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1 INTERNATIONAL JOURNAL OF LEPROSY^ INTERNATIONAL JOURNAL OF LEPROSY and Other Mycobacterial Diseases Volume 68, Number 3 Printed in the U.S.A. (ISSN X) VOLUME 68, NUMBER 3^ SEPTEMBER 2000 Single Lesion Paucibacillary Leprosy: Baseline Profile of the Brazilian Multicenter Cohort Study' Celina M. T. Martelli, Mariane M. A. Stefani, Maria Katia Gomes, Paula F. B. Rebello, Silmara Peninni, Kasue Narahashi, Ana Lucia O. Maroclo, Mauricio B. Costa, Simonne A. Silva, Sylvana C. Sacchetim, Jose Augusto C. Nery, Ana Maria Salles, Thomas P. Gillis, James L. Krahenbuhl, and Ana Lucia S. S. Andrade 2 In the context of leprosy elimination, there has been an increased effort to detect and treat leprosy as early as possible with short drug regimens. Single skin lesion pau- ' Received for publication on 4 April Accepted for publication in revised forro on I August 'C. M. T. Martelli, M.D., Ph.D.; M. M. A. Stefani, Ph.D.; A. L. O. Maroclo, M.D.; M. B. Costa, M.D., Ms.C.; S. A. Silva, M.D., Ms.C.; S. C. Sacchetim, M.D.; A. L. S. S. Andrade, M.D., Ph.D., Federal University of Goias, Goiania, Goias, Brazil. M. K. Gomes, M.D., Ms.C., Federal University of Rio de Janeiro, Hospital Clementino Fraga Filho, Rio de Janeiro, Rio de Janeiro, Brazil. P. F. B. Rebello, M.D.; S. Peninni, M.D., Alfredo da Matta Foundation - WHO Leprosy Reference Center, Amazon, Brazil. K. Narahashi, M.D., Secretariat of Health, Porto Velho, Rondonia, Brazil. J. A. C. Nery, M.D., Ph.D.; A. M. Salles, M.D., Ms.C., Reference Leprosy Laboratory, Oswaldo Cruz Foundation, Rio de Janeiro, Rio de Janeiro, Brazil. T. P. Gillis, Ph.D.; J. L. Krahenbuhl, Ph.D., Laboratory Research Branch, GWL Hansen's Disease Center at Louisiana State University, P.O. Box 25072, Baton Rouge, LA 70894, U.S.A. Reprint requests to Dr. Celina M. T. Martelli, Universidade Federal de Goias, Instituto de Patologia Tropical e Saude Publica, Rua Delenda Rezende de Mello, S/N, Setor Universitario, Goiania/GO, Brazil or FAX ; cibacillary leprosy (SSL-PB) may be considered an early chronic stage of the disease, with reported high prevalence in India (s e.26) In Brazil, only recently has the official notification system distinguished leprosy patients with monolesion within the paucibacillary (PB) group (Ministerio da Saude Brasil. Alterações nas instruções normativas do Plano Nacional de Eliminação da Hanseníase. Ofício Circular No. 67, CNDS/CENEPI, 1998). Therefore, epidemiological information regarding patient characteristics is limited to one outpatient clinic in the Southeast Brazilian region ( 2). Since 1998, the World Health Organization (WHO) has recommended a single-dose ROM therapeutic regimen consisting of rifampin (600 mg), ofloxacin (400 mg) and minocycline (100 mg) based on a multicenter, double-blind field trial conducted among SSL-PB patients in India. In this study, similar cure rates were observed for the ROM regimen when compared to the standard 6-month WHO multidrug therapy (WHO/MDT) (23). So far the scientific evidence from the available publications on single-dose ROM 247
2 248^International Joumal of Leprosy^ 2000 efficacy has raised many polemic issues concerning both the clinical outcome in long-term follow up and the immune profile among SSL-PB patients (10. "). Although there is a lack of in-depth investigations about the immune status of this category of patients, a minimal therapy schedule has been recommended under the assumption that this group has low bacterial load, preserved cell-mediated immunity and high spontaneous cure rates. However, it has been argued that single lesion leprosy patients may not comprise a homogeneous group regarding immunological and clinicai parameters, and these differences may distinctly influence the clinicai prognosis within this category ( R16). Recently, the Pan-American Health Organization and the Brazilian Ministry of Health sponsored a multicentric study to implement the ROM therapy for single lesion PB leprosy patients in selected arcas of Brazil. This represented a unique opportunity to assess the comparability of an SSL- PB cohort recruited in Reference Centers located in different endemic settings. In this paper we describe the baseline clinicai features of patients enrolled in the Brazilian monolesion leprosy cohort study. The predictive value of the clinicai screening to diagnose single lesion leprosy and the immunological background of this particular group of patients treated with the one-dose ROM therapy are also presented. MATERIALS AND METHODS This study was preceded by the National Dermatologic Campaign launched by the Brazilian Ministry of Health in October 1997 which invoived radio, newspaper and television publicity. Announcements were placed in public health centers and in physicians' offices in order to optimize population-based screening for the detection of early leprosy. Before the nationwide implementation of single-dose ROM therapy in the routine attendance of the Leprosy Control Program, we started a standardized surveillance in outpatient clinics for recruiting monolesion PB leprosy patients in three endemic Brazilian regions. Selection of centers The requirements for the selection of the sites were to have: a local leprosy control program with expertise in implementing WHO/MDT regimens; an adequately trained staff for clinicai exams, reading skin smears and case management; the capability to recruit around 50 monolesion leprosy patients within 12 months; a reasonably equipped base hospital in the arca for patient admission in case of severe side effects or reactions that might occur. SSL-PB patients were recruited from health centers from four Brazilian states located in the following regions (Fig. 1): a) North = "Fundação Alfredo da Matta," a WHO Leprosy Reference Center located in the city of Manaus (1,280,000 inhabitants), Amazon state, and in two health centers in the municipalities of Porto Velho and Ariquemes (300,000 and 70,000 inhabitants, respectively), Rondônia state. b) Southeast = "Fundação Oswaldo Cruz," a National Leprosy Reference Center and outpatient clinic of the University Hospital Clementino Fraga Filho in the city of Rio de Janeiro (5,730,000 inhabitants), Rio de Janeiro state. c) Center-West = Regional reference leprosy outpatient clinic located in the city of Goiânia (1,000,000 inhabitants), Goiás state. Ascertainment of cases SSL-PB cases were defined taking into account clinicai assessment, bacilloscopy and histopathoiogy. Patients were clinically screened by well-trained doctors in the participating health care centers. Potential eligible cases were newly detected, untreated monolesion leprosy with a skin lesion characterized by hypopigmentation or erythema or both, with or without infiltration, definite sensory loss without thickened nerve involvement. All monolesion cases suspected of leprosy had a skin smear and a skin biopsy for bacilloscopy and conventional histopathologic exams. Patients were categorized as paucibacillary (PB) if they had a negative bacterial index (BI) on slit-skin smear and if the biopsy was classified as indeterminate (I), tuberculoid (TT) or borderline tuberculoid (BT) according to Ridiey and Jopling criteria (17). Criteria for exclusion from the study were: patients with histopathological readings consistent with multibacillary (MB) types of leprosy or with evidence of other skin diseases; children younger than 7 years
3 68, 3^Martelli, et al.: Single Lesion PB-Cohort Baseline^249 FI6. I. Brazilian Single-lesion leprosy cohort study cites. of age; individuais with sensory loss without a visible skin lesion; pregnant women or those breast feeding at the time of drug intake; known HIV seropositive test; chronic diseases (liver dysfunction, diabetes), or an allergy that might interfere with any of the proposed drugs. The multicenter study design is presented in Figure 2. Baseline data collection Clinicai features. At the time of enrollment a questionnaire was used to obtain information on age, sex, height, weight, time of lesion perception and intra-domiciliary contacts of leprosy cases. A clinicai examination was performed including the number and size of lesion measured by the larger diameter and characteristics of the skin lesion; nerve enlargement; and the presence of a BCG scar. To assess neurological sensory loss on the lesion (anesthesia), thermal, pain sensation and standard monofilament devices were used for ali patients. Motor function was also tested to grade disability. The Mitsuda test was performed by intradermally injecting 0.1 ml of lepromin (same batch, produced in Brazil, 1997) on the volar surface of the forearm. The largest transverse diameter of palpable induration was measured 4 weeks )ater. A positive Mitsuda test was defined as having an induration of >_5 mm as assessed by the clinicai staff. Laboratory tests. A slit-skin smear, skin biopsy and blood samples were taken before ROM therapy. Smears were collected from earlobes, elbows, and the skin lesion, and the BI was determined in each of the participating centers. Skin biopsies were collected, fixed in 10% buffered formalin, and processed for paraffin sections (5 gm). The sections were stained with hematoxylin and eosin (H&E) and Fite-Faraco for acidfast bacilli (AFB). The histopathological diagnosis of leprosy was based on Ridley and
