The association of middle ear effusion with trigeminal nerve mass lesions in dogs.

The trigeminal nerve is involved in the opening of the pharyngeal orifice of the Eustachian tube by operating the tensor veli palatini muscle. The hypothesis was investigated that middle ear effusion occurs in a more severe disease phenotype of canine trigeminal nerve mass lesions compared with dogs without middle ear effusion. Three observers reviewed canine MRIs with an MRI-diagnosis of trigeminal nerve mass lesion from three institutions. Various parameters describing the musculature innervated by the trigeminal nerve were scored and compared between dogs with and without middle ear effusion. Nineteen dogs met the inclusion criteria. Ipsilateral middle ear effusion was observed in 63 per cent (95% CI 48.4 per cent to 77.6 per cent) of the dogs. The size of the trigeminal nerve mass lesions was positively correlated with the severity of masticatory muscle mass loss (Spearman r=0.5, P=0.03). Dogs with middle ear effusion had a significantly increased generalised masticatory muscle mass loss (P=0.02) or tensor veli palatini muscle loss score (P=0.03) compared with those without. Larger trigeminal nerve mass lesions were associated with a greater degree of masticatory muscle mass loss. Masticatory muscle mass and, importantly, tensor veli palatini muscle mass was more severely affected in dogs with middle ear effusion suggesting an associated Eustachian tube dysfunction.

The urokinase plasminogen activator system in cancer: a putative therapeutic target?

The urokinase plasminogen activator (uPA) system is an endogenous proteolytic cascade which can be actively subverted by the neoplastic process to facilitate progression and metastasis. Abundant experimental and clinical evidence supports such a role and elevated levels of components of the uPA system are strong negative prognosis indicators in a wide variety of tumor types. Collectively this data makes the uPA system an attractive option for targeted intervention. This review examines the role of the uPA system in tumor invasion and metastasis and assess the various therapeutic modalities developed to selectively exploit this system.

Urinary, faecal and sexual dysfunction in patients with multiple sclerosis.

The prevalence and nature of bladder and bowel dysfunction were examined in a population-based study of 221 patients with multiple sclerosis who returned postal questionnaires. This preliminary investigation was supplemented by personal review which also provided information on sexual dysfunction in 174 and laboratory and urodynamic tests in 152 participants. Thirty of 221 (14%) currently used an indwelling catheter, and 84 of the remaining 190 (44%) reported symptoms of urinary dysfunction, of which the most common were urgency and frequency. Thirteen of 144 (9%) patients had biochemical evidence of renal dysfunction, and 40 of 132 (30%) had infected urine samples. Eleven of 54 patients in whom investigation of upper urinary tract was thought to be appropriate demonstrated abnormalities. Sixty-four of 221 (29%) patients had experienced faecal incontinence, and 120 of 221 (54%) were constipated. Fifty-six of 68 (82%) men and 55 of 106 (52%) women reported a deterioration in sexual activity, the commonest symptoms being erectile failure in men and fatigue in women.

Rhythms of glutamic acid decarboxylase mRNA in the suprachiasmatic nucleus.

The purpose of the present study was to determine whether there is a rhythm in glutamic acid decarboxylase (GAD) message in the suprachiasmatic nucleus (SCN) of rats housed in a light:dark cycle. The mRNAs encoding two isoforms of GAD (i.e., GAD65 and GAD67) were examined using in situ hybridization histochemistry. Computerized image analysis of film autoradiographs revealed that GAD65 mRNA was significantly higher in the light than it was in the dark. GAD67 mRNA levels were lower overall and did not decrease significantly in the dark. Following emulsion autoradiography, silver grain counts over individual SCN cells indicated that GAD65 mRNA was highest in the dorsomedial hypothalamus during the light. These data suggest that GAD mRNA varies rhythmically in the SCN and that mRNA levels are regulated differently within SCN subdivisions during the light:dark cycle.

Dose-dependent decrements in adult male rat sexual behavior after neonatal clorimipramine treatment.

