Experience with the use of intravitreal bevacizumab in cases with type I retinopathy of prematurity in a Latin American country.

In retinopathy of prematurity (ROP) type I, the use of intravitreal bevacizumab (IVB), which is an inhibitor of endothelial growth factor (VEGF), has become popular despite not being a therapy approved by regulatory agencies. However, IVB has shown positive effects in halting disease progression at lower costs compared to other anti-VEGF therapies (ranibizumab or aflibercept). In this report, we present the experience during the treatment with IVB of 102 Colombian children with ROP type I, with a success rate of 98% (100). Complications occurred in 3.9% (4). Finally, we conclude that a single dose of IVB is an effective therapy for the management of ROP type I, with a lower risk of complications and retreatment.

Screening sarcopenia through SARC-F in postmenopausal women: a single-center study from South America.

Objective: This study aimed to estimate the prevalence of postmenopausal women at high risk of sarcopenia and to compare their quality of life (QOL) with those at low risk using the SARC-F questionnaire. Methods: We performed a cross-sectional study of postmenopausal women who attended a menopause clinic in Colombia. The risk of sarcopenia was determined through the SARC-F questionnaire; a score ≥4 was considered high risk. The Menopause Rating Scale, the International Physical Activity Questionnaire, and the Short Physical Performance Battery (SPPB) tool were applied. Results: A total of 112 postmenopausal women with an average age of 68.4 ± 8.5 years were included. The prevalence of women at high risk of sarcopenia was 15.2% (n = 17) (95% confidence interval: 9.7; 23.0). Among the high-risk group there was a higher proportion of women with severe symptoms in the three domains when compared to the low-risk group (somatic 7% vs. 24%, psychological 15% vs. 44%, and urogenital 28% vs. 53%; p < 0.05). A tendency to a lower physical performance was found in the high-risk group (SPPB: 8 [interquartile range: 6-11] vs. SPPB: 10 [interquartile range: 8-11), p = 0.059). Conclusion: Our results suggest that women with high risk of sarcopenia have a poor QOL. The SARC-F questionnaire is a brief and non-invasive screening tool to detect postmenopausal women at high risk of sarcopenia.

Resultados funcionales de hemiartroplastía bipolar en pacientes mayores de 65 años con fracturas intracapsulares de cadera / Functional results of bipolar hemiarthroplasty in patients over 65 years of age with intracapsular hip fractures

Resumen: Introducción: La hemiartroplastía bipolar (HA) es una alternativa para el tratamiento de las fracturas desplazadas de cuello femoral en pacientes de edad avanzada con baja demanda funcional y comorbilidades asociadas. El objetivo fue describir la funcionalidad en pacientes mayores de 65 años con fracturas intracapsulares de cadera tratados con HA. Material y métodos: Revisión retrospectiva de pacientes mayores de 65 años entre Enero de 2012 y Mayo de 2017. Se evaluó con la escala de Harris (HHS) y Oxford a los seis meses y al año posterior a la cirugía. Se documentaron las complicaciones y la mortalidad durante el primer año postquirúrgico. Resultados: 48 casos (12 hombres; 36 mujeres), edad promedio de 80.8 ± 7.7 años. Comorbilidades más frecuentes: hipertensión arterial (77.1%), osteoporosis (37.5%), diabetes (33.3%) e hipotiroidismo (29.2%). El porcentaje de complicaciones postoperatorias asociadas fue de 8.3% (cuatro casos). La mediana del HHS a los seis y 12 meses fue de: 90.5 (DE: 77.5-96.0) y 96 (DE: 92-98), respectivamente. La escala de Oxford fue de 45.5 (DE: 38.5-48.0) a los seis meses y de 47.0 (DE: 43.5-48) al año postoperatorio. El 4.2% (dos casos) fallecieron durante el primer año postquirúrgico y ninguno estuvo asociado al procedimiento. Discusión: La HA ofrece buenos resultados funcionales en pacientes mayores de 65 años, con una tasa baja de complicaciones. En nuestra serie y en el corto plazo no se observó mortalidad asociada al procedimiento quirúrgico.

