Experience with Cyclosporine in Children with Chronic Idiopathic Urticaria

Abstract: Background: The identification of an autoimmune mechanism for many patients with chronic idiopathic urticaria (CIU) was used as a rational for a controlled clinical trial of cyclosporine for adults with CIU not responsive to usual measures. That randomized placebo controlled clinical trial demonstrated clinical efficacy, acceptable safety, and a suggestion of inducing remission in such patients. Objective: To report our experience with cyclosporine in pediatric patients with CIU. Methods: Fifty‐four patients with CIU were referred to us during the period from 2000 through June of 2005. Seven of those, aged 9–16, failed therapy with high dose antihistamines even with the addition of alternate morning prednisone. Neoral brand of cyclosporine, 3 mg/kg/day divided b.i.d., was initiated in these patients. Cyclosporine serum concentrations, blood urea nitrogen (BUN), creatinine, and blood pressure were routinely monitored. Results: All had cessation of hives. This occurred after 1–4 weeks for six of the seven and 8 weeks for one. While some experienced relapses, all were eventually off of all medications and free of hives. None of the seven experienced any adverse effects. Conclusions: Our experience in children is consistent with a previous controlled clinical trial in adults and supports the efficacy and safety of cyclosporine for CIU. However, we recommend that it be reserved for those whose CIU that is resistant to conventional measures and that patients be carefully monitored with cyclosporine serum concentrations and measures of renal function.     

The effect of apomorphine on regional cerebral blood flow in schizophrenia

A double-blind, placebo-controlled crossover study of the effects of apomorphine on regional cerebral blood flow (rCBF) during a prefrontal cortex activation task was undertaken to explore the role of dopamine on cortical function. The subjects were eight drug-free, chronically psychotic patients; six patients had schizophrenia. In each, apomorphine increased the relative prefrontal flow. The results suggest that enhanced prefrontal dopamine activity may reverse deficits in prefrontal cortex metabolism in schizophrenia.     

A phase I/II study of continuous infusion suramin in patients with hormone-refractory prostate cancer : toxicity and response

 Introduction: Suramin is a synthetic polysulfonated naphthylurea which has been used for the treatment of African trypanosomiasis and onchocerciasis, but since the mid-1980s has received attention as a possible antiretroviral and antineoplastic agent. Objective: This clinical trial of suramin was undertaken as a phase I/II study in patients with hormone-refractory prostate cancer, with the hypothesis that the intensity of therapy with suramin could be increased significantly if measures were undertaken to maintain the plasma concentrations of the drug under 300 μg/ml. Methods: We report the clinical results of this trial, wherein patients were treated at three different targeted plasma suramin concentrations (275, 215 and 175 μg/ml) for varying periods of time (2, 4 or 8 weeks), with delivery of the drug by continuous intravenous infusion. Results: The major toxicity observed in this trial was neurologic, consisting of a motor and sensory peripheral neuropathy that resulted in both paresis and paralysis of the limbs. Nearly all of this severe (CTEP grade III, IV) neurologic toxicity was observed in the patients treated at a plasma suramin concentration of 275 μg/ml for 4 or more weeks. A single patient treated at 215 μg/ml for 8 weeks developed moderate (CTEP grade III) proximal lower extremity weakness, and no patient treated at 175 μg/ml developed this toxicity. The second most common toxicity observed was infection of the central venous catheter. The overall response rate for all of the evaluable patients was 17% (13 of 75 patients). In addition, prostate-specific antigen (PSA)-defined responses were observed in six patients receiving therapy at 175 μg/ml, but these responses were confounded by cessation of therapy with flutamide during suramin treatment. Conclusions: In summary, although plasma suramin concentrations were maintained below 300 μg/ml, neurologic toxicity nonetheless occurred with high frequency in patients treated at 275 μg/ml for 4 or more weeks. Therapy at 215 and 175 μg/ml was in general well tolerated, but central venous catheter-related infection, as well as the inconvenience and expense of continuous infusional therapy, make this method of drug delivery impractical. Only moderate antitumor activity was observed during this trial, but it is possible that both continuation of flutamide and flutamide withdrawal during suramin therapy confounded the assessment of suramin’s activity in hormone-refractory prostate cancer. Received: 9 June 1995/Accepted: 18 March 1996     

Long-term outcome of vocal cord dysfunction.

