-impaired detoxified alcoholics. The two groups were indistinguishable from one another under placebo conditions on all measures of cognitive functioning. Under Halcion test conditions (0.375 mg p.o.), both groups were about equally impaired in their recall of to-be-remembered information. However, alcoholics, were more likely to recall information that they were not asked to remember (intrusion errors) on all measures of explicit remembering. Alcoholics also generated relatively uncommon (low frequency) responses from semantic memory, rather than common, categorically related associations in response to stimuli such as types of vegetables, flowers, and fruit following the administration of Halcion, but were not different from normal volunteers in the types of responses generated under placebo conditions. These findings suggest that a drug challenge that simulates many of the effects of acute alcohol administration induces alcoholics to think and remember differently (qualitatively) from normal volunteers.     

Antibody to Mac-1 or monocyte chemoattractant protein-1 inhibits monocyte recruitment and promotes tumor growth

Human tumors are frequently infiltrated by numerous monocytes/macrophages, which can be found within the tumor mass (intratumoral) or surrounding the tumor (peritumoral). The functional role that these monocytes/macrophages play in tumor growth is controversial. To address this issue we inhibited intratumoral monocyte/macrophage recruitment with mAbs that either blocked integrin function or neutralized a tumor-produced chemotactic protein. Both treatments significantly increased tumor formation and accelerated tumor growth. Surprisingly, the same results were obtained when recruitment of peritumoral or intratumoral monocytes/macrophages was blocked. Our findings are contrary to one of the purported roles of monocytes/macrophages, particularly in the peritumoral area, since we found no evidence for monocyte/macrophage-supported tumor growth. These results provide direct evidence that intratumoral as well as peritumoral monocytes/macrophages act to limit tumor size in the early stages following tumor inoculation and provide a mechanism that accounts for monocyte/macrophage recruitment to human tumors.