Overwhelming genetic heterogeneity and exhausting molecular diagnostic process in chronic and progressive ataxias: facing it up with an algorithm, a gene, a panel at a time.

Ataxias are one of the most frequent complaints in Neurogenetics units worldwide. Currently, more than 50 subtypes of spinocerebellar ataxias and more than 60 recessive ataxias are recognized. We conducted an 11-year prospective, observational, analytical study in order to estimate the frequency of pediatric and adult genetic ataxias in Argentina, to describe the phenotypes of this cohort and evaluate the diagnostic yield of the algorithm used in our unit. We included 334 ataxic patients. Our diagnostic approach was successful in one-third of the cohort. A final molecular diagnosis was reached in 113 subjects. This rate is significantly higher in the subgroup of patients with a positive family history, where the diagnostic yield increased to 55%. The most prevalent dominant and recessive ataxias in Argentina were SCA-2 (36% of dominant ataxias) and FA (62% of recessive ataxias), respectively. Next generation sequencing-based assays were diagnostic in the 65% of the patients requiring these tests. These results provide relevant epidemiological information, bringing a comprehensive knowledge of the most prevalent subtypes of genetic ataxias and their phenotypes in our territory and laying the groundwork for rationally implementing genetic diagnostic programs for these disorders in our country.

Copper Content and Resistance Mechanisms in the Terrestrial Moss Ptychostomum capillare: A Case Study in an Abandoned Copper Mine in Central Spain.

We present a case study on the tissue absorption of copper of a widely distributed moss species, Ptychostomum capillare in the polluted soil of an abandoned copper mine in central Spain. We studied the soil properties in a copper soil pollution gradient and sampled the moss tufts growing on them in four plots with contrasted soil copper levels. We determined the copper content in the soil and in the moss tissues. On these moss samples, we also performed histochemical tests and X-ray dispersive spectrometry coupled with scanning electron microscopy (SEM-EDX), both in untreated shoots and in samples where surface waxes were removed. We checked the behavior of this species using a metallophillous moss, Scopelophila cataractae, for comparative purposes. Copper contents in P. capillare seem to depend more on available, rather than total soil copper contents. Our results indicate that this moss is able to concentrate 12-fold the available soil copper in soil with low available copper content, whereas in the most polluted soil the concentration of Cu in the moss was only half those levels. Both histochemical and SEM-EDX tests show no surface copper in the mosses from the least polluted plot, whereas in samples from the soil with highest copper content, the removal of surface waxes also reduces or removes copper from the moss shoots. Our observations point at a mixed strategy in P. capillare in this copper mine, with metal accumulation behavior in the lowest Cu plot, and an exclusion mechanism involving wax-like substances acting as a barrier in the most polluted plots. These distortions impede the estimation of environmental levels and thus compromise the value of this moss in biomonitoring. We highlight the need of extending these studies to other moss species, especially those used in biomonitoring programs.

Phylogenetic and paleobotanical evidence for late Miocene diversification of the Tertiary subtropical lineage of ivies (Hedera L., Araliaceae).

BACKGROUND: Hedera (ivies) is one of the few temperate genera of the primarily tropical Asian Palmate group of the Araliaceae, which extends its range out of Asia to Europe and the Mediterranean basin. Phylogenetic and phylogeographic results suggested Asia as the center of origin and the western Mediterranean region as one of the secondary centers of diversification. The bird-dispersed fleshy fruits of ivies suggest frequent dispersal over long distances (e.g. Macaronesian archipelagos), although reducing the impact of geographic barriers to gene flow in mainland species. Genetic isolation associated with geographic barriers and independent polyploidization events have been postulated as the main driving forces of diversification. In this study we aim to evaluate past and present diversification patterns in Hedera within a geographic and temporal framework to clarify the biogeographic history of the genus. RESULTS: Phylogenetic (biogeographic, time divergence and diversification) and phylogeographic (coalescence) analyses using four DNA regions (nrITS, trnH-psbA, trnT-trnL, rpl32) revealed a complex spatial pattern of lineage divergence. Scarce geographic limitation to gene flow and limited diversification are observed during the early-mid Miocene, followed by a diversification rate increase related to geographic divergence from the Tortonian/Messinian. Genetic and palaeobotanical evidence points the origin of the Hedera clade in Asia, followed by a gradual E-W Asian extinction and the progressive E-W Mediterranean colonization. The temporal framework for the E Asia - W Mediterranean westward colonization herein reported is congruent with the fossil record. Subsequent range expansion in Europe and back colonization to Asia is also inferred. Uneven diversification among geographic areas occurred from the Tortonian/Messinian onwards with limited diversification in the newly colonized European and Asian regions. Eastern and western Mediterranean regions acted as refugia for Miocene and post-Miocene lineages, with a similar role as consecutive centers of centrifugal dispersal (including islands) and speciation. CONCLUSIONS: The Miocene Asian extinction and European survival of Hedera question the general pattern of Tertiary regional extinction of temperate angiosperms in Europe while they survived in Asia. The Tortonian/Messinian diversification increase of ivies in the Mediterranean challenges the idea that this aridity period was responsible for the extinction of the Mediterranean subtropical Tertiary flora. Differential responses of Hedera to geographic barriers throughout its evolutionary history, linked to spatial isolation related to historical geologic and climatic constraints may have shaped diversification of ivies in concert with recurrent polyploidy.

