Intravenous Vitamin C as an Add-on Therapy for the Treatment of Sepsis in an Intensive Care Unit: A Prospective Cohort Study.

Background and Objectives: According to the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3), sepsis is defined as "life-threatening organ dysfunction caused by a dysregulated host response to infection". The increased presence of free radicals causes an increase in oxidative stress. Vitamin C is an essential water-soluble vitamin with antioxidant activity and immunoregulatory effects that plays a potential role in the treatment of bacterial infections. Our aim was to evaluate the effectiveness of adding vitamin C to the conventional treatment of sepsis to decrease its mortality rate. Materials and Methods: In a prospective cohort study, we included patients with a diagnosis of sepsis and a SOFA score ≥ 9 who were evaluated in an Intensive Care Unit at a secondary-care hospital. According to the intensive care specialist, they were treated using two different strategies: Group 1-patients with sepsis treated with conventional treatment without vitamin C; Group 2-patients with sepsis with the addition of vitamin C to conventional treatment. Results: We included 34 patients with sepsis. The incidence of mortality was 38%, and 47% of patients used vitamin C as an adjuvant to the basic treatment of sepsis. In the basal analyses, patients treated with use of vitamin C compared to patients treated without vitamin C required less use of glucocorticoids (75% vs. 100%, p = 0.039). At follow-up, patients treated without vitamin C had higher mortality than patients treated with vitamin C as an adjuvant for the treatment of sepsis (55.6% vs. 18.8%, p = 0.03). We observed that the use of vitamin C was a protective factor for mortality in patients with sepsis (RR: 0.54, 95% CI: 0.31-0.96, p = 0.03). Conclusions: The use of vitamin C as an adjuvant to treatment decreases the risk of mortality by 46% in patients with sepsis and SOFA ≥ 9 compared to patients treated without vitamin C as an adjuvant to sepsis.

Risk Factors Associated with Adverse Events Leading to Methotrexate Withdrawal in Elderly Rheumatoid Arthritis Patients: A Retrospective Cohort Study.

Background: Rheumatoid arthritis (RA) in elderly population represents a challenge for physicians in terms of therapeutic management. Methotrexate (MTX) is the first-line treatment among conventional synthetic-disease-modifying anti-rheumatic drugs (cs-DMARDs); however, it is often associated with adverse events (AEs). Therefore, the objective of this study was to identify the incidence and risk factors of MTX discontinuation due to AEs in elderly patients with RA in a long-term retrospective cohort study. Methods: Clinical sheets from elderly RA patients taking MTX from an outpatient rheumatology consult in a university centre were reviewed. To assess MTX persistence, we used Kaplan-Meir curves and Cox regression models to identify the risk of withdrawing MTX due to adverse events. Results: In total, 198 elderly RA patients who reported using MTX were included. Of them, the rates of definitive suspension of MTX due to AEs were 23.0% at 5 years, 35.6% at 10 years and 51.7% at 15 years. The main organs and system involved were gastrointestinal (15.7%) and mucocutaneous (3.0%). Factors associated with withdrawing MTX due to AEs were MTX dose ≥ 15 mg/wk (adjusted HR: 2.46, 95% CI: 1.22-4.96, p = 0.012); instead, the folic acid supplementation was protective for withdrawal (adjusted HR: 0.28, 95% CI: 0.16-0.49, p < 0.001). Conclusions: Higher doses of MTX increase the risk of withdrawals in elderly RA, while folic acid supplementation reduces the risk. Therefore, physicians working in therapeutic management for elderly patients using MTX must focus on using lower MTX doses together with the concomitant prescription of folic acid.

Nitrofurantoin as an Add-On to Conventional Prophylaxis for the Treatment of Urinary Tract Infections in Kidney Recipients: A Prospective Cohort Study.