Abstract: Introduction: Bipolar hemiarthroplasty is an alternative for the treatment of displaced femoral neck fractures in elderly patients with low functional demand and associated comorbidities. The goal was to describe functionality in patients over 65 years of age with intracapsular fractures of the hip. Material and methods: Retrospective review of patients over 65 years of age between January 2012 and May 2017. It was evaluated with the Harris Hip Score (HHS) and Oxford scale at six months and the year after surgery. Complications and mortality were documented during the first post-surgical year. Results: 48 cases (12 men; 36 women), average age of 80.8 ± 7.7 years. Most common diseases: high blood pressure (77.1%), osteoporosis (37.5%), diabetes (33.3%) hypothyroidism (29.2%). The percentage of associated postoperative complications was 8.3% (four cases). The median HHS at six and 12 months was: 90.5 (DE: 77.5-96.0) and 96 (DE: 92-98), respectively. The Oxford scale was 45.5 (DE: 38.5-48.0) at six months and 47.0 (DE: 43.5-48.0) per postoperative year. 4.2% (two cases) died during the first post-surgical year and none were associated with the procedure. Discussion: HA provides good functional outcomes in patients over 65 years of age, with a low rate of complications. No mortality associated with the surgical procedure was observed in our series and in the short term.

[Functional results of bipolar hemiarthroplasty in patients over 65 years of age with intracapsular hip fractures]. / Resultados funcionales de hemiartroplastía bipolar en pacientes mayores de 65 años con fracturas intracapsulares de cadera.

INTRODUCTION: Bipolar hemiarthroplasty is an alternative for the treatment of displaced femoral neck fractures in elderly patients with low functional demand and associated comorbidities. The goal was to describe functionality in patients over 65 years of age with intracapsular fractures of the hip. MATERIAL AND METHODS: Retrospective review of patients over 65 years of age between January 2012 and May 2017. It was evaluated with the Harris Hip Score (HHS) and Oxford scale at six months and the year after surgery. Complications and mortality were documented during the first post-surgical year. RESULTS: 48 cases (12 men; 36 women), average age of 80.8 ± 7.7 years. Most common diseases: high blood pressure (77.1%), osteoporosis (37.5%), diabetes (33.3%) hypothyroidism (29.2%). The percentage of associated postoperative complications was 8.3% (four cases). The median HHS at six and 12 months was: 90.5 (DE: 77.5-96.0) and 96 (DE: 92-98), respectively. The Oxford scale was 45.5 (DE: 38.5-48.0) at six months and 47.0 (DE: 43.5-48.0) per postoperative year. 4.2% (two cases) died during the first post-surgical year and none were associated with the procedure. DISCUSSION: HA provides good functional outcomes in patients over 65 years of age, with a low rate of complications. No mortality associated with the surgical procedure was observed in our series and in the short term.

INTRODUCCIÓN: La hemiartroplastía bipolar (HA) es una alternativa para el tratamiento de las fracturas desplazadas de cuello femoral en pacientes de edad avanzada con baja demanda funcional y comorbilidades asociadas. El objetivo fue describir la funcionalidad en pacientes mayores de 65 años con fracturas intracapsulares de cadera tratados con HA. MATERIAL Y MÉTODOS: Revisión retrospectiva de pacientes mayores de 65 años entre Enero de 2012 y Mayo de 2017. Se evaluó con la escala de Harris (HHS) y Oxford a los seis meses y al año posterior a la cirugía. Se documentaron las complicaciones y la mortalidad durante el primer año postquirúrgico. RESULTADOS: 48 casos (12 hombres; 36 mujeres), edad promedio de 80.8 ± 7.7 años. Comorbilidades más frecuentes: hipertensión arterial (77.1%), osteoporosis (37.5%), diabetes (33.3%) e hipotiroidismo (29.2%). El porcentaje de complicaciones postoperatorias asociadas fue de 8.3% (cuatro casos). La mediana del HHS a los seis y 12 meses fue de: 90.5 (DE: 77.5-96.0) y 96 (DE: 92-98), respectivamente. La escala de Oxford fue de 45.5 (DE: 38.5-48.0) a los seis meses y de 47.0 (DE: 43.5-48) al año postoperatorio. El 4.2% (dos casos) fallecieron durante el primer año postquirúrgico y ninguno estuvo asociado al procedimiento. DISCUSIÓN: La HA ofrece buenos resultados funcionales en pacientes mayores de 65 años, con una tasa baja de complicaciones. En nuestra serie y en el corto plazo no se observó mortalidad asociada al procedimiento quirúrgico.