Burden of serious fungal infections in Guatemala.

Guatemala is a developing country in Central America with a high burden of HIV and endemic fungal infections; we attempted to estimate the burden of serious fungal infections for the country. A full literature search was done to identify epidemiology papers reporting fungal infections from Guatemala. We used specific populations at risk and fungal infection frequencies in the population to estimate national rates. The population of Guatemala in 2013 was 15.4 million; 40% were younger than 15 and 6.2% older than 60. There are an estimated 53,000 adults with HIV infection, in 2015, most presenting late. The estimated cases of opportunistic fungal infections were: 705 cases of disseminated histoplasmosis, 408 cases of cryptococcal meningitis, 816 cases of Pneumocystis pneumonia, 16,695 cases of oral candidiasis, and 4,505 cases of esophageal candidiasis. In the general population, an estimated 5,568 adult asthmatics have allergic bronchopulmonary aspergillosis (ABPA) based on a 2.42% prevalence of asthma and a 2.5% ABPA proportion. Amongst 2,452 pulmonary tuberculosis patients, we estimated a prevalence of 495 for chronic pulmonary aspergillosis in this group, and 1,484 for all conditions. An estimated 232,357 cases of recurrent vulvovaginal candidiasis is likely. Overall, 1.7% of the population are affected by these conditions. The true fungal infection burden in Guatemala is unknown. Tools and training for improved diagnosis are needed. Additional research on prevalence is needed to employ public health measures towards treatment and improving the reported data of fungal diseases.

Downed woody debris carbon emissions in a European temperate virgin forest as driven by species, decay classes, diameter and microclimate.

Downed woody debris (DWD) plays an important role as regulator of nutrient and carbon (C) cycling in forests, accounting for up to the 20 % of the total C stocks in primary forests. DWD persistence is highly influenced by microbial decomposition, which is determined by various environmental factors, including fluctuations in temperature and moisture, as well as in intrinsic DWD properties determined by species, diameter, or decay classes (DCs). The relative importance of these different drivers, as well as their interactions, remains largely unknown. Moreover, the importance of DWD for C cycling in virgin forests remains poorly understood, due to their scarcity and poor accessibility. To address this research gap, we conducted a study on DWD respiration (RDWD), in a temperate virgin forest dominated by European beech and silver fir. Our investigation analysed the correlation between RDWD of these two dominant tree species and the seasonal changes in climate (temperature and moisture), considering other intrinsic DWD traits such as DCs (1, 2 and 4) and diameters (1, 10 and 25 cm). As anticipated, RDWD (normalized per gram of dry DWD) increased with air temperature. Surprisingly, DWD diameter also had a strong positive correlation with RDWD. Nonetheless, the sensitivity to both variables and other intrinsic traits (DC and density) was greatly modulated by the species. On the contrary, water content, which exhibited a considerable spatial variation, had an overall negative effect on RDWD. Virgin forests are generally seen as ineffective C sinks due to their lack of net productivity and high respiration and nutrient turnover. However, the rates of RDWD in this virgin forest were significantly lower than those previously estimated for managed forests. This suggests that DWD in virgin forests may be buffering forest CO2 emissions to the atmosphere more than previously thought.

Contribution of the MP2RAGE 7T Sequence in MS Lesions of the Cervical Spinal Cord.