Urinary tract infections (UTIs) constitute one of the main complications in kidney recipients, increasing both morbidity and mortality. Due to the resurgence of antimicrobial resistance, new prophylactic approaches are being investigated. Nitrofurantoin is an antibiotic from the nitrofuran group that is effective against several Gram-negative and Gram-positive organisms; hence, there has been a resurgence in its prescription for treating MDR pathogens. Objectives: This study aims to assess the effectiveness of nitrofurantoin as an add-on to conventional therapy (amikacin + ceftriaxone or cefotaxime) for the treatment of urinary tract infections in kidney recipients. Methods: In a prospective cohort study, we included patients who received a kidney in a tertiary-care hospital. According to the intensive care specialist, group 1 patients were treated with the conventional prophylactic treatment plus nitrofurantoin as an add-on. Group 2 patients were treated only with the conventional prophylactic treatment. They were followed-up for 3 months, and the incidence of urinary tract infections was reported. Results: The UTI incidence for group 1 at 3 months was 20.6%, and for group 2, it was 20.0%; no statistical difference between treatments was observed (p = 0.9). The most commonly isolated pathogens were E. coli (28.5) and K. pneumonie (28.5%). The factor most associated with developing a UTI was female gender (aHR: 7.0; 95% IC 2.3-20.9, p < 0.001). Conclusions: In our cohort study, nitrofurantoin as an add-on in conventional therapy did not prove to be effective in preventing UTI development; therefore, other treatment options should be considered as a part of prophylactic treatment.

Small-calibre percutaneous nephrolithotomy (SC-PCNL). Therapeutic decision algorithm. / Nefrolitectomía percutánea de calibre reducido (NLP-CR). Algoritmo de decisión terapéutica.

INTRODUCTION: The progressive reduction in the calibre of the tract in percutaneous kidney surgery to the point of miniaturisation has expanded its use to smaller stones that until now have been treated with extracorporeal shock wave lithotripsy (ESWL) and retrograde intrarenal surgery (RIRS). OBJECTIVE: To provide an update on the various techniques of small-calibre nephrolithotomy (SC-PCNL) analyse their efficacy, safety and indications and determine their degree of implantation at this time. MATERIAL AND METHODS: We performed a review in PubMed of Spanish and English medical literature on the various techniques of SC-PCNL. RESULTS: The use of SC-PCNL has reduced the morbidity associated with standard PCNL, particularly bleeding, and has enabled tubeless nephrolithotomy with greater safety. There are various techniques with blurred terminology (Miniperc, Microperc, Mini-microperc, Ultraminiperc), which differ in terms of gauge employed and in certain technical aspects that require their indications be specified. Currently, SC-PCNL competes with techniques that are less invasive than standard PCNL such as ESWL and the RIRS in treating small stones, but the role of SC-PCNL is still not sufficiently understood and continues to be the subject of debate. CONCLUSIONS: The indications for PCNL are expanding to small stone sizes due to the miniaturisation of the technique. PCNL competes in this field with ESWL and RIRS. Larder studies are needed to establish the specific indications for PCNL in treating nephrolithiasis.

Substantia nigra compacta neurons that innervate the reticular thalamic nucleus in the rat also project to striatum or globus pallidus: implications for abnormal motor behavior.

The projections of the substantia nigra pars compacta (SNc) to the reticular thalamic nucleus (RTn) were assessed by measuring dopamine content and counting tyrosine hydroxylase positive (TH (+)) cells in rats with unilateral lesions induced by 6-hydroxydopamine (6-OHDA), and by using a fluorescent tract-tracing technique in rats without lesions. Injection of 6-OHDA in the RTn reduced dopamine content and the number of TH (+) cells in the SNc by about 50%. Branching of SNc was suggested by the finding that 6-OHDA deposited in the RTn significantly reduced dopamine in the striatum and globus pallidus. Moreover, injections of 6-OHDA into either the striatum or the globus pallidus significantly reduced dopamine content in the RTn. Fluorescent tracers injected into the RTn labeled TH (+) cells in the SNc. A high proportion of these TH (+) cells was double labeled when tracers were also injected into either the globus pallidus or striatum. Other experiments showed that systemic injection of apomorphine or methamphetamine induced turning behavior in rats with local deposits of 6-OHDA in either the RTn or the studied basal ganglia nuclei. The extensive dopaminergic branching suggests that the abnormal motor behavior of rats with 6-OHDA deposits in the RTn may be caused by dopaminergic denervation of more than one structure. The fact that lesion of a single dopaminergic neuron can reduce dopamine transmission in more than one structure is probably important in generating the manifestations of Parkinson's disease.

