Dorit Ravid

Use of Enalapril To Attenuate Decline in Renal Function in Normotensive, Normoalbuminuric Patients with Type 2 Diabetes Mellitus: A Randomized, Controlled Trial

The concept of microalbuminuria has had a major impact on diabetes research and clinical care of patients with diabetes [1-5]. Initial albuminuria is regarded by most researchers as an independent predictor of subsequent progression of nephropathy and risk for cardiovascular morbidity and mortality [6-8]. Angiotensin-converting enzyme (ACE) inhibitors have been found to attenuate progression of nephropathy in both types of diabetes in hypertensive [9-12] and normotensive patients [13-15] with microalbuminuria. They were also found to lower urinary albumin excretion in normotensive and normoalbuminuric patients with type 1 diabetes [16]. The relation between albuminuria and later progression of nephropathy in these patients has not been established, possibly because of short follow-up periods. No data are available on the effect of early introduction of ACE inhibitors in normotensive and normoalbuminuric patients with type 2 diabetes mellitus. We designed a randomized, double-blind, placebo-controlled trial of the effect of ACE inhibition on the course of nephropathy in 156 patients with type 2 diabetes. These patients had normal blood pressure and normal urinary albumin excretion at baseline. Methods Patients Potential candidates were identified through the computerized records of the central regional laboratory for the northern part of the greater Tel-Aviv area. Persons with hyperglycemia and normal urinalysis results were located through their family physicians. Consent was sought once eligibility was established. Inclusion criteria were age younger than 60 years; age 40 years or older at diagnosis; duration of diabetes mellitus less than 10 years with no clinical evidence of malignant, autoimmune, hepatic, cardiovascular, or renal disease; body mass index less than 30 kg/m2; normal blood pressure on at least two consecutive visits (systolic pressure 140 mm Hg and diastolic pressure 90 mm Hg; mean pressure 107 mm Hg); serum creatinine concentration of 123 mol/L or less; and urinary albumin excretion of 30 mg/24 h or less. All baseline data were obtained twice during the run-in prerandomization period. Patients were eligible only if values within the predetermined range were found on both examinations. The average of the values was used as the baseline value. A total of 255 patients who had type 2 diabetes according to World Health Organization criteria [17] and attended one of eight clinics in the greater Tel-Aviv area were found to be eligible and were contacted during 1990 and 1991. Of these patients, 214 gave informed consent to participate. Twenty patients were excluded during the observation period: Six had blood pressure values above normal, 5 had microalbuminuria, 3 had serum creatinine concentrations above the trial criterion, 1 patient developed unstable angina pectoris, and 5 withdrew consent. Of the 194 patients included in the study, 102 were women and 92 were men (mean age SD, 54.9 3.2 years [range, 37 to 59 years]). The known duration of diabetes was 0 to 9 years (mean duration, 5.75 2.8 years). Patients were instructed to use the standard isocaloric diet recommended by the Israeli Diabetic Association, and 69 study patients used diet alone to control their hyperglycemia. Pharmacologic therapy for diabetes was insulin in 34 patients and oral hypoglycemic agents in 91 patients. Protocol The protocol was approved by the hospital review board. After a 2-month observation period, patients were randomly assigned in a double-blind manner to receive enalapril (Assia-Riezel Ltd., Ramat-Gan, Israel), 10 mg/d, or placebo. Ninety-seven patients were assigned to receive enalapril, and 97 were assigned to receive placebo. Randomization was done centrally by telephone with a random number table [18]. Patient allocation to placebo or enalapril was recorded and kept by one of the authors. The placebo tablets were similar in appearance to the enalapril tablets. The medications, which came in sealed, numbered packages, were centrally prepared and were given to the patients at each visit by one nurse who was otherwise not involved in the study. Patients were followed by their family physicians, who were unaware of allocation. Two semiannual prescheduled visits took place each year, and interim visits were scheduled as clinically indicated. At the semiannual visits, hemoglobin A1c values, serum creatinine concentrations, serum electrolyte levels, and 24-hour albumin excretion and urinary creatinine concentrations were measured. Blood pressure was measured by the physicians twice at each visit by using mercury sphygmomanometers with the patients seated after a 5-minute rest; physicians recorded the average of the two values. The diastolic pressure was determined at Korotkoff phase V. If a systolic blood pressure of 145 mm Hg or more or a diastolic blood pressure of 95 mm Hg or more was found, measurements were repeated weekly. If