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Biomedical subjects

A May

Publications and source records attributed to A May.

At least 91 records · Page 5Linked to original sources
PubMed2001

X-linked cerebellar ataxia and sideroblastic anaemia associated with a missense mutation in the ABC7 gene predicting V411L.

Two brothers with X-linked ataxia (XLA) were found to have hypochromic red cells and increased erythrocyte protoporphyrin despite normal iron stores. The mother was unaffected by ataxia and had normal iron stores but showed evidence of some red cell hypochromia with heavy basophilic stippling that stained positive for iron. Bone marrow biopsy confirmed the presence of ring sideroblasts in one of the brothers. The absence of mutations in the ALAS2 gene and the predominance of zinc over free protoporphyrin led to a search using a combination of DNA and cDNA analysis for the presence of mutations in the ABC7 gene. ABC7 encodes a mitochondrial half-type ATP Binding Cassette transporter involved in iron homeostasis. The published cDNA sequence was used to search databases for the genomic sequence of which 12 exons spanning 23.4 kb were mapped leaving the most 5' nucleotides unaccounted for. The identified exons and their exon-intron boundaries were amplified from DNA while the most 5' sequence including the initiation codon was amplified from cDNA of peripheral blood cells. Direct sequencing revealed hemizygosity in the brothers and heterozygosity in the mother for a G-->C transversion at position 1299 of the published cDNA. This predicts a V411L substitution at the beginning of the last of six putative transmembrane regions of the protein. Restriction enzyme digestion confirmed the presence of this mutation in the three family members but could not detect it in 200 normal alleles. An uncle affected by ataxia also carried this mutation. This study supports the recently hypothesized involvement of the ABC7 gene in XLSA/A and highlights a protein structure region of importance to this syndrome.

ATP-Binding Cassette Transporters↗
PubMed2001

Paracellin-1 is critical for magnesium and calcium reabsorption in the human thick ascending limb of Henle.

BACKGROUND: A new protein, named paracellin 1 (PCLN-1), expressed in human thick ascending limb (TAL) tight junctions, possibly plays a critical role in the control of magnesium and calcium reabsorption, since mutations of PCLN-1 are present in the hypomagnesemia hypercalciuria syndrome (HHS). However, no functional experiments have demonstrated that TAL magnesium and calcium reabsorption were actually impaired in patients with HHS. METHODS: Genetic studies were performed in the kindred of two unrelated patients with HHS. Renal magnesium and calcium reabsorption in TAL were analyzed in one homozygous affected patient of each family, one patient with extrarenal hypomagnesemia (ERH), and two control subjects (CSs). RESULTS: We found two yet undescribed mutations of PCLN-1 (Gly 162 Val, Ala 139 Val). In patients with HHS, renal magnesium and calcium reabsorptions were impaired as expected; NaCl renal conservation during NaCl deprivation and NaCl tubular reabsorption in diluting segment were intact. Furosemide infusion in CS markedly increased NaCl, Mg, and Ca urinary excretion rates. In HHS patients, furosemide similarly increased NaCl excretion, but failed to increase Mg and Ca excretion. Acute MgCl(2) infusion in CS and ERH patient provoked a dramatic increase in urinary calcium excretion without change in NaCl excretion. When combined with MgCl(2) infusion, furosemide infusion remained able to induce normal natriuretic response, but was unable to increase urinary magnesium and calcium excretion further. In HHS patients, calciuric response to MgCl(2) infusion was blunted. CONCLUSION: This study is the first to our knowledge to demonstrate that homozygous mutations of PCLN-1 result in a selective defect in paracellular Mg and Ca reabsorption in the TAL, with intact NaCl reabsorption ability at this site. In addition, the study supports a selective physiological effect of basolateral Mg(2+) and Ca(2+) concentration on TAL divalent cation paracellular permeability, that is, PCLN-1 activity.

Adolescent↗
PubMed2001

Management of Barrett's oesophagus, dysplasia and early adenocarcinoma.