Noradrenaline-induced inositol phosphate formation in rat striatum is mediated by alpha 1A-adrenoceptors.

The aim of this study was to assess the contribution of alpha 1-adrenoceptor subtypes to noradrenaline (NA)-induced inositol phosphate formation in rat striatum. In cross-chopped slices and in the presence of 10 mM LiCl, NA stimulated the accumulation of [3H]inositol phosphates. After 60-min incubation with 100 microM NA, [3H]IP1 was the major product detected (82 +/- 3% of total [3H]inositol phosphates). Best-fit values for the concentration-response curve for NA-induced [3H]IP1 accumulation yielded an EC50 of 9.4 +/- 1.1 microM, maximum effect of 210 +/- 3% of basal, and Hill coefficient (nH) of 1.1 +/- 0.1. Pre-treatment of the slices for 30 min with the alkylating agent chloroethylclonidine (100 microM) failed to decrease significantly the response to 100 microM NA. Inhibition curves for four alpha 1-antagonists, (+)-niguldipine, prazosin, WB-4101 and 5-methylurapidil (5-MU), best-fit to a single-site model with pKi values of 9.4 ((+)-niguldipine), 9.2 (prazosin and WB-4101) and 8.8 (5-MU). The putative alpha 1 D-selective antagonist BMY 7378 reduced the response to NA only partially (30 +/- 3% inhibition at 1 microM: pKi 7.24). NA-induced [3H]IP1 accumulation was significantly reduced (to 20 +/- 9% of controls) by Ca2+ removal and increased as the extracellular Ca2+ concentration was raised from nominally zero (no added Ca2+) to 1 mM Ca2+. NA-induced [3H]IP1 accumulation was reduced by both the non-selective Ca2+ channel blocker Ni2+ (58 +/- 3% inhibition at 2 mM) and nimodipine, an antagonist of L-type voltage-operated Ca2+ channels (77 +/- 4% inhibition at 3 microM). Taken together these results indicate that NA-induced inositol phosphate formation in striatal slices is mediated by activation of alpha 1A-adrenoceptors coupled to Ca2+ entry and Ca2+ activation of phospholipase C.

Gamma-aminobutyric acid (GABAB) receptor-mediated inhibition of tyrosine hydroxylase activity in the striatum of rat.

The effects of GABA and GABA agonists on calcium and depolarization-dependent stimulation of tyrosine hydroxylase activity in striatal slices were studied. gamma-Aminobutyric acid and (-)baclofen inhibited, while muscimol and (+)baclofen did not affect, the stimulation of tyrosine hydroxylase. The inhibitory effect of GABA and (-)baclofen was blocked by the GABAB antagonist, phaclofen but not by the GABAA antagonist, picrotoxin. The data suggest that the activity of tyrosine hydroxylase on dopaminergic nigrostriatal terminals may be modulated by GABA via GABAB receptors.

Inhibitory control of the GABAergic transmission in the rat neostriatum by D2 dopamine receptors.

The aim of the study was to determine the role of dopamine on the GABAergic input to striatal projection neurons. Accordingly, the effect of the activation of dopamine D2-like receptors on GABA-mediated depolarizing postsynaptic potentials evoked in striatal slices by local stimulation was studied. Conventional intracellular recording techniques were used to record the synaptic responses. The experiments were done in the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (20 microM) and (+)-2-amino-5-phosphonovaleric acid (40 microM) to block the participation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate/kainate and N-methyl-D-aspartate receptors in the synaptic response. The GABAergic nature of the response was assessed by its potentiation by pentobarbital (50 microM) and by its elimination by bicuculline or picrotoxin. At 100 nM, a concentration already maximal, dopamine inhibited by 55% the GABAergic synaptic response. The inhibitory effect was totally blocked by the selective antagonist of D2-like receptors, sulpiride (100 nM). The dopamine inhibition was observed only in one-third of the studied neurons and was concentration dependent (IC50 = 14 nM). The inhibition was not associated with changes in the input resistance or any other membrane property. In addition, dopamine (50 nM) reduced the frequency but not the amplitude of spontaneous, bicuculline-sensitive depolarizing postsynaptic potentials. The D2-like receptor agonist quinpirole also dose-dependently (IC50 = 10 nM) inhibited the GABAergic synaptic response. As with dopamine, the inhibition did not change the membrane properties of the studied neurons. In addition, the quinpirole induced inhibition of the GABA response was accompanied by increased paired-pulse facilitation. The results indicate that D2-like receptors located on intrinsic GABAergic terminals in the rat striatum exert an inhibitory control of the GABAergic input to striatal projection neurons. The dopaminergic effect would be translated in facilitation of the firing of the neurons upon the arrival of the cortical input.

