Biomedical subjects

N Patronas

Publications and source records attributed to N Patronas.

At least 37 records · Page 2Linked to original sources

PubMed1997

Linkage mapping and phenotypic analysis of autosomal dominant Pallister-Hall syndrome.

Pallister-Hall syndrome is a human developmental disorder that is inherited in an autosomal dominant pattern. The phenotypic features of the syndrome include hypothalamic hamartoma, polydactyly, imperforate anus, laryngeal clefting, and other anomalies. Here we describe the clinical characterisation of a family with 22 affected members and the genetic mapping of the corresponding locus. Clinical, radiographic, and endoscopic evaluations showed that this disorder is a fully penetrant trait with variable expressivity and low morbidity. By analysing 60 subjects in two families using anonymous STRP markers, we have established linkage to 7p13 by two point analysis with D7S691 resulting in a lod score of 7.0 at theta = 0, near the GLI3 locus. Deletions and translocations in GLI3 are associated with the Greig cephalopolysyndactyly syndrome. Although Greig cephalopolysyndactyly syndrome has some phenotypic overlap with Pallister-Hall syndrome, these two disorders are clinically distinct. The colocalisation of loci for these distinct phenotypes led us to analyse GLI3 for mutations in patients with Pallister-Hall syndrome. We have previously shown GLI3 mutations in two other small, moderately affected families with Pallister-Hall syndrome. The linkage data reported here suggest that these larger, mildly affected families may also have mutations in GLI3.

Abnormalities, Multiple↗

PubMed1997

An autosomal recessive disorder with posterior column ataxia and retinitis pigmentosa.

We report an autosomal recessive form of ataxia that is not allelic to Friedreich's disease in six individuals from a large kindred with family origins traced to a common founder of German-Swiss descent. The disorder begins during early childhood with a concentric contraction of the visual fields and proprioceptive loss. Eventually blindness, a severe sensory ataxia, achalasia, scoliosis, and inanition develop by third decade. Inversion recovery MRIs of the spinal cord in affected individuals demonstrate a hyperintense signal in the posterior columns. Finding the gene responsible for this disorder may aid in our understanding of the mechanisms that cause sensory neuronal degeneration.

Adolescent↗

PubMed1996

Corpus callosum morphology, as measured with MRI, in dyslexic men.

To test the hypothesis of anomalous anatomy in posterior brain regions associated with language and reading, the corpus callosum was imaged in the midsagittal plane with magnetic resonance. The areas of the anterior, middle, and posterior segments were measured in 21 dyslexic men (mean age 27 yrs, SD 6) and in 19 matched controls. As predicted, the area of the posterior third of the corpus callosum, roughly equivalent to the isthmus and splenium, was larger in dyslexic men than in controls. No differences were seen in the anterior or middle corpus callosum. The increased area of the posterior corpus callosum may reflect anatomical variation associated with deficient lateralization of function in posterior language regions of the cortex and their right-sided homologues, hypothesized to differ in patients with dyslexia.

Adult↗

PubMed1996

Lack of correlation between prostate-specific antigen and the presence of measurable soft tissue metastases in hormone-refractory prostate cancer.

Appropriate staging procedures for patients with hormone-refractory prostate cancer are poorly defined. In particular, there are no studies correlating prostate-specific antigen (PSA) with more traditional methods of staging. We have evaluated the abdominal/pelvic CT scan, bone scan, and PSA results following initial diagnosis of hormone-refractory prostate cancer in 177 consecutive patients (median age = 63.1 years, range 45-80). Thirty-four patients (19.2%) had measurable lesions (> or = 2 cm) on CT scan compatible with metastatic disease. Of the patients with measurable lesions, 29/34 (85.3%) had retroperitoneal and/or pelvic adenopathy; 5 patients (14.7%) had measurable lesions in the liver. Other sites of metastatic disease were detected in less than 1% of the patients receiving scans. All patients had bone scan abnormalities compatible with metastatic disease. Results of these imaging studies were then compared to PSA serum concentration (Abbott IMx). The mean PSA concentration was not different in those patients with soft tissue disease as compared to those without soft tissue involvement and there was no correlation between PSA concentration and the presence or absence of measurable soft tissue disease. In contrast to previously published studies in hormone-naïve prostate cancer patients, these studies in hormone-refractory patients indicate that the detection of metastatic disease by standard radiological procedures cannot be predicted by measurement of serum PSA.