There has been a dramatic increase in recent years in the incidence of Barrett's oesophagus and the oesophageal adenocarcinoma associated with it. Adequate monitoring strategies and improved diagnostic procedures are therefore essential. Alongside conventional video-endoscopy with four-quadrant biopsies, many additional diagnostic procedures are now available to improve monitoring. These allow the early diagnosis of dysplastic areas and early carcinomas. Both thermal procedures (argon plasma coagulation, multipolar electrocoagulation and KTP laser and Nd∶YAG laser treatment) and non-thermal ablation procedures (photodynamic therapy) are used for the endoscopic ablation of Barrett's mucosa without dysplasia, being employed in addition to acid suppression treatment. On the basis of the data currently available, it is, however, not yet possible to offer a general recommendation in favour of endoscopic ablation. Alongside surgical treatment for high-grade dysplasia and early carcinoma, endoscopic treatment procedures, which have a much lower complication and mortality rate, will probably play an important role in the future. Endoscopic mucosal resection and photodynamic therapy are particularly promising. Long-term results with these procedures are, however, still awaited.

Adenocarcinoma↗
PubMed2001

Magnetic resonance angiography in facial and other pain: neurovascular mechanisms of trigeminal sensation.

For much of the twentieth century migraine and cluster headache have been considered as vascular headaches whose pathophysiology was determined by changes in cranial vascular diameter. To examine nociceptive neural influences on the cranial circulation, the authors studied healthy volunteers' responses to injection of the pain-producing compound capsaicin in terms of the caliber of the internal carotid artery. The study was conducted using magnetic resonance angiographic techniques. Injection of capsaicin into the skin innervated by the ophthalmic (first) division of the trigeminal nerve elicited 40% +/- 27% (mean +/- SD) increase in vascular cross-sectional area in the right (ipsilateral) internal carotid artery when compared with the mean baseline ( P < 0.001). Injection of capsaicin into the skin of the chin to stimulate the mandibular (third) division of the trigeminal nerve and into the leg led to a similar pain perception and failed to produce any significant change in vessel caliber. The data suggest that there is a highly functionally organized, somatotopically congruent trigeminal innervation of the cranial vessels, with a potent vasodilator effect of the ophthalmic division on the large intracranial vessels. The data are consistent with the notion that pain drives changes in vessel caliber in migraine and cluster headache, not vice versa. These conditions therefore should be regarded as primary neurovascular headaches not as vascular headaches.

Adult↗
PubMed2001

Pharmacological opportunities and pitfalls in the therapy of migraine.

The mild vasoconstrictor effects of modern antimigraine drugs, such as serotonin (5-HT; 5-hydroxytryptamine)1B/D agonists, have led to a search for nonvasoconstrictor approaches to therapy. Such approaches have included substance P (neurokinin I) antagonists, endothelin antagonists and highly specific 5HT1D agonists. All of these substances are effective in animal models and have no significant vasoconstrictive effects. However, all of them failed to demonstrate any antimigraine effects. Current clinical and experimental evidence therefore supports the view that isolated peripheral trigeminal nerve inhibition is insufficient to relieve acute migraine.

Animals↗
PubMed2001

Substance P receptor antagonists in the therapy of migraine.

Clinical observations, the vascular component of migraine pain, its pulsating or throbbing pain character, have focused attention on the trigeminal innervation of pain-sensitive intracranial structures, such as the dura mater and large vessels. These intracranial structures are innervated by the ophthalmic branch of the trigeminal nerve, which is marked by the presence of vasoactive peptides, such as substance P and calcitonin gene-related peptide. Substance P is a mediator of the sterile inflammation of the dura mater, which has been considered to be the source of migraine pain. Modern antimigraine drugs, such as 5-HT(1B/D) agonists (triptans), block this dural neurogenic inflammation dose-dependently in an animal model but their vasoconstrictor effects have led to a search for non-vasoconstrictor approaches. One such approach has been substance P (neurokinin-1) antagonists. These are highly effective in animal models of dural inflammation and have no significant vasoconstrictive effect. However, several NK(1) antagonists failed to demonstrate any effect in acute migraine. Current clinical and experimental evidence therefore supports the view that NK(1) receptor antagonists may have no significant antimigraine properties.

Animals↗
PubMed2000

Familial-skewed X-chromosome inactivation as a predisposing factor for late-onset X-linked sideroblastic anemia in carrier females.