Adenosine A1 receptors control dopamine D1-dependent [(3)H]GABA release in slices of substantia nigra pars reticulata and motor behavior in the rat.

Abnormalities in dopaminergic control of basal ganglia function play a key role in Parkinson's disease. Adenosine appears to modulate the dopaminergic control in striatum, where an inhibitory interaction between adenosine and dopamine receptors has been demonstrated. However the interaction has not been established in substantia nigra pars reticulata (SNr) where density of both receptors is high. Here we have explored the interaction between A1/D1 receptors in SNr. In SNr slices, SKF 38393, a selective D1 receptor agonist, produced a stimulation of depolarization-induced Ca(2+)-dependent [(3)H]GABA release that was inhibited by adenosine. The adenosine inhibition was abolished by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective adenosine A1 receptor antagonist. DPCPX per se enhanced GABA release, indicating inhibition of the release by endogenous adenosine. When D1 receptors were blocked with SCH 23390 or the slices were depleted of dopamine, the effect of DPCPX was suppressed, showing that activation of dopamine receptors was necessary for the adenosine inhibition. In normal slices, 2-chloro-n(6)-cyclopentyladenosine (CCPA), a selective A1 agonist, inhibited GABA release, but the inhibition was prevented by the blockade of D1 receptors with SCH 23390. Superperfusion with 8-bromo-cAMP produced a stimulation of GABA release that was not blocked by CCPA: this finding indicates that the blockade of D1 effects caused by activation of A1 receptors is specific. To see if these actions on GABA release were correlated with changes in motor behavior we studied the effect of unilateral intranigral injections of modifiers of adenosine A1 and dopamine D1 receptors in rats challenged with systemic methamphetamine. Both the A1 agonist CCPA and the D1 antagonist SCH 23390 produced ipsilateral turning whereas the A1 antagonist DPCPX caused contralateral turning. These motor effects are consistent with the findings on GABA release. The results indicate the presence of an inhibitory A1/D1 receptor interaction in SNr. The inhibition exerted by A1 adenosine receptors on GABAergic striatonigral transmission would be due exclusively to blockade of the facilitation resulting from activation of D1 dopamine receptors. The data permit to better understand the action of adenosine antagonists in the treatment of Parkinson's disease.

Circling behavior elicited by cholinergic transmission in the substantia nigra pars compacta: involvement of nicotinic and muscarinic receptors.

The influence of cholinergic transmission within the substantia nigra pars compacta on circling behavior was assessed in male rats. Microinjection of physostigmine (6-37 nmol) into the caudal part of the substantia nigra pars compacta elicited a dose-dependent contralateral circling. The circling was inhibited 93 +/- 3% by the dopamine antagonist haloperidol (53 nmol) injected into the neostriatum 90 min before the injection of physostigmine (37 nmol) into the ipsilateral substantia nigra pars compacta. The effect of haloperidol was reversible, since the circling behavior was fully restored when physostigmine was applied to the same animals 24 h later. The circling was completely blocked when physostigmine (37 nmol) was applied simultaneously with the muscarinic M1 antagonist pirenzepine (2 nmol). The M2 antagonist AF-DX 116 (2 nmol) only partially blocked the circling induced by a lower dose of physostigmine (12 nmol). The nicotinic antagonist mecamylamine (5 nmol) also inhibited the circling, but only during the 5 min following co-injection of the drugs. These results indicate that endogenous acetylcholine stimulates muscarinic and nicotinic receptors of nigrostriatal dopaminergic neurons which, in turn, increase their firing rate and cause the circling behavior. We conclude that the pedunculopontine cholinergic neurons, which innervate the substantia nigra pars compacta, modulate the motor behavior by increasing the activity of dopaminergic nigrostriatal pathway.