Previous studies found that months after clorimipramine (CLI) treatment of male neonatal rats, the mature animals developed behavioral deficits and REM sleep abnormalities that modeled human endogenous depression. In the initial studies neonatal rats received CLI 30 mg/kg/IP daily from age 8 through 21 days. Diminished sexual activity of the adult rats treated neonatally in this manner was a behavioral deficit that supported the depression model. However, in subsequent studies in our laboratory, the same neonatal treatment occasionally failed to produce adult sexual deficiencies found in the initial studies. The inconsistency raised the possibility that neonatal CLI treatment was not a reliable method to produce an animal model of depression. An alternative hypothesis was that the CLI dose was too low. The present study tested this hypothesis. Placebo or one of four CLI doses was administered daily to male neonatal rats (n = 12/treatment group) from age 8 days through 21 days: 30 (the original dose), 40, 50, and 60 mg/kg/IP. Six components of adult sexual behavior were measured at age 5 months. Deficiency of each sexual behavior was found to be dose-dependent (r = 0.5, p < 0.001). The 30 mg/kg/day dose caused deficiencies in some, but not all, sexual behavior measures. Higher doses caused deficiencies in all measures of sexual behavior. The results support the hypothesis that neonatal CLI treatment at doses higher than the original 30 mg/kg/day caused reliable impairments in adult male rat sexual behavior, and therby support the reliability of neonatal CLI treatment to produce an animal model of endogenous depression.

Somatostatin mRNA levels within the periventricular nucleus are regulated by estradiol and insulin-like growth factor-I in immature female rats.

Adolescent growth is regulated by developmental increases in growth hormone (GH) secretion. Although the hypothalamic release of GH-releasing hormone (GHRH) stimulates and the release of SRIF inhibits GH secretion, it is not known how these regulatory mechanisms change developmentally. In addition, GH secretion is facilitated during maturation by increases in peripheral estradiol and may be inhibited, via a negative feedback mechanism, by insulin-like growth factor-I (IGF-I). It is not clear whether these act through the hypothalamic regulation of GHRH and somatostatin (SRIF). In order to further understand the regulation of GH secretion during development, the present study determined how estradiol and IGF-I altered SRIF mRNA in the hypothalamus in immature female rats. The working hypotheses were that estradiol would decrease SRIF mRNA accounting, in part, for its positive effect on GH release and IGF-I would increase SRIF mRNA representing a negative feedback mechanism regulating GH secretion. Preprosomatostatin (ppSRIF) mRNA levels within the periventricular nucleus (PeVN) were measured with in situ hybridization in ovariectomized female rat pups (n = 5 per group). Infusions were delivered sc via either a Silastic capsule (oil, 10 or 60 micrograms/ml estradiol) or an osmotic minipump (acetic acid, 120 or 240 micrograms IGF-I/day). Following ovariectomy on Day 21, animals were treated for either 1 or 7 days beginning on Day 24 of age. A total of 18 treatment groups were evaluated, including control, estradiol alone, IGF-I alone, and estradiol and IGF-I combined at both doses and treatment durations.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasopressin and sex differences in hamster flank marking.

Vasopressin (AVP) within the medial preoptic-anterior hypothalamic continuum (MPOA-AH) plays an essential role in the control of flank marking in Syrian hamsters. Sex differences are found in the scent marking of many mammalian species, including hamsters. The first two experiments tested the hypothesis that sex differences in flank marking are the result of sex differences in the availability of AVP for release in several CNS sites. No support for this hypothesis was provided because neither immunohistochemical analysis nor radioimmunoassay of tissue punches revealed sex differences in AVP immunoreactivity in the MPOA-AH or other sites likely to be involved in flank marking. The third experiment, which tested the hypothesis that sex differences in flank marking are the result of sex differences in the sensitivity or response of the MPOA-AH to AVP, found no sex differences in the amount of flank marking stimulated by microinjection of AVP in the MPOA-AH. These data provide no support for the hypothesis that sex differences in vasopressinergic activity are responsible for sex differences in flank marking.

The control of circadian rhythms and the levels of vasoactive intestinal peptide mRNA in the suprachiasmatic nucleus are altered in spontaneously hypertensive rats.