Abdominal Neoplasms↗

PubMed1996

Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer.

Lovastatin, an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (the major regulatory enzyme of the mevalonate pathway of cholesterol synthesis), displays antitumor activity in experimental models. We therefore conducted a Phase I trial to characterize the tolerability of lovastatin administered at progressively higher doses to cancer patients. From January 1992 to July 1994, 88 patients with solid tumors (median age, 57 +/- 14 years) were treated p.o. with 7-day courses of lovastatin given monthly at doses ranging from 2 to 45 mg/kg/day. The inhibitory effects of lovastatin were monitored through serum concentrations of cholesterol and ubiquinone, two end products of the mevalonate pathway. Concentrations of lovastatin and its active metabolites were also determined, by bioassay, in the serum of selected patients. Cyclical treatment with lovastatin markedly inhibited the mevalonate pathway, evidenced by reductions in both cholesterol and ubiquinone concentrations, by up to 43 and 49% of pretreatment values, respectively. The effect was transient, however, and its magnitude appeared to be dose independent. Drug concentrations reached up to 3.9 micrometer and were in the range associated with antiproliferative activity in vitro. Myopathy was the dose-limiting toxicity. Other toxicities included nausea, diarrhea, and fatigue. Treatment with ubiquinone was associated with reversal of lovastatin-induced myopathy, and its prophylactic administration prevented the development of this toxicity in a cohort of 56 patients. One minor response was documented in a patient with recurrent high-grade glioma. Lovastatin given p.o. at a dose of 25 mg/kg daily for 7 consecutive days is well tolerated. The occurrence of myopathy, the dose-limiting toxicity, can be prevented by ubiquinone supplementation. To improve on the transient inhibitory activity of this dosing regimen on the mevalonate pathway, alternative schedules based on uninterrupted administration of lovastatin should also be studied.

Adult↗

PubMed1995

Phase I study of phenylacetate administered twice daily to patients with cancer.

BACKGROUND: The growth-inhibiting and differentiating effects of sodium phenylacetate against hematopoietic and solid tumor cell lines has aroused clinical interest in its use as an anticancer drug. In an earlier Phase I trial of phenylacetate aimed at maintaining serum drug concentrations in the range that proved active in vitro (> 250 micrograms/ml) for 2 consecutive weeks, infusion rates approached the maximum velocity of drug elimination and commonly resulted in drug accumulation and reversible dose-limiting neurologic toxicity. In this study, the authors described the nonlinear pharmacokinetics, metabolism, toxicity, and clinical activity of phenylacetate. METHODS: The treatment regimen of this Phase I study was designed to expose patients intermittently to drug concentrations exceeding 250 micrograms/ml and to allow time for drug elimination to occur between doses to minimize accumulation. Sodium phenylacetate was administered as a 1-hour infusion twice daily (8 a.m., 5 p.m.) at two dose levels of 125 and 150 mg/kg for a 2-week period. Therapy was repeated at 4-week intervals for patients who did not experience dose-limiting toxicity or disease progression. RESULTS: Eighteen patients (4 of whom previously were treated with phenylacetate by continuous intravenous infusion) received 27 cycles of therapy. Detailed pharmacokinetic studies for eight patients indicated that phenylacetate induced its own clearance by a factor of 27% in a 2-week period. Dose-limiting toxicity, consisting of reversible central nervous system depression, was observed for three patients at the second dose level. One patient with refractory malignant glioma had a partial response, and one with hormone-independent prostate cancer achieved a 50% decline in prostate specific antigen level, which was maintained for 1 month. CONCLUSIONS: Phenylacetate administered at a dose of 125 mg/kg twice daily for 2 consecutive weeks is well tolerated. High grade gliomas and advanced prostate cancer are reasonable targets for Phase II clinical trials.

Adult↗

PubMed1995

Magnetic resonance imaging of brain iron in health and disease.