Manejo endoscópico del atrapamiento del nervio ciático en el síndrome de glúteo profundo: resultados clínicos / Endoscopic treatment of sciatic nerve entrapment in deep gluteal syndrome: Clinical results

Introducción: El síndrome de glúteo profundo (SGP) es una enfermedad caracterizada por la compresión a nivel extra-pélvico del nervio ciático (NC) por cualquier estructura en el espacio glúteo profundo. El objetivo de este estudio fue evaluar los resultados clínicos en pacientes con SGP manejados con técnica endoscópica. Métodos: Estudio retrospectivo de pacientes con SGP intervenidos con técnica endoscópica entre 2012 al 2016 con seguimiento mínimo de 12 meses. Los pacientes fueron evaluados antes de la intervención y durante el primer año de seguimiento con las escalas WOMAC y VAIL. Resultados: Se incluyeron 44 cirugías en 41 pacientes (36 mujeres y 5 varones) con un promedio de edad de 48,4±14,5 años. La causa más frecuente de atrapamiento fueron las bandas fibrovasculares, hubo 2 casos de variante anatómica en la salida del nervio, y en un caso aislado, el atrapamiento del NC fue atribuido a la aplicación de biopolímeros en la región glútea. Se encontró mejoría de la funcionalidad y dolor valorado con la escala WOMAC con una mediana de 63 a 26 puntos después de la intervención (p<0,05). Al final del seguimiento un paciente continuaba con dolor residual del nervio cutáneo femoral posterior. Cuatro casos requirieron de revisión a los 6 meses posteriores al procedimiento, por atrapamiento de tejido de cicatrización alrededor del NC. Conclusión: La liberación endoscópica del NC es una alternativa en el manejo del SGP al mejorar la función y disminuir el grado de dolor, cuando existe una adecuada selección de pacientes

Introduction: Deep gluteal syndrome (DGS) is characterized by compression, at extra-pelvic level, of the sciatic nerve within any structure of the deep gluteal space. The objective was to evaluate the clinical results in patients with DGS treated with endoscopic technique. Methods: Retrospective study of patients with DGS treated with an endoscopic technique between 2012 and 2016 with a minimum follow-up of 12 months. The patients were evaluated before the procedure and during the first year of follow-up with the WOMAC and VAIL scale. Results: Forty-four operations on 41 patients (36 women and 5 men) were included with an average age of 48.4±14.5. The most common cause of nerve compression was fibrovascular bands. There were two cases of anatomic variant at the exit of the nerve; compression of the sciatic nerve was associated with the use of biopolymers in the gluteal region in an isolated case. The results showed an improvement of functionality and pain measured with the WOMAC scale with a mean of 63 to 26 points after the procedure (P<.05). However, at the end of the follow-up one patient continued to manifest residual pain of the posterior cutaneous femoral nerve. Four cases required revision at 6 months following the procedure due to compression of the scarred tissue surrounding the sciatic nerve. Conclusion: Endoscopic release of the sciatic nerve offers an alternative in the management of DGS by improving functionality and reducing pain levels in appropriately selected patients

Endoscopic treatment of sciatic nerve entrapment in deep gluteal syndrome: Clinical results. / Manejo endoscópico del atrapamiento del nervio ciático en el síndrome de glúteo profundo: resultados clínicos.