4 250^International Journal of Leprosy^2000 Outpatient recruitment Clinicai screening Single lesion leprosy patients 25 exclusions 12 not leprosy 7 MB leprosy 6 biopsies not available 299 smear negative patients 284 Histopathological exams 15 exclusions 8 refusals 3 neural involvement 2 pregnancy/breastfeeding 1 diabetes 1 liver dysfunction Mitsuda test Blood collection IgM anti-pgl 1 ROM intervention 259 SLPB patients enrolled FIG. 2. Multicenter study profile. Jopling criteria ("). All exams were centrally read by one experienced pathologist at the Federal University of Goiás in Central Brazil. (Details of histopathological findings are out of the scope of this paper.) Blood samples were collected and serum samples were sent to the Immunology Laboratory of the Federal University of Goiás (UFG), stored at 20 C and tested at once. IgM antibodies specific to Mycobacterium leprae phenolic glycolipid-i (PGL-I) were assayed by ELISA, using PGL-I synthetic disaccharide provided by Dr. M. J. Colston (IMMLEP, London). The laboratory staff were kept blind from the previous clinical, bacteriological and histopathological assessments. The cut-off point for positivity was 0.2 optical density (OD) as described previously (24). Biochemical tests (hemogram, AST, ALT, blood sugar and a pregnancy test) were performed for ROM exclusion criteria purposes. All eligible patients were treated with the single-dose ROM regímen (25). Children received a half dose according the Brazilian Ministry of Health recommendation. Side effects were actively investigated after drug administration or recorded by passive reporting during the first month of follow up. Data analysis The data were entered and analyzed centrally at the Coordinator Center in Goiânia, Central Brazil, where a master file with a copy of ali protocols was archived. The baseline characteristics of each participating center were polled by the state of recruitment. The body mass index (BMI) was calculated as weight in kilograms divided by the square of the height in meters for participants older than 13 years of age (22). The differences in the distribution of the variables were tested by the ANOVA or the chi-squared test to compare continuous or
5 68, 3^Martelli, et al.: Single Lesion PB-Cohort Baseline^251 TABLE 1. Baseline characteristics of single-lesion paucibacillary leprosy patients enrolled at each of the study sites. Variables North Southeast Center-West Amazonas^Rondônia (N = 75)^(N = 45) Rio de Janeiro (N = 80) Goiás (N = 59) Total (N = 259) Age (yrs.) Mean (S.D.) 27.8 (14.1)^29.4 (13.2) 38.6 (18.0) 32.0 (15.2) 32.4 (16.0) Median (range) 23.0 (7-66)^29.0 (10-64) 39.5 (7-84) 32.0 (7-62) 31.0 (7-84) Females (%) 40 (53.3)^23 (51.1) 59^(73.8) 38^(64.4) 160 (61.8) Schooling Illiterate (%) 2 (2.7)^7 (15.6) 5^(6.3) 12^(20.3) 26 (10.0) <8 years (%) 73 (97.3)^38 (84.4) 75^(93.7) 47^(79.7) 233 (90.0) Household contact (%) 14 (18.7)^16 (35.6) 24^(27.9) 32^(54.2) 86 (33.2) Lesion perception (yrs.) <1 45 (60.0)^34 (75.6) 48^(60.8) 46^(78.0) 173 (67.1) (33.3)^9 (20.0) 23^(29.1) 12^(20.3) 69 (26.7) >5 5 (6.7)^2 (4.4) 8^(10.1) 1^(1.7) 16 (6.2) BCG vaccinationa (%) 47 (62.7)^19 (42.2) 24^(30.0) 26^(44.1) 116 (44.8) BMP mean (S.D.) 22.9 (4.8)^22.3 (4.1) 24.4^(5.0) 23.2^(4.5) 21.2 (8.0) One missing. 'For adult population. categorical variables, respectively. The SPSS/PC program was used for descriptive and exploratory data analysis. Written informed consent was obtained from ali participants, according to the approved protocol in each of the institutions, by the National Human Research Ethical Committee (CONEP) and by the Leprosy Control Program at the national levei. RESULTS Figure 2 summarizes the screening procedures for selecting the participants from the Brazilian recruitment centers between December 1997 and December Among patients clinically screened to detect SSL-PB, 299 patients had negative skin smears. Fifteen patients were excluded on clinical/laboratory criteria, and the remaining 284 had skin biopsies taken. Additionally, 25 cases (8.8%) were excluded because either the histopathological results were not consistent with PB leprosy or because a skin biopsy was not available. Leprosy was classified as TT (33.6%), BT (33.6%) and 1(29.7%) according to Ridley and Jopling clinico-pathological criteria (17), and 3.1% of the patients were considered to have leprosy by clinical criteria only. Taking histopathology as the gold standard, 12 biopsies were diagnosed as other skin diseases and 7 were considered MB cases, yielding a total of 19 false-positive SSL-PB. Therefore, the positive predictive value of the clinical screening was 93.2% (259/278). As shown in Table 1, 259 (86.6%) SSL- PB patients fultilled the eligibility criteria for ROM intervention. Patients recruited ia the North region accounted for the majority of participants (46.3%), followed by the Southeast (30.9%) and Central-West (22.8%) regions. There was a preponderance of adults, mean age 32.4 (S.D. = 16.0), and patients from the city of Rio de Janeiro were older than patients assembled in the other regions (F3258) = 7.0; p <0.001). There was a 1: I male/female ratio ia the North region, but in the other regions females represented 66.5% of the adult population and 38.6% of patients younger than 15 years of age. The presence of a BCG scar varied from 30.0% to 62.7% among patients from different sites. Overall, 33.2% of the participants had knowledge of a previous leprosy case in the household; 67.1% of the participants reported that the lesion had been perceived within a time span of less than 1 year. BMI values were within the normal range for patients older than 13 years, and there was no statistically significant difference among regions. Analysis of the dermatological features showed marked similarity among the sites. Children (<15 years) had smaller lesion size than adults, 3.7 cm (95%CI ) versus
6 252^ International Journal of Leprosy^ 2000 TABLE 2. Clinical features of single-lesion paucibacillary leprosy patients by age group.a Variables 515 years >15 years No. % No. % Females Lesion size (cm) < < >> Lesion description Macular Plaque Nodular Body area Face Trunk Limbs BCG scar Percentages based on nonmissing data. 5.1 cm (95%CI ), yielding a statistically significant difference. Independent of the age group, most skin lesions were described as a macular hypochromic or erythematous lesion (47.9%) and only one child presented with a nodule on the face. Most of the skin lesions were detected on the limbs of children and adults (Table 2). A BCG scar was detected in 76.7% of the children and in 42.3% of adults (x2 = 19.5; p <0.001). All patients were considered to have at least moderate sensory loss on the lesion by monofilament evaluation, and no grade of disability was detected. Figures 3 and 4 show box-plot distributions of the Mitsuda readings and the anti- PGL-I serology, respectively. Similar patterns were obtained among patients from different geographical regions: 75.0% of the patients were Mitsuda positive (5 mm); in 67 patients (24.9%) the induration was smaller than the arbitrary "positive-negative" cut-off Mitsuda response at 5 mm. The prevailing values of anti-pgl-i serology were negative, below the cut-off point (OD of 0.2), among participante from all regions. Only 17.3% of the patients were con- 20 -^ O 15 O O O 10 N = 73 Amazonas G 42 Rondônia 80^55 Rio de Janeiro^Goiás FIG. 3. Box-plot distribution of Mitsuda skin readings among single-lesion paucibacillary leprosy patients enrolled at each of the study sites. Boxes = 25th and 75th percentiles with a median bar between. O and * = outliers and extreme values of the distribution. Dashed fine = cut-off value.
