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Biomedical subjects

R L Hoffman

Publications and source records attributed to R L Hoffman.

At least 19 recordsLinked to original sources
PubMed2003

A siphonotid millipede (Rhinotus) as the source of spiropyrrolizidine oximes of dendrobatid frogs.

Poison frogs of the neotropical family Dendrobatidae contain a wide variety of lipophilic alkaloids, which are accumulated from alkaloid-containing arthropods. A small millipede, Rhinotus purpureus (Siphonotidae), occurs microsympatrically with the dendrobatid frog Dendrobates pumilio on Isla Bastimentos, Bocas del Toro Province, Panamá. Methanol extracts of this millipede contain the spiropyrrolizidine O-methyloxime 236, an alkaloid previously known only from skin extracts of poison frogs, including populations of D. pumilio. Thus, R. purpureus represents a likely dietary source of such alkaloids in dendrobatid frogs.

Alkaloids↗
PubMed2002

Preclinical studies characterizing the anti-migraine and cardiovascular effects of the selective 5-HT1D receptor agonist PNU-142633.

The present study describes the preclinical pharmacology of a highly selective 5-HT1D receptor agonist PNU-142633. PNU-142633 binds with a Ki of 6 nm at the human 5-HT1D receptor and a Ki of> 18 000 nm at the human 5-HT1B receptor. The intrinsic activity of PNU-142633 at the human 5-HT1D receptor was determined to be 70% that of 5-HT in a cytosensor cell-based assay compared with 84% for that of sumatriptan. PNU-142633 was equally effective as sumatriptan and a half-log more potent than sumatriptan in preventing plasma protein extravasation induced by electrical stimulation of the trigeminal ganglion. Like sumatriptan, PNU-142633 reduced the increase in cat nucleus trigeminal caudalis blood flow elicited by electrical stimulation of the trigeminal ganglion compared with the vehicle control. The direct vasoconstrictor potential of PNU-142633 was evaluated in vascular beds. Sumatriptan increased vascular resistance in carotid, meningeal and coronary arteries while PNU-142633 failed to alter resistance in these vascular beds. These data are discussed in relation to the clinical findings of PNU-142633 in a phase II acute migraine study.

Analgesics↗
PubMed2000

Histidine decarboxylase expression in human melanoma.

Histamine has been implicated as one of the mediators involved in regulation of proliferation in both normal and neoplastic tissues. Histidine decarboxylase, the only enzyme that catalyzes the formation of histamine from L-histidine, is an essential regulator of histamine levels. In this study, we investigated the gene and protein expression of histidine decarboxylase in melanoma. Reverse transcriptase polymerase chain reaction and in situ hybridization studies of WM-35, WM-983/B, HT-168, and M1 human melanoma cell lines both resulted in positive signals for histidine decarboxylase messenger RNA. A polyclonal chicken antibody was developed against human histidine decarboxylase and protein expression was confirmed by western blot analysis of the cell lysates, revealing a predominant immunoreactive band at approximately 54 kDa corresponding to monomeric histidine decarboxylase. Protein expression of histidine decarboxylase was also shown by flow cytometric analysis and strong punctate cytoplasmic staining of melanoma cell lines. Moreover, both primary and metastatic human melanoma tissues were brightly stained for histidine decarboxylase. When compared with the very weak or no reactions on cultivated human melanocytes both western blot and immunohistochemical studies showed much stronger histidine decarboxylase expression in melanoma cells. These findings suggest that expression of histidine decarboxylase is elevated in human melanoma.

Blotting, Western↗
PubMed1999

Differential pharmacology between the guinea-pig and the gorilla 5-HT1D receptor as probed with isochromans (5-HT1D-selective ligands).

1. Both the 5-HT1D and 5-HT1B receptors are implicated in migraine pathophysiology. Recently isochromans have been discovered to bind primate 5-HT1D receptors with much higher affinity than 5-HT1B receptors. In the guinea-pig, a primary animal model for anti-migraine drug testing, however, isochromans bound the 5-HT1D receptor with lower affinity than the gorilla receptor. 2. This species-specific pharmacology was investigated, using site-directed mutagenesis on cloned guinea-pig receptors heterologously expressed in human embryonic kidney 293 cells. Mutations of threonine 100 and arginine 102 at the extracellular side of transmembrane II of the guinea-pig 5-HT1D receptor to the corresponding primate residues, isoleucine and histidine, respectively, enhanced its affinity for isochromans to that of the gorilla receptor, with little effects on its affinities for serotonin, sumatriptan and metergoline. Free energy change from the R102H mutation was about twice as much as that from the T100I mutation. 3. For G protein-coupling, serotonin marginally enhanced GTPgamma35S binding in membranes expressing the guinea-pig 5-HT1D receptor and its mutants, but robustly in membranes expressing the gorilla receptor. Sumatriptan enhanced GTPgamma35S binding in the latter nearly as much as serotonin, and several isochromans by 30-60% of serotonin. 4. We discovered key differences in the function and binding properties of guinea-pig and gorilla 5-HT1D receptors, and identified contributions of I100 and H102 of primate 5-HT1D receptors to isochroman binding. Among common experimental animals, only the rabbit shares I100 and H102 with primates, and could be useful for studying isochroman actions in vivo.

