Ibotenic acid lesions in the pedunculopontine region result in recovery of visual orienting in the hemianopic cat.

Cats rendered hemianopic by a unilateral visual cortical ablation can recover the visual orienting response in the hemianopic visual field following disruption of the caudal non-tectotectal containing half of the commissure of the superior colliculus. Ibotenic acid lesions of a small 'critical zone' in the contralateral substantia nigra result in a similar recovery effect. A conceptual framework developed by Wallace et al. (1990) [J. Comp. Neurol. 296, 222-252] proposed that elimination of contralateral substantia nigra 'critical zone' inhibition on the superior colliculus ipsilateral to a visual cortical lesion is responsible for the recovery. This model is insufficient, however, to explain the observation that hemi-decorticate cats with contralateral substantia nigra 'critical zone' lesions which include but extend beyond the 'critical zone' do not demonstrate the recovery. In these cats, subsequent transection of the commissure of the superior colliculus does lead to the recovery. We hypothesize that another projection through the caudal commissure of the superior colliculus, from the pedunculopontine nucleus, is involved in the recovery effect. Visual orienting behavior was recorded before and after ibotenic acid lesions made in the pedunculopontine nucleus region contralateral to a visual cortical ablation in 16 cats. Four cats with lesions in a small rostral region of the contralateral pedunculopontine nucleus recovered the visual orienting response in the previously hemianopic visual field. Contralateral tectal projections from the pedunculopontine nucleus are thought to be cholinergic and terminate as distinct patches in the intermediate gray layers of the superior colliculus. Since this region of the pedunculopontine nucleus also receives GABA-ergic afferents from the substantia nigra, we propose that a subcortical neural circuit including the substantia nigra, pedunculopontine nucleus, and superior colliculus is involved in the recovery of visual orienting.

Optimization of a somatostatin mimetic via constrained amino acid and backbone incorporation.

Constrained analogues 5-7 of the potent and subtype selective somatostatin mimetic 1 were prepared by incorporating conformational constraints into the nine-membered heterocyclic scaffold. Each constrained peptidomimetic showed an altered activity profile relative to lead compound 1, with compound 7 exhibiting a 25-fold and 2-fold binding enhancement against somatostatin receptor subtypes sst4 and sst5, respectively.

Compounds that activate the mouse melanocortin-1 receptor identified by screening a small molecule library based upon the beta-turn.

A library of 951 compounds based upon the beta-turn motif were examined for their ability to stimulate the melanocortin-1 receptor. From this screening process, we have identified two compounds possessing low micromolar agonist activity at the mMC1R. The compound EL1 with racemic Nal(2') in the i + 1 position, DPro in the i + 2 position, and Trp in the i + 3 position possesses an EC(50) of 42.5 +/- 6.9 microM. Compound EL2 with Trp in the i + 1 position, DLys in the i + 2 position, and Phe in the i + 3 position possesses an EC(50) value of 63.4 +/- 26.9 microM. The results of the library screening process are consistent with a hypothesis dating back to the 1980s proposing that a beta-turn conformation involving the melanocortin "Phe-Arg-Trp" core amino acids provides the key recognition element. Additionally, these compounds represent the first nonpeptidic heterocyclic molecules reported to date that are able to activate the MC1R, a melanocyte receptor involved in skin pigmentation and animal coat coloration.

Optimizing hospital-based home care for dying cancer patients: a population-based study.

In many reports the percentage of home deaths in cancer is based on selected populations. In this population-based study all cancer patients who died within 12 months within a specified area were studied (n = 108). This area is covered by hospital-based home care (HBHC) on a 24-h basis, which doctors available by day and at night. Forty people (37%) out of the total cancer population died in their own homes. Another 11% would theoretically have been ideal candidates for home care at the end of life. Thus, a home death rate of about 50% of the cancer patients is a realistic figure, and much higher than the usual 5-15% reported, provided that an effective HBHC is offered.

Disinhibition of the superior colliculus restores orienting to visual stimuli in the hemianopic field of the cat.

