A1298C methylenetetrahydrofolate reductase mutation and coronary artery disease: relationships with C677T polymorphism and homocysteine/folate metabolism

5, 10-Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme in homocysteine/methionine metabolism. The most-studied C677T polymorphism in the MTHFR gene results in a thermolabile variant with reduced activity, and is associated with increased levels of total plasma homocysteine, a risk factor for coronary artery disease. A new mutation in the MTHFR gene (A1298C) has also been reported to lower enzyme activity. Whether A1298C is a risk factor for coronary artery disease, separately or in combination with C677T, and/or relative to total plasma homocysteine and folate status, is unclear to date. We evaluated this hypothesis in 470 angiographically characterized subjects, 302 with coronary artery disease, and 168 with normal coronary arteries. The frequency of the 1298C allele was 0.33 and that of combined heterozygosity 0.315. No difference was found in the frequency of the genotypes or when analyzed for combined heterozygosity between patients with coronary artery disease and normals. Independent of folate status, the 1298C allele was not associated with increased total plasma homocysteine. No additional effect of A1298C on total plasma homocysteine was observed in 148 combined heterozygotes compared with 98 heterozygotes for the C677T alone. These findings do not support a major role for the A1298C mutation in homocysteine metabolism and emphasize the hypothesis that MTHFR genotypes may interfere with coronary artery disease risk only when an unbalanced nutritional status leads to raised total plasma homocysteine levels.     

Separating the direct effect of hypoxia from the indirect effect of changes in cardiac output on the maximum pressure difference across the tricuspid valve in healthy humans

In healthy humans, changes in cardiac output are commonly accommodated with minimal change in pulmonary artery pressure. Conversely, exposure to hypoxia is associated with substantial increases in pulmonary artery pressure. In this study we used non-invasive measurement of an index of pulmonary artery pressure, the maximum systolic pressure difference across the tricuspid valve (P_max), to examine the pulmonary vascular response to changes in blood flow during both air breathing and hypoxia. We used Doppler echocardiography in 33 resting healthy humans breathing air over 6–24 h to measure spontaneous diurnal variations in P_max and cardiac output. Cardiac output varied by up to ~2.5 l/min; P_max varied little with cardiac output [0.61±0.74 (SD) mmHg min l^–1]. Eight of the volunteers were also exposed to eucapnic hypoxia (end-tidal ) for 8 h. In this group P_max rose progressively from 21 mmHg to 37 mmHg over 8 h. By comparing diurnal variations in P_max during air breathing with changes in P_max during hypoxia in the same eight individuals, we concluded that only approximately 5% of the changes in P_max during hypoxia could be attributed to concurrent changes in cardiac output. The low sensitivity of P_max to changes in cardiac output makes it a useful index of hypoxic pulmonary vasoconstriction in healthy humans.     

Relationships between allergic inflammation and nasal airflow in children with persistent allergic rhinitis due to mite sensitization

BACKGROUND: Allergic rhinitis is associated with Th2-dependent inflammation. Nasal obstruction is the most typical symptom in children with mite allergy. OBJECTIVES: The aim of this study was to evaluate the possible relationships among nasal symptoms, allergic inflammation, including inflammatory cells and cytokine pattern, and nasal airflow in children with persistent allergic rhinitis because of mite sensitization. METHODS: Twenty children (13 males and seven females, mean age 13.4 +/- 1.6 years) with persistent rhinitis because of mite allergy were evaluated. All of them had moderate-severe grade of nasal obstruction. Total symptom score (TSS), rhinomanometry, nasal lavage, and nasal scraping were obtained in all subjects. Inflammatory cells were counted by conventional staining; interleukin (IL)-5, and IL-8 were measured by immunoassay on fluids recovered from nasal lavage. RESULTS: Eosinophils were significantly associated with TSS (R = 74.4%, P = 0.0002), with IL-5 (R = 90.6%, P < 0.0001) and with nasal flow (R = -69%, P = 0.0007), but not with IL-8 (R = 0.1%, P = 0.995). Eosinophil levels were shown to independently predict nasal flow (P < 0.001), with flow decreasing linearly for increasing eosinophils, together with a significant effect of neutrophils (P = 0.016, linear increase in flow) and a borderline effect of IL-8 (P = 0.063, linear increase in flow). CONCLUSIONS: This study demonstrates the close association between IL-5 concentration and eosinophil infiltration. In addition, there is clear evidence concerning the relationship between eosinophil infiltration and nasal airflow. Thus, nasal eosinophils can be regarded as the most important predictor of upper airway function. These findings constitute first evidence of the relationship between nasal airflow impairment and Th2-related eosinophilic inflammation in children with persistent allergic rhinitis because of mite sensitization.     