Vasoactive intestinal peptide (VIP) has been localized within the suprachiasmatic nucleus of the hypothalamus (SCN) and appears to play an important role in the entrainment of circadian rhythms with the light-dark (LD) cycle. The spontaneously hypertensive rat (SHR), an inbred strain used extensively in research on primary hypertension, has significantly more VIP mRNA in its brain than normotensive Wistar-Kyoto control (WKY) rats. Because VIP levels are abnormally high in SHR rats the present study examined whether the mechanisms controlling circadian rhythms are also altered in SHR rats. When entrained to a 24 h LD cycle, SHR rats began their wheel-running rhythm approximately 1.5 h earlier than WKY controls. SHR rats re-entrained to a phase delay in the LD cycle more slowly than did WKY rats, but tended to re-entrain to a phase advance more rapidly. The free-running period of SHR rats in both constant light and constant dark was significantly shorter than that of WKY rats. In SHR rats, phase delays produced by 1-h pulses of light were less than one-half the magnitude of the delays seen in WKY rats; however, the phase advances were nearly twice that of WKY rats. Using in situ hybridization, the SCN levels of mRNA encoding VIP were found to be significantly greater in SHR rats, but the mRNA levels of another peptide important for entrainment, gastrin releasing peptide, did not differ between SHR and WKY rats. These data indicate that the mechanisms controlling circadian rhythms in SHR rats differ significantly from those controlling rhythms in WKY rats and that VIP mRNA is significantly elevated within the SCN of SHR rats. The role of VIP in the entrainment of circadian rhythms is discussed.

Microinjection of arginine-vasopressin into the periaqueductal gray stimulates flank marking in Syrian hamsters (Mesocricetus auratus).

Syrian hamsters can communicate using a distinctive form of scent marking called flank marking. Vasopressin-sensitive neurons within the medial preoptic-anterior hypothalamic continuum (MPOA-AH) play a critical role in the control of this form of olfactory communication. Extrahypothalamic regions may also mediate hamster flank marking. Since the MPOA-AH and the periaqueductal gray (PAG) are reciprocally connected, the present study investigated whether PAG neurons are involved in the control of flank marking. The first study found that microinjection of vasopressin, but not oxytocin or saline, into the PAG induced high levels of flank marking in male (n = 8) and female (n = 5) hamsters (P less than 0.01). The second study demonstrated that microinjection of vasopressin into the PAG stimulated flank marking in a dose-dependent manner in both male (n = 7) and female (n = 11) hamsters (P less than 0.01). These data suggest that vasopressin-responsive neurons within the periaqueductal gray participate in the control of hamster flank marking.

Norepinephrine inhibits vasopressin-stimulated flank marking in the Syrian hamster by acting within the medial preoptic-anterior hypothalamus.

Syrian hamsters exhibit a form of scent marking behavior called flank marking. Flank marking, which is elicited during social contact with other hamsters and by the odors of other hamsters, communicates socially important information such as mate choice and dominance status. Vasopressinergic activity within the medial preoptic-anterior hypothalamic continuum (MPOA-AH) is essential for the expression of flank marking. In female hamsters, an inverse relationship exists between the expression of flank marking and sexual receptivity during the 4-day estrous cycle. Since norepinephrine (NE) appears to facilitate sexual receptivity, the present study investigated whether NE might have an inhibitory effect on flank marking by acting on Vasopressinergic activity within the MPOA-AH. Microinjection of 9.0 µM arginine vasopressin (AVP) into the MPOA-AH stimulated high levels of flank marking. Microinjection of 9.0 µM AVP combined with NE in concentrations of 4.0, 0.4 or 0.2 nM, drastically reduced or eliminated flank marking. In contrast, AVP in combination with 0.09, 0.04 or 0.004 nM NE produced no significant reductions in flank marking. In addition, microinjection of 9.0 µM AVP, in combination with epinephrine (4.0 nM), but not dopamine (4.0 nM), serotonin (4.0 nM) or neuropeptide Y (900 µM), significantly reduced AVP-induced flank marking. In male hamsters, microinjection of NE (4.0 nM) combined with AVP (9.0 µM) into the MPOA-AH was not found to inhibit AVP-stimulated flank marking. These results suggest that NE is involved in regulating the expression of flank marking during the estrous cycle by acting on Vasopressinergic activity within the MPOA-AH.

Connections between the pontine central gray and the ventromedial hypothalamus are essential for lordosis in female rats.