7 68, 3^Martelli, et al.: Single Lesion PB-Cohort Baseline 253 1,4 ^ 1,2. 1,0 0,8 0,6 0,4 0,2 0,0 N= 67 Amazonas 40 Rondônia 74 Rio de Janeiro 59 Goiás FIG. 4. Box-plot distribution of anti-pgl-i antibodies (OD) among single-lesion paucibacillary leprosy patients enrolled at each of the study sites. Boxes = 25th and 75th percentiles with a median bar between. O and * = outliers and extreme values of the distribution. Dashed line = cut-off value. sidered positive for anti-pgl-i antibodies compatible with the low bacillary load of PB patients; 61.0% (142/233) of SSL-PB patients had a simultaneously positive Mitsuda reading and negative anti-pgl-i serology. The ROM regimen was well tolerated among adults and children. Slight adverse side effects, mainly gastrointestinal symptoms such as nausea, stomach ache, and diarrhea, were reported for approximately 15% of the patients shortly after drug intake. No patient required specific medical attendance for these symptoms. DISCUSSION Only recently has single skin lesion been distinguished as a subtype of leprosy in the Brazilian National Control Program following the classitication proposed by WHO taking into account the number of lesions (" and Ministerio da saude Brasil. Alterações nas instruções normativas do Plano Nacional de Eliminação da Hanseníase. Ofício Circular No. 67, CNDS/CENEPI, 1998). The baseline characteristics of the SSL-PB patients enrolled in this Brazilian ROM multicentric study provide a unique and comprehensive picture of the clinicai and immunological profile of monolesion leprosy patients in different epidemiological settings. Patients recruited from the different sites had similar features, however, with a common pattern of variability concerning dermatological aspects, size and location of the lesion. Regardless of the endemicity of the recruitment site, patients were mainly adults, a different situation from other studies in which the majority of single-lesion leprosy cases were reported among children ("). In our multicentric study, the majority of patients with monolesion were indeed paucibacillary with no grade of disability, suggesting early leprosy detection. However,
8 254^ International Journal of Leprosy^ 2000 among 299 clinically suspected SSL-PB leprosy patients screened, seven MB (2.4%) monolesion cases were detected, in concordance with some case reports of multibacillary monolesion (9' 28). A wide variation of dermatological features was observed within SSL-PB patients, but lesions smaller than 5 cm predominated among children and adults and the limbs were the prevailing affected body areas. It has been suggested by other authors that the monolesion can mainly be distributed on body regions exposed to trauma, suggesting the cutaneous surface as a possible portal of entry (8). However, it is outside the scope of this study to make any assumption about the possible transmission routes in leprosy. Several methodological issues have been raised about previously published single-lesion studies. The main concern refers to case ascertainment and the lack of specificity of an early leprosy diagnosis based solely on clinicai evaluation (11.16). Taking into account the lack of an independent gold standard for the diagnosis of the paucibacillary type of leprosy, clinicai examination and conventional histopathology still remain the standard for diagnosis in the early chronic stage of the disease for research purposes (181 21). In our study, clinical, smear-bacilloscopy data and histopathology results were combined in an attempt to improve the specificity of the monolesion leprosy diagnosis. It is well known that in many settings around the world, including Brazil, clinicians will not have histopathology support for leprosy diagnosis. Considering the casemanagement expertise of our recruitment sites, there was a high positive predictive value of the clinicai evaluation (around 90%). Only 19 (12 not leprosy and 7 MB cases) out of 278 patients were excluded when histopathology was taken as the gold standard for early leprosy diagnosis. This represents less than 3% of multibacillary forms among monolesion patients diagnosed using clinicai and bacilloscopic enteria in the three endemic Brazilian regions studied. Our observations indicated that in Brazil case ascertainment of SSL-PB can be accurately defined under a routine control program based upon clinicai examination and bacilloscopy of skin smears. However, we should keep in mind the difficulties of assessing false-negative or -positive results when only clinically suspected leprosy is submitted to skin biopsy, leading to a possible verification bias (19). Refined molecular biology tools, such as the detection of M. leprae DNA by polymerase chain reaction, may contribute to improve the specificity of early leprosy diagnosis ( ), but this still remains to be validated under the field conditions of a control program. Single lesion paucibacillary leprosy has been considered the earliest clinicai manifestation of the disease that may undergo self-healing or progress to any form of the disease spectrum, eventually evolving to nerve damage (12). It has been widely accepted that the local cellular immunity dictates the outcome of leprosy, with the Th l CD4+ lymphocyte as the pivotal cell for protection or pathogenesis (13. 27). This is a well-established model for the chronic stage of the disease; however, the usefulness of these markers for prognosis in the early chronic stage of leprosy remains to be demonstrated. Up to now, the Mitsuda test has been one of the most used field tools to assess cellular immunity in leprosy patients, particularly useful in the early stage of disease. In general, our SSL-PB patients had a strong positive response to lepromin with a strikingly similar profile among the recruitment sites, suggesting intact cell-mediated immunity and, therefore, favorable clinicai prognosis. Since it is widely accepted that PGL-I positivity refiects bacillary load (18. 24) the predominance of seronegative patients is compatible with low bacillary load. Taking the Mitsuda and anti-pgl-i results together, it seems reasonable to envision a favorable outcome for most of the single-lesion participants of this cohort. Only an extended clinicai follow up in progress, incorporating additional molecular markers, may provide insights about the importance of the immune profile in the disease prognosis among these early lesion patients. SUMMARY In Brazil, there is little information about the clinicai and epidemiological characteristics of paucibacillary, single skin lesion leprosy patients (SSL-PB). Only recently has the official notification system distinguished leprosy patients with a single lesion