Histamine H3 receptor activation selectively inhibits dopamine D1 receptor-dependent [3H]GABA release from depolarization-stimulated slices of rat substantia nigra pars reticulata.

The release of [3H]GABA from slices of rat substantia nigra pars reticulata induced by increasing extracellular K+ from 6 to 15 mM in the presence of 10 microM sulpiride was inhibited by 73 +/- 3% by 1 microM SCH 23390, consistent with a large component of release dependent upon D1 receptor activation. The histamine H3 receptor-selective agonist immepip (1 microM) and the non-selective agonist histamine (100 microM) inhibited [3H]GABA release by 78 +/- 2 and 80 +/- 2%, respectively. The inhibition by both agonists was reversed by the H3 receptor antagonist thioperamide (1 microM). However, in the presence of 1 microM SCH 23390 depolarization-induced release of [3H]GABA was not significantly decreased by 1 microM immepip. In rats depleted of dopamine by pretreatment with reserpine, immepip no longer inhibited control release of [3H]GABA, but in the presence of 1 microM SKF 38393, which produced a 7 +/- 1-fold stimulation of release, immepip reduced the release to a level not statistically different from that in the presence of immepip alone. Immepip (1 microM) also inhibited the depolarization-induced release of [3H]dopamine from substantia nigra pars reticulata slices, by 38 +/- 3%. The evidence is consistent with the proposition that activation of histamine H3 receptors leads to the selective inhibition of the component of depolarization-induced [3H]GABA release in substantia nigra pars reticulata slices which is dependent upon D1 receptor activation. This appears to be largely an action at the terminals of the striatonigral GABA projection neurons, which may be enhanced by a partial inhibition of dendritic [3H]dopamine release.

Cholinergic stimulation of rostral and caudal substantia nigra pars compacta produces opposite effects on circling behavior and striatal dopamine release measured by brain microdialysis.

Turning in circles is among the behaviors elicited by unilateral cholinergic stimulation of the substantia nigra. Recent studies have shown that microinjection of cholinergic agonists into the substantia nigra pars compacta increases dopamine release and turnover in the striatum of anesthetized rats [Hernández-López et al. (1992) Brain. Res. 598, 114-120; Blaha and Winn (1993) J. Neurosci, 13, 1035-1044]. In this study, the relationship between circling behavior and striatal dopamine release following cholinergic stimulation of the substantia nigra pars compacta neurons was assessed by brain microdialysis in awake rats. The results indicate that cholinergic stimulation of the substantia nigra pars compacta with the mixed nicotinic-muscarinic cholinergic agonist carbachol modulates striatal dopamine release, and this effect is accompanied by circling behavior and stereotypies. Microinjection of carbachol (109 nmol) in the caudal portions of the substantia nigra pars compacta induced contralateral circling associated with an increase of dopamine release in neostriatum. On the contrary, ipsilateral circling and reduction of striatal dopamine release was elicited when the same dose of the drug was applied in the rostral portions of the substantia nigra pars compacta. The above findings are in accordance with recent electrophysiological studies suggesting the existence of sub-populations of nigrostriatal dopaminergic neurons, and indicate that the substantia nigra pars compacta is functionally compartmentalized. We conclude that the cholinergic input to the substantia nigra pars compacta could modulate the motor behavior through regulating the firing rate of nigrostriatal dopaminergic neurons and dopamine release in the neostriatum.

Reciprocal interaction between glutamate and dopamine in the pars reticulata of the rat substantia nigra: a microdialysis study.