Animals↗
PubMed1999

Elevated tryptase, nerve growth factor, neurotrophin-3 and glial cell line-derived neurotrophic factor levels in the urine of interstitial cystitis and bladder cancer patients.

PURPOSE: The 2 prominent features of interstitial cystitis are pain and increased numbers of mast cells in the bladder. In this pilot study we determined the concentration of soluble mediators associated with activation of sensory neurons and/or mast cells that were present in the urine. MATERIALS AND METHODS: The study groups included 4 interstitial cystitis patients, 7 kidney donors with no history of bladder disease as negative controls, 6 bladder cancer patients and 7 patients with urinary tract infection as reference controls. Urine samples were assayed for different soluble mediators using immunoassays for tryptase (a marker for mast cell activation), neurotrophic factors (markers of neuronal plasticity) and chemokines (markers of inflammatory cell activity). Results were normalized based on creatinine concentration. RESULTS: There was a marked increase in the average amounts of tryptase and 3 neurotrophic factors in patient urine. Interestingly, the mediator profile in the urine of bladder cancer patients was indistinguishable from that of interstitial cystitis patients with respect to these same 4 proteins. There was no difference between normal control and urinary tract infection urine samples. CONCLUSIONS: These findings may account for several clinical and pathological features found in interstitial cystitis and bladder cancer. Although preliminary due to the limited numbers of patients, they also suggest that increased levels of neurotrophin-3, nerve growth factor, glial cell line-derived neurotrophic factor and tryptase in the urine could serve as a basis for adjunct diagnosis, monitoring and treatment of interstitial cystitis.

Adult↗
PubMed1998

Inositol--clinical applications for exogenous use.

Recent advances in nutritional and biochemical research have documented inositol as an important dietary and cellular constituent. The processes involved in inositol metabolism and its derivatives in the tissues of mammals have been characterized in vivo as well as at the enzymatic level. Biochemical functions defined for phosphatidylinositol in biological membranes include the regulation of cellular responses to external stimuli and/or nerve transmission as well as the mediation of enzyme activity through interactions with various specific proteins. Altered production of inositol has been documented in patients with diabetes mellitus, chronic renal failure, galactosemia, and multiple sclerosis. Inositol has been reported to be effective in treating central nervous system disorders such as depression, Alzheimer's disease, panic disorder, and obsessive-compulsive disorder. It has documented benefit for use in pediatric respiratory depression syndrome. In addition, recent studies have evaluated its usefulness as an analgesic. Inositol has been studied extensively as potential treatment to alleviate some negative effects associated with lithium therapy. The use of inositol in pregnant women remains controversial. Although its benefit in preventing neural tube defects in embryonic mice is documented, the risk of inducing uterine contractions limits its usefulness in pregnancy.

Animals↗
PubMed1997

Schwann cell invasion of the central nervous system of the myelin mutants.

Schwann cells are excluded from the CNS during development by the glial limiting membrane, an area of astrocytic specialisation present at the nerve root transitional zone, and at blood vessels in the neuropil. This barrier, however, can be disrupted and, with the highly migratory nature of Schwann cells, can result in their invasion and myelination of the CNS in many pathological situations. In this paper we demonstrate that this occurs in a number of myelin mutants, including the myelin deficient (md) and taiep rats and the canine shaking (sh) pup. While it is still relatively uncommon in the rodent mutants, the sh pup shows extensive Schwann cell invasion along the neuraxis. This invasion involves the spinal cord, brain stem, and cerebellum and increases in amount and distribution with age. In situ hybridisation studies using a Pzero riboprobe suggest that the likely origin of these cells in the sh pup is the nerve roots, primarily the dorsal roots. Paradoxically, Schwann cell myelination of the CNS increases with time in the sh pup despite a marked, progressive gliosis involving the glia limitans and neuropil. Thus the mechanism by which these cells migrate into the CNS through the gliosed nerve root transitional zone or from vasa nervorum remains unknown. Extensive Schwann cell CNS myelination may have therapeutic significance in human myelin disease.

Animals↗
PubMed1996

Maxillary sinus cysts in two cattle.

