Public health. Give me fever.
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Communicable Disease Control↗
Biomedical subjects
A May
Publications and source records attributed to A May.
DNA repair of pyrimidine dimers and 6-4 photoproducts in the ribosomal DNA.
The nucleolus is a unique structural component of interphase nuclei where the ribosomal genes, trans-cribed by RNA polymerase I (RNA pol I), are organized. In the present study, the repair of UV-induced photolesions was investigated in the ribosomal DNA (rDNA) in relation to RNA pol I transcription. We used hamster cells because their repair phenotype permits the separate analysis of the major photo-products induced by UV light. Immunofluorescent labeling of UV-induced DNA repair and transcription sites showed that the nucleolar regions were defic-ient in DNA repair despite the presence of abundant RNA pol I transcription foci. Immunological staining indicated that various NER proteins, including TFIIH (subunits p62 and p89), p53, Gadd 45 and prolifer-ating cell nuclear antigen are all enriched in the nuclei but distinctly absent in nucleoli. This lack of enrichment of NER factors in the nucleolus may be responsible for the inefficient repair of photo-products in the rDNA. UV irradiation generates two major photoproducts, the cyclobutane pyrimidine dimers (CPDs) and the 6-4 photoproducts (6-4 PPs). The repair kinetics of these two lesions were assessed simultaneously by the immunological isolation of bromodeoxyuridine (BudR) containing excision repair patches using an antibody to BudR. We found that the repair of the photolesions was less efficient in the rDNA compared to that of the endo-genous housekeeping gene, dihydrofolate reductase (DHFR). Gene specific repair of each of these two photoproducts was then measured separately in the rDNA and in the DHFR gene, which is transcribed by RNA pol II. The removal of CPDs was deficient in the rDNA as compared to the DHFR gene. On the contrary, 6-4 PPs were removed efficiently from the rDNA although somewhat slower than from the DHFR gene. The relatively efficient repair of 6-4 PPs in the rDNA is consistent with the notion that the 6-4 PPs are repaired efficiently in different genomic regions by the global genome repair pathway.
Animals↗
PET demonstration of hypothalamic activation in cluster headache.
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Cluster Headache↗
Four new mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causing X-linked sideroblastic anemia: increased pyridoxine responsiveness after removal of iron overload by phlebotomy and coinheritance of hereditary hemochromatosis.
X-linked sideroblastic anemia (XLSA) in four unrelated male probands was caused by missense mutations in the erythroid-specific 5-aminolevulinate synthase gene (ALAS2). All were new mutations: T647C, C1283T, G1395A, and C1406T predicting amino acid substitutions Y199H, R411C, R448Q, and R452C. All probands were clinically pyridoxine-responsive. The mutation Y199H was shown to be the first de novo XLSA mutation and occurred in a gamete of the proband's maternal grandfather. There was a significantly higher frequency of coinheritance of the hereditary hemochromatosis (HH) HFE mutant allele C282Y in 18 unrelated XLSA hemizygotes than found in the normal population, indicating a role for coinheritance of HFE alleles in the expression of this disorder. One proband (Y199H) with severe and early iron loading coinherited HH as a C282Y homozygote. The clinical and hematologic histories of two XLSA probands suggest that iron overload suppresses pyridoxine responsiveness. Notably, reversal of the iron overload in the Y199H proband by phlebotomy resulted in higher hemoglobin concentrations during pyridoxine supplementation. The proband with the R452C mutation was symptom-free on occasional phlebotomy and daily pyridoxine. These studies indicate the value of combined phlebotomy and pyridoxine supplementation in the management of XLSA probands in order to prevent a downward spiral of iron toxicity and refractory anemia.
5-Aminolevulinate Synthetase↗
Functional magnetic resonance imaging in spontaneous attacks of SUNCT: short-lasting neuralgiform headache with conjunctival injection and tearing.