BACKGROUND AND PURPOSE: The detection of spinal cord lesions in patients with MS is challenging. Recently, the 3D MP2RAGE sequence demonstrated its usefulness at 3T. Benefiting from the high spatial resolution provided by ultra-high-field MR imaging systems, we aimed to evaluate the contribution of the 3D MP2RAGE sequence acquired at 7T for the detection of MS lesions in the cervical spine. MATERIALS AND METHODS: Seventeen patients with MS participated in this study. They were examined at both 3T and 7T. The MR imaging examination included a Magnetic Imaging in MS (MAGNIMS) protocol with an axial T2*-WI gradient recalled-echo sequence ("optimized MAGNIMS protocol") and a 0.9-mm isotropic 3D MP2RAGE sequence at 3T, as well as a 0.7-mm isotropic and 0.3-mm in-plane-resolution anisotropic 3D MP2RAGE sequences at 7T. Each data set was read by a consensus of radiologists, neurologists, and neuroscientists. The number of lesions and their topography, as well as the visibility of the lesions from one set to another, were carefully analyzed. RESULTS: A total of 55 lesions were detected. The absolute number of visible lesions differed among the 4 sequences (linear mixed effect ANOVA, P = .020). The highest detection was observed for the two 7T sequences with 51 lesions each (92.7% of the total). The optimized 3T MAGNIMS protocol and the 3T MP2RAGE isotropic sequence detected 41 (74.5%) and 35 lesions (63.6%), respectively. CONCLUSIONS: The 7T MP2RAGE sequences detected more lesions than the 3T sets. Isotropic and anisotropic acquisitions performed comparably. Ultra-high-resolution sequences obtained at 7T improve the identification and delineation of lesions of the cervical spinal cord in MS.

Refractory hypotension secondary to chronic treatment with high doses of quetiapine.

Quetiapine is an atypical antipsychotic used in the treatment of depressive, schizophrenic, or bipolar disorders. It acts on dopamine D1 and D2, histamine, and 5HT1A and 5HT2 receptors. However, it also acts as an antagonist for α1 receptors causing cardiovascular side effects, including hypotension. We present the case of a patient chronically medicated with Quetiapine who developed hypotension refractory to vasoconstrictors and intraoperative fluid therapy. Noradrenalin has a strong α1 effect with lower affinity for ß2 receptors unlike adrenalin. This translates into peripheral vasoconstriction and an improved clinical picture. Therefore, it should be considered the vasoactive drug of choice in patients on high doses of Quetiapine.

[Prevalence of neurodevelopmental disorders in children from the rural population of Oaxaca evaluated by means of the Child Development Evaluation test]. / Prevalencia de alteraciones en el neurodesarrollo en niños de población rural de Oaxaca evaluados mediante la prueba Evaluación de Desarrollo Infantil.

INTRODUCTION: During child's growth, access to health, nutrition, opportunities for stimulation, and early learning are necessary for an optimal development of the central nervous system. In rural areas there is a lack of access to them, and this has an impact on children's neurodevelopment. OBJECTIVE: To identify the prevalence of lag or delay in the development of children in rural areas. SUBJECTS AND METHODS: A descriptive, cross-sectional and prospective study, with non-probabilistic convenience sampling, where 97 infants from 1 month of age to one day before their 5th birthday, all belonging to rural communities in the state of Oaxaca, Mexico, were applied the Child Development Evaluation, designed and validated for the Mexican population in the early detection of neurodevelopmental problems. RESULTS: The prevalence of developmental disorders was 43%, with predominance in the male sex. The area of development with the greatest affectation was language, with a total of 29%, and in second place gross motor skills, with 18%; however, neurological affectation as the only one occurred in 2% of the participants, the most prevalent risk factors were the urinary tract infections in 56% of mothers. CONCLUSION: There is a percentage greater than 30% of neurodevelopmental disorders in rural communities due to social risk factors that infants face, such as the difficult access to medical care, a poorly stimulating environment and bad nutrition.