BACKGROUND: Vocal cord dysfunction (VCD) is an involuntary functional disorder commonly misdiagnosed as asthma. Previous reports describe the disorder and treatment but not the long-term outcome. OBJECTIVE: To determine the long-term outcome of VCD. METHODS: A retrospective medical record review identified 49 patients, ages 8 to 25 years, diagnosed as having VCD from 1989 to 2002. Telephone contact was attempted in all. RESULTS: Of the 49 patients, 41 had previously been treated for asthma; that diagnosis was confirmed by us as a comorbidity in only 12 patients. Two distinct phenotypes of VCD were observed. Symptoms were limited to exercise-induced VCD (EIVCD) in 29 and spontaneously occurring VCD (SVCD) in 20, only 4 of whom additionally had EIVCD. Twenty-eight of the 49 were successfully contacted by telephone. Eight of the 11 contacted patients with SVCD followed the recommendation to see our speech therapist, all of whom learned to control symptoms. However, 2 who also had EIVCD continued with that problem. Pretreatment with an anticholinergic inhaler prevented EIVCD in 6 patients in whom this was tried. Complete absence of symptoms, at times ranging from 1 week to 5 years (median, 5 months), was reported in 26 of the 28 contacted patients. CONCLUSIONS: VCD continues to be frequently misdiagnosed as asthma. Two phenotypes of VCD are apparent: EIVCD and SVCD. Speech therapy provides relief of symptoms for SVCD. Prevention of EIVCD with an anticholinergic inhaler in 6 patients suggests that a controlled clinical trial is warranted. Regardless of treatment, eventual spontaneous resolution was common.     

Is size-reducing ascending aortoplasty with external reinforcement an option in modern aortic surgery?

OBJECTIVE: Enlargement of the ascending aorta is often combined with valvular, coronary, or other cardiac diseases. Reduction aortoplasty can be an optional therapy; however, indications regarding the diameter of aorta, the history of dilatation (poststenosis, bicuspid aortic valve), or the intraoperative management (wall excision, reduction suture, external reinforcement) are not established. METHODS: In a retrospective study between 1997 and 2005, we investigated 531 patients operated for aneurysm or ectasia of the ascending aorta (diameter: 45-76mm). Of these, in 50 patients, size-reducing ascending aortoplasty was performed. External reinforcement with a non-coated dacron prosthesis was added in order to stabilize the aortic wall. RESULTS: Aortoplasty was associated with aortic valve replacement in 47 cases (35 mechanical vs 12 biological), subvalvular myectomy in 29 cases, and CABG in 13 cases. The procedure was performed with low hospital mortality (2%) and a low postoperative morbidity. Computertomographic and echocardiographic diameters were significantly smaller after reduction (55.8+/-9mm down to 40.51+/-6.2mm (CT), p<0.002; 54.1+/-6.7mm preoperatively down to 38.7+/-7.1mm (echocardiography), p<0.002), with stable performance in long-term follow-up (mean follow-up time: 70 months). CONCLUSIONS: As demonstrated in this study, size reduction of the ascending aorta using aortoplasty with external reinforcement is a safe procedure with excellent long-term results. It is a therapeutic option in modern aortic surgery in patients with poststenotic dilatation of the aorta without impairment of the sinotubular junction of the aortic valve and root.     