INTRODUCTION: Deep gluteal syndrome (DGS) is characterized by compression, at extra-pelvic level, of the sciatic nerve within any structure of the deep gluteal space. The objective was to evaluate the clinical results in patients with DGS treated with endoscopic technique. METHODS: Retrospective study of patients with DGS treated with an endoscopic technique between 2012 and 2016 with a minimum follow-up of 12 months. The patients were evaluated before the procedure and during the first year of follow-up with the WOMAC and VAIL scale. RESULTS: Forty-four operations on 41 patients (36 women and 5 men) were included with an average age of 48.4±14.5. The most common cause of nerve compression was fibrovascular bands. There were two cases of anatomic variant at the exit of the nerve; compression of the sciatic nerve was associated with the use of biopolymers in the gluteal region in an isolated case. The results showed an improvement of functionality and pain measured with the WOMAC scale with a mean of 63 to 26 points after the procedure (P<.05). However, at the end of the follow-up one patient continued to manifest residual pain of the posterior cutaneous femoral nerve. Four cases required revision at 6 months following the procedure due to compression of the scarred tissue surrounding the sciatic nerve. CONCLUSION: Endoscopic release of the sciatic nerve offers an alternative in the management of DGS by improving functionality and reducing pain levels in appropriately selected patients.

The phenotype and course of inflammatory bowel disease in UK patients of Bangladeshi descent.

BACKGROUND: We have tested the hypotheses that compared with local white Caucasians, UK-resident patients of Bangladeshi descent develop inflammatory bowel disease (IBD) at a younger age; more often have Crohn's disease than ulcerative colitis (UC); and have a more aggressive disease course. AIM: To test the hypotheses that compared to white Caucasian patients of English, Scottish or Welsh descent, patients of Bangladeshi descent develop IBD at a younger age; more often have Crohn's disease; and have a more aggressive disease course by screening case-records of these patients. METHODS: We screened the case-records of 132 Bangladeshi and 623 white Caucasian consecutive out-patients. We then matched each Bangladeshi to a patient of white Caucasian descent for age at diagnosis and disease duration. Data on migration status, phenotype, disease course, treatments and extra-intestinal manifestations and complications were obtained. RESULTS: No differences were seen in the adjusted age at diagnosis of IBD between Bangladeshi and white Caucasian patients. More Bangladeshis than white Caucasian patients (P < 0.01) were diagnosed with Crohn's disease than UC. Crohn's phenotype at diagnosis was similar in both groups. However, multivariate Cox logistic regression analyses showed that Bangladeshis developed perianal complications (HR [95% confidence interval CI] 8.6 [1.4, 53.1], P = 0.02), and received anti-TNFs (HR [95% CI] 3.0 [1.2, 7.7], P = 0.02) earlier and underwent surgery later (HR [95% CI] 0.4 [0.2, 0.9], P = 0.03) than white Caucasians. More Bangladeshis with UC had extensive disease (24/40 [60%]) than white Caucasians (16/49 [33%], P = 0.02). Overall, more Bangladeshis were anaemic and vitamin D deficient. CONCLUSIONS: Bangladeshi patients with IBD more frequently have Crohn's than UC. Bangladeshis with Crohn's more frequently develop perianal disease, have earlier medication escalation and undergo surgery later than white Caucasians. Bangladeshis have more extensive UC than white Caucasians. The relative contributions of genotype and environmental factors, including vitamin D, to these phenotypic differences require additional study.

Construction of a mini-intein fusion system to allow both direct monitoring of soluble protein expression and rapid purification of target proteins.