Following unilateral removal of all known visual cortical areas, a cat is rendered hemianopic in the contralateral visual field. Visual orientation can be restored to the blind hemifield by transection of the commissure of the superior colliculus or by destruction of the superior colliculus (SC) or the substantia nigra pars reticulata (SNpr) contralateral to the cortical lesion. It is hypothesized that a mechanism mediating recovery is disinhibition of the SC ipsilateral to the cortical lesion. The ipsilateral nigrotectal projection exerts a robust inhibitory tone onto cells in the SC. However, ibotenic acid destruction of SNpr neurons, which should decrease inhibition onto the SC, does not result in recovery. The failure of ipsilateral SNpr lesions to produce recovery puts into question the validity of SC disinhibition as a mechanism of recovery. We directly tested the disinhibition hypothesis by reversibly disinhibiting the SC ipsilateral to a visual cortical lesion with a gamma-aminobutyric acid (GABA)A antagonist, bicuculline methiodide. In accordance with the hypothesis, transient disinhibition of the SC restored visual orienting for several hours in three of eight animals. Recovery was not a volume or pH effect and was distinct from the release of irrepressible motor effects (i.e., approach and avoidance behaviors) seen within the first hour after injection. Thus, in the absence of all visual cortical areas unilaterally, disinhibition of the SC can transiently restore the ability of the cat to orient to visual stimuli in the previously "blind" hemifield.

Ibotenic acid lesions of the substantia nigra pars reticulata ipsilateral to a visual cortical lesion fail to restore visual orienting responses in the cat.

Unilateral removal of all known visual cortical areas in the cat renders the animal hemianopic in the contralateral visual field as measured by visual perimetry and other behavioral tests. We have shown that visual orientation behavior can be restored to the previously blind hemifield by destruction of a critical zone in the substantia nigra pars reticulata contralateral to a cortical lesion (Wallace et al., J. Comp. Neurol. 296:222-252, 1990). The model proposed to explain this recovery postulates that damage to the crossed nigrotectal projection disinhibits the superior colliculus ipsilateral to the cortical lesion and this leads to recovery. If disinhibition can account for recovery, then destruction of the uncrossed nigrotectal projection, which is known to exert a tonic inhibition on the superior colliculus, should also result in recovery. We made unilateral visual cortical ablations and ipsilateral ibotenic acid lesions of the substantia nigra pars reticulata. Visual orienting behavior was assessed in animals for a period of 4 to 31 weeks. Contrary to the prediction of the model, we failed to observe a recovery of visual orienting behavior in the blind hemifield in any of 23 animals.

Synthesis of Enantiomerically Pure Bis(hydroxymethyl)-Branched Cyclohexenyl and Cyclohexyl Purines as Potential Inhibitors of HIV.

The synthesis of the enantiomerically pure bis(hydroxymethyl)-branched cyclohexenyl and cyclohexyl purines is described. Racemic trans-4,5-bis(methoxycarbonyl)cyclohexene [(+/-)-6] was reduced with lithium aluminum hydride to give the racemic diol (+/-)-7. Resolution of (+/-)-7 via a transesterification process using lipase from Pseudomonas sp. (SAM-II) gave both diols in enantiomerically pure form. The enantiomerically pure diol (S,S)-7was benzoylated and epoxidized to give the epoxide 9. Treatment of the epoxide 9 with trimethylsilyl trifluoromethanesulfonate and 1,5-diazabicyclo[5.4.0]undec-5-ene followed by dilute hydrochloric acid gave (1R,4S,5R)-4,5-bis[(benzoyloxy)methyl]-1-hydroxycyclohex-2-ene (10). Acetylation of 10 gave (1R,4S,5R)-1-acetoxy-4,5-bis[(benzoyloxy)methyl]cyclohex-2-ene (11). (1R,4S,5R)-1-Acetoxy-4,5-bis[(benzoyloxy)methyl]cyclohex-2-ene (11) was converted to the adenine derivative 12 and guanine derivative 13 via palladium(0)-catalyzed coupling with adenine and 2-amino-6-chloropurine, respectively. Hydrogenation of 12 and 13 gave the correspondning saturated adenine derivative 14 and guanine derivative 15. (1R,4S,5R)-4,5-Bis[(benzoyloxy)methyl]-1-hydroxycyclohex-2-ene (10) was converted to the adenine derivative 16 and guanine derivative 17 via coupling with 6-chloropurine and 2-amino-6-chloropurine, respectively, using a modified Mitsunobu procedure. Hydrogenation of 16 and 17 gave the corresponding saturated adenine derivative 18 and guanine derivative 19. Compounds 12-19 were evaluated for activity against human immunodeficiency virus (HIV), but were found to be inactive. Further biological testings are underway.

Nutritional value of micro-encapsulated fish oils in rats.