TITLE: Prevalencia de alteraciones en el neurodesarrollo en niños de población rural de Oaxaca evaluados mediante la prueba Evaluación de Desarrollo Infantil.Introducción. Durante el desarrollo del niño, el acceso a la salud, la nutrición, las oportunidades de estimulación y el aprendizaje temprano son necesarios para un óptimo desarrollo del sistema nervioso central. En zonas rurales se denota la falta de acceso a ellas, y esto repercute en el neurodesarrollo de los niños. Objetivo. Identificar la prevalencia de rezago o retraso en el desarrollo de niños de población rural. Sujetos y métodos. Estudio descriptivo, transversal y prospectivo, con muestreo no probabilístico de conveniencia, en el que a 97 niños a partir de 1 mes de edad y hasta un día antes de cumplir los 5 años, pertenecientes a comunidades rurales del estado de Oaxaca, México, se les aplicó la Evaluación de Desarrollo Infantil, diseñada y validada para la población mexicana en la detección de problemas del neurodesarrollo. Resultados. La prevalencia de las alteraciones del desarrollo fue del 43%, con predominio en el sexo masculino. El área de desarrollo con mayor afectación fue el lenguaje, con un 29%, y en segundo lugar la motricidad gruesa, con un 18%; sin embargo, las afectaciones neurológicas sólo se presentaron en el 2% de los participantes. Los factores de riesgo de mayor prevalencia fueron las infecciones de las vías urinarias, presentes en el 56% de las madres. Conclusión. Existe un porcentaje mayor del 30% de alteraciones en el neurodesarrollo en comunidades rurales debido a los factores de riesgo social que viven los niños, como el difícil acceso a la atención médica, un ambiente poco estimulante y una mala nutrición.

The Diagnostic Laboratory Hub: A New Health Care System Reveals the Incidence and Mortality of Tuberculosis, Histoplasmosis, and Cryptococcosis of PWH in Guatemala.

BACKGROUND: A Diagnostic Laboratory Hub (DLH) was set up in Guatemala to provide opportunistic infection (OI) diagnosis for people with HIV (PWH). METHODS: Patients newly presenting for HIV, PWH not receiving antiretrovirals (ARVs) for >90 days but returned to care (Return/Restart), and PWH on ARVs with symptoms of OIs (ARV treatment) were prospectively included. Screening for tuberculosis, nontuberculous mycobacteria (NTM), histoplasmosis, and cryptococcosis was done. Samples were couriered to the DLH, and results were transmitted electronically. Demographic, diagnostic results, disease burden, treatment, and follow-up to 180 days were analyzed. RESULTS: In 2017, 1953 patients were included, 923 new HIV infections (an estimated 44% of all new HIV infections in Guatemala), 701 on ARV treatment, and 315 Return/Restart. Three hundred seventeen (16.2%) had an OI: 35.9% tuberculosis, 31.2% histoplasmosis, 18.6% cryptococcosis, 4.4% NTM, and 9.8% coinfections. Histoplasmosis was the most frequent AIDS-defining illness; 51.2% of new patients had <200 CD4 cells/mm3 with a 29.4% OI incidence; 14.3% of OIs in new HIV infections occurred with CD4 counts of 200-350 cells/mm3. OIs were the main risk factor for premature death for new HIV infections. At 180 days, patients with OIs and advanced HIV had 73-fold greater risk of death than those without advanced disease who were OI-free. CONCLUSIONS: The DLH OI screening approach provides adequate diagnostic services and obtains relevant data. We propose a CD4 screening threshold of <350 cells/mm3. Mortality remains high, and improved interventions are required, including expansion of the DLH and access to antifungal drugs, especially liposomal amphotericin B and flucytosine.

SAFIIRA: A heavy-ion multi-purpose irradiation facility in Brazil.

This work describes the new facility for applied nuclear physics at the University of Sao Paulo, mainly for irradiation of electronic devices. It is a setup composed of a quadrupole doublet for beam focusing/defocusing plus multiple scattering through gold foils to produce low intensity, large-area, and high-uniformity heavy-ion beams from 1H to 107Ag. Beam intensities can be easily adjusted from 102 particles cm2/s to hundreds of nA for an area as large as 2.0 cm2 and uniformity better than 90%. Its irradiation chamber has a high-precision motorized stage, and the system is controlled by a LabViewTM environment, allowing measurement automation. Design considerations and examples of use are presented.