Sensitivity of pulmonary chemo reflexes and lung inflation reflexes to repetitive stimulation and to inhibition with lidocaine and morphine

Summary To study reflex responses caused by stimulation of pulmonary C-fibers and lung inflation, we used a preparation in which the left pulmonary artery and veins were ligated and cannulated and the right and left bronchi were cannulated separately in open-chest dogs. These experiments were performed to establish whether the reflex responses to injections of 150 g of capsaicin through the left pulmonary circulation and inflations of this left lung to 30 cm H₂O would be diminished if repeated frequently. Furthermore, the sensitivities of the reflex responses evoked by these capsaicin injections and by left lung inflations (LLI) to blockade with lidocaine or with morphine were studied. Both repeated injections of capsaicin into the left pulmonary circulation and repeated inflations of the left lung for up to 100 min produced a persistent triad of reflex responses: bradycardia, hypotension, and cessation of diaphragmatic contractions. Lidocaine injections (50 mg) into the pulmonary artery of the vascularly isolated lung abolished all reflex responses to subsequent injections of capsaicin, but only attenuated the triad of responses to subsequent left lung inflations by half. Morphine sulfate (60 mg) administered to the pulmonary vascular bed of the isolated lung reduced, but did not eliminate, the triad of reflex responses to subsequent capsaicin injections and lung inflations. The influences of morphine upon capsaicin and lung inflation responses were not abolished by naloxone. These results indicate: (a) the sensory fibers which initiate the triad of pulmonary depressor reflex responses are not desensitized by repeated exposure to capsaicin or by repeated lung inflations; (b) sensory fibers other than pulmonary C-fiber receptors contribute to the lung inflation reflex; and (c) morphine and lidocaine interfere with the excitation of pulmonary C-fibers.     

Ketanserin causes surmountable antagonism of 5-hydroxytryptamine-induced contractions of large coronary arteries of dog

Summary Large coronary arteries of the dog were contracted with 5-hydroxytryptamine (5-HT). The 5-HT₂-receptor antagonist ketanserin antagonized the 5-HT-induced effects. Unlike Brazenor and Angus (Europ J Pharmacol 81: 569–576, 1982), who reported insurmountable antagonism of the effects of 5-HT in dog coronaries, we found that the antagonism by ketanserin can be surmounted, provided the concentrations of 5-HT are high enough. Ketanserin also unmasked a saturable component of the 5-HT-induced contractions. Although ketanserin (0.1–1 mol/l) depressed the maximal force of the saturable component, it did not change its EC₅₀ (-log mol/l 8.0). We conclude that large coronary arteries of dog are contracted by 5-HT mainly though 5-HT₂-receptors and to a smaller extent through receptors different from 5-HT₂.     

Pulmonary sequestration complicated by anomalies of pulmonary venous return

Five anomalies of pulmonary venous drainage were seen among 12 children operated for lung sequestration. In two children, venous drainage from the sequestrated lobe and the rest of the right lung was via a single channel into the inferior vena cava ("scimitar syndrome"). In one of these children, the sequestrated lobe was resected and repair of the scimitar syndrome was delayed; in the second patient, the anomalous pulmonary venous drainage was not recognized preoperatively and the vein was ligated, resulting in acute hemorrhagic infarction of the right lung and death of the patient. Three patients had less severe anomalies of pulmonary venous drainage. We recommend very careful evaluation of patients with lung sequestration with special reference to pulmonary venous drainage.     