We studied the interactions between glutamate and dopamine in the pars reticulata of the substantia nigra by using microdialysis in unanaesthetized rats. Increased extracellular levels of glutamate in the pars reticulata were obtained by microinjecting the muscarinic agonist carbachol into the ipsilateral subthalamic nucleus. The increase of glutamate levels was followed by increments in extracellular levels of dopamine and GABA. Increased levels of the three neurotransmitters were also observed during the administration of N-methyl-D-aspartate through the microdialysis probe. The increase in glutamate and GABA caused by N-methyl-D-aspartate was blocked by SCH 23390, a selective D1 antagonist. However, the D1 antagonist did not prevent the increase in dopamine levels. The selective D1 agonist SKF 38393, added to the microdialysis probe, increased the levels of the three neurotransmitters. However, after the lesion of the subthalamic nucleus with kainic acid, SKF 38393 increased only the level of GABA but not those of glutamate and dopamine. In addition, the lesion of the subthalamic nucleus produced a drastic (80%) fall in the extracellular levels of glutamate. These data suggest that glutamate, through N-methyl-d-aspartate receptors, stimulates the release of dopamine from dopaminergic dendrites present in the substantia nigra pars reticulata, and that dopamine in turn stimulates the release of glutamate and GABA. Both effects are mediated by D1 dopamine receptors present on subthalamonigral and striatonigral axon terminals, respectively.

Expression of dopamine receptors in the subthalamic nucleus of the rat: characterization using reverse transcriptase-polymerase chain reaction and autoradiography.

We analysed the expression of dopamine receptor subtypes in the subthalamic nucleus by means of reverse transcriptase-polymerase chain reaction. We also studied, using autoradiography, all pharmacologically characterized dopamine receptors in four subregions of the subthalamic nucleus. For comparison, dopamine receptor subtypes were also evaluated in brain regions where they are more abundant and well characterized. The radioligands used were: [3H]SCH-23390, [3H]emonapride and [3H]2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphthalene for dopamine D1, D2 and D3 receptors, respectively; and [3H]YM-09151-2 in the presence of raclopride for dopamine D4 receptors. Finally, we also evaluated the effect of unilateral 6-hydroxydopamine injection into the medial forebrain bundle on dopamine receptor levels expressed in the ipsilateral subthalamic nucleus. The lesion was estimated by decrease in the binding of [3H]WIN-35428, a specific dopamine transporter label. D1, D2 and D3 receptor messenger RNAs and binding sites were present in the subthalamic nucleus, but no messenger RNA for D4 receptors was found, although specific binding sites for these receptors were observed. As compared to the intact side, the 6-hydroxydopamine lesion did not change D1 receptors, increased D2 receptors, and decreased D3 receptors and the dopamine transporter. The results suggest that postsynaptic D1, D2 or D3 receptors can mediate the effect of dopamine on subthalamic nucleus neuronal activity. D4 receptors would mediate exclusively presynaptic effects. These results reinforce the idea that dopamine receptors in the subthalamic nucleus may play an important role in the physiology of the basal ganglia and in the pathophysiology of Parkinson's disease.

Research in pediatric residency programs.

BACKGROUND AND OBJECTIVES: We have required residents in pediatrics at the Cleveland Clinic Foundation to give research presentations since 1989; this article reviews our experience with this program. Additionally, we sought to determine how many other accredited pediatric programs in the United States also require this. METHODS: Retrospective review of the Cleveland Clinic program; descriptive statistics of other United States residency programs, obtained by questionnaire. RESULTS: Pediatric residents at the Cleveland Clinic have given 108 research presentations since 1989, and have developed 33 (30.5%) of them into manuscripts or abstracts. We mailed questionnaires to 215 pediatric residency program directors and received responses from 177 (82%). Of these, 48 (27%) indicated their programs had a research requirement; residents could present their findings in departmental meetings or submit an abstract or manuscript to a professional society or journal. Respondents cited several barriers to research: residents are too busy, there are too few faculty members to mentor them, financial resources are limited, and there is no residency review committee requirement. CONCLUSIONS: Even though only approximately one fourth of the pediatric residency programs in the United States require research, we feel it is worthwhile experience. Despite barriers, residents can and do perform research and publish their findings.

American Academy of Pediatrics. Committee on Psychosocial Aspects of Child and Family Health. The child in court: a subject review.

When children come to court as witnesses, or when their needs are decided in a courtroom, they face unique stressors from the legal proceeding and from the social predicament that resulted in court action. Effective pediatric support and intervention requires an understanding of the situations that bring children to court and the issues that will confront children and child advocates in different court settings.

The mechanism of the paralysing action of tetramisole on Ascaris somatic muscle.