elevated values persisted on two consecutive visits, a long-acting calcium-channel blocker (diltiazem or verapamil), hydrochlorothiazide, or both were administered. If systolic blood pressure values of 100 mm Hg or less were repeatedly found, the enalapril dosage was reduced to 5 mg/d (half of a 10-mg enalapril tablet or half of a placebo tablet). Fundoscopy was done yearly by an ophthalmologist, and the presence of retinopathy was recorded. For each patient, follow-up was terminated 6 years after randomization. Measurements All blood and urine samples were examined by a central laboratory. Assays were not changed during the study period. Glycosylated hemoglobin values were measured by affinity chromatography with a commercial kit (Isolab, Biochemical Methodology, Akron, Ohio). The normal range of this assay is a hemoglobin A1c value of 3.5% to 5.6% and an intra-assay and interassay coefficient of variability of less than 3%. Urinary albumin concentration was measured twice in 24-hour urine samples by an automated immunoturbidimetric method [19]. This procedure has intra-assay and interassay coefficients of variability of 5.9% and 7.6%, respectively. Creatinine concentrations were determined by using the automated method of Bartels and colleagues [20]. Creatinine clearance, normalized for 1.73 m2 of body surface area, was calculated for each visit by using the standard formula (urine creatinine x urine volume/plasma creatinine). The mean blood pressure (defined as the diastolic pressure plus one third of the pulse pressure) was calculated at each visit. Statistical Analysis Data are expressed as the mean (SD) with ranges. A P value less than 0.05 was considered significant. On the basis of the assumptions that 15% of normotensive, normoalbuminuric patients with type 2 diabetes will develop microalbuminuria during 6 years and that treatment with enalapril will reduce the risk for microalbuminuria by 12%, we calculated that 69 patients were required in each group for a type 1 error of 0.05 and a power of 0.80 [21]. To test for adequate randomization and to compare the patients who completed the trial with those who did not complete the trial, the enalapril and placebo groups and the 38 patients who dropped out were compared for mean age; mean duration of diabetes; and mean baseline albumin excretion, creatinine clearance, glycosylated hemoglobin value, and blood pressure by using pooled-variance Student t-tests for independent groups and one-way analysis of variance. To compare the annual means of the various measurements between the two groups and within each group, one between-group factor and one repeated-measures factor were used in analysis of variance. For variables shown to be different by analysis of variance, unpaired t-tests were used for between-group parallel annual means and paired t-tests were used for comparison of intragroup sequential annual means. The rate of decrease of creatinine clearance and the rate of increase of albumin excretion were computed by doing linear regression analysis with all of the semiannual values included in the equation. Urinary albumin values were logarithmically transformed before analysis. The degree of albuminuria at baseline was used as a covariate. The funding source had no involvement in the design, conduct, or reporting of the trial. Results Figure 1 shows the flow of participants during the trial. Thirty-eight patients did not complete the trial. Five patients died (3 in the enalapril group and 2 in the placebo group); death was related to coronary heart disease in 3 patients, stroke in 1 patient, and ovarian carcinoma in 1 patient. Six patients violated the protocol (2 patients in the enalapril group stopped taking their medication for more than 6 months, and 4 patients in the placebo group took an ACE inhibitor prescribed by consultant physicians for more than 6 months). Ten patients were lost to follow-up (6 in the enalapril group and 4 in the placebo group). The trial medication was discontinued in 12 patients: Six developed a disturbing cough (4 in the enalapril group and 2 in the placebo group), 4 had an allergic skin reaction (2 in the enalapril group and 2 in the placebo group), 1 patient in the enalapril group developed leukopenia, and 1 patient in the placebo group developed hyperkalemia. Finally, 5 patients developed severe urinary tract infections that had a detectable influence on renal function (2 in the enalapril group and 3 in the placebo group). A total of 156 patients completed the trial, of whom 77 received enalapril and 79 received placebo. Figure 1. Flow of participants through the trial. Baseline data for the two groups and for patients who did not complete the trial are shown in Table 1. The baseline characteristics of patients in the study groups and those who dropped out did not differ significantly. A modest but steady decrease in hemoglobin A1c values was seen in the enalapril and the placebo groups and may reflect the change in attitude toward glucose control among family physicians in the early 1990s. However, t

