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Biomedical subjects

R A Hoffman

Publications and source records attributed to R A Hoffman.

At least 55 records · Page 3Linked to original sources
PubMed1995

Regulation of inducible nitric oxide production by intracellular calcium.

BACKGROUND: Because increased nitric oxide (NO) production during sepsis can be detrimental to the host, inhibition of NO synthesis by various antagonists has been proposed as a therapeutic option. However, none of these approaches has addressed the possible regulation of inducible NO synthesis (iNOS) by endogenous intracellular signaling mechanisms. The purpose of our study was to determine whether intracellular calcium ([Ca2+]i) regulates iNOS. METHODS: The macrophage cell line RAW 264.7 cells stimulated to produce NO were cultured in the presence or absence of the calcium ionophore A23187, ionomycin, or the Ca(2+)-adenosine triphosphatase inhibitor thapsigargin. Supernatants and total cellular RNA were recovered for measurement of iNOS messenger RNA (Northern blot) and NO2- (stable end product of NO), respectively. Simultaneous measurement of [Ca2+]i was performed by fluorescence spectrophotometry. RESULTS: The calcium ionophore A23187, ionomycin, and thapsigargin all produced a dose-dependent inhibition of NO end product and iNOS messenger RNA (confirmed by densitometry) with a simultaneous increase in [Ca2+]i, confirmed by fluorescence spectrophotometry. This could not be reversed by exogenous L-arginine and was not observed if these agents were added beyond 0 hours of culture. CONCLUSIONS: Although iNOS is traditionally viewed as calcium independent, these data clearly show that [Ca2+]i regulates iNOS messenger RNA induction and end product synthesis. Endogenous cellular second messenger may thus be important in autoregulation of NO synthesis. Alternatives to pharmacologic or antagonist inhibition of NO deserve further investigation.

Arginine↗
PubMed1995

Evaluation and management of spontaneous temporal bone cerebrospinal fluid leaks.

Spontaneous temporal bone cerebrospinal fluid leak may be defined as a leak without an apparent precipitating cause. These transdural fistulas occur rarely, and diagnosis is predicated upon a high index of suspicion. Leaks have been reported through both middle and posterior fossa defects, although the vast majority involve the middle fossa plate. In a previous study we reported 7 cases of spontaneous temporal bone cerebrospinal fluid leaks, all involving the middle fossa tegmen. Upon further review of these cases and 5 previously unreported cases, the defect was localized to the tegmen tympani in 9 of the total 12 cases. Diagnostic methods are discussed, with the importance of high-resolution computed tomography stressed. The role of contrast cisternography is also evaluated. An outline for surgical management is presented based upon residual hearing and defect location and accessibility. A transmastoid procedure offers the advantage of visualization of both the middle and posterior fossa plates, and this approach can be supplemented with an obliterative procedure when indicated. The middle fossa approach provides optimal exposure of the tegmen plate with less likelihood of ossicular injury when dealing with tegmen tympani defects. Adjuncts to surgical therapy include intrathecal fluorescein dye and continuous postoperative lumbar cerebrospinal fluid drainage.

Journal Article↗
PubMed1995

Autologous fibrin glue in the prevention of cerebrospinal fluid leak following acoustic neuroma surgery.

Postoperative cerebrospinal fluid (CSF) leak is a serious complication of acoustic neuroma surgery. The authors retrospectively reviewed the charts of 492 patients who underwent acoustic neuroma surgery to determine the efficacy of fibrin glue in preventing postoperative CSF leak. Thirteen of 92 patients (14%) undergoing retrosigmoid/transmeatal surgery experienced CSF leak when fibrin glue was used; 29 of 199 patients (15%) when it was not used. Nineteen of 85 patients (22%) experienced CSF leak when fibrin glue was used following translabyrinthine surgery; 23 of 116 patients (20%) when it was not used. No decrease was noted in the incidence of CSF leak following acoustic neuroma surgery with the use of autologous fibrin glue.

Cerebrospinal Fluid Otorrhea↗
PubMed1995

Comparison of the nitric oxide synthase inhibitors methylarginine and aminoguanidine as prophylactic and therapeutic agents in rat adjuvant arthritis.

