Pulmonary angiography in severe chronic pulmonary hypertension

We have analyzed the safety of doing pulmonary angiography in 67 consecutive patients with moderate-to-severe primary pulmonary hypertension or hypertension secondary to chronic thromboembolic occlusions of the pulmonary arteries. The average (+/- SD) pulmonary arterial systolic and diastolic pressures were 74 +/- 19 and 34 +/- 10 mm Hg, respectively. Fourteen patients had a right ventricular end-diastolic pressure of 20 mm Hg or more. Selective left and right main pulmonary artery injections were done using ionic contrast agents in 56 patients and nonionic contrast agents in 11. No major rhythm disturbances or systemic hypotension requiring therapy occurred, and there were no deaths. Thrombotic occlusions of the pulmonary arteries were identified in 52 patients and confirmed in all 42 of those who had a thromboendarterectomy. At autopsy, 3 of the 15 patients who had normal angiograms were found not to have had thrombotic occlusions. We conclude that pulmonary angiography can be done safely despite the presence of severe pulmonary hypertension and right ventricular failure, and that the procedure leads to the identification of chronic, major-vessel thromboembolic pulmonary hypertension that may be alleviated by thromboendarterectomy.     

Safety and effectiveness of amphotericin B deoxycholate for the treatment of visceral leishmaniasis in Uganda

Between September 2003 and April 2004, the supply of antimonial drugs to Amudat Hospital, in north-eastern Uganda, was interrupted and all cases of visceral leishmaniasis presenting at the hospital could only be treated with amphotericin B deoxycholate (AmB). This allowed the safety and effectiveness of the AmB to be evaluated, in comparison with an historical cohort of patients treated, at the same hospital, with meglumine antimoniate (Sb(V)). Demographic and clinical data were collected before and after treatment. Adverse effects were recorded passively in all the subjects, and actively, using a standardized questionnaire, in a sub-group of the patients given AmB. The in hospital case-fatality 'rates' were 4.8% [95% confidence interval (CI) = 2.4%-8.8%] among the 210 patients treated with AmB and 3.7% (CI = 1.4%-7.9%) among the 161 patients treated with Sb(V) (P>0.20). Adverse effects requiring treatment interruption were rare in both cohorts. Treatment failures (i.e. non-responses or relapses) were observed in 2.9% (CI = 1.2%-6.4%) of the patients treated with AmB and 1.2% (CI = 0.1%-4.4%) of the patients treated with Sb(V) (P>0.20). For the treatment of visceral leishmaniasis in Uganda, AmB therefore had a similar effectiveness and safety profile to that of meglumine antimoniate.     

Genetic differences in hemoglobin influence on erythrocyte oxidative stress hemolysis

The RBC from mice of certain inbred strains hemolyzed under oxidative stress (2.0 mmol/L hydrogen peroxide), whereas red cells from mice of other strains did not. In the experimental system human erythrocytes did not hemolyze. The rate of formation of malonyldialdehyde (a fatty acid oxidative breakdown product) was fourfold higher in hemolytic v nonhemolytic red cells. There was insufficient variation in the levels of glutathione, peroxidase activity or its substrate, reduced glutathione, to explain these hemolysis differences. On the other hand, the antioxidants butylated hydroxyanisole and hydroxytoluene, and histidine protected the hemolysis-prone red cells from breaking open. The hemolysis trait demonstrated autosomal recessive Mendelian inheritance. When using inbred, recombinant inbred, and congenic inbred mice, this hemolysis/nonhemolysis trait correlated 1:1 with the type of hemoglobin beta chain in the RBC. This experimental system is a potential model for investigating the role of hemoglobin in prehemolytic events.     

Evaluation of a newly developed dipstick test for the rapid diagnosis of scrub typhus in febrile patients

Scrub typhus is a potentially fatal, febrile disease prevalent in rural Asia. The etiological agent, Orientia tsutsugamushi, is transmitted to humans by the bite of a larval trombiculid mite. No current diagnostic test is sufficiently practical for use by physicians working in rural areas. A new dipstick test using a dot blot immunoassay format has been developed for the serodiagnosis of scrub typhus. We evaluated this test on 83 patients presenting with acute fever of unknown origin at Maharaj Hospital, a tertiary care medical center in Nakhon Ratchasima, Northeast Thailand. The diagnosis of scrub typhus was confirmed in 30 of these patients (36%) by the indirect immunoperoxidase test. The sensitivity of the test was 87% and its specificity was 94%. The dot blot immunoassay dipstick is accurate, rapid, easy to use, and relatively inexpensive. It appears to be the best currently available test for diagnosing scrub typhus in rural areas where this disease predominates.     