Cross-Linguistic Evidence for the Nature of Age Effects in Second Language Acquisition.

Few researchers would doubt that ultimate attainment in second language grammar is negatively correlated with age of acquisition, but considerable controversy remains about the nature of this relationship: the exact shape of the age-attainment function and its interpretation. This article presents two parallel studies with native speakers of Russian: one on the acquisition of English as a second language in North America (n = 76), and one on the acquisition of Hebrew as a second language in Israel (n = 64). Despite the very different nature of the languages being learned, the two studies show very similar results. When age at testing is partialed out, the data reveal a steep decline in the learning of grammar before age 18 in both groups, followed by an essentially horizontal slope until age 40. This is interpreted as evidence in favor of the critical period. Both groups show a significant correlation between ultimate attainment and verbal aptitude for the adult learners, but not for the early learners. This is interpreted as further evidence that the learning processes in childhood and adulthood not only yield different levels of proficiency but are also different in nature.

Morphology and spelling among Hebrew-speaking children: from kindergarten to first grade

This study had two major objectives: (1) to analyse the development of two morphological structures in Hebrew, one inflectional and the other derivational and (2) to examine the mutual contribution of morphological knowledge and learning the written code. In a longitudinal design, 40 children were tested twice, first in kindergarten (mean age: 5; 11) and again in first grade (mean age: 6;5), on two oral tasks--inflecting nouns for possession and deriving denominal adjectives--and one written task of writing a series of noun-adjective pairs. The derivational task was found to be harder than the inflectional task, both on the stem and the suffix level, attributable to its higher semantic opacity. In both oral tests, correct stem production when suffixed was related to the morphophonological level of stem change. Correlations were found between morphological and writing scores. Moreover, children who were more advanced in morphology in kindergarten progressed more in writing vowels from kindergarten to first grade, and those who were more advanced in writing in kindergarten improved more in derivational morphology with grade.

Semantic development in textual contexts during the school years: noun scale analyses.

The paper examines the nominal lexicon in later language acquisition as a window on linguistic knowledge and usage across childhood and adolescence. The paper presents a psycholinguistically motivated and cognitively grounded analysis of the distribution of ten semantic noun categories (the Noun Scale) across development, modality, and genre. Eighty Hebrew-speaking children (9;0 to 10;0), adolescents (12;0 to 13;0 and 16;0 to 17;0), and a group of adult university graduate students participated in the study. Each produced four different texts: a spoken and written narrative and a spoken and written expository, yielding a total of 320 texts. All lexical noun tokens in each of the 320 texts were analysed to determine their score on the Noun Scale. Results indicate that nominal density, which underlies much of the syntactic architecture of texts, increases dramatically in adolescence, towards adulthood. The paper analyses the developmental patterns of each of the ten Noun Scale categories, showing that the nominal lexicon of schoolaged children is already very different from that of young children in having only a small amount of genuinely concrete nouns, and these too only in narrative texts. The quantitative analysis shows that nouns grow more categorical and abstract with age and schooling, especially in adolescence. Written expository texts are the preferred habitat of abstract, categorical nouns from early on. The systematic qualitative analysis of noun tokens in their textual context demonstrates how the nominal lexicon undergoes fundamental changes that are affected by linguistic, cognitive and social development, in interaction with text genre and modality.

Awareness of linear and nonlinear morphology in Hebrew: a developmental study

The study explores the interface of language typology, universal predispositions, language awareness and school instruction through the examination of two morphological domains in Hebrew: linear formation of stem-and-suffix words and nonlinear Semitic formation of root-and-pattern affixation. One hundred children, adolescents and adults were administered five tasks testing awareness of roots, morphological patterns, stems and suffixes in inflection and in derivation. Two major findings are reported and analysed: awareness of linear constructions emerges earlier than awareness of nonlinear forms, and stems (roots and word stems) are easier to construe than affixes (morphological patterns and suffixes). The paper discusses the inter-action of language acquisition and use with linguistic awareness, and the effect of tasks on different degrees of morphological awareness in Hebrew.

Developing Noun Phrase Complexity at School Age: A Text-Embedded Cross-Linguistic Analysis

Development of noun phrase structure and use is analyzed as an important facet of syntactic acquisition from middle childhood to adolescence. Noun phrases occurring in narrative and expository texts produced in both speech and writing by 96 native speakers of English and Hebrew were identified and examined by a set of specially devised criteria including length in words, syntactic depth, abstractness of head nouns, and nature of modifiers. Results reveal a clear and consistent developmental increment in NP complexity from age 9 to 12, and particularly from age 16 years; written expository texts emerge as a favored site for use of syntactically complex constructions; and nominal elements play a more central role in the discursive syntax of Hebrew than English. Findings are discussed in terms of the interplay between psycholinguistic factors of cognitive processing constraints and the impact of increased literacy in later language development.