Brain iron is a major contributor to magnetic resonance imaging (MRI) contrast in normal gray matter, and its role in the pathogenesis of different neurological disorders has also become apparent. Non-heme brain iron is present in the brain mainly in the form of ferritin. The unique magnetic properties of ferritin determine different signal changes on both T1- and T2-weighted images, and the T2 relaxation rates have a linear dependence on applied field strength. This finding is typical for ferric oxyhydroxide cores. The resulting T2-shortening also depends on echo-spacing used in the imaging sequence as well as on the water diffusion coefficient and the size of the ferritin cluster. Quantitation of non-heme brain iron by MRI aids in the diagnosis and monitoring of different neurological diseases.

Brain↗

PubMed1994

Neurofibromatosis 2 (NF2): clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity.

To determine the spectrum of manifestations in neurofibromatosis 2 (NF2) and to assess possible heterogeneity, we evaluated 63 affected individuals from 32 families. Work-up included skin and neurologic examinations, audiometry, a complete ophthalmology examination with slit-lamp biomicroscopy of the lens and fundus, and gadolinium-enhanced MRI of the brain and, in some, of the spine. Mean age-at-onset in 58 individuals was 20.3 years; initial symptoms resulted from vestibular schwannomas (44.4%), other CNS tumors (22.2%), skin tumors (12.7%), and ocular manifestations including cataracts and retinal hamartomas (12.7%). Five asymptomatic individuals were diagnosed through screening. Vestibular schwannomas were documented in 62 individuals (98.4%); other findings included cataracts (81.0%), skin tumors (67.7%), spinal tumors (67.4%), and meningiomas (49.2%). Usually, clinical manifestations and course were similar within families but differed among families. To assess possible heterogeneity, we assigned affected individuals to three proposed subtypes (representing mild, intermediate, and severe NF2) based on age-at-onset, presence or absence of CNS tumors other than vestibular schwannomas, and presence or absence of retinal hamartomas. Comparisons among the three subtypes for many clinical parameters demonstrated that patients in the mild subtype differed from those in the other two subtypes for most parameters, but that none of the parameters distinguished patients in the intermediate subtype from those in the severe subtype. Thus, there are likely two rather than three subtypes of NF2. Classification of patients to subtype may aid in counseling about long-term prognosis and in formulating individualized guidelines for medical surveillance.

Adolescent↗

PubMed1994

Anti-Ro(SS-A) autoantibodies in central nervous system disease associated with Sjögren's syndrome (CNS-SS): clinical, neuroimaging, and angiographic correlates.

OBJECTIVE: To examine in Sjögren's syndrome (SS) the interrelationship between the presence of the anti-Ro(SS-A) antibody response and (1) concomitant presence and type (ie, focal or nonfocal) of CNS disease (CNS-SS), (2) cross-sectional brain MRI or CT, and (3) abnormal cerebral angiography. METHODS: Neurologic, neuroimaging, and angiographic features of CNS-SS patients were correlated with the presence of precipitating anti-Ro(SS-A) autoantibodies detected by gel double-immunodiffusion or quantitative ELISA, which detects antibodies directed against the 60-kd peptide. Statistical analyses were performed using Fisher's exact test (two-tailed) with Haldane's adjustment and odds ratio with Cornfield 95% confidence intervals. RESULTS: Precipitating antibodies against the Ro(SS-A) antigen, determined by gel double-immunodiffusion, were present in an increased frequency in CNS-SS patients with (1) documented clinical CNS disease, (2) focal clinical CNS manifestations and serious complications, (3) large regions of increased signal intensity, consistent with ischemia/infarcts on brain MRI scans or regions of decreased attenuation consistent with infarcts on CT, and (4) abnormal cerebral angiograms consistent with small-vessel angiitis. Finally, the anti-Ro(SS-A) antibody response in CNS was directed against the 60-kd peptide specificity, determined by ELISA. CONCLUSIONS: Clinical, neuroimaging (cerebral CT), and angiographic observation suggest that a subset of anti-Ro(SS-A) antibody-positive, in contrast with -negative, CNS-SS patients have more serious and extensive CNS disease, some with frank cerebral angiopathy. Anti-Ro(SS-A) antibodies are postulated to play a role in mediating or potentiating vascular injury in CNS-SS.

Autoantibodies↗

PubMed1994

A clinical and neuropathologic study of silk suture as an embolic agent for brain arteriovenous malformations.