A 71-year-old woman presented with a short history of episodes of severe left-sided orbital and temporal pain in paroxysms lasting 60 to 90 seconds, and accompanied by ipsilateral lacrimation of the eye, rhinorrhea, and conjunctival injection. Results of clinical examination and structural imaging were normal and a clinical diagnosis of SUNCT (short-lasting unilateral neuralgiform pains with conjunctival injection and tearing) was made. The patient had a BOLD contrast-magnetic resonance imaging study in which significant activation was seen in the region of the ipsilateral hypothalamic gray, comparing the pain to pain-free state. The region of activation was the same in this patient as has been reported in acute attacks of cluster headache.
Aged↗
Intracranial vessels in trigeminal transmitted pain: A PET study.
The underlying principle in interpreting data from positron emission tomography (PET) is that increases and decreases of synaptic activity in the brain are accompanied by equivalent changes in regional blood flow. However, given the relatively low spatial resolution of PET, regional indices of neural activity can be influenced by signals from nonneural elements in the intracranial space. We have used PET to study the functional neuroanatomy of headache syndromes, such as cluster headache and experimental headache, by observing activation in brain that is due to synaptic activity. In these studies we noted a bilateral activation in midline structures over several planes that, based on its anatomy, is likely to arise from bilateral large intracranial arteries in the region of the cavernous sinus. We have observed this activity in two different group studies and in 11 of 17 single-subject studies. The most likely explanation for this "activation" is the increased volume of space occupied by dilated large vessels containing H215O. We further defined the anatomy of the PET findings using magnetic resonance angiography, which showed bilateral vasodilatation of the internal carotid artery and the basilar artery in nitroglycerin-induced cluster headache attacks. While the fact that vascular structures can contaminate PET-based blood flow studies may be well known to methodological experts, the issue is less well recognized outside the immediate field.
Adult↗
[Immunoglobulin subclass defects in patients with therapy refractor chronic rhinosinusitis].
In the present study 220 patients suffering from recurrent rhinosinusitis and not responding to antibiotic treatment were evaluated for a defect in IgG-immunoglobulin subclasses. Twenty-one of these patients were found to have an antibody deficiency. These included deficiencies of IgG-2 (n = 10), IgG-1 (n = 6), IgG-3 (n = 1) and IgG-4 (n = 1). A common variable immune disease was diagnosed in three patients that was characterized by an additional defect in the IgG main class. However, an IgG subclass deficiency can only be ascertained by an immunological evaluation. The significance of a deficiency can be identified by a reaction to vaccination using (for example) protein or polysaccharide antigens. Treatment consists of antibiotics, intravenous immunoglobulins and long-term follow-up. Endonasal microsurgery should only be performed in cases that do not respond to conservative treatment. It is particularly necessary to observe these patients because a deficiency of immunoglobulin subclass in certain cases is the first sign of an immunological impairment that can advance to a severe immunodeficiency and predispose to the development of malignancy.
Adolescent↗
Immunoglobulin deficiency and determination of pneumococcal antibody titers in patients with therapy-refractory recurrent rhinosinusitis.
We examined 245 patients with chronic rhinosinusitis not responding to prolonged antibiotic treatment and tested each patient for humoral antibody deficiencies. Low immunoglobulin levels were found in 22 patients. Five of them had defects of two or more immunoglobulin isotypes that were diagnosed as common variable immunodeficiency (CVI). Seventeen had an IgG-subclass deficiency. Before and after immunization with pneumococcal vaccine, serotype-specific pneumococcal antibody levels were determined to further evaluate the relevance of the underlying deficiency. Significantly reduced antibody titers of pneumococcal serotypes were found in CVI patients (n = 5), while immunization of 17 patients with IgG-subclass deficiency gave different results. Three of the 17 patients responded poorly to pneumococcal immunization and were prone to a polysaccharide specific immunodeficiency. Patients with CVI or IgG-subclass deficiency failing to produce protective antibody levels in more than five serotypes were chosen for antibiotic and/or immunoglobulin substitution therapy. Since recurrent sinusitis in these patients did not resolve with adequate conservative therapy, endonasal microsurgery was then performed and was seen to be a valuable therapeutic option. Our study suggests that an IgG-subclass deficiency may be the first sign of a basic immunological change, resulting in persisting sinus infections.