9 68, 3^Martelli, et al.: Single Lesion PB-Cohort Baseline^255 as a clinicai entity, for whom the singledose ROM (rifampin, ofloxacin and minocycline) regimen has been recommended. In this paper, we describe the baseline clinicai features and the immunological background of a multicenter cohort of SSL- PB leprosy cases enrolled between December Patients were recruited at health centers located in the following regions: Southeast = Rio de Janeiro; North = Amazon and Rondônia states and Center- West = Goiás state. Eligible cases were newly detected, untreated single-lesion leprosy patients without thickened nerve involvement, and were assessed by clinicai, bacilloscopic and histopathological exams. The Mitsuda skin test and anti-pgl-i serology (ELISA) were also performed. Of the 299 SSL-PB leprosy patients, 259 (86.6%) fulfilled the criteria for single-dose ROM intervention. Our results showed that patients recruited from different sites had similar features, considering the clinicai and immunological profiles. There was a predominance of adults (mean age 32.4; S.D. = 16.0), and a BCG scar was detected in 76.7% of the children (515 years old). Only 7 cases were diagnosed as the multibacillary type, representing less than 3% of the patients being misclassified. Our data indicate that in Brazil SSL-PB case ascertainment based on clinicai and bacilloscopic criteria can be accurately defined under a routine control program; 75.0% of SSL-PB cases were Mitsuda positive (5 mm) and seropositivity for anti-pgl-i was detected in 17.3% of the patients. These data are compatible with effective cell-mediated immunity and low bacillary load, suggesting favorable clinicai outcomes for most SSL- PB participants of this cohort. RESUMEN En Brasil hay poca información sobre las características clínicas y epidemiológicas de los pacientes paucibacilares con una sola lesión dérmica (SSL-PB). Sólo recientemente el sistema de notificación oficial ha reconocido a los pacientes con lepra con lesiones únicas, como una entidad clínica definida para la cual se ha recomendado el tratamiento con una sola dosis de rifampina-ofloxacina-minociclina (ROM). En este trabajo se describen las características clínicas e inmunológicas de un grupo de pacientes SSL-PB registrados entre Diciembre de 1997 y Diciembre de Los pacientes fueron reclutados en los centros de salud de los estados de Rio de Janeiro (Sureste), Amazonia y Rondonia (Norte) y Goias (Centro-oeste). Los casos elegibles fueron casos nuevos, no tratados, con lesiones únicas y sin engrosamiento de nervios valorados por exámen clínico, baciloscópico e histopatológico. En estos pacientes también se realizaron la reacción de Mitsuda y la búsqueda de anticuerpos por ELISA contra cl GLP-I. De los 200 pacientes SSL-PB, 259 (86.6%) cumplieron con los criterios necesarios para su tratamiento con ROM. Los resultados mostraron que los pacientes reclutados de diferentes sitios tuvieron características clínicas e inmunológicas similares. Hubo un predominio de adultos (32.4 -± 16.0 aiios) y se detectó una cicatriz de BCG en el 76.7% de los nifios (<15 afios de edad) Sólo 7 casos se diagnosticaron como multibacilares y representaron menos del 3% de los pacientes mal clasificados. Nuestros datos indican que en Brasil la identificación de casos SSL-PB basada en criterios clínicos y baciloscópicos puede lograrse acertadamente bajo un programa rutinario de control. Setenta y cinco porciento de los casos SSL-PB fueron Mitsuda-positivos (>5 mm), y el 17% de los pacientes tuvieron anticuerpos contra el PGL-I. Estos datos, compatibles con una efectiva inmunidad celular y haja carga bacteriana, sugieren una evolución favorable en la mayoría de los pacientes SSL-PB de esta cohorte. RÉSUMÉ Peu d'informations existent au Brésil en ce qui concerne les caractéristiques cliniques et épidémiologiques des patients qui présentent une lésion cutanée unique paucibacillaire (LCU-PB). II n'y a que très récemment que le système officiel de dépistage a distingué les patients hanséniens présentant un seule lésion comme une entité clinique distincte, pour lesquels une administration unique de rifampicine, ofloxacine et minocylcine (ROM) a été recommandée. Nous décrivons ici les caractéristiques cliniques et immunologiques d'une cohorte de LCU-PB sélectionnée entre décembre 1997 et décembre Les patients furent recrutés dans des centres de soins localisés dans les régions suivantes: sud-est = Rio de Janeiro; nord = états de Rondônia et de l'amazone; centre ouest = état de Gaia. Les cas sélectionnés étaient des patients hanséniens nouvellement détectés, non-traités, présentant une lésion unique sans évidence de lésion d'épaississement des nerfs. Ces cas furent évalués par des examens cliniques, bacilloscopiques et histopathologiques, ainsi que des réactions de Mitsuda et des test sérologiques (ELISA) anti-pgl-i. Parmi 299 patients hanséniens LCU-PB, 259 (86,6%) présentaient les critères pour un traitement unique ROM. Nos résultats montrent que les patients enrôlés à partir de sites différents présentaient des caracteres similaires, si l'on considère les profils cliniques et immunologiques. Les patients étaient en majorité adultes (moyenne de 32,4 ans; D.S. = 16,0) et une cicatrice de BCG fut détectée chez 76,7% des enfants (515 ans). II n'y eut que 7 cas qui furent diagnostiqués comme étant du type multibacillaire, ce qui ne represente que 3% des pa-
10 256^ International Journal of Leprosy ^ 2000 ^tients qui furent re classifiés à posteriori. Nos données ^9. suggèrent que, au Brésil, l'évaluation des cas LCU-PB basée sur des critères cliniques et bactérioscopiques peut être définie de façon précise dans le cadre d'un programme de contrôle de routine; 75,0% des cas^10. SLC-PB étaient positifs à la réaction de Mitsuda (>_5 mm), et 17,3% des patients étaient séropositifs au test anti-pgl-l Ces données sont compatibles avec une ef-^11. ficace immunité à médiation cellulaire et une charge basse en bacilles, suggérant une issue clinique favorable pour la majorité des patients LCU-PB de cette co-^12. horte. Acknowledgment. We thank Dr. Euzenir Nunes 13. Sarno, Dr. Maria Leide W. de Oliveira and Dr. David Scollard for helpful suggestions and Dr. M. J. Colston for the PGL-I antigen. We also thank Dr. Ilma M. Silva, Dr. Juan Pinem Maceira, Dr. Antonio Pedro M. Schettini, and Dr. Emilia Sayurii Ueda for their help^14. and encouragement in setting up this project. Karen Marcelo de Deus received a fellowship (PIBIC/^15. CNPq). This study could not be done without the cooperation of the participante. This study was partially^16. sponsored by PAHO, the Brazilian Ministry of Health, and FUNAPE-Federal University of Goiás in This investigation received financial support from the^17. UNDP/World Bank/WHO Special Program for Research and Training in Tropical Diseases (TDR). 18. REFERENCES 1. ABRAHAM, S., MOZHI, N. M., JOSEPH, G. A., KURIAN, N., SUNDAR RAO, P. S. S. and JOB, C. K. Epidemiological significance of first skin lesion in leprosy. Int. J. Lepr. 66 (1998) ^ AVELLEIRIA, J. C. R., VIANNA, R. F., COUTINHO, R. B., MARQUES BOECHAT, A. and GOMES DE AN- 20. DRADE, V. R. Distribution of single cutaneous lesion in paucibacillary leprosy. Acta Leprol. 8 (1993) BECHELLI, L. M., GARBAJOSA, G. P., GYI, M. G., DOMINGUEZ, V. M. and QUALIATO R. Site of early 21. lesions in children with leprosy. Bull. WHO 48 (1973) CHO, S.-N. and BRENNAN, P. J. New biological^22. tools for leprosy surveillance. Int. J. Lepr. 67 (1999) S59-S GILUS, T. P. and KRAHENBUHL, J. L. Global elimi- ^nation of leprosy. Rev. Med. Microbiol. 