PURPOSE: To evaluate the safety and efficacy of silk suture as an agent for preoperative embolization of cerebral arteriovenous malformations. METHODS: Clinical and histopathologic results were analyzed in six patients who underwent embolization of cerebral arteriovenous malformations using silk suture in combination with other agents. RESULTS: Three of the patients treated with silk hemorrhaged after embolization, and two of these patients died. Neuropathologic analysis of four patients showed acute perivascular inflammation, sometimes quite severe. CONCLUSIONS: The inflammatory response to silk may explain its effectiveness in producing vascular occlusion. However, a fulminate vasculitis theoretically can predispose to delayed hemorrhage. Other problems with silk include the pressure required to inject the agent and the inability to determine the final site of deposition of the silk. Although other embolic agents may share some of these potential difficulties, we feel that the disadvantages outweigh the advantages of silk as an embolic agent.

Adult↗

PubMed1993

Diffusion and perfusion magnetic resonance imaging in brain tumors.

The article reviews recent progress made in the field of diffusion and perfusion magnetic resonance (MR) imaging and presents possible applications in brain tumors. Diffusion, a new parameter, provides useful data to assess tissue structure and function. Perfusion MR imaging gives results that are somewhat similar to those obtained with classic non-MR imaging methods, but it offers several potential advantages.

Brain Neoplasms↗

PubMed1992

Using gadolinium-enhanced magnetic resonance imaging lesions to monitor disease activity in multiple sclerosis.

The highly variable clinical course and the lack of a direct measurement of disease activity have made evaluation of experimental therapies in multiple sclerosis (MS) difficult. Recent studies indicate that clinically silent lesions can be demonstrated by magnetic resonance imaging (MRI) in patients with mild relapsing-remitting MS. Thus, MRI may provide a means for monitoring therapeutic trials in the early phase of MS. We studied 12 patients longitudinally for 12 to 21 months with monthly gadolinium (Gd)-enhanced MRIs. The data have been used to identify the most effective design of a clinical trial using Gd-enhanced lesions as the outcome measure. Frequent ( > 1/mo) Gd-enhancing lesions were observed in 9 of the 12 patients, indicating that the disease is active even during the early phase of the illness. The frequency of the lesions was not constant; there was marked fluctuation in lesion number from month to month. However, the magnitude of the peak number of lesions and the frequency of the peaks varied among patients. Because of this variability, the most effective use of Gd-enhancing lesions as an outcome measure in a clinical trial was a crossover design with study arms of sufficient duration to allow accurate estimation of lesion frequency. Monitoring Gd-enhancing lesions may be an effective tool to assist in the assessment of experimental therapies in early MS.

Adult↗

PubMed1992

Cerebral artery aneurysms in children infected with human immunodeficiency virus.

More than 250 children treated at our institution on antiretroviral treatment protocols have been monitored with brain imaging studies. We documented the occurrence and progression of aneurysms of major cerebral arteries in two children with advanced human immunodeficiency virus infection. In both cases these lesions remained clinically silent initially, despite progression to marked dilation.

Brain↗

PubMed1992

Diffusion MR imaging: clinical applications.

Water self-diffusion, a recently discovered source of contrast on MR images, has already shown promise for some clinical applications. Most studies have been of the brain, essentially for technical reasons. Diffusion is useful in distinguishing the different components of brain tumors (cystic regions, edema, necrosis) from the tumor core itself. Recent studies have shown that diffusion is anisotropic in brain white matter (i.e., dependent on the fiber tract's orientation in space), offering new insights into myelin disorders. Diffusion is also dramatically altered in the minutes following ischemic injury in the cat brain, which may have tremendous impact for the diagnosis and management of hyperacute stroke. With ultrafast acquisition schemes, diffusion imaging has also been used outside the CNS, for instance, in the eye and kidney. Future applications include diffusion-localized spectroscopy and temperature imaging. This article reviews recent progress in this field and suggests potential applications.

Body Water↗

PubMed1991

Serial gadolinium-enhanced magnetic resonance imaging scans in patients with early, relapsing-remitting multiple sclerosis: implications for clinical trials and natural history.