OBJECTIVE: To compare the nitric oxide synthase (NOS) inhibitors NG-methyl-L-arginine (L-NMA) and aminoguanidine (AG) as prophylactic and therapeutic agents in rat adjuvant induced arthritis (AIA). METHODS: Arthritis was induced in male Lewis rats by the injection of adjuvant into the base of the tail. L-NMA or AG was administered twice daily by gastric intubation starting at the time of adjuvant injection, just before the onset of clinical symptoms, or after the onset of clinical symptoms. Paw swelling, plasma fibrinogen levels and urinary NO2-/NO3- excretion were measured to assess the effect of the inhibitors on the arthritis response and whole body NO biosynthesis. Selected joints were also evaluated histopathologically. The abilities of L-NMA, AG and another NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), to inhibit NO production by chondrocytes and synoviocytes were also compared. RESULTS: Treatment with L-NMA (400 mg/kg/day) or AG (500 mg/kg/day) reduced the urinary excretion of NO2-/NO3- to the control level. L-NMA suppressed the development of AIA when administered prophylactically; however, its antiarthritic properties declined with increasing delay of application. It was only weakly effective against established AIA. AG had neither a prophylactic nor a therapeutic antiarthritic effect. AG and L-NAME were much weaker inhibitors of NO production by chondrocytes and synoviocytes than L-NMA. CONCLUSION: Although L-NMA completely suppresses the development of AIA when administered prophylactically, it is much less effective when administered therapeutically. Furthermore, not all inhibitors of NOS show equal prophylactic activity against AIA. In addition, NOS inhibitors may be only weakly therapeutic, or even detrimental, in established disease. These findings should be considered when evaluating NOS inhibitors as potential therapeutic agents for the treatment of established human arthritis.

Animals↗
PubMed1994

The effects of administration of nitric oxide inhibitors during small bowel preservation and reperfusion.

The effects of nitric oxide (NO) during small bowel preservation and reperfusion were studied in a rat model of heterotopic, syngeneic LEW-->LEW transplantation. A 6-hr preservation interval was chosen, which leads consistently to moderate graft injury permitting graft and recipient survival. To evaluate the function of NO during preservation and reperfusion, two inhibitors (NitroG-L-arginine methyl ester [L-NAME] and NG-monomethyl-L-arginine [NMA]) were administered and compared with a transplanted group receiving no treatment. The extent of preservation and reperfusion injury were delineated by histologic study and by the measurement of mucosal glutaminase on tissue specimens obtained 20 min after revascularization and 24 hr and 4 weeks postoperatively. Serum and mucosal NO(2-)+NO3- levels were determined at the same time points. Graft function and survival was inferior in all cases where NO production was inhibited. When recipients were treated with NO inhibitors, graft function and survival was more impaired when L-NAME was administered compared with NMA administration. Donor and graft pretreatment with NO inhibitors impaired graft function but not survival, and was less detrimental than recipient treatment. Mucosal NO(2-)+NO3- levels significantly increased in untreated transplanted animals 20 min after reperfusion. This increase was abolished in groups treated with NO inhibitors. Serum NO(2-)+NO3- levels increased significantly after 24 hr, and this increase was even more pronounced when NO inhibitors were administered. Furthermore, liver function deteriorated after inhibition of NO, indicating a more severe inflammatory response of the recipient after NO inhibition. These data indicate that mucosal NO production within the graft during preservation, and especially during reperfusion, has beneficial effects, but increased serum NO(2-)+NO3- levels coincided with inferior graft condition due to preservation and reperfusion injury.

Animals↗
PubMed1994

Bivariate flow karyotyping with air-cooled lasers.

An experimental flow cytometer was constructed using a quartz flow cell optically coupled to a 1.22 NA lens. A pair of crossed cylindrical quartz lenses allowed multilaser excitation. Two helium-cadmium (HeCd) lasers, emitting 16 mW at 442 nm and 35 mW at 325 nm, were used to excite chromomycin A3 and Hoechst 33258 fluorescence, respectively. Bivariate flow karyotypes from normal human male chromosomes and from the Daudi cell line were obtained and were compared to those from a standard instrument using dual water-cooled lasers. The new experimental instrument exhibited comparable resolution to that from the standard instrument. In further experiments with Daudi chromosomes, the 35 mW HeCd laser was replaced with a 10 mW HeCd laser, and the system still gave good, though slightly decreased, resolution.

Air↗
PubMed1994

Androgen receptor in the harderian glands of the golden hamster: characterization and the effects of androgen deprivation, the pituitary, and gender.