Lesions and knife cuts were used to study central gray (CG) and ventromedial hypothalamic (VMH) mediation of sexual receptivity in female rats. Lesions of the midbrain-pontine CG eliminated lordosis in female rats. Bilateral sagittal knife cuts that bracketed the rostral pontine CG also eliminated lordosis, and an experiment with the retrograde tracer Fluoro-Gold confirmed the effectiveness of these cuts in severing the lateral connections linking the VMH and the CG. Finally, females with a unilateral hypothalamic cut combined with a contralateral CG transection almost never showed lordosis. Each cut, at a different level for each side of the brain, transected axons linking the VMH and the CG. The demonstration that this combination eliminated lordosis provides new evidence that the lateral connections between the VMH and the CG are essential for the display of sexual receptivity in female rats.

Diminished sexual activity in a new animal model of endogenous depression.

Our laboratory has proposed a new animal model of endogenous depression. The proposal is that in rats neonatal clomipramine (CLI) produces adult animals that model endogenous depression. Diminished sexual activity is a salient behavioral abnormality found in endogenous depression. This suggests that an animal model of endogenous depression should show diminished sexual activity. We report here a test of the prediction that after neonatal treatment with CLI, adult male rats show decreased sexual activity. We found that after neonatal CLI, adult male Long-Evans rats had a pervasive diminution of sexual activities including decreased mounts, intromissions, ejaculations, and increased mount latencies and postejaculatory pause. Sprague-Dawley and Wistar strains also tended to show decreased intromissions and ejaculations, but their baseline sexual activity was too low to give interpretable data. The results with the sexually active Long-Evans strain are consistent with the hypothesis that neonatal CLI produces adult rats that model human endogenous depression.

Drug effects on REM sleep and on endogenous depression.

In earlier work REM sleep deprivation (RSD) by arousals improved endogenous depression. This suggested that drugs producing a similar RSD would have antidepressant activity. The arousal RSD was large, persisted for weeks, and was followed by a REM rebound. We call RSD with these properties arousal-type RSD. The present study reviewed literature from 1962 to 1989 on drug REM sleep effects to examine the hypothesis that drugs producing arousal-type RSD improve endogenous depression. The literature reviewed concerned the REM sleep effects of amine precursors, antidepressants, antihistamines, antipsychotics, barbiturates, benzodiazepines, other hypnotics, drugs affecting cholinergic and noradrenergic neurotransmission, ethanol, lithium and narcotics. Four hundred and sixty-eight relevant papers were read and 215 contributed information that could be used in the review. The findings indicated that all drugs producing arousal-type RSD improved endogenous depression. Four drugs that improved endogenous depression did not produce arousal-type RSD.

An experimental comparison of four hearing aid prescription methods.

Four hearing aid prescription methods were compared. A digital master hearing aid was used to produce the prescribed frequency gain characteristics. Measures of speech recognition and paired comparison judgments of relative speech intelligibility and speech quality were obtained at three output levels for each of the experimental frequency gain characteristics. No single prescriptive method emerged as being clearly superior. Relative performance of the four prescriptive methods varied as a function of output level. Similar results were observed for both speech recognition testing and paired comparison testing.

Preoptic lesions increase the display of lordosis by male rats.

Male rats do not normally show feminine patterns of sexual behavior even when injected with the ovarian hormones estrogen and progesterone. We find that brain lesions which damage the preoptic-anterior hypothalamic continuum augment the display of lordosis in hormone-treated male rats. The most effectively feminizing brain lesions are ones which bilaterally destroy a substantial portion of the medial preoptic area encompassing the sexually dimorphic nucleus of the preoptic area (SDN-POA). Males with particularly large preoptic lesions are receptive following estrogen treatment and show a progesterone facilitation of receptivity. In this respect, they cannot be behaviorally distinguished from females. Thus, axons originating in and/or passing through the preoptic area apparently inhibit the display of feminine sexual behaviors in males. Preoptic development and lordosis are each predictably affected by perinatal stimulation by testicular hormones, and hormone-stimulated preoptic development may form the neurological basis for some of the defeminizing effects of perinatal hormonal exposure. Our results raise the possibility that the site of this behavioral defeminization is the SDN-POA.