The nutritional value of a micro-encapsulated fish oil product has been investigated. Three groups of 10 male Wistar rats each were fed diets containing 20% (w/w) of fat, and only the type and form of the fat added was different. In the test groups 5% (w/w) of fish oil either as such or in a micro-encapsulated form was incorporated in the diets. The remaining fat was lard supplemented with corn oil to a dietary content of linoleic acid at 10% (w/w). The control group received lard and corn oil only. A mixture similar to the dry matter in the micro-encapsulated product was also added to the diets not containing this product. The uptake of marine (n-3) polyunsaturated fatty acids (PUFA) from both types of fish oil supplement was reflected in the fatty acid profiles of liver phosphatidyl cholines (PC), phosphatidyl ethanolamines (PE), triglycerides (TG) and cardiolipin (CL). A suppression of the elongation of linoleic acid leading to a higher concentration of this fatty acid in liver PC and PE was also observed. The concentration of total lipids, triglycerides, cholesterol and phospholipids in liver was similar in all groups. Supplements of long chain (n-3) PUFA did not influence the concentration of plasma TG but lowered the level of plasma cholesterol. No change in the oxidative status, measured as glutathione peroxidase activity and cytochrome P450 concentration in the liver, was found after feeding with fish oil either directly or in the micro-encapsulated form. Intake of (n-3) PUFA lowered the concentration of vitamin E in plasma while the content of vitamin E in the liver was unchanged. Overall, fish oil and micro-encapsulated fish oil resulted in the same fatty acid pattern in the major lipid classes and the same concentrations of liver and plasma lipids. Furthermore, supplementation of fish oil or micro-encapsulated fish oil did not induce oxidative stress when the diets were supplemented with ambient concentrations of anti-oxidants. It is concluded that micro-encapsulated fish oil is suitable for increasing the intake of (n-3) PUFA by fortification of normal daily food ingredients.

Clinicopathologic study of paraneoplastic brainstem encephalitis and ophthalmoparesis.

We report three patients who exhibited ophthalmoparesis as an early manifestation of progressive paraneoplastic brainstem encephalitis. In two patients, anti-Hu antibodies were detected, whereas in a third, found at postmortem to have thyroid cancer, no antibodies were identified. Postmortem examination of two patients disclosed extensive gliosis, perivascular inflammation, and cell loss in the midbrain and pontine tegmentum. In one of these patients, there was selective neuronal loss within the third, fourth, and sixth nerve nuclei. We conclude that supranuclear or nuclear ophthalmoparesis may be the initial manifestation of paraneoplastic brainstem encephalitis. Our pathologic data suggest that the ophthalmoparesis may result from selective neuronal death within the brainstem tegmentum and ocular motor nuclei.

Ibotenic acid lesions of the superior colliculus produce longer lasting deficits in visual orienting behavior than aspiration lesions in the cat.

We compared the effects of unilateral surgical aspiration and ibotenic acid produced lesions of the superior colliculus (SC) on visual orienting behavior in 20 cats. Four animals with aspiration lesions initially showed an hemianopia in the contralateral hemifield which recovered fully in 4.5 weeks or less. These lesions also destroyed axons in the commissure of the superior colliculus (CS). In 9 animals we produced complete loss of cells in one SC, with preservation of axons in the CSC, by injections of ibotenic acid. In these animals the contralateral hemianopia persisted for an average of 16.6 weeks, but may have persisted longer had we not intervened by either sacrificing the animal or ablating the visual cortex contralateral to the SC lesion. The cortical lesion produced an immediate hemianopia in the contralateral hemifield and a recovery in the previously hemianopic ('collicular') hemifield. In the remaining 7 animals with attempted ibotenic acid lesions, 5 had incomplete lesions and 2 others sustained major damage to the SC as well as the CSC. These 7 animals recovered visual orienting on an average of 3.0 weeks postoperatively. We conclude that unilateral loss of collicular cell function and the presence of fibers coursing through the commissure of the superior colliculus are both necessary for the prolonged deficit in visual orienting behavior. We suggest that competition between the two hemifields may play a role in the hemianopia caused by collicular manipulations and that the cholinergic pathway from the pedunculopontine nucleus to the contralateral SC via the CSC may be involved.

The spatial relationship between the cerebral cortex and fiber trajectory through the corpus callosum of the cat.