Adolescent↗
Extraction of migrated self-expanding esophageal metal stents.
BACKGROUND: When self-expanding metal stents are used in the palliative treatment of malignant stenoses complications can occur and require the endoscopic extraction of the stent. METHODS: Three Gianturco-Z stents and two EsophaCoil stents had to be extracted because of migration (4 patients) and strangulation of healthy esophageal tissue between the coil loops during EsophaCoil stent release (1 patient). Because of the strong expansion force of the Gianturco-Z stent, the plastic sheath of a polypectomy snare was replaced by the steel sheath of a basket used for mechanical lithotripsy of bile duct stones. The sufficient resistance of the steel sheath allowed the stents to be compressed. The EsophaCoil stents were gradually retracted with a polypectomy snare over a plastic tube. RESULTS: All stents could be extracted successfully. There were no severe complications related to extraction. CONCLUSION: By means of the endoscopic extraction techniques described above, it is possible to safely remove self-expanding esophageal stents.
Aged↗
KTP laser destruction of dysplasia and early cancer in columnar-lined Barrett's esophagus.
BACKGROUND: The rising incidence of esophageal adenocarcinoma in western countries requires a new strategy in the management of dysplasia in Barrett's esophagus. Esophagectomy, which has high morbidity and mortality rates, has been recommended to treat patients with severe dysplasia. Strictly superficial laser coagulation with tissue ablation therefore is a desirable option for the management of dysplasia in Barrett's esophagus because the tissue to be ablated is only about 2 mm thick. Potassium-titanyl-phosphate (KTP) laser light with a wavelength of 532 nm is preferentially absorbed by hemoglobin and therefore combines excellent coagulation with limited tissue penetration. We report first clinical results with KTP laser superficial vaporization of dysplasia and early cancer in Barrett's esophagus. METHODS: Eight men and 2 women 43 to 84 years of age with short segments of Barrett's esophagus or traditional Barrett's esophagus and histologically proved low-grade (n = 4) and high-grade (n = 4) dysplasia or early adenocarcinoma (n = 2) were selected for this pilot study. For all patients thermal endoscopic destruction was conducted with a frequency-doubled neodymium:yttrium-aluminum-garnet (Nd:YAG) KTP laser system. Laser therapy was performed by means of the free-beam method with coaxial insufflation of gas. An average of 2.4 sessions per patient were required for ablation of the Barrett's mucosa. RESULTS: Two to three days after laser treatment the response of the ablated mucosa was assessed with endoscopy and biopsy. Samples taken showed fibrinoid necrosis of the mucosal layer. A complete response was obtained for all 10 patients. Replacement by normal squamous cell epithelium was induced in combination with acid suppression therapy of up to 80 mg omeprazole daily. No complications occurred. In two patients biopsy showed specialized mucosa beneath the restored squamous cell epithelial layer. Follow-up times were as long as 15 months (mean value 10.6 months). CONCLUSIONS: KTP laser destruction of Barrett's esophagus induced mucosal regeneration with normal squamous cell epithelium in combination with acid suppression. Limitation of the depth of thermal destruction in Barrett's esophagus minimizes risk for perforation or stricture formation. KTP laser ablation of Barrett's esophagus seems to be feasible and safe in short segments of Barrett's esophagus with dysplasia or early cancer.
Adenocarcinoma↗
Correlation between structural and functional changes in brain in an idiopathic headache syndrome.