Angiotensin-Converting Enzyme Inhibitors and Cough: A Prospective Evaluation in Hypertension and in Congestive Heart Failure

Angiotensin‐converting enzyme inhibitors (ACE‐I) have become the mainstem of antihypertensive therapy and first‐choice agents for vasodilatation in congestive heart failure (CHF). A typical dry cough is the main cause for discontinuation of ACE‐I therapy. Data about the incidence, course, and clinical significance of this side effect are conflicting. This study determined the incidence of cough in ACE‐I treated patients with hypertension and with CHF and to appreciate its clinical significance; 268 ACE‐I treated patients, 164 with hypertension and 104 with CHF were prospectively followed for at least 1 year and specifically questioned about cough and other side effects. In those in whom cough developed, a second and then a third ACE‐I were tried. Cough developed in 50 (18.6%) of the 268 patients; 23 patients with hypertension (14%) had coughs 24.7 ± 17.1 (SD) weeks after initiation of therapy; 27 patients with CHF (26%) had coughs 12.3 ± 12 (SD) weeks after the start of ACE‐I therapy (P = 0.005). All but three patients had coughs also on the second and third ACE‐I. The time from the beginning of therapy to the onset of cough was significantly shorter with the second than the first drug. ACE‐I agents had to be discontinued in 50% of the patients in whom coughs developed, most of them in the CHF group. In the others, cough was well tolerated or disappeared during subsequent months. The incidence of cough, which necessitated discontinuation of ACE‐I treatment, was 4% among patients with hypertension and 18% among patients with CHF (P < 0.001). ACE‐I‐induced cough is common in patients with CHF and usually dictates the interruption of this treatment. In hypertension, ACE‐I therapy may be continued in most patients despite the cough, which will subsequently regress in intensity or disappear. Alternative ACE‐I agents should not be tried because cough will reappear.

Information Density in the Development of Spoken and Written Narratives in English and Hebrew

This study compares what we term information density in spoken versus written discourse by distinguishing between 2 broad classes of material in narrative texts: narrative information as conveyed through three types of propositional content—events, descriptions, and interpretations (Berman, 1997)—and ancillary information as conveyed by nonnovel, nonreferential, or nonnarrative material. One hundred sixty texts were analyzed across the variables of modality (writing, speech), development (4th-, 7th-, and 11th-grade students compared with adults), and language (English, Hebrew). Calculation of information density revealed no significant differences between languages, indicating that the analysis has general applicability. Increase in narrative information proved to be a function of modality rather than age, because, across the population, spoken texts contained far more ancillary material than written. By contrast, the nature of narrative content changed as a function of development, with interpretive material increasing with age. The study thus underscores 2 key features of narrative text construction: Modality has a distinct effect on information density, and, with age, the core of narrative information (events and descriptions) becomes fleshed out by interpretive and story-external elements.

Early noun plurals in German: regularity, productivity or default?

The acquisition of German plurals has been the focus of controversy in the last decade. In this paper we claim that degree of productivity (i.e. the capacity of nouns to form potential plurals) plays a key role in determining pace of acquisition. A plural elicitation task was administered to 84 Viennese German-speaking children aged 2;6 to 6;0. Analyses of correct responses showed that the highest scores were obtained with -e plurals, followed by the plural markers -e + U, -er + U, -s and -(e)n. The lowest score was observed for pure Umlaut (U) plurals. Analyses suggested an impact of productivity on the number of correct scores: fully productive and productive plural patterns obtained higher correct scores than weakly productive and non-productive ones. The results of the study support our productivity scale and are compatible both with single-route models and with a race-model variant of the dual-route view.

Morphological Analysis in Learning to Read Pseudowords in Hebrew.

This paper examines the role of morphology in gradeschool childrens learning to read nonpointed Hebrew. It presents two experiments testing the reading of morphologically based nonpointed pseudowords. One hundred seventy-one Hebrew-speaking children and adolescents in seven age/schooling groups (beginning and end of 2nd, 3rd, 4th, 7th, and 11th grade) and a group of adults participated in the study. Participants were administered two tasks of reading aloud nonpointed pseudowords with morphological composition: words in isolation and words in sentential context. Results pinpoint the developmental milestones on the way to efficient nonpointed word recognition in Hebrew: learning to use morphological pattern cues to fill in missing phonological information, where second grade is an important “watershed” period; and overcoming homography by learning to detect morphosyntactic cues, an ability that develops more gradually and over a longer period than pattern recognition.