We related fiber trajectory through the feline corpus callosum to the site of fiber origin in the cortical mantle and to functional modality. The cortical fields which contribute axons to the different portions of the corpus callosum were revealed by applying horseradish peroxidase (HRP) to the cut ends of selected groups of callosal axons in twelve adult cats. Overall, the application of HRP at progressively more caudal positions in the corpus callosum labels fields of neurons at successively more caudal positions in the cerebral cortex. Comparison of these data to functionally distinct cortical zones shows that the callosal body conveys a mixture of fibers arising from functionally diverse regions of the cerebrum, whereas portions of the rostral and caudal ends appear to be essentially unimodal, conveying motor and visual signals, respectively.

Fragmentation of the Golgi apparatus of motor neurons in amyotrophic lateral sclerosis (ALS). Clinical studies in ALS of Guam and experimental studies in deafferented neurons and in beta,beta'-iminodipropionitrile axonopathy.

Previous morphological immunoenzymatic studies with organelle-specific antibodies have disclosed an apparent fragmentation of the Golgi apparatus in large numbers of motor neurons in 12 cases of sporadic, non-Guamanian amyotrophic lateral sclerosis (ALS) in three cases of other types of motor neuron disease and in one case of a mitochondrial myopathy with cytochrome c oxidase deficiency. Motor neurons with fragmented Golgi apparatus were moderately atrophic; in these cells, discrete immunostained elements of the organelle were twice as many as in normal neurons, and the size of each Golgi element and the percentage of the cytoplasmic area occupied by the Golgi apparatus were reduced (Am J Pathol 1992, 140: 731-737). In this report we have confirmed the fragmentation of the organelle of motor neurons in the spinal cord in six sporadic cases of Guamanian ALS. In four of the six cases the clinical course was 1 to 2 years. The percentages of motor neurons with fragmented Golgi apparatus varied from 38 to 92. Motor neurons from three additional cases of Guamanian ALS of clinical duration from 5 to 7 years did not show fragmentation of the Golgi apparatus. In two cases of Guamanian ALS and in one non-Guamanian ALS, all neurons with ubiquitin-positive skein-like or granular inclusions believed to be pathognomonic for ALS had fragmented Golgi apparatus. To examine whether the fragmentation of the Golgi apparatus results from reactions to either neuronal deafferentation or to lesions of proximal axons, we conducted two experimental studies. In the first study, we examined in cats the Golgi apparatus of deafferented neurons of the dorsal lateral geniculate nucleus. In the second study, we examined the Golgi apparatus of motor neurons in the spinal cord of rats with proximal axonopathy induced by beta,beta'-iminodipropionitrile. In these two experiments, the neuronal Golgi apparatus studied by immunoenzymatic techniques and morphometry, was not fragmented. Taken together, the results of these studies strongly suggest that the fragmentation of the Golgi apparatus of motor neurons in ALS represents an important and perhaps early change of the organelle that may be involved in the pathogenesis of ALS. The fragmentation of the Golgi apparatus of motor neurons is a fairly specific and easily recognizable marker of ALS and may be used together with other criteria for comparisons between the human disease and proposed animal models of the disorder.

Dyke Award paper. MR of wallerian degeneration in the feline visual system: characterization by magnetization transfer rate with histopathologic correlation.

PURPOSE: To examine the utility of measuring magnetization transfer ratio for for delineating the dynamic changes of wallerian degeneration which occur after controlled injury in a feline model in which anatomic pathways are well understood. METHODS: Using standard neurosurgical techniques, discrete lesions were made to ablate the visual cortex. Gradient imaging was performed serially at 1.5 T, with and without a saturation pulse to create a magnetization transfer effect. At varying intervals, the animals were killed for histologic analysis. RESULTS: Within the first 2 weeks there is a statistically significant increase in magnetization transfer ratio relative to the control hemisphere within the white matter connections between the lateral geniculate nucleus and the visual cortex at a time when no effects are visually detectable on spin-echo images. Between 16 and 28 days, this reverses to a decrease in magnetization transfer ratio in both the lateral geniculate nucleus itself and the adjacent superolateral white matter. More remote white matter tracts remained stable, without significant change. CONCLUSIONS: Magnetization transfer ratio seems to be more sensitive for early detection of degeneration than conventional spin-echo imaging. Moreover, temporal changes in magnetization transfer ratio seem to correspond well with known histologic phases of wallerian degeneration.

Trapeziectomy and ligament reconstruction for osteoarthrosis of the base of the thumb. A prospective study of 100 operations.