X-linked sideroblastic anemia (XLSA) is caused by mutations in the erythroid-specific 5-aminolevulinic acid synthase (ALAS2) gene. An elderly woman who presented with an acquired sideroblastic anemia is studied. Molecular analysis revealed that she was heterozygous for a missense mutation in the ALAS2 gene, but she expressed only the mutated gene in reticulocytes. Her 2 daughters and a granddaughter were heterozygous for this mutation, had normal hemoglobin levels, and expressed the normal ALAS2 gene in reticulocytes. A grandson with a previous diagnosis of thalassemia intermedia was found to be hemizygous for the ALAS2 mutation. Treatment with pyridoxine completely corrected the anemia both in the proband and her grandson. All women who were analyzed in this family showed skewed X-chromosome inactivation in leukocytes, which indicated a hereditary condition associated with unbalanced lyonization. Because the preferentially active X chromosome carried the mutant ALAS2 allele, acquired skewing in the elderly likely worsened the genetic condition and abolished the normal ALAS2 allele expression in the proband. (Blood. 2000;96:4363-4365)

5-Aminolevulinate Synthetase↗
PubMed2000

PET and MRA findings in cluster headache and MRA in experimental pain.

BACKGROUND: Cluster headache (CH), like migraine, is still regarded as a vascular headache although in both conditions a CNS cause has been suggested. OBJECTIVE: To examine neurovascular mechanisms in CH. METHODS: The authors used functional imaging with PET to investigate 18 CH patients (25 to 62 years old). Ten were in the active period (nine patients with induced attacks and one with spontaneous attack) and eight were out of their bout. In addition, the authors studied spontaneous CH and experimental pain in volunteers using MR angiography. RESULTS: When an acute CH attack was triggered with nitroglycerin (NTG), activation occurred in the ipsilateral posterior inferior hypothalamic gray, the contralateral ventroposterior thalamus, the anterior cingulate cortex, the ipsilateral basal ganglia, the right anterior frontal lobe, and both insulae. In patients out of the bout who experienced only a mild NTG headache, activation was seen bilaterally in the insulae and frontal cortices, the anterior cingulate cortex, the right thalamus, and the left basal ganglia, but not in the hypothalamic gray area. In addition, the authors found a significant activation (vasodilatation) in the region of the major basal arteries that was caused in part by NTG but was also observed in the spontaneous case and could be induced by capsaicin injection into the forehead. Therefore, the vasodilatation is likely to be mediated by neural mechanisms involved in the acute CH attacks that are present in every human being. CONCLUSIONS: Dilatation of cranial vessels is not specific to any particular headache syndrome but generic to cranial neurovascular activation, probably mediated by the trigeminoparasympathetic reflex. These data confirm that CH is a CNS disorder best considered as a form of neurovascular headache.

Adult↗
PubMed2000

Gene-specific repair of gamma-ray-induced DNA strand breaks in colon cancer cells: no coupling to transcription and no removal from the mitochondrial genome.

We have measured gene-specific DNA damage and repair of alkaline-sensitive sites and DNA strand breaks after gamma-irradiation. Although fairly high doses are used in order to introduce sufficient DNA damage, we find that there is efficient and almost complete repair within 2 h. Human colon cancer cells were exposed to gamma-irradiation, and the repair was measured in various nuclear regions and in the mitochondrial genome. In the essential housekeeping gene, dihydrofolate reductase (DHFR), there was about 80% repair of the strand breaks after 2 h. There was no difference in the repair activities between the two individual DNA strands of the DHFR gene, and thus no evidence of strand bias, or transcription coupling of the repair process. There was no preferential repair of the DHFR gene compared to repair in an inactive, X-linked, noncoding gene. We can thus not detect any nuclear heterogeneity of the formation and repair of these lesions. In contrast, the formation and processing of gamma-irradiation introduced lesions differ in the mitochondrial DNA. Here, we detect about twofold more alkaline-sensitive sites and strand breaks after gamma-irradiation than observed in the DHFR gene. The repair of these lesions is deficient in the mitochondria, where only about 25% are removed within 2 h.

Colonic Neoplasms↗
PubMed2000

[Family study of patients with aspirin intolerance and rhinosinusitis].

The high prevalence of aspirin intolerance in asthmatics and patients with nasal polyps as well as reports of familial clustering suggest a genetic disposition of this disease. Our study aimed at obtaining further evidence of hereditary factors in this disease. We included 33 unselected patients from 28 families with aspirin intolerance and rhinosinusitis in this study. Controls were recruited from individuals treated in our ENT clinic for diseases other than aspirin intolerance (n = 52). A questionnaire focused on family histories as well as reports on diseases of the upper respiratory tract or allergies. ASS intolerance was verified either by bronchial or nasal provocation tests. We found cases of aspirin intolerance among parents, siblings, and children of ASS intolerant probands. The children of probands had nasal polyps and rhinosinusitis more often than the children of controls. We propose that ASS intolerance with nasal polyps and asthma represents a complex phenotype, with genetic and environmental factors contributing to its manifestation.