Deleterious effects of low-dose oestrogen theraphy on coronary status in patients with prostatic cancer

The effects of oestrogen therapy and of orchidectomy on coronarystauts, as reflected by exercise ECG-testing before and afteryear of tretment, were assessed in a randomized study of patients(N=100) prostatic cancer. Oestrogen was given as polyestradiolphosphate 80 mg i.m. per month in combination with 150 µgor in pre-traetment exercise test results Twelve months afterstart of therapy the oestrogen group showed a significantlygreater depression of the ST-segment during maximal exercisein leads CH₂ (P<0.0005) and CH⁵)P<0.01) compared withthe pre-treatment depression. Twenty-five per cent (N=13) ofthe patients in the oestrogen group suffered cardiovascularcomplications during the yera the of therapy, whereas no suchcomplications were observed in the orchidectomy group. However,even the patients in the oestrogen group who had not sufferedcardiovascular complications had significantly greater depressionsof the ST-segment during exercise both in lead CH₂ (P<0.0005)and in CH₅ (P<0.05). There was no significant change in theST-segment level in the orchidectomy group twelve months aftersurgery. In summary, we found of an induction of myocardialishaemia during treatment with exogenous oestrogens at low dosagein patients with prostatic. This deleterious effect of oestrogenon the coronary status argues against oestrogen therapy, sinceoedtrogen has not been shown to be more beneficial than orhidectomyagainst prostatic carcinoma.     

“Pulmonary tongue” a right ventricle phase abnormality in muga studies in patients with pulmonary hypertention

Pulmonary hypertension (PH) produces strain followed by hypertrophy and later dilatation of the right ventricle (RV) and pulmonary artery. The signs and symptoms are nonspecific. There is a need for a noninvasive sensitive way to diagnose PH. The purpose of this study is to evaluate phase abnormalities in radionuclide MUGA studies of patients with referred diagnosis of PH. In a retrospective analysis of 44 patients who had a radionuclide multigated study (MUGA) and contrast ventriculography (CV), 19 had high mean pulmonary pressure (over 20 mmHg) and a high pulmonary vascular resistance index (over 2.0). In 15 patients, a delayed phase segment in the RV corresponding to the pulmonary infundibulum and pulmonary conus was noted The Pulmonary Tongue sign (PT), 12 had PH (True positive) and 3 did not (false positive) on CV. No PT was seen in the remaining 29 patients, only 7 of them had PH (False negative). The sensitivity, specificity and accuracy of the PT sign in detecting PH was 80%, 72% and 77% respectively. The number of patients was too small to calculate the correlation of the grade of PT with the severity of PH. We conclude that The Pulmonary Tongue sign on a MUGA study is clinically useful in detecting PH.This project is supported by research project MLNO13 and funded by research Council, Kuwait University     

Anterior displacement of the mandible for better exposure of the distal segment of the extracranial carotid artery

Summary Anterior displacement of the mandible (ADM) was performed in 34 patients undergoing surgery for malformations or atheromatous lesions of the distal segment of the extracranial internal carotid artery (ICA). This procedure greatly facilitates surgical access to the upper cervical region and has several advantages over mandibulotomy-mandibulectomy, namely: A shorter operating time, sparing of the inferior alveolar nerve and of the mandibular branch of cranial nerve VII, with no need for post-operative immobilization of the mandible. ADM permits the correction of ICA lesions extending as far as the first cervical vertebra. For lesions extending into the carotid canal ADM needs to be supplemented by various other procedures via the base of the skull.     

“Cross-over” duplication of middle cerebral artery,agenesis of internal carotid artery and saccular aneurysms

Summary The authors describe a patient with anomalous branches of the left internal carotid artery, cross-over duplication of its middle cerebral artery and agenesis of the contra-lateral internal carotid artery associated with two aneurysms successfully clipped. Pertinent literature is reviewed.