100 thumbs with primary osteoarthrosis of the joints of the trapezium were treated by trapeziectomy and a FCR sling arthroplasty to reconstruct a first intermetacarpal ligament by the method described by Burton and Pellegrini (1986). Pain at rest remained in five. Some pain at or after exertion persisted in 46, and 49 became completely pain-free. 88 were satisfied with the procedure and there was a significant increase in pinch strength and in the ability to perform activities of daily life. It has become our preferred procedure for treating osteoarthrosis of the basal joint of the thumb.

Ibotenic acid lesions of the lateral substantia nigra restore visual orientation behavior in the hemianopic cat.

Transection of non-tectotectal fibers in the caudal one-half of the commissure of the superior colliculus restores visual orienting to a cat previously rendered hemianopic by a large unilateral visual cortical lesion. Other observations related to this recovery phenomenon (i.e., the Sprague effect) have suggested that the caudal commissural fibers whose destruction produces the recovery 1) are contralateral afferents to the superior colliculus on the side of the cortical lesion, and 2) profoundly influence visuo-motor processing in this superior colliculus. We performed anatomical and behavioral experiments to determine which of the more than 40 contralateral collicular afferents are directly involved in the Sprague effect. To guide subsequent behavioral studies, we performed a pilot anatomical experiment in which we injected WGA-HRP unilaterally into one superior colliculus at identical retinotopic loci in each of a pair of cats. One cat was normal (control), and the other (experimental) had previously received a caudal transection of the collicular commissure. Quantitative comparison of the retrograde labeling in collicular afferents revealed that a number of mesencephalic regions contain neurons that project to the colliculus via the caudal collicular commissure. Additional collicular injections of WGA-HRP demonstrated the exact location and distribution of collicular afferent neurons within these nuclei. In the behavioral experiments, we attempted to replicate the Sprague effect by destroying the neurons giving rise to the axons in the caudal collicular commissure. Ibotenic acid lesions of these neurons were performed in cats that were hemianopic following the removal of the contralateral visual cortex. Small lesions of a "critical zone" in the rostro-lateral substantia nigra pars reticulata and possibly the overlying ventral zona incerta consistently produced a visual recovery whereas lesions of the other collicular afferents did not. Paradoxically, large nigral lesions that also included the critical zone did not result in a recovery. A conceptual framework for these findings involving striato-nigro-tecto-preoculomotor interactions is presented.

Recovery from cortical blindness mediated by destruction of nontectotectal fibers in the commissure of the superior colliculus in the cat.

Transection of the commissure of the superior colliculus restores visual orientation behavior to a cat previously rendered hemianopic by a unilateral visual cortical lesion (the Sprague effect). Using two methods, we asked whether this recovery resulted from the severing of the tectotectal component of the commissure or whether the destruction of some other connection was responsible. First, we transected either the rostral or the caudal one-half of the tectal commissure in hemianopic cats. If destruction of tectotectal fibers is responsible for the Sprague effect, then only rostral transections should produce the recovery since nearly all tectotectal connections lie in the rostral one-half of the commissure. However, rostral cuts failed to produce a recovery, whereas caudal commisurotomies did. Second, ibotenic acid was used to destroy the cells in the superior colliculus contralateral to the cortical lesion. This lesion eliminated the contralateral tectotectal pathway from the contralateral colliculus but left other fibers (originating elsewhere but coursing through the commissure) largely intact. These ibotenic acid lesions failed to produce the recovery; but when the caudal portion of the tectal commissure was subsequently transected in the same animals, the recovery was observed. The results of both experiments support the conclusion that the transection of a nontectotectal component of the commissure of the superior colliculus is responsible for the recovery of visual orientation behavior in a cortically blind cat.

Cerebral metabolism and patterned visual stimulation: a positron emission tomographic study of the human visual cortex.

We studied the impact of visual stimulation upon cerebral metabolism in normal young men using FDG-PET. Results obtained from subjects receiving patterned visual stimulation while performing an ocular fixation task were compared with results from ocular fixation alone. Visual stimulation in the macular region of either hemifield produced significant increases in metabolism of the contralateral posterior striate cortex. Visual stimulation induced highly significant asymmetries in metabolism of the prefrontal and inferior parietal cortices. Metabolic activation in extrastriate areas tended to be right-sided. These findings support the classic notion of retinotopic organization within the primary visual sensory cortex. They also indicate that the patterns of cerebral metabolism are not equivalent between the two cerebral hemispheres. This latter finding suggests that in humans the right cerebral hemisphere may be specialized for visual processing.