Fundamental to the concept of idiopathic or primary headache, including migraine, tension-type headache and cluster headache, is the currently accepted view that these conditions are due to abnormal brain function with completely normal brain structure. Cluster headache is one such idiopathic headache with many similarities to migraine, including normal brain structure on magnetic resonance imaging and abnormal function in the hypothalamic grey matter by positron emission tomography. Given the consistency of the positron emission tomography findings with the clinical presentation, we sought to assess whether the brains of such patients were structurally normal. We used voxel-based morphometry, an objective and automated method of analyzing changes in brain structure, to study the structure of the brains of patients with cluster headache. We found a co-localization of structural changes and changes in local brain activity with positron emission tomography in the same area of the brain in the same patients. The results indicate that the current view of the neurobiology of cluster headache requires complete revision and that this periodic headache is associated with a hitherto unrecognized brain abnormality in the hypothalamic region. We believe that voxel-based morphometry has the potential to change in the most fundamental way our concept of primary headache disorders, requiring a radical reappraisal of the tenet of structural normality.
Adult↗
Means of increasing sensitivity of an in vitro diagnostic test for aspirin intolerance.
BACKGROUND: Pseudo-allergic reactions caused by aspirin (acetyl salicylic acid; ASA) often resemble immediate-type hypersensitivity reactions consisting of urticaria and angioedema or rhinoconjunctivitis, asthma and nasal polyps. In the last few years, a new in vitro assay based on determination of sulfidoleucotrienes from isolated leucocytes (cellular allergen stimulation test - CAST) has been introduced for type I allergies and pseudoallergic reactions. In ASA intolerance, there is only limited experience using this assay with - in some studies - only moderate sensitivity. Furthermore, the necessity to use freshly isolated leucocytes from untreated patients is inconvenient for routine settings. OBJECTIVE: The purpose of our study was to search for possibilities of increasing the sensitivity of the test and to use stored blood samples which would permit shipping, two requirements for the clinical suitability of this test. PATIENTS AND METHODS: Leucotriene release in response to ASA and other non-steroidal anti-inflammatory drugs (NSAIDs) was analysed in 38 ASA-intolerant patients (predominantly airway-related symptoms n = 22; predominantly cutaneous symptoms n = 16) and 50 controls. The diagnosis of ASA intolerance was established by history and placebo-controlled oral challenge tests. RESULTS: Using 24 h-stored leucocytes obtained from 10 ASA-intolerant patients and 10 healthy controls there were no significant differences of leucotriene release by resting, ionomycin-, and anti FcepsilonRIalpha-stimulated leucocytes compared with freshly isolated leucocytes. Analysis of ASA + C5a-mediated leucotriene release by stored blood samples in combination with indomethacin- and diclofenac-mediated leucotriene release in ASA-intolerant patients (n = 38) resulted in an increased sensitivity (from 50 to 72.7% in ASA-intolerant patients with predominantly airway-related symptoms and from 81 to 100% in ASA-intolerant patients with predominantly skin symptoms) compared with assays in which only ASA + C5a-mediated leucotriene release has been determined. Moreover, the specificity of the assay remained high (96.7% when analysing different NSAIDs compared with > 99% when analysing only ASA + C5a-mediated leucotriene release). CONCLUSION: In vitro stimulation with ASA + C5a leucocyte stimulation with other NSAIDs should be performed to achieve a higher sensitivity. This finding can be explained by the clinical observation of a high ratio of cross-reactivities between the mentioned NSAIDs.
Adult↗
Vasodilator agents and supracollicular transection fail to inhibit cortical spreading depression in the cat.
It remains an open question as to whether cortical spreading depression (CSD) is the pathophysiological correlate of the neurological symptoms in migraine with aura. In the experimental animal, CSD is an electrophysiological phenomenon mainly mediated via NMDA receptors. However, according to case reports in humans, visual aura in migraine can be alleviated by vasodilator substances, such as amyl nitrite and isoprenaline. There is also circumstantial evidence that brainstem nuclei (dorsal raphe nucleus and locus coeruleus) may play a pivotal role in the initiation of aura. In this study, CSD was elicited in alpha-chloralose anesthetized cats by cortical needle stab injury and monitored by means of laser Doppler flowmetry. Topical application of isoprenaline (0.1-1%) and amyl nitrite (0.05%) onto the exposed cortex had no effect on the elicitation or propagation of CSD. Also, after supracollicular transection, subsequent CSDs showed no differences in the speed of propagation and associated flow changes. We conclude from these data that--given CSD probably exists in humans during migraine--spreading neurological deficits during migraine aura are independent of brainstem influence and have a primarily neuronal rather than vascular mechanism of generation.