9 (1998)^ JACOBSON, R. R. and KRAHENBUHL, J. L. Leprosy. Lancet 353 (1999) JOB, C. K., BASKARAN, B. JAYAKUMAR, J. and ASCH-^24. HOFF, M. Histopathologic evidence to show that indeterminate leprosy may be a primary lesion of the disease. Int. J. Lepr. 65 (1997) JOB, C. K., JAYAKUMAR, J., WILLIAMS, D. L. and GILLIS, T. P. Role of polymerase chain reaction in^25 the diagnosis of early leprosy. Int. J. Lepr. 65 (1997) JOB, C. K., KAHKONEN, M. E., JACOBSON, R. R. and HASTINGS, R. C. Single lesion subpolar lepromatous leprosy and its possible mode of origin. Int. J. Lepr 57 (1989) KATOCH, V. M. Is there a microbiological rationale for single-dose treatment of leprosy? Lepr. Rev. 69 (1998) 2-5. LocKwoOD, D. N. J. Rifampicin/minocycline and ofloxacin (ROM) for single lesions-what is the evidence? Lepr. Rev. 68 (1997) LUCAS, S. Bacterial disease. In: Lever's Histopathology of the Skin. 8th edn. Philadelphia: Lippincott-Raven Publishers, 1997, pp MODLIN, R. L., MELANCON-KAPLAN, J., YOUNG, S. M. M., PIRMEZ, C., KINO, H., CoNVIT, J., REA, T. H. and BLOOM, B. R. Learning from lesions: patterns of tissue inflammation in leprosy. Proc. Natl. Acad. Sci. U.S.A. 85 (1988) OPROMOLLA, D. V. A. Single lesion leprosy. Hansen. Int. 21 (1996) 1-2. PANNIKAR, V. K. Defining a case of leprosy. Lepr. Rev. 63 (1992) 61s-65s. PONNIGHAUS, J. M. Diagnosis and management of single lesion in leprosy. Lepr. Rev. 67 (1996) RIDLEY, D. S. and JOPLING, W. H. Classification of leprosy according to immunity; a five-group system. Int. J. Lepr. 34 (1966) ROCHE, P. W., FAILBUS, S. S., BRITTON, W. J. and COLE, R. Rapid method for diagnosis of leprosy by measurements of antibodies to the M. leprae 35-kDa protein: comparison with PGL-I antibodies detected by ELISA and "dipstick" methods. Int. J. Lepr. 67 (1999) SACKET, D. L. Bias in analytic research. J. Chron. Dis. 32 (1979) SANTOS, A. R., NERY, J. C., DUPPRE, N. C., GALLO, M. E., GOES FILHO, J. T., SUFFYS, P. N. and DE- GRAVE, W. M. Use of the polymerase chain reaction in the diagnosis of leprosy. J. Med. Microbiol. 46 (1997) SCOLLARD, D. M. Time and change: new dimensiona in the immunopathologic spectrum of leprosy. Ann. Soc. Belg. Méd. Trop. 73 (1993) SHETTY, P. S., JAMES, W. P. T. and FERRO-LUZZI, A. Malnutrition and the immune response. I. Malnutrition in the community: recent concepts. Trans. R. Soc. Trop. Med. Hyg. 88 (1994) SINGLE-LESION MULTICENTRIC TRIAL GROUP. Efflcacy of single dose multidrug therapy for the treatment of single-lesion paucibacillary leprosy. Indian J. Lepr. 69 (1997) STEFANI, M. M. A., MARTELLI, C. M. T., MORAIS- NETO, O. L., MARTELLI, P., COSTA, M. B and AN- DRADE, A. L. S. S. Assessment of anti-pgl-i as a prognostic marker of leprosy reaction. Int. J. Lepr. 66 (1998) WHO EXPERT COMMITrEE ON LEPROSY. Seventh report. Geneva: World Health Organization, 1998, p. 7. Tech. Rep. Ser. 874.
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text:
Okay everyone probably knows she was spayed this week. On Tuesday to be exact. Well she cannot go outside except on a leash right now due to her stitches. Well she is driving us all crazy she wants to play and since she can't she is getting very antzy. Well today I took her and Lilly for about a mile long walk and I wanted to know if anyone thinks that was a bad idea. She is up on the move right now. And my vet said that she wouldn't do anything to hurt herself but I am not letting her outside with the other dogs because they want to play as badly as she does. And I don't want to deal with the pent up energies of a boxer so I am deciding to walk her a bit more to expell some of it in a safe manner. Only trouble today its so cold I put my hood on and the wind blew it off two or three times. And Macy was so excited she started pulling which is unusuall for her because I use a choke collar with her because if I don't she drags me. And she has learned not to pull well today she decided she was going to try it and choked herself. It was while I was trying to put my hood back on. And I want to know if I should walk her and Lilly at the same time. They are both hyper dogs so they have to let out energy somewhere. And I thought it would be good for us to walk together. And also I am trying to walk Macy correctly but she doesn't seem to know how to listen. That sounds weird but when I give her leash corrections she ignores them so should I simply walk her seperately. I need to work on leash manners with her anyway.
post #1 of 6
2/2/07 at 1:40pm
Thread Starter


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text: So I've decided I NEED a 3" .357. Now I just have to narrow it down to which one. This may see some CCW/woods use plus it just looks like a nice revolver. I've been thinking about a: 3" J-frame 3" SP101 3" K-frame I've about eleminated the J-frame due to recoil and not handling the stouter loads as well. The K frame holds an extra round but the SP101 can be found new for about the same cost. Thoughts/suggestions.


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text:
Restoring forces, which are generated when the left ventricle contracts below its equilibrium volume (Veq), are responsible for diastolic suction. Their magnitude is inversely related to end-systolic volume (ESV). In previous studies in which the mitral valve was replaced with a prosthesis, increased contractility was shown to augment restoring forces independently of ESV. In the present study, we quantified restoring forces in the presence of an intact mitral valve in open-chest dogs (n = 6) as the fully relaxed pressure (FRP) after completion of left ventricular pressure (LVP) fall during nonfilling diastoles produced by a servomotor system that clamped left atrial pressure below LVP. A negative FRP indicated a restoring force was present. We related FRP to ESV during control, intravenous, and left anterior descending coronary artery (intracoronary) administration of dobutamine. With intravenous dobutamine, we observed an approximately parallel downward and rightward shift of the FRP-ESV relation, indicating increased restoring forces at any ESV less than Veq. The downward shift averaged −2.6 ± 1.6 (SD) mmHg at the control Veq. A similar shift occurred with intracoronary dobutamine. In additional experiments (n = 2), we found that over a common range of ESV dobutamine slightly increased wall thickness (<10%) during nonfilling diastoles, consistent with an increase in coronary blood volume. We conclude that dobutamine increases restoring forces independently of changes in ESV in conjunction with an increase in Veq. This effect may partly be related to increased coronary blood volume.
- ventricular suction
- isovolumic relaxation
- diastolic function
restoring forces are generated during contraction when the left ventricle (LV) contracts below its equilibrium volume (Veq), defined as the volume when the transmural pressure is zero in the fully relaxed state (5, 13,18). Their magnitude is thus inversely related to end-systolic volume (ESV). When present, restoring forces cause diastolic suction, which allows filling to occur at a lower pressure than would otherwise be the case (5, 7, 8, 13, 16, 18). Complex transmural and three-dimensional deformations of the LV during contraction and relaxation have been considered to be at least partly responsible for the generation of restoring forces (9, 15). For example, it has been hypothesized that differences in subendocardial-subepicardial contraction-relengthening, especially in the anterior wall, play an important role (15). Restoring forces have been quantified by measuring the fully relaxed pressure (FRP) in the LV during a nonfilling diastole (3, 7, 8, 13, 14, 18). The latter has been accomplished by either inserting an electronically controlled prosthetic mitral valve that is maintained in the closed position after end systole (13, 18) or, more recently, by using a left atrial (LA) servomotor system that lowers LA pressure (LAP) below LV diastolic pressure, thus eliminating the gradient for LV filling (3). A negative transmural FRP indicates the presence of restoring forces.