Affinity purification of recombinant proteins has been facilitated by fusion to a modified protein splicing element (intein). The fusion protein expression can be further improved by fusion to a mini-intein, i.e. an intein that lacks an endonuclease domain. We synthesized three mini-inteins using overlapping oligonucleotides to incorporate Escherichia coli optimized codons and allow convenient insertion of an affinity tag between the intein (predicted) N- and C-terminal fragments. After examining the splicing and cleavage activities of the synthesized mini-inteins, we chose the mini-intein most efficient in thiol-induced N-terminal cleavage for constructing a novel intein fusion system. In this system, green fluorescent protein (GFP) was fused to the C-terminus of the affinity-tagged mini-intein whose N-terminus was fused to a target protein. The design of the system allowed easy monitoring of soluble fusion protein expression by following GFP fluorescence, and rapid purification of the target protein through the intein-mediated cleavage reaction. A total of 17 target proteins were tested in this intein-GFP fusion system. Our data demonstrated that the fluorescence of the induced cells could be used to measure soluble expression of the intein fusion proteins and efficient intein cleavage activity. The final yield of the target proteins exhibited a linear relationship with whole cell fluorescence. The intein-GFP system may provide a simple route for monitoring real time soluble protein expression, predicting final product yields, and screening the expression of a large number of recombinant proteins for rapid purification in high throughput applications.

Cleavage and purification of intein fusion proteins using the Streptococcus gordonii spex system.

A gram-positive bacterial expression vector using Streptococcus gordonii has been developed for expression and secretion, or surface anchoring of heterologous proteins. This system, termed Surface Protein Expression system or SPEX, has been used to express a variety of surface anchored and secreted proteins. In this study, the Mycobacterium xenopi (Mxe) GyrA intein and chitin binding domain from Bacillus circulans chitinase Al were used in conjunction with SPEX to express a fusion protein to facilitate secretion, cleavage, and purification. Streptococcus gordonii was transformed to express a secreted fusion protein consisting of a target protein with a C-terminal intein and chitin-binding domain. Two target proteins, the C-repeat region of the Streptococcus pyogenes M6 protein (M6) and the nuclease A (NucA) enzyme of Staphylococcus aureus, were expressed and tested for intein cleavage. The secreted fusion proteins were purified from culture medium by binding to chitin beads and subjected to reaction conditions to induce intein self-cleavage to release the target protein. The M6 and NucA fusion proteins were shown to bind chitin beads and elute under cleavage reaction conditions. In addition, NucA demonstrated enzyme activity both before and after intein cleavage.

Intein-mediated rapid purification of Cre recombinase.

Cre recombinase produced by bacteriophage P1 catalyzes site-specific recombination of DNA between loxP recognition sites in both prokaryotic and eukaryotic cells and has been widely used for genome engineering and in vitro cloning. Recombinant Cre has been overproduced in Escherichia coli and its purification involves multiple steps. In this report, we used an "intein" fusion system to express Cre as a C-terminal fusion to a modified protein splicing element, i.e., intein. The modified intein contained a Bacillus circulans chitin-binding domain which allowed binding of the fusion protein on a chitin column and could be induced to undergo in vitro peptide bond cleavage which specifically released Cre from the column. Using the intein system, we have obtained highly pure nontagged Cre after just a single chromatographic step, which corresponded to approximately 80% recovery and 27-fold purification. The activity of the purified Cre was determined in an in vitro assay system and was found to remain stable over a period of more than 6 months.

Utilizing the C-terminal cleavage activity of a protein splicing element to purify recombinant proteins in a single chromatographic step.

A conventional affinity protein purification system often requires a separate protease to separate the target protein from the affinity tag. This paper describes a unique protein purification system in which the target protein is fused to the C-terminus of a modified protein splicing element (intein). A small affinity tag is inserted in a loop region of the endonuclease domain of the intein to allow affinity purification. Specific mutations at the C-terminal splice junction of the intein allow controllable C-terminal peptide bond cleavage. The cleavage is triggered by addition of thiols such as dithiothreitol or free cysteine, resulting in elution of the target protein while the affinity-tagged intein remains immobilized on the affinity column. This system eliminates the need for a separate protease and allows purification of a target protein without the N-terminal methionine. We have constructed general cloning vectors and demonstrated single-column purification of several proteins. In addition, we discuss several factors that may affect the C-terminal peptide bond cleavage activity.