Prevalencia de alteraciones en el neurodesarrollo en niños de población rural de Oaxaca evaluados mediante la prueba Evaluación de Desarrollo Infantil / Prevalence of neurodevelopmental disorders in children from the rural population of Oaxaca evaluated by means of the Child Development Evaluation test

Introducción: Durante el desarrollo del niño, el acceso a la salud, la nutrición, las oportunidades de estimulación y el aprendizaje temprano son necesarios para un óptimo desarrollo del sistema nervioso central. En zonas rurales se denota la falta de acceso a ellas, y esto repercute en el neurodesarrollo de los niños. Objetivo: Identificar la prevalencia de rezago o retraso en el desarrollo de niños de población rural.Sujetos y métodos: Estudio descriptivo, transversal y prospectivo, con muestreo no probabilístico de conveniencia, en el que a 97 niños a partir de 1 mes de edad y hasta un día antes de cumplir los 5 años, pertenecientes a comunidades rurales del estado de Oaxaca, México, se les aplicó la Evaluación de Desarrollo Infantil, diseñada y validada para la población mexicana en la detección de problemas del neurodesarrollo. Resultados: La prevalencia de las alteraciones del desarrollo fue del 43%, con predominio en el sexo masculino. El área de desarrollo con mayor afectación fue el lenguaje, con un 29%, y en segundo lugar la motricidad gruesa, con un 18%; sin embargo, las afectaciones neurológicas sólo se presentaron en el 2% de los participantes. Los factores de riesgo de mayor prevalencia fueron las infecciones de las vías urinarias, presentes en el 56% de las madres. Conclusión: Existe un porcentaje mayor del 30% de alteraciones en el neurodesarrollo en comunidades rurales debido a los factores de riesgo social que viven los niños, como el difícil acceso a la atención médica, un ambiente poco estimulante y una mala nutrición.(AU)

Introduction: During child’s growth, access to health, nutrition, opportunities for stimulation, and early learning are necessary for an optimal development of the central nervous system. In rural areas there is a lack of access to them, and this has an impact on children’s neurodevelopment. Objective: To identify the prevalence of lag or delay in the development of children in rural areas. Subjects and methods: A descriptive, cross-sectional and prospective study, with non-probabilistic convenience sampling, where 97 infants from 1 month of age to one day before their 5th birthday, all belonging to rural communities in the state of Oaxaca, Mexico, were applied the Child Development Evaluation, designed and validated for the Mexican population in the early detection of neurodevelopmental problems. Results: The prevalence of developmental disorders was 43%, with predominance in the male sex. The area of development with the greatest affectation was language, with a total of 29%, and in second place gross motor skills, with 18%; however, neurological affectation as the only one occurred in 2% of the participants, the most prevalent risk factors were the urinary tract infections in 56% of mothers. Conclusion: There is a percentage greater than 30% of neurodevelopmental disorders in rural communities due to social risk factors that infants face, such as the difficult access to medical care, a poorly stimulating environment and bad nutrition.(AU)

Fine organization of Bombyx mori fibroin heavy chain gene.

The complete sequence of the Bombyx mori fibroin gene has been determined by means of combining a shotgun sequencing strategy with physical map-based sequencing procedures. It consists of two exons (67 and 15 750 bp, respectively) and one intron (971 bp). The fibroin coding sequence presents a spectacular organization, with a highly repetitive and G-rich (approximately 45%) core flanked by non-repetitive 5' and 3' ends. This repetitive core is composed of alternate arrays of 12 repetitive and 11 amorphous domains. The sequences of the amorphous domains are evolutionarily conserved and the repetitive domains differ from each other in length by a variety of tandem repeats of subdomains of approximately 208 bp which are reminiscent of the repetitive nucleosome organization. A typical composition of a subdomain is a cluster of repetitive units, Ua, followed by a cluster of units, Ub, (with a Ua:Ub ratio of 2:1) flanked by conserved boundary elements at the 3' end. Moreover some repeats are also perfectly conserved at the peptide level indicating that the evolutionary pressure is not identical along the sequence. A tentative model for the constitution and evolution of this unusual gene is discussed.

Draft Genome Sequence of a Hypermucoviscous Extended-Spectrum-ß-Lactamase-Producing Klebsiella quasipneumoniae subsp. similipneumoniae Clinical Isolate.

A clinical isolate of extended-spectrum-ß-lactamase-producing Klebsiella quasipneumoniae subsp. similipneumoniae 06-219 with hypermucoviscosity phenotypes obtained from a urine culture of an adult patient was used for whole-genome sequencing. Here, we report the draft genome sequences of this strain, consisting of 53 contigs with an ~5.6-Mb genome size and an average G+C content of 57.36%. The annotation revealed 6,622 coding DNA sequences and 77 tRNA genes.