Adolescent↗
PubMed2000

Endoscopic mucosal resection of early cancer and high-grade dysplasia in Barrett's esophagus.

BACKGROUND & AIMS: In view of the mortality and morbidity rates of esophagectomy and the relatively large group of inoperable patients, local therapeutic techniques are required for high-grade dysplasia and early Barrett's cancer. METHODS: A prospective investigation of endoscopic mucosal resection was conducted in 64 patients (mean age, 65 +/- 10 years) who had early carcinoma (61 patients) or high-grade dysplasia (3 patients) in Barrett's esophagus. Thirty-five patients met the criteria for low risk: macroscopic types I, IIa, IIb, and IIc; lesion diameter up to 20 mm; mucosal lesion; and histological grades G1 and G2 and/or high-grade dysplasia (group A). The remaining 29 patients were included in group B (high risk). RESULTS: A total of 120 resections were performed, with no technical problems encountered. The mean number of treatment sessions per patient was 1. 3 +/- 0.6 in group A and 2.8 +/- 2.0 in group B (P < 0.0005). Only one major complication occurred, a case of spurting bleeding, which was managed endoscopically. Complete local remission was achieved significantly earlier (P = 0.008) in group A than in group B. In May 1999, complete remission had been achieved in 97% of the patients in group A and in 59% of those in group B; however, 1 patient in group A and 9 in group B are still undergoing treatment or awaiting the first check-up. During a mean follow-up of 12 +/- 8 months, recurrent or metachronous carcinomas were found in 14%. CONCLUSIONS: Endoscopic mucosal resection of early carcinoma in Barrett's esophagus is associated with promisingly low morbidity and mortality rates. The procedure may offer a new minimally invasive therapeutic alternative to esophagectomy, especially in low-risk situations. Comparisons with surgical results will need to be done when the long-term results of this procedure become available.

Adult↗
PubMed2000

Abnormal cerebral processing of oesophageal stimuli in patients with noncardiac chest pain (NCCP).

In noncardiac chest pain (NCCP), altered visceral perception may result from abnormal cerebral processing of sensory input rather than abnormalities of afferent pathways. However, the interactions between symptoms, autonomic function and oesophageal stimuli are poorly studied. Oesophageal stimulation elicits reproducible cortical evoked potentials [CEP] and modulates heart rate variability via vagal pathways, as visible on power spectrum analysis of heart rate variability [PS-HRV]. These methods are increasingly used to study the function of visceral afferent neural pathways in human. The aim of this study was to compare EP and PS-HRV during oesophageal stimuli in NCCP and controls. Twelve healthy volunteers (one female, 11 male; aged 24-51 years; mean 32 +/- 8 years), and eight NCCP patients (three female, five male; age range 26-58, mean 40.5 +/- 10 years) were studied. Electrical oesophageal stimulation (EOS; 200 microseconds, 0.2 Hz, 25 stimuli) was applied to the oesophageal wall 5 cm above the lower oesophageal sphincter (LOS), and perception thresholds (measured in mA) determined. EP responses were recorded using 22 standard electroencephalogram scalp electrodes. Autonomic activity was assessed using PS-HRV, before, during, and after oesophageal stimulation. Measured PS-HRV indices included high frequency (HF; 0. 15-0.5 Hz) and low frequency (LF; 0.06-0.15 Hz) power, respectively, assessing vagal and sympathetic activity, and the LF/HF ratio. EOS perception occurred at lower thresholds in NCCP than in controls (3. 6 +/- 1 vs. 7.8 +/- 2 mA, P < 0.05). EP amplitude was greater (13 +/- 2 vs. 6 +/- 1 microV, P < 0.0001), and latency longer in controls vs. NCCP (191 +/- 7 ms vs. 219 +/- 6 ms, P < 0.001). In NCCP, EOS decreased sympathetic outflow (low frequency peak on PS-HRV) and increased cardiovagal activity (high frequency peak, P < 0.02) to a significantly higher degree in comparison with controls. During EOS, heart rate decreased in NCCP from 68 vs. 62 beats min-1 (P < 0.003) but not in controls. In NCCP patients, EOS was perceived at lower intensities and was associated with a greater cardiovagal reflex response. EP responses associated with EOS were smaller in NCCP than in controls, suggesting that an increased perception of oesophageal stimuli results from an enhanced cerebral processing of visceral sensory input in NCCP, rather than from hyperalgesic responses in visceral afferent pathways.