Development of medullary thyroid carcinoma in transgenic mice expressing the RET protooncogene altered by a multiple endocrine neoplasia type 2A mutation

Multiple endocrine neoplasia type 2 (MEN 2) is a dominantly inherited cancer syndrome that comprises three clinical subtypes: MEN type 2A (MEN-2A), MEN type 2B (MEN-2B), and familial medullary thyroid carcinoma (FMTC). Medullary thyroid carcinoma (MTC), a malignant tumor arising from calcitonin-secreting thyroid C cells, is the cardinal disease feature of this syndrome, and mortality in affected MEN-2 patients is mainly caused by this malignancy. Germ-line mutations of the RET protooncogene, which encodes a receptor tyrosine kinase, are responsible for these three neoplastic-prone disorders. MEN2 mutations convert the RET protooncogene in a dominantly acting oncogene as a consequence of the ligand-independent activation of the tyrosine kinase. The majority of MEN2A and FMTC mutations are located in the extracellular domain and cause the replacement of one of five juxtamembrane cysteines by a different amino acid. To examine whether expression of a MEN2A allele of RET results in transformation of C cells, we have used the transgenic approach. Expression of the RET gene altered by a MEN2A mutation was targeted in C cells by placing the transgene under the control of the calcitonin gene-related peptide/calcitonin promoter. Animals of three independent transgenic mouse lines, which expressed the transgene in the thyroid, displayed overt bilateral C cell hyperplasia as early as 3 weeks of age and subsequently developed multifocal and bilateral MTC. Moreover, these tumors were morphologically and biologically similar to human MTC which afflicts MEN- 2 individuals. These findings provide evidence that the MEN2A mutant form of RET is oncogenic in parafollicular C cells and suggest that these transgenic mice should prove a valuable animal model for hereditary MTC.     

通过刺激自主神经结丛建立持续局灶性心房颤动动物模型

目的探讨一种通过刺激自主神经结丛来建立持续局灶性心房颤动(房颤)动物模型的新方法。方法共选取20只雄性杂交狗,随机分为乙酰胆碱(Acetylcholine)组(10只)和卡巴胆碱(Carbachol)组(10只)。用苯巴比妥钠麻醉,行右侧开胸及心包切开手术,暴露出右肺静脉与右心房之间的脂肪垫,将一注射针插入该脂肪垫中,以备注入乙酰胆碱或卡巴胆碱。将多电极导管(CordisWebster公司,美国)缝合在右上肺静脉、右心房、左心房上。分别在给药前后(乙酰胆碱组:10 mmol/L乙酰胆碱0.5 mL;卡巴胆碱组:10 mmol/L卡巴胆碱0.5 mL),于右心房处行程序期前刺激,来测定有效不应期及诱发房颤,刺激强度分别采用2倍、4倍、10倍及20倍起搏域值,如出现房颤,则记录房颤持续最长时间及房颤时心房电活动的平均周期。结果向右心房脂肪垫注射乙酰胆碱或卡巴胆碱后可明显缩短心房有效不应期,增加诱发房颤最大与最小偶联间期之差,延长房颤持续的时间,缩短房颤时心房电活动的平均周期。乙酰胆碱组,未注射乙酰胆碱时,在刺激强度为2倍、4倍、10倍及20倍起搏域值时,在右心房处所测心房有效不应期分别为(116.3±17.8)ms,(102.3±22.7)ms,(91.7±21.9)ms和(80.0±23.0)ms,注入乙酰胆碱后则分别缩短为(103.8±26.1)ms(P>0.05),(94.7±21.9)ms(P<0.05),(74.3±20.0)ms(P<0.01)和(65.5±17.8)ms(P<0.05)。未注射乙酰胆碱或卡巴胆碱时,所诱发房颤均为短阵性房颤,持续时间为(9.7±6.0)s(乙酰胆碱组)和(10.4±8.0)s(卡巴胆碱组),心房平均电活动周期为(122.0±9.0)ms(乙酰胆碱组)和(120.0±8.0)ms(卡巴胆碱组);注入乙酰胆碱后持续时间延长为(596.7±281.0)s(P<0.01),心房平均电活动周期缩短为(76.0±32.0)ms(P<0.05);注入卡巴胆碱后则诱发出频率极快、持续时间更长的房颤,持续时间延长为(2 364.0±1169.0)s(P<0.01),心房平均电活动周期缩短为(39.0±12.0)ms(P<0.01)。结论向狗右心房脂肪垫注射卡巴胆碱可成功建立持续性房颤的动物模型。     

Estimates of the duration of the early and late stage of gambiense sleeping sickness

Background  

The durations of untreated stage 1 (early stage, haemo-lymphatic) and stage 2 (late stage, meningo-encephalitic) human African trypanosomiasis (sleeping sickness) due to Trypanosoma brucei gambiense are poorly quantified, but key to predicting the impact of screening on transmission. Here, we outline a method to estimate these parameters.     

A comparative study of the effectiveness of diagnostic tests for visceral leishmaniasis

We compared the validity of pancytopenia, the formol-gel test (FGT), the indirect fluorescence antibody test (IFAT), the direct agglutination test (DAT), and the rK39 dipstick test as diagnostic criteria for visceral leishmaniasis (VL) in Nepal. Between September 2000 and January 2002, 310 clinical suspects had a bone marrow aspirate, and if negative, a spleen aspirate smear examined for Leishmania donovani. Sensitivity and specificity of all tests were determined compared with parasitology and by latent class analysis (LCA). Compared with parasitology, the sensitivities of the other tests were as follows: pancytopenia = 16.3% (95% confidence interval [CI] = 11.3-22.5%), FGT = 39.9% (95% CI = 32.7-47.4%), IFAT = 28.4% (95% CI = 22.0-35.5%), DAT = 95.1% (95% CI = 90.8-97.7%), and the rK39 dipstick test = 87.4% (95% CI = 81.7-91.9%). Sensitivity estimates obtained by LCA were similar, but specificity estimates were substantially higher (DAT = 93.7% versus 77.8%; rK39 dipstick test = 93.1% versus 77.0%). The DAT or the rK39 dipstick test can replace parasitology as the basis of a decision to treat VL in Nepalese peripheral health services.