Animals↗
A new long-range through-the-scope balloon applicator for photodynamic therapy in the esophagus and cardia.
BACKGROUND AND STUDY AIMS: Photodynamic therapy (PDT) is a new local, endoscopically controlled therapeutic technique based on the sensitization of malignant and precancerous lesions prior to light-induced tissue destruction. PDT of Barrett's esophagus with severe dysplasia, or of mucosal carcinomas and superficial squamous-cell cancer of the esophagus, requires light application devices allowing homogeneous illumination of the tissue surface in spite of esophageal motility and respiratory movement. On the basis of a commercially available through-the-scope balloon system, we developed a long-range light applicator for homogeneous and circumferential irradiation during PDT, and describe here the initial clinical experience with the device. PATIENTS AND METHODS: The new balloon applicator consists of a flexible cylindrical diffuser fiber with a length of up to 10 cm, depending on the lesion to be illuminated, and an inflatable balloon based on the type of balloon used for esophageal dilation. The balloon is made of a transparent polyurethane membrane with negligible absorption (<5%) at lambda = 600-700 nm, and it can be positioned through the biopsy channel of a conventional endoscope, with direct endoscopic visualization of the targeted lesion. The light intensity distribution perpendicular to the optical axes of the diffuser was measured for red laser light (lambda = 632.8 nm) and for green laser light (lambda = 542 nm). The study of photodynamic treatment included two women and four men (aged 48-79 years) with histologically proved high-grade dysplasia (n = 2) or mucosal cancer in Barrett's esophagus (n = 2) and superficial squamous-cell cancer (SCC) (n = 2), who had undergone EUS staging showing uT0 or uT1N0. Laser light irradiation was conducted after oral ingestion of 5-aminolevulinic acid (5-ALA) or intravenous administration of meta-(tetrahydroxyphenyl)chlorin (mTHPC). RESULTS: Both in vitro and in vivo, precise positioning of the new application system at the targeted tissue and homogeneous illumination were feasible, safe and effective. The total efficiency of transmitted light at wavelengths of lambda = 632.8 nm and lambda = 542 nm was 85-90%. A high degree of homogeneity was measured with applicator lengths of between 15 mm and 95 mm, and the maximum deviation from the mean intensity extended over a range of 40% over the total length of 80 mm. High-grade dysplasia was eradicated in all patients, and in addition mucosal cancer was successfully destroyed in three-quarters of them, requiring an average of 1.3 treatment sessions, with a mean follow-up of 12 months (range 10-15 months). CONCLUSIONS: This centering balloon system may in the future be capable of improving light application techniques during esophageal photodynamic therapy, making PDT a more reliable alternative modality for minimally invasive treatment of high-grade dysplasia and early Barrett's esophagus or squamous-cell carcinoma, as compared with esophagectomy.
Adenocarcinoma↗
Local treatment of early cancer in short Barrett's esophagus by means of argon plasma coagulation: initial experience.
In recent years endoscopically controlled local therapeutic methods, such as photodynamic therapy, mucosectomy, or laser therapy, have been used with a curative aim for the destruction of early esophageal or gastric cancers. We report on our experience of treating histologically proven mucosal cancer in Barrett's esophagus with argon plasma coagulation (APC), in three patients. All the mucosal esophageal cancers, with a mean diameter of 4 mm, were successfully destroyed after one or two treatment sessions. Additionally, in two of the three patients the specialized columnar epithelium was replaced by normal squamous cell epithelium when APC treatment was combined with omeprazole. In the third patient with Barrett's esophagus, a partial squamous cell re-epithelialization was induced. No method-related mortality and morbidity were observed. During the mean follow-up of 24.3 +/- 1.1 months (range 23-25 months) one tumor recurrence developed which was successfully treated with photodynamic therapy. In patients with small early Barrett's carcinoma APC might offer an effective, minimally invasive alternative to mucosectomy or photodynamic therapy, as the treatment procedure is less cumbersome and the equipment less expensive.