Two adult Holstein cattle were found to have unilateral maxillary sinus cysts. One had dyspnea and partial airway obstruction; the other had a swelling over the sinus. Both had a nonfetid, mucoid nasal discharge. Deviation of the nasal septum away from the cyst, soft-tissue opacity involving the left maxillary sinus, and a gas-capped fluid line on lateral projection were identified radiographically. The cyst fluid did not have an odor, was relatively acellular, and was of a mucoid (animal 1) or gelatinous (animal 2) nature. In 1 animal, the cyst wall and fluid were removed through a dorsolateral bone flap. The owner reported that the animal improved rapidly and remained clinically normal 27 months after surgery. In the second animal, the cyst was drained and the cyst lining was curetted through a trephine hole in the sinus. The animal improved, but was euthanatized 4 days after surgery because of concurrent problems (displaced abomasum, poor milk production) and financial constraints of the owner. The cyst walls were composed of granulation tissue and were line with stratified squamous epithelium.

Animals↗
PubMed1995

Structure-activity relationships in the 8-amino-6,7,8,9-tetrahydro-3H-benz[e]indole ring system. 1. Effects of substituents in the aromatic system on serotonin and dopamine receptor subtypes.

A series of 1-, 3-, and 4-substituted analogs to the potent 5-HT1A against 8-(dipropylamino)-6,7,8,9-tetrahydro-3H-benz[e]indole-1-carbaldehyde (5) were prepared and tested in vitro at 5-HT1A, 5-HT1D alpha, 5-HT1D beta, D2, and D3 receptors and in vivo for agonist activity in the 5-HTP and DOPA accumulation assays in reserpine-pretreated rats. Some of the compounds were resolved. The substituents used in the 1-position were chosen from a principal component analysis (PCA) plot constructed from both tabulated variables and variables calculated by semiempirical methods (PM3) and molecular mechanics software (MMX). Among the analogs prepared, some, e.g., compound 21, were equipotent to compound 5 with respect to 5-HT1A effects. All compounds were more or less selective for the 5-HT1A receptor, but many of the compounds displayed higher affinities for 5-HT1D alpha than for 5-HT1D beta receptors.

Animals↗
PubMed1995

Structure-activity relationships in the 8-amino-6,7,8,9-tetrahydro-3H-benz[e]indole ring system. 2. Effects of 8-amino nitrogen substitution on serotonin receptor binding and pharmacology.

A series of analogs of the potent and selective 5-HT1A agonist 8-(di-n-propylamino)-6,7,8,9-tetrahydro-3H-benz[e]indole-1-carbaldehyde (2b) (OSU191) was prepared in which the dipropylamino group was modified to bear a variety of substituents. These compounds were evaluated for both in vitro and in vivo effects, including the establishment of a receptor binding profile for these analogs at the 5-HT1A, dopamine D-2, dopamine D-3, 5-HT1D alpha, and 5-HT1D beta sites. Several of the analogs were evaluated for their biochemical effects in reserpinized rats, specifically with regard to in vivo changes in brain levels of 5-HTP and DOPA. Nearly all of the compounds prepared for this study were exceedingly potent at the 5-HT1A receptor, although most also displayed significant affinity for the dopamine D-2 receptor. A strong preference for the 5-HT1D alpha over the 5-HT1D beta receptor was also apparent. An analog bearing a butylglutarimide side chain, S-7k, was extremely selective for the 5-HT1A receptor. Although this compound possessed a Ki of 0.6 nM, it elicited only modest changes in 5-HTP brain levels. However, this compound did not appear as an antagonist when tested in a cyclic-AMP-based intrinsic activity assay.

Animals↗
PubMed1995

Oligodendrocyte survival and function in the long-lived strain of the myelin deficient rat.

This study has examined cellular and molecular aspects of glial cell function in a newly described long-lived myelin deficient rat mutant. In contrast to the shorter-lived mutants which died at 25-30 days, the longer-lived mutant rats lived to 75-80 days of age. Despite living longer, these mutants had a similar frequency of seizures to their younger counterparts. In the spinal cord and optic nerves of the older mutants, myelinated fibres in similar numbers to those seen in the younger myelin deficient rats were present. However, the total glial cell numbers were markedly reduced with few remaining normal appearing oligodendrocytes, and very few microglia compared to the younger mutants. In addition, little or no cell death or division was seen in the longer-lived rats. However, there was some evidence of ongoing myelination and the persistence of immature oligodendrocytes or their progenitors in the older mutant. There was some continued myelin gene expression, although this was at much reduced levels compared to normal, with proteolipid protein and myelin basic protein being most affected. In situ hybridization analysis for proteolipid protein mRNA showed that few proteolipid protein expressing oligodendrocytes remained in the 70-80-day-old mutant. Polymerase chain reaction analysis of exon 3 of the long-lived mutant revealed the same point mutation as described in the younger myelin deficient rat.