Localized echo-volume imaging methods for functional MRI

To perform true three-dimensional activation experiments in the human brain, dedicated localized echo-volume imaging (L-EVI) methods were developed. Three-dimensional acquisition allows generation of activation maps with minimal vascular enhancement related to inflow effects. The rapid acquisition of the L-EVI (～100 msec) reduces signal instabilities caused by motion, facilitating the detection of the small intensity changes expected with brain activation. Single-shot L-EVI was performed on normal volunteers at 1.5 T, imaging a three-dimensional predefined volume (240 × 45 × 45 mm³) in the superior portion of the brain with a spatial resolution of 3.75 × 5 × 5 mm³. Increased brain coverage was achieved with a multi-volume imaging (three-shot) version, which simultaneously achieved effective suppression of signals from cerebrospinal fluid. In addition, both asymmetric spin-echo (ASE) and spin-echo (SE) versions of the technique were used to detect blood oxygenation level dependent (BOLD) signal changes in the motor cortex with a finger-tapping paradigm. Images obtained by the L-EVI sequence were qualitatively comparable to standard multislice two-dimensional echo-planar images. Both ASE and SE functional MRI (fMRI) experiments showed consistent activation in the contralateral primary sensorimotor cortex. Furthermore, significant differences in location and magnitude of activation was observed between the two methods, confirming theoretical predictions.     

Opioid receptors are involved in an NMDA receptor-independent mechanism of LTP induction at hippocampal mossy fiber-CA3 synapses.

Long-term potentiation (LTP) of mossy fiber responses in area CA3 of the rat hippocampus in vivo is blocked by naloxone, an opioid receptor antagonist, in a stereospecific and dose-dependent manner. LTP of commissural afferents to the same population of CA3 pyramidal cells is not attenuated by naloxone. This suggests that opioid receptors are involved in a mechanism of LTP induction that is specific to mossy fiber synapses, and that endogenous opioid receptors are involved in a mechanism of LTP induction that is specific to mossy fiber synapses, and that endogenous opioid peptides, presumably released as a result of mossy fiber stimulation, may be necessary for the induction of mossy fiber LTP. The naloxone sensitivity is limited to the induction phase of LTP, since naloxone does not reverse previously established LTP. These data suggest that LTP at the mossy fiber-CA3 synapse constitutes an NMDA receptor-independent, opioid receptor-dependent, form of hippocampal synaptic plasticity.     

Acetylcholine produces stimulus-specific receptive field alterations in cat auditory cortex

Frequency receptive fields (RFs) were determined before and after pairing iontophorectic administration of acetylcholine (ACh) with a repeated single-frequency stimulus in the auditory cortex of barbiturate-anesthesized cats. In 58% of the cells, the paired ACh + tone treatment produced subsequent alterations of frequency RFs. In half of these cases, the RF modifications were highly specific to the frequency that had been paired with ACh. Atropine antagoized the frequency-effects of ACh, suggesting that they were mediated via muscarinic cholinergic receptors.     

Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia. III. A new cohort and evidence for a monoaminergic mechanism

We previously reported that compared with normals, patients with chronic schizophrenia have reduced regional cerebral blood flow (rCBF) in dorsolateral prefrontal cortex (DLPFC) during performance of the Wisconsin Card Sort Test (WCS), a DLPFC-related cognitive task, but not during nonprefrontal tasks, such as a simple number-matching (NM) test. We also found that unlike normals, patients failed to activate DLPFC during the WCS over their own baseline (NM) level. To explore the reproducibility of these findings, a new cohort of 16 medication-free patients underwent a series of xenon 133 inhalation rCBF studies under the following conditions: at rest, while performing the WCS, and while performing NM. The results confirmed our earlier findings. In addition, the concentrations in cerebrospinal fluid of homovanillic acid and 5-hydroxyindoleacetic acid correlated with prefrontal rCBF during the WCS but not during the NM test or at rest. The results show that behavior-specific hypofunction of DLPFC in schizophrenia is reproducible, and they implicate a monoaminergic mechanism.