Effects of amino acid side-chain volume on chain packing in genetically engineered periodic polypeptides.

The fidelity of bacterial protein synthesis allows the production of architecturally well-defined polymeric materials through precise control of chain length, sequence, stereochemistry, and interchain interactions. In the present paper, we examine the relation between amino acid residue volume and crystalline unit cell dimensions, in a set of periodic protein polymers of repeating unit sequence -(AlaGly)3-X-Gly-, where X is Asn, Phe, Ser, Val, or Tyr. The proteins were overexpressed in Escherichia coli, purified by simple procedures based on acid/ethanol precipitation or insolubility in aqueous sodium dodecyl sulfate, and processed to form oriented crystalline mats by precipitation from formic acid under mechanical shear. X-ray diffraction analyses revealed that the basic structures of the -(AlaGly)3-X-Gly- polymers are identical to that previously reported for [(AlaGly)3-GluGly]36, [Krejchi, M.T., Atkins, E.D.T., Waddon, A.J., Fournier, M.J., Mason, T.L., and Tirrell, D.A. (1994) Science 265, 1427-1432], with the oligoalanylglycine segments forming antiparallel beta-sheets and the substituted amino acids occurring within three-residue folds at the lamellar surfaces. The X-ray diffraction signals for each member of the family index on an orthorhombic unit cell; the a-axis (hydrogen bond direction) and c-axis (chain direction) spacings remain invariant but the b-axis (sheet stacking direction) spacing increases with increasing volume of the substituted amino acid. The results obtained from a variant with alternating Glu and Lys substitution at the X position, together with the results previously reported for poly(L-alanylglycine) [Panitch, A., Matsuki, K., Cantor, E.J., Cooper, S.J., Atkins, E.D.T., Fournier, M.J., Mason, T.L., and Tirrell, D.A. (1997) Macromolecules 30, 42-49] are included for comparison. The average intersheet stacking distance (b/2) increases linearly with the volume of the amino acid inserted at position X. Because the chain-folded lamellar architecture adopted by these periodic polypeptides accommodates a wide range of residues differing in charge, steric bulk, and hydrophobicity, these results illustrate a new approach to the engineering of intermolecular interactions in polymeric solids.

(Imidazolylphenyl)pyrrol-2-one inhibitors of cardiac cAMP phosphodiesterase.

Seven 3-alkyl-4-aryl-1,5-dihydro-2H-pyrrol-2-ones were prepared as potential inhibitors of cardiac cAMP phosphodiesterase (PDE). The design of these compounds made use of rolipram, a known inhibitor of the brain cAMP PDE isozyme, as a lead structure and was guided by a model which describes the features required for potent inhibition of the cardiac isozyme. Syntheses for the new compounds are described, together with the results of theoretical and crystallographic studies aimed toward ascertaining their three-dimensional structures. The activities of these compounds as inhibitors of the cardiac and brain cAMP PDE isozymes and their positive inotropic activity in ferret papillary muscle are also reported. Selected compounds were further examined in an in vivo hemodynamic model. One compound 1,5-dihydro-4-[4-(1H-imidazol-1- yl)phenyl]-3-methyl-2H-pyrrol-2-one, was identified as a potent and selective positive inotropic agent and inhibitor of cardiac cAMP PDE.

Cytoprotective function of nitric oxide: inactivation of superoxide radicals produced by human leukocytes.