Six patients with early, mild, relapsing-remitting multiple sclerosis were studied with monthly gadolinium-enhanced magnetic resonance imaging scans for 8 to 11 months. Numerous enhancing lesions were observed irrespective of clinical activity. Four of the 6 patients had one or more enhancing lesions present on each examination. The other 2 patients had enhancing lesions noted in 7 and 9 of 11 months. In contrast, only two clinical exacerbations were observed during the study period. Neither the exacerbations nor other changes in symptoms or signs correlated with occurrence of the enhancing lesions. Enhancement generally persisted for less than 1 month. The opening of the blood-brain barrier as reflected by gadolinium enhancement on magnetic resonance imaging may represent ongoing disease activity in patients with mild, relapsing-remitting multiple sclerosis who are clinically stable. The frequency of these lesions appears to be sufficient to use as an outcome measure in clinical trials testing clinical efficacy in patients with early, relapsing-remitting multiple sclerosis.

Adult↗

PubMed1990

Neurologic, computed cranial tomographic, and magnetic resonance imaging abnormalities in patients with small-cell lung cancer: further follow-up of 6- to 13-year survivors.

To determine the subsequent evolution of neurologic, neuropsychologic, and intracranial anatomic findings in long-term survivors of small-cell cancer, we repeated an evaluation done 4 years previously in patients 6 to 13 years after treatment. Fifteen patients were reevaluated with a history and physical examination, mental status examination, neuropsychologic testing, computed cranial tomographic (CCT) scans, and magnetic resonance imaging (MRI). All but one was ambulatory and none were institutionalized. Thirteen of 15 had neurologic complaints, 10 of 15 had an abnormal neurologic examination, seven of 14 had an abnormal mental status examination, 12 of 14 had abnormal neuropsychologic testing, 12 of 15 had abnormal CCT scans, and seven of 15 had white-matter abnormalities on MRI scans. No dramatic decline in performance status, functional status, neurologic symptoms, or neurologic examination occurred in these patients with 4 years of additional follow-up. More patients showed a decline in mental status examinations and neuropsychologic testing than demonstrated improvement. Anatomic studies showed no dramatic changes in the CCT scans and MRI confirmed these findings. From these data we conclude that there is a slow decline in neuropsychologic function in some of the patients surviving more than 6 years from a diagnosis of small-cell lung cancer. The anatomic abnormalities documented by CCT scans and MRI are more frequent in patients with abnormal neuropsychologic function.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1990

Pathology of temporal lobe foci: correlation with CT, MRI, and PET.

Twenty-six patients with medically refractory complex partial seizures had temporal lobectomy after evaluation, which included prolonged scalp EEG recordings, positron emission tomography (PET), MRI, and x-ray CT. PET showed a region of focal interictal temporal hypometabolism corresponding to electrographic localization of seizure onset in 21. Five patients had a region of increased MRI signal intensity on the spin echo image in the region of the EEG focus, 2 had an abnormality ipsilateral to but distinct from the EEG focus, and 1 had bilateral findings. CT was abnormal in 3 cases; 2 had tumors. Three patients had low grade tumors (1 with a normal PET). PET can detect metabolic dysfunction associated with mild pathologic changes in epileptic foci, but increased signal intensity on MRI does not necessarily correlate with the degree of pathologic abnormality. Tumors may be less likely when both CT and MRI are normal.

Adolescent↗

PubMed1989

Divided attention, as measured by dichotic speech performance, in dementia of the Alzheimer type.

To determine if impaired dichotic performance in patients with dementia of the Alzheimer type is due to the inability to divide attention or the inability to perceive degraded auditory stimuli, we measured performance on tasks of both dichotic and degraded monotic speech materials. We also examined whether perception of degraded speech stimuli presented monaurally is related to abnormalities of temporal lobe anatomy and physiology, as we have shown for dichotic performance. Although the patients were impaired on both dichotic and monotic tests, significantly greater impairment was seen on the dichotic test. Our earlier finding of a significant relation between dichotic performance and measures of anterior temporal lobe atrophy and reduced glucose metabolism was replicated, but no significant relation was found between monotic tests and measures to temporal lobe integrity. We conclude that the inability to divide attention, rather than abnormal processing of degraded stimuli per se, is reflected in poor dichotic performance in patients with dementia of the Alzheimer type, and that dichotic performance, unlike degraded monotic perception, depends directly on the integrity of temporal cortex in these patients.

Aged↗