The harderian glands of the golden hamster were found, by a competitive binding assay using [3H]mibolerone as the ligand, to have a high affinity androgen receptor. In intact male hamsters, this receptor was present in both cytosolic and nuclear KCl-extractable fractions. Castration or hypophysectomy led to 3- to 5-fold increases in the concentrations of cytosolic receptor with decreased dissociation constants. Hypophysectomy with maintenance of prolactin levels (by removal of pituitaries and their implantation either in the sella turcica or under the kidney capsule) had no effect on androgen receptor binding, compared to hypophysectomy alone. Female hamsters had androgen receptor levels which were 2 to 4 times higher than those of intact males. Hypophysectomy led to elevated receptor binding in ovariectomized female hamsters and this rise was prevented by maintaining prolactin levels. Binding of [3H]mibolerone in male glands was effectively inhibited by 5 alpha-dihydrotestosterone, whereas the parent molecule, testosterone, required approximately a 10-fold greater molar excess to achieve the same amount of inhibition. Estradiol and progesterone were relatively poor inhibitors of the observed binding of [3H]mibolerone, while dexamethasone was ineffective. Sucrose gradient studies indicated that the harderian androgen receptor migrated to the 8S region, as expected for this receptor in molybdate-containing gradients. These results indicate that the androgen receptor in the hamster harderian gland is a 5 alpha-dihydrotestosterone receptor.

Androgens↗
PubMed1994

Evaluation of preservation conditions and various solutions for small bowel preservation.

The aim of the study was to delineate the most optimal preservation conditions for small bowel grafts. Established preservation solutions such as EuroCollins, University of Wisconsin, histidine-tryptophane-ketoglutarate-Brettschneider, phosphate-buffered sucrose (PBS 140), and 3 new solutions--extracellular fluid (ECF), lactobionate fructose, and a modified lactobionate fructose solution--were compared with saline to determine the most optimal solution for the intestine. Recipient survival, standard histology, and glutaminase activity were used to assess the degree of injury encountered after 12 hr of preservation followed by transplantation. To evaluate the various preservation conditions, ECF was used at pH 6.8 (original ECF). Grafts were preserved most optimally when a vascular washout after the cold storage period was omitted and when topical rewarming of the graft with 37 degrees C saline before reperfusion was performed. Graft survival was not significantly different after preservation with any solution tested (50-83%). Highest graft survival (83%) was achieved with lactobionate fructose and PBS140. Histologic evaluation 20 min after reperfusion revealed minor differences between most groups; a slight advantage was observed for PBS140-preserved grafts. Mucosal glutaminase activity of PBS140-preserved grafts was significantly higher 20 min after reperfusion compared with any other solution evaluated, indicating a superior graft function. These data indicate that different preservation conditions have a great impact on postoperative graft survival and that PBS140 might be preferable to any of the other preservation solutions tested.

Adenosine↗
PubMed1994

Androgenic control of porphyrin in the Harderian glands of the male Syrian hamster is modulated by the photoperiod, which suggests that the sexual differences in porphyrin concentrations in this gland are important functionally.

BACKGROUND: The porphyrin concentrations of the Harderian glands of Syrian hamsters show marked sexual differences, with male levels being much lower than those of females. Porphyrinogenesis is inhibited by androgens, so orchidectomy leads to elevated male porphyrin concentrations; however, a number of other procedures (some of which also lower androgen levels) prevents this. We studied the effects of short-day photoperiods and melatonin on Harderian porphyrin concentrations. METHODS: Intact, castrated, or pinealectomized hamsters of both sexes were exposed to long-day or short-day photoperiods. Intact or castrated hamsters were given melatonin injections in the morning or the afternoon, or were given beeswax pellets containing melatonin. After a variable period, Harderian glands were dissected and porphyrins were measured. RESULTS: Prolonged short-day exposure (13 weeks) led to increased Harderian porphyrin concentrations and this rise was prevented by pinealectomy. The rise in Harderian porphyrins following short-day exposure was small, compared with that following castration. Short-day photoperiods also prevented the rise in porphyrin levels associated with castration and this effect was prevented by removal of the pineal. Melatonin injections, whether given in the morning or in the afternoon, had no effect on Harderian porphyrin concentration of castrated male hamsters. Continuous release melatonin pellets reduced the postcastrational rise in porphyrin levels in one experiment, while having no effect in another. In female hamsters, neither short photoperiods nor melatonin pellets influenced Harderian porphyrin concentrations. CONCLUSIONS: These results suggested that a factor from the pineal gland helps maintain the low levels of porphyrin which are characteristic of male Harderian glands, despite the decrease in androgen levels which typically results from exposure to short days. Morning and afternoon injections of melatonin and continuous release melatonin pellets failed to resolve the question of whether this pineal factor is melatonin. Our results demonstrated that low male and high female porphyrin levels are maintained in Syrian hamsters, despite seasonal variations in the hormonal milieu, suggesting that these sexual differences are important for the (still unestablished) function of the Harderian glands in this species.