Catecholamines influence diastolic function by increasing the rate of removal of calcium from the myofilaments and thus speeding relaxation rate (11, 12). Nikolic et al. (13) reported that dobutamine decreases the FRP at any ESV less than Veq. Hori et al. (7) reported a similar finding with increased calcium concentration. This suggests that catecholamines and increased contractility in general may also influence diastolic function by increasing restoring forces independent of effects on ESV. However, these results (7, 13) were obtained in a prosthetic mitral valve preparation. Subsequently, we and others could not substantiate restoring forces as large in magnitude as those reported with the prosthetic mitral valve and associated disrupted mitral apparatus (3,14). The current study was therefore designed to test the hypothesis that dobutamine increases restoring forces independent of changes in ESV in a preparation in which the mitral valve and apparatus are intact.
Surgical preparation.
Eleven adult mongrel dogs [weight, 23.7 ± 1.9 (SD) kg] of either sex were anesthetized with thiopental sodium (15–30 mg/kg iv), intubated, and mechanically ventilated with O2 and 0.5–1.5% halothane. The dogs were positioned in right lateral recumbency on a heating pad to maintain body temperature, and blood gases were maintained in the physiological range. A surgical plane of anesthesia was confirmed, and succinylcholine (0.5 mg/kg iv) was administered. A left thoracotomy and pericardiotomy were performed to expose the heart. Vascular constrictors were placed around the pre- and postcava and the ascending aorta. After heparin sodium (300 U/kg iv) was administered, the carotid artery was dissected and a 7-Fr catheter-tip micromanometer with fluid port (SPC 471A, Millar Instrument, Houston, TX) was inserted and advanced into the LV. A dual-excitation volume conductance catheter (Leycom, Sigma 5, CardioDynamics) was inserted through the apex of the LV and its tip positioned just below the aortic valve. We did not calibrate the conductance catheter by estimating the parallel conductance because we did not require knowledge of the absolute LV volume to assess shifts in the relation between FRP and ESV. A large-bore (8-mm ID) rigid cannula was placed in the LA via the appendage, positioned just above and at the midpoint of the mitral valve, and attached to the servomotor. A 5-Fr high-fidelity pressure transducer (MPC 500, Millar) inserted into a rigid sheath with multiple side holes and a fluid-filled catheter attached to the large-bore cannula were used to measure LAP. Pacing electrodes were attached to the LA and connected to a stimulator (SD-9, Grass Instruments, Quincy, MA) that was controlled by a computer (486/33 MHz, Gateway 2000, North Sioux City, SD). A 26-gauge angiocath was then inserted retrograde in the left anterior descending (LAD) coronary artery with the tip proximal to the first diagonal branch and secured in place while allowing flow to be maintained. In two additional dogs, in addition to the instrumentation previously described, we implanted epicardial and subendocardial ultrasonic crystals to measure anterior wall thickness in the perfusion zone of the LAD artery. The LAD catheter was inserted in only one of these dogs.
After instrumentation was completed, the calcium channel blocker zatebradine (UL-FS 49, 1 mg/kg iv, Boehringer Ingelheim, Ridgefield, CT) was administered to reduce native heart rate. Atrial pacing was then initiated at a rate as close to 90 beats/min as possible and maintained constant. Average heart rate was 91 ± 5 (SD) beats/min. We then applied brief partial caval constrictions and aortic constrictions to generate a range of steady-state ESVs. At each ESV, data were recorded during filling and nonfilling diastoles with respiration suspended at end expiration. To produce nonfilling diastoles, the servomotor system was used to rapidly clamp the LAP below the LV diastolic pressure during ventricular systole, as described previously (3). The LV was allowed to fully relax at its ESV, and the FRP was measured. To ensure that no LV filling occurred during LAP clamp beats, we required that there be no change in the conductance catheter volume signal after the time of the LV-LA crossover pressure determined from the normal filling beat preceding the LAP clamp beat and that the LV pressure (LVP) decline monotonically to a plateau value during the LAP clamp. After return to baseline conditions, dobutamine was administered intravenously and titrated to produce a 20–30% increase in steady-state LV peak positive dP/dt. Peak positive dP/dt averaged 1,205 ± 218 mmHg/s before and 1,523 ± 365 mmHg/s after dobutamine (P < 0.05, pairedt-test). Recordings were then made as the caval-aortic constriction protocol was repeated. After the effects of intravenous dobutamine had worn off, we infused dobutamine into the LAD cannula at 10% of the dose administered intravenously and repeated caval-aortic constrictions once more. The purpose of the experiments in the two dogs with wall thickness crystals was to determine whether dobutamine alters wall thickness independent of its effects on ESV by measuring wall thickness during nonfilling diastoles at overlapping ranges of ESV before and during dobutamine administration. To maximize the chance of achieving multiple overlapping ESV data points in these experiments, we performed larger numbers of graded caval-aortic constrictions than in the other experiments. Other than this, the protocol was the same except that dobutamine was not administered into the LAD artery in the one dog lacking an LAD cannula.
Data analysis.
All data were digitized on line at 200-Hz sampling frequency and analyzed using custom-designed software for heart rate, peak systolic LVP, peak positive and negative LV dP/dt, LV end-diastolic pressure (estimated as LVP when LV +dP/dtreached 10% of its maximum value), and FRP during the LAP clamp. FRP was taken as the plateau pressure after completion of LV pressure fall. The conductance catheter signal was used to determine ESV as the smallest LV volume preceding peak negative LV dP/dt. As indicated earlier, conductance catheter volumes were not corrected for parallel conductance.
An intrinsic difficulty in detecting changes in the relation between FRP and ESV after an intervention using our preparation and this protocol is that FRP usually varied over a small range of pressure, typically no more than 2–3 mmHg above and 2–3 mmHg below zero. As a result, even modest amounts of noise in these data resulted in large confidence intervals regardless of how they were fitted and difficulty in detecting changes. To overcome this problem, for the dogs without wall thickness crystals we fit all positive and negative FRP-ESV data points by least-squares linear regression. We then excluded all experiments in which ther 2 value for the regression line was <0.85. Six experiments met this criterion for control and intravenous dobutamine, and four of the six for intracoronary dobutamine. For these experiments, we used the confidence intervals of the control FRP-ESV relation to determine whether dobutamine caused a change. The slopes of the control and intravenous dobutamine FRP-ESV relations were compared using a pairedt-test. The magnitude of shifts in the relation was quantified by using the regression statistics of the control relation to calculate Veq(i.e., volume with FRP at 0 mmHg) and the intravenous dobutamine regression statistics to calculate the FRP at the same LV volume. We then compared the dobutamine FRP at this LV volume to the control value (0 mmHg) using a paired t-test. All data are reported as means ± SD. Because the experiments with wall thickness crystals were performed for the specific purpose of determining whether dobutamine alters the relation between ESV and wall thickness during nonfilling diastoles, we did not require that the control FRP-ESV data meet any specific goodness-of-fit criteria in these two dogs.