1. Tetramisole (100 mug/ml) paralysed live Ascaris in 3 min.2. Tetramisole (10 mug/ml) caused a sustained contraction of the isolated somatic muscles of the worm. This contraction was not blocked by curare nor by piperazine.3. Tetramisole reduced the resting potential of Ascaris muscle from 34+/-4 to 10+/-1 mV.4. Tetramisole caused contraction of Ascaris muscle previously depolarized with high K(+) solutions. This observation suggests that tetramisole can induce a contracture that is independent of membrane depolarization.

The binding of doxepin to histamine H1-receptors in guinea-pig and rat brain.

The affinity constant for doxepin obtained from inhibition of histamine-induced contraction of guinea-pig intestinal smooth muscle at 30 degrees C was 2.6 +/- 0.18 X 10(10)M-1. The slope of a Schild plot was not significantly different from unity. The affinity constant of doxepin did not vary markedly with temperature. At 37 degrees C it was 3.75 +/- 0.02 X 10(10)M-1 and at 25 degrees C 2.1 X 10(10)M-1. Doxepin was a competitive inhibitor of [3H]-mepyramine binding to guinea-pig cerebellar homogenates. The affinity constant derived for doxepin at 30 degrees C was 1.12 +/- 0.45 X 10(10)M-1. Hill coefficients for curves of doxepin or mepyramine inhibition of [3H]-mepyramine binding in guinea-pig cerebellum, cerebral cortex and hippocampus did not differ significantly from unity. The mean affinity of mepyramine for histamine H1-receptors in rat brain homogenates at 30 degrees C was 3.5 X 10(8)M-1. Hill coefficients for curves of doxepin or mepyramine inhibition of [3H]-mepyramine binding to homogenates of rat cerebral cortex or rat whole brain were near unity. These studies provide no evidence that doxepin binds preferentially to a sub-class of histamine H1-receptors in rat brain.

Histamine H(3) receptor-mediated inhibition of depolarization-induced, dopamine D(1) receptor-dependent release of [(3)H]-gamma-aminobutryic acid from rat striatal slices.

1. A study was made of the regulation of [(3)H]-gamma-aminobutyric acid ([(3)H]-GABA) release from slices of rat striatum by endogenous dopamine and exogenous histamine and a histamine H(3)-agonist. Depolarization-induced release of [(3)H]-GABA was Ca(2+)-dependent and was increased in the presence of the dopamine D(2) receptor family antagonist, sulpiride (10 microM). The sulpiride-potentiated release of [(3)H]-GABA was strongly inhibited by the dopamine D(1) receptor family antagonist, SCH 23390 (1 microM). Neither antagonist altered basal release. 2. The 15 mM K(+)-induced release of [(3)H]-GABA in the presence of sulpiride was inhibited by 100 microM histamine (mean inhibition 78+/-3%) and by the histamine H(3) receptor-selective agonist, immepip, 1 microM (mean inhibition 81+/-5%). The IC(50) values for histamine and immepip were 1.3+/-0.2 microM and 16+/-2 nM, respectively. The inhibitory effects of histamine and immepip were reversed by the H(3) receptor antagonist, thioperamide, 1 microM. 3. The inhibition of 15 mM K(+)-induced [(3)H]-GABA release by immepip was reversed by the H(3) receptor antagonist, clobenpropit, K(d) 0.11+/-0.04 nM. Clobenpropit alone had no effect on basal or stimulated release of [(3)H]-GABA. 4. Elevated K(+) caused little release of [(3)H]-GABA from striatal slices from reserpinized rats, unless the D(1) partial agonist, R(+)-SKF 38393, 1 microM, was also present. The stimulated release in the presence of SKF 38393 was reduced by 1 microM immepip to the level obtained in the absence of SKF 38393. 5. These observations demonstrate that histamine H(3) receptor activation strongly inhibits the dopamine D(1) receptor-dependent release of [(3)H]-GABA from rat striatum; primarily through an interaction at the terminals of GABA neurones.

Congenital optic atrophy and brachytelephalangy: the Berk-Tabatznik syndrome.

Here we report on a prepubertal boy with the Berk-Tabatznik syndrome. Manifestations included short stature, congenital optic atrophy, and hypoplasia of the cervical vertebral bodies and distal phalanges. Prognosis was adversely affected by visual and auditory difficulties. The cause of this condition remains unknown.