Animals↗
PubMed1994

N-monomethyl arginine, an inhibitor of nitric oxide synthase, suppresses the development of adjuvant arthritis in rats.

OBJECTIVE: To test the hypothesis that nitric oxide (NO) is involved in the pathophysiology of arthritis. METHODS: Arthritis was induced in male Lewis rats by the injection of adjuvant into the base of the tail. The NO synthase (NOS) inhibitor, NG-monomethyl-L-arginine (L-NMA), was administered daily by the oral route for 19 days. Paw swelling, plasma fibrinogen levels, and urinary NO2/NO3 levels were measured to assess the effect of L-NMA on the arthritic response and whole-body NO production, respectively. On day 20, the ankle joints were processed for histopathologic evaluation. RESULTS: The onset of clinical symptoms was preceded by elevated biosynthesis of NO. In a dose-dependent manner, L-NMA inhibited both NO biosynthesis and paw swelling; histopathologic changes in the ankle joints were also prevented. D-NMA had no effect on the development of arthritis, while L-arginine reversed the effects of L-NMA. Fibrinogen levels in rats with arthritis were unaffected by L-NMA. CONCLUSION: NO is critical to the development of both the inflammatory and erosive components of adjuvant arthritis in rats. There may be a future clinical role for suitable inhibitors of NO production or activity.

Amino Acid Oxidoreductases↗
PubMed1994

Mucosal glutaminase activity and histology as parameters of small bowel preservation injury.

The present study in Lewis rats was designed to assess the predictive value of the mucosal enzyme activities of glutaminase, maltase, and xanthine oxidase and of histology as parameters to delineate the degree of small bowel preservation injury. Small bowel grafts were flushed with saline or a modified phosphate-buffered sucrose (PBS) solution, stored at 8 degrees C for 1, 6, or 12 hr, and transplanted heterotopically. Tissue samples for determination of mucosal enzyme activities were taken after the cold storage period, 20 min after reperfusion and 2 and 7 days postoperatively. Biopsies for light microscopic evaluations were obtained at the same time points, but not after cold storage. Glutaminase activity was well maintained after cold storage, regardless of the duration of preservation. Enzyme activities measured 20 min after reperfusion decreased with increasing duration of preservation (saline: R2 = 32.8%; P < 0.01; PBS: R2 = 52.3%; P < or = 0.001) and with increasing histologic preservation injury. Glutaminase activities were predictive for survival of grafts preserved with the PBS solution (R2 = 49.6%; P < or = 0.001; sensitivity 92%; specificity 100%), while the activities of maltase and of xanthine oxidase failed to do so. The degree of histologic preservation injury seen in graft specimens obtained 20 min after reperfusion was a good predictor of graft survival with a sensitivity of 90% for saline-preserved grafts and 92% for PBS-preserved grafts and a specificity of 88 and 67%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Macrophage synthesis of nitric oxide in the mouse mixed leucocyte reaction.

The production of nitric oxide (.N = O) in the splenocyte mixed leucocyte reaction (MLR) results in inhibition of allospecific lymphocyte effector function. In order to more clearly define the circumstances which promote .N = O synthesis in the MLR, responder accessory cell depleted spleen cells (ACDSC) were co-cultured with allogeneic macrophage cell lines or peritoneal macrophages. .N = O synthesis and C57BL/6 (H-2b) ACDSC proliferation were concurrently monitored in cultures comparing RAW 264.7 (H-2d, a high .N = O producer), P388D1 (H-2d, a low .N = O and BALB/c (H-2d) peritoneal macrophages as allogeneic antigen presenting cells (APC). A concentration-dependent increase in lymphocyte proliferation was observed in the presence of 1 x 10(4) to 1 x 10(5) P388D1. In contrast, addition of NG-monomethyl-L-arginine (NMA), a competitive inhibitor of .N = O synthase, was necessary in order to observe lymphocyte proliferation in the presence of increasing numbers of RAW 264.7 and BALB/c peritoneal macrophages. The addition of both anti-IL-2 and anti-IFN gamma (interferon-gamma) monoclonal antibodies inhibited .N = O synthesis in alloantigen-stimulated cultures. The IFN gamma induced expression of class II antigen, as well as the constitutive expression of class I antigen, on RAW 264.7 was similar in the presence or absence of NMA, indicating that induction of .N = O synthesis by IFN gamma does not inhibit H-2 antigen expression. Thus, cytokines produced as a result of alloimmune interaction initiate macrophage .N = O synthesis. However, allogeneic APC function, as assessed by H-2 antigen expression and subsequent stimulatory capacity of MLR, is not affected by initiation of the .N = O pathway.