Adverse hemodynamic and clinical effects of calcium channel blockade in pulmonary hypertension secondary to obliterative pulmonary vascular disease.

The hemodynamic and clinical responses to calcium channel blockade with verapamil and nifedipine were compared with those of hydralazine in 12 patients with pulmonary hypertension secondary to obliterative pulmonary vascular disease. All three drugs produced a marked and similar decrease in pulmonary vascular resistance; however, this was accompanied by a significant increase in cardiac index with hydralazine (+0.71 liter/min per m2, p less than 0.01), no change in cardiac index with nifedipine and a significant decrease in cardiac index with verapamil (-0.25 liter/min per m2, p less than 0.05). Mean pulmonary artery pressure decreased markedly with both calcium channel blocking drugs (-16.0 mm Hg with verapamil and -14.5 mm Hg with nifedipine, both p less than 0.01), but this was associated with a concomitant increase in mean right atrial pressure (+6.2 mm Hg with verapamil and +4.4 mm Hg with nifedipine, both p less than 0.01); neither variable changed after hydralazine. Hence, right ventricular performance (as reflected by right ventricular stroke work index) deteriorated during treatment with both calcium channel blocking drugs, despite the decrease in resistance to right ventricular ejection; in contrast, right ventricular stroke work index increased after hydralazine. The unfavorable hemodynamic effects of calcium channel blockade were accompanied by severe adverse clinical events, including profound hypotension and cardiogenic shock during acute drug administration and the exacerbation of right heart failure during long-term treatment. These deleterious responses to verapamil and nifedipine are likely the result of a direct depressant effect exerted by these drugs on right ventricular function independent of their pulmonary vasodilatory actions.

Relation between serum sodium concentration and the hemodynamic and clinical responses to converting enzyme inhibition with captopril in severe heart failure.

The relation between pretreatment serum sodium concentration and the early and late effects of captopril was examined in 77 consecutive patients with severe chronic heart failure, in whom cardiac catheterization was performed during initiation of treatment and after 2 to 8 weeks. Two groups of patients were defined: 37 patients had hyponatremia (serum sodium less than 135 mEq/liter, group A) and 40 patients had a normal serum sodium concentration (greater than or equal to 135 mEq/liter, group B). With first doses of captopril, patients in group A showed more marked hemodynamic responses than did patients in group B (p less than 0.02). The changes in mean arterial pressure and left ventricular filling pressure seen with first doses of the drug varied linearly and inversely with the pretreatment serum sodium concentration (r = -0.58 and r = -0.53, respectively); this was likely related to the finding that, before administration of captopril, the serum sodium concentration varied linearly and inversely with the logarithm of the plasma renin activity (r = -0.78). However, the pretreatment serum sodium concentration did not predict the long-term hemodynamic or clinical responses to converting enzyme inhibition. Symptomatic hypotension occurred early in the course of therapy (within 24 hours of initiating captopril therapy) in 9 (12%) of the 77 patients; 8 of these 9 had severe hyponatremia (serum sodium less than 130 mEq/liter) and comprised 53% of the 15 patients in our study with such low serum sodium concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of the renin-angiotensin system in the development of hemodynamic and clinical tolerance to long-term prazosin therapy in patients with severe chronic heart failure.

Right heart catheterization was performed before and during long-term therapy with prazosin in 27 patients with severe chronic heart failure who underwent serial hemodynamic studies during 3 to 12 weeks of treatment with the drug. Doses of digoxin and furosemide remained constant during the trial; in addition, 11 of the 27 patients were assigned to concomitant therapy with spironolactone, while the remaining 16 patients did not receive the aldosterone antagonist. First doses of prazosin produced marked increases in cardiac index and marked decreases in mean arterial pressure, left ventricular filling pressure and systemic vascular resistance in both groups of patients (all p less than 0.01), but these effects became rapidly attenuated (p less than 0.01) in both groups after 48 hours and remained attenuated during long-term therapy. After 3 to 12 weeks, values for cardiac index returned to pretreatment levels and did not decrease when the drug was withdrawn; values for mean arterial pressure, left ventricular filling pressure and systemic vascular resistance remained significantly decreased (although attenuated) after 3 to 12 weeks (p less than 0.01) and increased to pretreatment values when the drug was withdrawn. The magnitude and time course of these responses were not altered by concomitant therapy with spironolactone. Complete loss of hemodynamic efficacy (prazosin tolerance) was noted in 14 (58%) of the 24 patients who underwent long-term hemodynamic study and was not accompanied by long-term changes in plasma renin activity or body weight. These data indicate that prazosin produces long-term hemodynamic and clinical benefits in only 30 to 40% of patients with severe chronic heart failure and do not support a role for the renin-angiotensin system in the development of tolerance to alpha-adrenergic blockade. This low response rate explains why most randomized double-blind trials of prazosin in heart failure have not been able to demonstrate a significant difference between patients treated with placebo and those receiving active drug.