Adenocarcinoma↗
The first reusable multiple-band ligator for endoscopic hemostasis of variceal bleeding, nonvariceal bleeding and mucosal resection.
A new multiband ligator is presented which is fully reusable. Experience in 67 patients (22 with varices and 45 with early cancers undergoing mucosal resection) showed good technical function and no significant complications. Use of this device may significantly reduce the costs of endoscopic ligation.
Adult↗
Microsurgical endonasal decompression in dysthyroid orbitopathy.
Diagnosis of thyroid eye disease can be established by its history, signs, symptoms, clinical and laboratory findings of an autoimmune thyroid disease. Therapy for this disease is limited to a few options, which should be administered depending on its stage and inflammatory activity. When medication and radiation therapy fail indications for decompression are: loss of visual acuity or visual field defects, increasing strabism and severe keratopathy due to eyelid retraction. Numerous surgical decompression techniques have been described in endocrine orbitopathy. We have adopted endonasal microsurgery, because this technique gives the freedom to work bimanually, ensures a stereomicoscopic view of the intranasal landmarks of orbital walls and allows simultaneous decompression of the medial and inferior orbital wall as well as a good relief of pressure at the orbital apex. Decompressions were performed on 27 orbits in 17 patients, via the endonasal microsurgical, 3 via external approach. The microscopic approach was entirely comparable with regard to reduction of proptosis with a mean improvement of 4.1 mm against a mean of 4.7 mm by external approach and a mean 0.2 of better visual acuity in both procedures. The microsurgical technique is considered superior to an external approach avoiding external scars, neural pains and reportedly less diplopia. Also, trauma to the nalolacrimal and nasofrontal ducts are avoided. The healing phase and the hospitalization time is shorter.
Adult↗
The Werner syndrome protein is involved in RNA polymerase II transcription.
Werner syndrome (WS) is a human progeroid syndrome characterized by the early onset of a large number of clinical features associated with the normal aging process. The complex molecular and cellular phenotypes of WS involve characteristic features of genomic instability and accelerated replicative senescence. The gene involved (WRN) was recently cloned, and its gene product (WRNp) was biochemically characterized as a helicase. Helicases play important roles in a variety of DNA transactions, including DNA replication, transcription, repair, and recombination. We have assessed the role of the WRN gene in transcription by analyzing the efficiency of basal transcription in WS lymphoblastoid cell lines that carry homozygous WRN mutations. Transcription was measured in permeabilized cells by [3H]UTP incorporation and in vitro by using a plasmid template containing the RNA polymerase II (RNA pol II)-dependent adenovirus major late promoter. With both of these approaches, we find that the transcription efficiency in different WS cell lines is reduced to 40-60% of the transcription in cells from normal individuals. This defect can be complemented by the addition of normal cell extracts to the chromatin of WS cells. Addition of purified wild-type WRNp but not mutated WRNp to the in vitro transcription assay markedly stimulates RNA pol II-dependent transcription carried out by nuclear extracts. A nonhelicase domain (a direct repeat of 27 amino acids) also appears to have a role in transcription enhancement, as revealed by a yeast hybrid-protein reporter assay. This is further supported by the lack of stimulation of transcription when mutant WRNp lacking this domain was added to the in vitro assay. We have thus used several approaches to show a role for WRNp in RNA pol II transcription, possibly as a transcriptional activator. A deficit in either global or regional transcription in WS cells may be a primary molecular defect responsible for the WS clinical phenotype.
Amino Acid Sequence↗