Animals↗
PubMed1994

Cystic fibrosis in the southern Midwest United States: molecular characterization of the common mutations.

The identification of different mutations that cause cystic fibrosis in the people of Kansas and Oklahoma has been performed by examining 124 independent cystic fibrosis genes for the 14 most commonly mutated loci. The delta F508 3bp deletion represented 79% of the alleles, and 7% of the remaining alleles were found to harbor the mutations of R553X, G542X, or G551D. None of the remaining 10 common mutations were identified. This pattern of results contrasts with the patterns found in major cities of the United States. The ethnic diversity in these cities is much greater than in the southern Midwest region, and the remaining mutations, therefore, may represent specific ethnic contributions absent in the Midwest population studies. These results directly affect the counseling given to the Midwest patient and impact on any strategies for screening.

Alleles↗
PubMed1994

Cerebrospinal fluid leak following acoustic neuroma removal.

Cerebrospinal fluid (CSF) leak has been a constant and unresolved complication of acoustic tumor surgery. This study retrospectively reviews 381 primary acoustic tumor surgeries performed by a single, senior, neurotologist and neurosurgeon team from 1979 through 1991. There were 68 cerebrospinal fluid leaks in 66 patients (66/381; 17%). There was no significant difference in the incidence of CSF leak between the translabyrinthine group (21%) and the retrosigmoid transmeatal group (16%). Translabyrinthine leaks were evenly divided between rhinorrhea and the postauricular wound while retrosigmoid transmeatal leaks were predominantly rhinorrhea. Eleven of 14 translabyrinthine wound leaks responded to pressure dressing and suture. The remaining 3 ceased with continuous lumbar cerebrospinal fluid drainage. Ten of 14 cases of translabyrinthine rhinorrhea responded to continuous lumbar cerebrospinal fluid drainage, and those in whom it failed were cured with revision of the mastoidectomy/labyrinthectomy cavity. Twenty-one of 28 cases of retrosigmoid transmeatal rhinorrhea responded to continuous lumbar cerebrospinal fluid drainage, and those in whom it failed were cured with extracranial, transmastoid revision. The incidence of cerebrospinal fluid leak was not influenced by age, sex, size of tumor, postoperative hydrocephalus, or the intraoperative use of autologous fibrin glue. Meningitis was an unusual complication, occurring in 3% of all patients.

Cerebrospinal Fluid Rhinorrhea↗
PubMed1994

Insulin-like growth factor-1 in Syrian hamsters: interactions of photoperiod, gonadal steroids, pinealectomy, and continuous melatonin treatment.

Four experiments in Syrian hamsters examined the role and possible interaction of photoperiod, gonadal steroids, and the pineal on circulating levels of insulin-like growth factor-1 (IGF-1). In the first experiment, female hamsters were exposed to long photoperiod (LP; 14:10 LD) or short photoperiod (SP; 8:16 LD); an additional group of SP-exposed females was pinealectomized (PX). SP induced a significant depression in IGF-1 concentrations which PX partially prevented. In Experiment 2, two groups (control and castrate [CX]) of adult male hamsters were kept in LP, and three groups (intact, CX, and CX+PX) of hamsters were kept in SP for five weeks. The four groups of animals that were CX and/or maintained in SP had approximately the same mean level of IGF-1, and all four groups were significantly (P < 0.001) higher than the LP-control hamsters. In Experiment 3, four groups (intact controls, CX, CX+melatonin pellet [MEL PEL], and MEL PEL only) were kept in LP. Melatonin pellets (1 mg melatonin/24 mg beeswax/every two weeks) were implanted sc twice during the experiment. Castration induced a rise (P < 0.001) in IGF-1 levels, and this was not prevented by MEL PEL. In Experiment 4, testosterone and dihydrotestosterone pellets implanted in LP-exposed CX males prevented the CX-induced rise in IGF-1; testosterone implants also reduced IGF-1 levels in CX males treated with progesterone. In conclusion, SP treatment depresses IGF-1 in female hamsters and raises it in males. These results substantiate previous studies in other models of gonadal steroid deficient animals. They lend further credence to the hypothesis that there is a sexual dimorphism in circulating IGF-1 concentrations in the Syrian hamster that may be at least partially related to the presence of gonadal steroids.

Animals↗