Figure 1 shows representative tracings of LVP and LV volume during nonfilling diastoles under control and intravenous dobutamine conditions. In five of six experiments, we observed a downward and rightward shift of the FRP-ESV relation after intravenous dobutamine (Fig.2 A), such that the confidence intervals of control and dobutamine data sets did not overlap. In one experiment, no shift was apparent (Fig.2 B). Using linear fits of the data, we found that after intravenous dobutamine, the slope of the relation between FRP and ESV was not significantly changed (0.17 ± 0.03 vs. 0.14 ± 0.03 mmHg/ml, P = 0.18). FRP averaged −2.6 ± 1.6 mmHg at the same LV volume as the control Veq(P < 0.05). Thus, even though there was no shift in one experiment based on the confidence intervals of the FRP-ESV relations, there was a statistically significant downward shift for the group. In three of four experiments, intracoronary dobutamine also resulted in a downward shift of the FRP-ESV relation (Fig. 2 A), which was not as great as that caused by intravenous dobutamine. It did not cause a shift in the one experiment in which a shift was also not observed with intravenous dobutamine (Fig.2 B). An example of wall thickness signals during a nonfilling diastole is shown in Fig.3. During nonfilling diastoles, we observed gradual wall thinning. Therefore, to assess the relation between ESV and wall thickness after completion of LVP fall, we arbitrarily measured wall thickness 600 ms after the QRS complex. Figure4 is a graph of the relation between wall thickness after completion of LVP fall during nonfilling diastoles and ESV for control, intravenous, and intracoronary dobutamine conditions for one of these experiments. As expected, wall thickness decreased as ESV increased. With both intravenous and intracoronary dobutamine, there were consistent but modest increases in wall thickness at overlapping ranges of ESV compared with control conditions. The increase was on the order of 8–10% with both intravenous and intracoronary administration. In the other wall thickness experiment, the increase with intravenous dobutamine was similar in magnitude.
Ventricular restoring forces, when present, are inversely related to the ESV. This study demonstrates that administration of systemic dobutamine induces a downward shift of the relation between FRP and ESV, indicating that this intervention increased restoring forces independent of changes in ESV. Regional dobutamine administered via the LAD coronary artery produced a similar effect. Previously, in preparations in which the mitral valve was replaced by a prosthesis used to prevent filling, Nikolic et al. (13) reported increased stiffness of this relation below Veq during dobutamine administration, whereas Hori et al. (7) reported a more negative FRP at ESV less than Veq during calcium administration. Thus, in both of these studies, increased contractility appeared to augment restoring forces. However, replacement of the mitral valve appears to increase the magnitude of restoring forces assessed as the FRP during a nonfilling diastole (3, 14). In the present study, we confirmed that dobutamine augments restoring forces in a preparation in which nonfilling diastoles were produced with an intact mitral valve.
At the level of the ventricle, restoring forces are thought to be generated in part as a result of transmural and three-dimensional deformations during contraction that allow storage of potential energy that is converted to suction during the succeeding diastole (8, 9, 15,16). These contraction-related deformations include differences in subepicardial and subendocardial fiber orientation, shear, and timing of relengthening, and twist, or counterclockwise rotation of the LV about its long axis (9, 15). However, because our measure of restoring forces was a negative pressure after completion of LVP fall during a nonfilling diastole, these deformations in theory should not have influenced the FRP. Another factor related to whether a restoring force is present at any ESV is the wall thickness. After full relaxation during a nonfilling diastole at ESV less than Veq, elastic elements in the wall, for example, titin (6), are below their rest length, accounting for a restoring force. Because, by conservation of mass, wall thickness is inversely related to ESV, the presence and magnitude of a restoring force should parallel the wall thickness. Our results in the two animals in which wall thickness was measured indicate that there is a detectable increase in wall thickness independent of ESV during dobutamine. Thus a component of the mechanism of increased restoring forces during dobutamine may be related to the drug's influence on wall thickness. Moreover, the increased wall thickness was also demonstrable in the anterior wall after intracoronary administration of dobutamine. Evidently, a regional increase in wall thickness can be associated with the same effects on the FRP. It is also logical that the shift in the FRP-ESV relation produced by intracoronary dobutamine did not appear to be as large as that produced by systemic dobutamine.
The only plausible explanation for the acute increase in wall thickness caused by dobutamine under these conditions is an increase in coronary blood volume. Thus it is highly likely that dobutamine increases coronary blood volume independent of ESV. We are unaware of any previous studies in which wall thickness was measured at common ranges of ESV before and after administration of dobutamine or other catecholamines. This observation suggests that there may be a dynamic relationship between coronary perfusion and the FRP-ESV relation. The effects of turgor on diastolic compliance at LV volumes greater than Veq are well known (2), but the possibility that coronary perfusion influences Veq and the FRP-ESV relation at volumes less than Veq has not previously been considered. We question, however, whether the increase in wall thickness is sufficient to explain the shift in the FRP-ESV relation we observed. The increase was quite modest. Moreover, an increase in wall thickness at a given ESV due to increased coronary blood volume would, if anything, be expected to shift the FRP-ESV relation downward at ESV values less than Veq but have the reverse effect at ESV values greater than Veq (2). Instead, we observed a rightward and downward shift of the relation both above and below Veq. Finally, during the course of a nonfilling diastole, we observed gradual wall thinning, which must have been related to a net decrease in coronary blood volume. The thinning was not dissimilar in magnitude to that observed during dobutamine (see Fig. 3). Despite this, the FRP remained constant. Thus this magnitude of change in blood volume did not measurably affect the LVP. These considerations led us to suspect that the mechanism of the shift in the FRP-ESV relation may be more complicated than that related to an increase in coronary blood volume. We have assumed that contraction-related deformations other than increased wall thickness do not contribute to the relation between FRP and ESV after completion of relaxation. However, it is possible that the process of constraining volume at the end-systolic level by preventing filling could alter the normal reversal of these deformations, for instance, by tethering effects. Alternatively, we previously reported evidence of "creep" during changes in loading conditions (10), i.e., deformable elements in the myocardium that return slowly to the undeformed state. If dobutamine influences these elements, it is conceivable that the time period of a nonfilling diastole is too short for them to return to the undeformed state. Thus, despite the presence of complete relaxation by conventional criteria, an alteration in contractile performance could possibly continue to influence wall forces.
A potential limitation of our study is the fact that we did not measure absolute LV volumes. Although it would have been ideal to do so, nonlinearities in the relation between true volume and conductance catheter volume because of volume-dependent variation in the parallel conductance, especially at small ESVs, indicate that this method of measuring LV volume may be most reliable for detection of relative changes (1, 4). In this regard, it is important to consider whether such differences in the parallel conductance could have invalidated our conclusions, which were based on the "raw" conductance catheter volumes uncorrected for parallel conductance. We believe this is unlikely for two reasons. First, the curvilinear relation between true volume and conductance volume is convex toward the conductance volume axis (4). As a result, the conductance catheter overestimate of true volume increases progressively as volume decreases. Because we observed a rightward shift in the relation between FRP and ESV (a larger volume at any pressure), this feature of the conductance catheter actually biases against the result we observed. Second, we used a dual-excitation conductance catheter system (17) that substantially reduces volume-dependent nonlinearity compared with single excitation systems (1, 4, 17). We also assumed that the parallel conductance did not change as a function of time during the course of our studies. Although there is no a priori reason to believe it should change, the assumption is supported by the work of Boltwood et al. (4), who made repeated parallel conductance measurements during a similar protocol in open-chest dogs and did not observe any time-dependent variation.
In addition to increasing relaxation rate, dobutamine decreases ESV in the intact heart and circulation. A smaller ESV enhances early diastolic filling by virtue of increased passive chamber compliance if ESV is greater than Veq or increased restoring forces if ESV is less than Veq, with consequent augmentation of the early diastolic gradient across the mitral valve. The present study identifies an additional mechanism, greater restoring forces at any level of ESV in association with an increase in Veq, which contributes to the effects of dobutamine on diastolic filling patterns. Future research directed at more precisely delineating global and regional deformation patterns will be helpful in better understanding the mechanism of this phenomenon.
This research was supported by National Heart, Lung, and Blood Institute Grant HL-51201.
Address for reprint requests: M. M. LeWinter, Cardiology Unit, Fletcher Allen Health Care, MCHV Campus, 111 Colchester Ave., Burlington, VT 05401.