Animals↗
PubMed1991

Neospora-like protozoan infection as a major cause of abortion in California dairy cattle.

Ninety-five aborted bovine fetuses received from California dairies over a 4.5-year period had histologic lesions of focal encephalitis. Protozoa that reacted with Neospora caninum antiserum were detected in the brain of 88 of these fetuses and in the heart of 1 fetus. Sarcocystis spp schizonts were seen in the vascular endothelium of 1 fetus. It was concluded that a Neospora-like cyst-forming coccidian may be a major cause of abortion in California dairy cattle.

Abortion, Veterinary↗
PubMed1990

A survey of causes of bovine abortion occurring in the San Joaquin Valley, California.

The causes of abortion in cattle in the San Joaquin Valley of California were surveyed from submissions to the California Veterinary Diagnostic Laboratory at Tulare. Four hundred sixty-eight abortion cases were examined. Most submissions (89%) were from large drylot dairies, milking an average of 814 cows. Abortion evaluations included necropsy, histopathology, bacteriology, virology, and other immunologic and serologic tests. A specific cause was identified in 29.5% of the abortions. Bacterial infections, most of which were sporadic, accounted for 16% of all abortions. Viral causes and protozoal infections were diagnosed in 5.6% and 3.2% of the abortions, respectively. Fetuses with protozoal infection had histologic lesions of focal nonsuppurative necrotizing encephalitis, and protozoa were detected. Similar histologic lesions were seen in 80 additional fetuses (17.1%), and although an etiologic agent was not identified for these cases, a protozoal infection was suspected.

Abortion, Veterinary↗
PubMed1987

Measurement of the effects of cadmium stress on protozoan grazing of bacteria (bacterivory) in activated sludge by fluorescence microscopy.

The effect of cadmium stress on protozoan bacterivory in sewage sludge was measured by experimentally exposing sludge communities to 0 to 150 mg of Cd per liter for up to 6 h and then determining the rates of protozoan grazing on bacteria, using a double-staining technique and epifluorescence microscopy. Bacterivory was measured by incubating the sludge with fluorescently labeled bacterium-sized latex beads and directly observing ingestion of the beads and bacterial cells in the sludge by epifluorescence microscopy of preserved samples. Staining with 4',6-diamidino-2-phenylindole and acridine orange permitted the simultaneous determination of protozoan numbers and bacterivory activity as estimated by the number of bacterial cells and bacterium-sized latex beads ingested by the representative ciliate Aspidisca costata. Enumeration with latex beads proved to be an effective way of estimating bacterivory in sludges subjected to heavy-metal stress. This technique should prove useful for determining the effects of other chemical stresses on protozoan numbers and bacterivory in organic-rich environments. Although the number of protozoa declined significantly only after exposure to 100 mg of Cd per liter for 4 h, grazing, as indicated by bead ingestion, was significantly inhibited by Cd concentrations of greater than 25 mg/liter in less than 1 h, and exposure to 100 mg of Cd per liter effectively stopped protozoan grazing within 1 h of exposure. Protozoan ingestion of latex beads and bacteria was inversely correlated to Cd concentration and exposure time. The reduction of protozoan bacterivory by Cd provides a possible explanation for the increase in suspended bacteria in the effluents of metal-stressed treatment facilities.

Analysis of Variance↗
PubMed1979

Surgical correction of severe mitral prolapse without mitral insufficiency but with pronounced cardiac arrhythmias.

Despite what was considered adequate pharmacological treatment, the condition of six patients with severe mitral valve prolapse but with trivial or no mitral regurgitation deteriorated. These patients had marked weakness, chest pain, dyspnea, and arrhythmias. Because these patients found their condition to be intolerable, the prolapsed mitral valve was repaired. Electrocardiography, treadmill stress testing, and left ventirculography performed following operation showed complete repair of the valve and significant improvement over the preoperative findings in all six patients. Repair of the floppy mitral valve did not eradicate all abnormalities; however, it did significantly improve the chest pain, weakness, dyspnea, and arrhythmias in all six patients. Five patients no longer require any medication. The prolapsed mitral valve contributed significantly to the symptoms and arrhythmias, but it could not have been the sole cause for these patients' signs and symptoms. With complete correction of the prolapse in all six patients, few of the signs and symptoms of the disease persisted. Repair of severe mitral valve prolapse without mitral regurgitation is recommended only for those patients who continue to be severely symptomatic from chest pain, dyspnea, or ventricular arrhythmias after an extensive trial of adequate medical therapy.

Adult↗