Adult↗
PubMed2000

Effects of esophageal stimulation in healthy subjects.

We studied the effects of esophageal electrical stimulation on heart rate variability power spectra (PS/HRV) and cortical evoked potentials (EPs) in healthy subjects. The intensity of stimulation was varied from 2.7 to 20 mA. We found that the amplitude of the cortical evoked potentials (amplitude of the N2/P2 peak) increased from 5.1 +/- 0.7 microV at 5 mA to 16.3 +/- 1.1 microV at 20 mA. The PS/HRV showed an increase in the vagal modulation of the sinus node. When the stimulation frequency was varied from 0.1 to 1 Hz at a constant intensity of 15 mA, the amplitude of cortical EPs (N2/P2 peak) decreased with increase in the frequency of stimulation (p < 0.05). The LF:HF ratio decreased significantly for all frequencies of stimulation (p < 0.005). An experimental paradigm to evoke the cognitive component in the cortical EPs yielded a peak around 354 ms following the stimulus.

Cerebral Cortex↗
PubMed2000

Effects of esophageal stimulation in patients with functional disorders of the gastrointestinal tract.

We studied the effects of esophageal electrical stimulation on cortical-evoked potentials (EPs) and power spectrum of heart rate variability (PS/HRV) in patients with diabetes and non-cardiac chest pain (NCCP). We also recorded cognitive-evoked potentials (P300 EPs) in response to an odd-ball stimulation in patients with NCCP. Diabetic patients did not yield reproducible cortical EPs. Their power spectra of heart rate variability (PS/HRV) showed an increased vagal modulation during stimulation. In patients with NCCP the P300 EPs were of greater amplitude (17 +/- 3 microV vs. 12 +/- 1 microV in controls, p < 0.04), while peak latencies were slightly elongated in patients (382 +/- 22 ms vs. 354 +/- 12 ms in controls). The PS/HRV in these patients also showed an increased vagal modulation of the sinus node activity. Our results suggest the following: (1) in patients with diabetes, afferent pathways and processing of sensory signals are likely to be impaired; (2) an increased perception of esophageal stimulation reflects an exaggerated brainstem response and altered cortical processing of visceral sensation in patients with NCCP.

Adolescent↗
PubMed1999

Photodynamic destruction of high grade dysplasia and early carcinoma of the esophagus after the oral administration of 5-aminolevulinic acid.

BACKGROUND: Photodynamic therapy (PDT) is a new local, endoscopically controlled therapeutic concept based on the selective sensitization of malignant and precancerous lesions prior to light-induced tissue destruction. 5-aminolevulinic acid (5-ALA) appears to be a promising alternative photosensitizer with a high mucosa specificity without phototoxic side effects on the skin. The authors report on their experiences with this new form of PDT in 27 patients. METHODS: Twenty-seven patients (6 females and 21 males; ages 47-79 years) with histologically proven high grade dysplasia (n = 9) and early carcinoma (normal endoultrasonography or classified as uT1N0M0; n = 19; 1 patient had 2 lesions) of the esophagus were included in this study. Approximately 4-6 hours after oral ingestion of 5-ALA in a dosage of 60 mg/kg of body weight, laser light irradiation was conducted with a dye laser system with a wavelength of 635 nanometers at a light dose of 150 J/cm(2). RESULTS: The length of the segment of the esophagus with severe dysplasia or carcinoma of the mucosa varied between 0.5-9.0 cm (mean length, 2.5 cm). High grade dysplasia was eradicated in all patients. In addition, 19 mucosal tumors in 18 patients were treated successfully in 10 of 19 cases with an average of 1.7 treatment sessions and a mean follow-up of 16.9 months (range, 3-37 months). Method-related morbidity and mortality were not observed. CONCLUSIONS: Severe dysplasia and superficial (</=2 mm) mucosal carcinoma of the esophagus can be ablated completely by 5-ALA-PDT. PDT with 5-ALA has few side effects and might offer an alternative to esophagectomy or radiochemotherapy.

Aged↗