- Copyright © 1998 the American Physiological Society


text: They actually didnt grow on the surface and had a very extensive network of traps but that may just be due to how fast livida spreads. They had easily reached the bottom of the green pot in the picture which is only a 4 inch by 4 inch pot but none of the traps wanted to go into the water. Like I said next up on my trial list is the darkness experiment to see how true that statement really is.


text:
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text:
The Beginnings of Modern Science: From 1450 to 1800.
BATON, Rene ed.
• Terms • Ask a Question
Description: Translated by A. J. Pomerans, with 55 b/w plates and 36 line illus. 667pp. 8vo, cloth, d.w. New York: Basic Books, Inc., (1964).Binding: hardcover
Language: English
Type: Books
Book ID: 47858


text:
"The necessaries of life occasion the great expense of the poor. They find it difficult to get food, and the greater part of their little revenue is spent in getting it. The luxuries and vanities of life occasion the principal expense of the rich, and a magnificent house embellishes and sets off to the best advantage all the other luxuries and vanities which they possess. ... It is not very unreasonable that the rich should contribute to the public expense, not only in proportion to their revenue, but something more than in that proportion."
-- Adam Smith
The demand aspect, will be just like before, with the price of gas up (say we can get it to hold at 3 dollars per gal) that is still expensive for working people. So they will once again do what was done before. Find cars that get better gas mileage and that will help reduce demand. It common knowledge and common sense. Gas goes up, the auto industry changes to smaller more efficient cars gas drops and you see more luxury autos on the road .
Lets move on to the so called destruction of land, maybe in the distance past this happened, I have 80 acres in Michigan, it has two gas wells on it, each one takes up less then an opened area of about 500 X 500 feet and is very well maintained the small building and fence around it as less then 50 X 50 feet.
The days of destruction of property is long since passed.
What I am saying, is that we have untapped resources here, we need jobs NOW tapping those resources produces jobs, more oil on the marketplace is going to stabilize or reduce the price to some degree. I see nothing bad with any of those things . Do you ?
At the same time I agree, we cant stop looking for that alternative source of energy that will eventually replace gas. We cant take our eye off that goal .. I dont think we have found it yet. The electric car isnt going to be the answer, as a 2nd car that is used around town , its suitable, beyond that its just not practicable .
Gas at nearly 4 dollars per gal and rising, only hurts the middle class people, it hurts not only at the pump, but every time they go to the grocery store. Im not doing anything here but arguing that we should be doing all we can to help those most effected by the high price of gas. Personally I dont give a flying f**k if the oil companies make another few billion dollars a year or not. What I do care about is helping people in these trying times. Lowering gas prices helps them, more good paying jobs helps them, less importing of oil helps our country. I just find it hard to find enough negatives to not be tapping the resources that we have .
"There is a lot of talk coming from CitiGroup about how Dodd-Frank isn't perfect, So let me say this to anyone listening at Citi I agree with you. Dodd-Frank isn't perfect. It should have broken you into pieces." -- Elizabeth Warren
Of course you can always volunteer to pay $4 a liter for gas but I don.t know what good it would do.


text:
The Way of Serenity
Father Jonathan Morris, Fox News religion analyst, bestselling author, and parish priest, has seen firsthand how easily our day-to-day lives are consumed with anxiety and stress as we focus on our failures and troubles, while peace feels unattainable. When he re-discovered the Serenity Prayer, he realized that this little prayer can be, in fact, a powerful roadmap for our spiritual journey toward God. As he began to share this prayer with others, he saw that living these simple lines became a source of profound peace and happiness:
Read alsoDie ästhetisch-narrativen Dimensionen des 3D-Films
Dieser Band untersucht den ästhetisch-narrativen Möglichkeitsraum des 3D-Films, der sich zwischen den (neuen) technisch-apparativen Bedingungen sowie den kulturellen und psychologischen Wahrnehmungsmechanismen eröffnet. Dabei werden dezidiert audiovisuelle Möglichkeiten des "Raumtonfilms" sowohl an klassischen als auch gegenwärtigen 3D-Filmen…
Lord, grant me the serenity to accept the things I cannot change,
The courage to change the things I can,
And the wisdom to know the difference.
For years a mainstay of recovery programs, this prayer has proven it can change lives. What's more, through it we all can find comfort and support, including an active collaboration with God's grace as he works alongside us to grant the serenity we seek. Unpacking the prayer phrase by phrase, Father Jonathan shows how we can gain a deeper spiritual understanding by practicing its message. Through powerful personal stories, illuminating historical anecdotes, and biblical passages that show us God's plan for our lives, The Way of Serenity will help us grow closer to God and find serenity, regardless of our circumstances.
Join Father Jonathan and the many others who have made this prayer an integral part of their lives, and find lasting peace and happiness today.


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Free forum : Roleplaying forum for the Roleplaying room on Pokemon Showdown!
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This is a forum for the Honda Silver Wing. Please feel free and join and post messages and pictures for your Silver Wing Touring Scooter.
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Free forum : A place to share your passion for the WR250R!
yamaha, wr250r, dirt, bike, dual, sport, adventure, riding, ride, reports, maintenance, reviews, forum, wr250x
Home of all things Battrick Related, Sports and Everything Else
Chess2U is a place to discuss and share anything related to Computer Chess! So you will need Chess2U to keep up with Chess progress!
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Lost Message Board, Lost and General Chat about the show and everything else.
The forum for the Super Smash Bros Crusade fangame.
#free, forum, super, smash, brothers, crusade, bros, jaklub, dettadeus, mario, link, kirby, pikachu, legend, zelda, pokemon, nintendo, ssbc
A site for the roleplaying of the all time favorite anime, Soul Eater
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Free forum : Beyond psychic chat is a community for people who are interested in all things spiritual, including readings, mediumship, tarot, runes and oracle cards.
#free, beyond, psychic, chat, community, people, interested, things, spiritual, including, readings, mediumship, tarot, runes, oracle
An RPG site that is based off of Rick Riordan's Percy Jackson series! Come join Camp Half-Blood and RP, chat, and meet new campers! Have fun and watch out for monsters!
#free, forum, rise, demigods, site, rick, riordan's, percy, jackson, series, camp, half, blood, half-blood, halfblood, role, play, roleplaying
Free forum : This forum is for those interested in the Zodiac Killer case.
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A free forum where everyone can meet, chat, make friends and inspire.
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Free forum : A fantasy roleplay based around an original idea.
#free, forum, elementorum, lupine, fantasy, roleplay, based, around, original, idea
Free forum : Adult Gaming Community
Free forum : a place to talk about your favorite shows, movies and current events
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A Percy Jackson and the Olympians RPG. Free forum : Half-Blood Hill
half, blood, hill, percy, jackson, olympians, role, playing, lightning, thief, monsters, titans, curse, battle, labyrinth
Free forum : This a place where art meets sims. Where you express yourself without limitations. Without fear. At Simmerty Design, everything is possible.
simmetry, design, modeling, sims, express, limitations, place, simming, custom, content, graphics, competitions, fashion, unique
Free forum : A Roleplay center for all of you Hetalia fans! Come in, pick a country, and enjoy Rping to your heart's content.
#free, forum, hetalia, roleplay, center, role, play, axis, powers, hetalia:
d Removed on: 12/05/2016
Free forum : Set in an alternate timeline about 100 years after the death of the Sage of Six paths.
ninja, revolution, naruto, alternate, timeline, years, death, sage, paths
Magical Girl Cafe is a magical girl forum where fans of the genre can come together for discussions in a drama free environment. We also offer roleplaying!
magical, girl, cafe, sailor, moon, tokyo, anime, forums, community, cardcaptor, sakura