Hemodynamic and clinical significance of the pulmonary vascular response to long-term captopril therapy in patients with severe chronic heart failure.

Exercise capacity in patients with left heart failure is closely related to the performance of the right ventricle and the pulmonary circulation. To determine the significance of changes in pulmonary resistance during long-term vasodilator therapy, hemodynamic studies were performed before and after 1 to 3 months of treatment with captopril in 75 patients with severe chronic left heart failure. Patients were grouped according to the relative changes in pulmonary and systemic resistances during long-term therapy: patients in Group I (n = 24) showed greater decreases in pulmonary arteriolar resistance (PAR) than in systemic vascular resistance (SVR) (% delta PAR/% delta SVR greater than 1.0), whereas patients in Group II showed predominant systemic vasodilation (% delta PAR/% delta SVR less than 1.0). Despite similar changes in systemic resistance, patients in Group I showed greater increases in cardiac index, stroke volume index and left ventricular stroke work index (p less than 0.01 to 0.001) but less dramatic decreases in mean systemic arterial pressure (p less than 0.02) than did patients in Group II. Despite similar changes in left ventricular filling pressure, patients in Group I showed greater decreases in mean pulmonary artery and mean right atrial pressures (p less than 0.02 to 0.01) than did patients in Group II. Pretreatment variables in Groups I and II were similar, except that plasma renin activity was higher (8.7 +/- 2.1 versus 3.0 +/- 0.6 ng/ml per h) and serum sodium concentration was lower (133.1 +/- 0.9 versus 137.1 +/- 0.6 mEq/liter) in Group II than in Group I (both p less than 0.05). Both groups improved clinically after 1 to 3 months, but symptomatic hypotension occurred more frequently in Group II than in Group I (36 versus 8%) (p less than 0.005). These findings indicate that changes in the pulmonary circulation modulate alterations in both right and left ventricular performance during the treatment of patients with left heart failure. Hyponatremic patients are likely to experience symptomatic hypotension with captopril because they are limited in their ability to increase cardiac output as a result of an inadequate pulmonary vasodilator response to the drug.

Identification of hyponatremia as a risk factor for the development of functional renal insufficiency during converting enzyme inhibition in severe chronic heart failure.

To identify patients with severe chronic heart failure who are at greatest risk of developing functional renal insufficiency during converting enzyme inhibition, creatinine clearance was measured in 59 patients before and after long-term therapy with captopril (39 patients) or enalapril (20 patients), while digitalis and diuretic therapy was kept constant. Creatinine clearance increased or remained constant in 33 of the 59 patients (Group I), but declined in the remaining 26 patients (Group II). The two groups were similar with respect to the cause of heart failure, pretreatment renal function and all pretreatment hemodynamic variables. Patients in Group II, however, had lower values for serum sodium concentration (134.8 +/- 1.0 versus 137.0 +/- 0.6 mmol/liter) and higher values for plasma renin activity (10.6 +/- 3.4 versus 3.0 +/- 0.5 ng/ml per hour), received larger doses of furosemide (108 +/- 11 versus 84 +/- 6 mg/day), were more frequently diabetic (42 versus 15%) and were more frequently treated with enalapril (50 versus 21%) than were patients in Group I (all p less than 0.05). By stepwise logistic analysis, only hyponatremia (or an elevated plasma renin activity) and enalapril therapy independently predicted the decline in creatinine clearance during converting enzyme inhibition. These observations could not be explained by changes in systemic blood pressure. In patients with a normal serum sodium concentration (greater than or equal to 137 mmol/liter), creatinine clearance increased with captopril (+21%, p less than 0.05), but not with enalapril (-6%, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)