The oxygen-derived free radical superoxide anion (.O2-) plays an important role in the pathogenesis of various diseases. Recent demonstrations that .O2- inactivates the potent vasodilator endothelium-derived relaxing factor (EDRF) and that EDRF is probably nitric oxide (NO) suggest that EDRF(NO) may act as an endogenous free radical scavenger. This hypothesis was tested in an in vitro system by analyzing the effect of authentic NO (dilutions of a saturated aqueous solution) on .O2- production (detected spectrophotometrically as reduction of cytochrome c) by fMet-Leu-Phe-activated human leukocytes (PMN). NO depressed the rate of reduction of cytochrome c by .O2- released from PMN's or generated from the oxidation of hypoxanthine by xanthine oxidase. This effect was concentration-dependent and occurred at dilutions of the saturated NO solution (1:250 to 1:10) which inhibited platelet aggregation. NO had no direct effect on cytochrome c or on xanthine oxidase. These observations indicate that NO(EDRF) can be regarded as a scavenger of superoxide anion and they suggest that EDRF(NO) may provide a chemical barrier to cytotoxic free radicals (.O2-).

Novel compounds possessing potent cAMP and cGMP phosphodiesterase inhibitory activity. Synthesis and cardiovascular effects of a series of imidazo[1,2-a]quinoxalinones and imidazo[1,5-a]quinoxalinones and their aza analogues.

A series of novel imidazoquinoxalinones and their aza analogues were prepared by the cyclization of o-amino(1H-imidazol-1-yl)aryls and heteroaryls with carbonyldiimidazole. The compounds were screened for inhibition of Type I and Type IV phosphodiesterases (PDE's) and evaluated for their vasorelaxant and positive inotropic activities in vitro. In general, compounds having potent PDE inhibitory activity also possessed good inotropic and vasodilator activity, although linear correlations between these activities could not be established.

Comparison of nicorandil-induced relaxation, elevations of cyclic guanosine monophosphate and stimulation of guanylate cyclase with organic nitrate esters.

Nicorandil increases cyclic 3'5'-guanosine monophosphate (cGMP) in vascular smooth muscle. However, high concentrations are required to activate guanylate cyclase (GC). We examined the relationship between activation of GC, increases in cGMP and relaxation in canine mesenteric artery and vein, renal and coronary artery and thoracic aorta. Nicorandil (10-100 microM) relaxed in each of the blood vessels. Relaxation was associated with elevations of cGMP but independent of release of endothelium-derived relaxing factor, and inhibited by methylene blue and hemoglobin. The organic nitrate esters nitroglycerin, pentaerythritol tetranitrate, isosorbide dinitrate, 2-isosorbide mononitrate, and 5-isosorbide mononitrate each behaved in a similar manner. In each blood vessel pentaerythritol tetranitrate was the most potent and 5-isosorbide mononitrate the least potent relaxant and stimulant of cGMP. Each of the organic nitrate esters (1 microM to 1 mM) except nicorandil stimulated soluble GC activity in the presence of 10 mM cysteine. Nicorandil (EC50 38 mM) increased GC activity. Moreover, nicorandil (0.1 microM to 30 microM) did not inhibit cGMP phosphodiesterase. The EC50 for vascular relaxation was directly correlated with the EC50 for elevation of cGMP for each of the agonists in each blood vessel type. The EC50 for activation of GC was directly related to the reciprocal of the rate constant for nitric oxide formation for each of the organic nitrate esters. However, a direct correlation existed between the EC50 for activation of GC and the EC50 for 1) elevation of cGMP and 2) relaxation, for each of the organic nitrate esters except nicorandil. Thus, the high concentrations of nicorandil required to activate GC cannot account for the low concentrations required to elevate cGMP or relax smooth muscle. We postulate that nicorandil may interact with a membrane receptor or release a second messenger, distinct from nitric oxide or endothelium-derived relaxing factor, which then activates GC. This may represent a physiologic mechanism for regulation of GC activity in smooth muscle.

Cyclic GMP modulates release of norepinephrine from adrenergic nerves innervating canine arteries.

Evidence is presented that compounds which stimulate the soluble form of the enzyme guanylate cyclase or which inhibit the enzyme cGMP phosphodiesterase (PDE), responsible for the degradation of cGMP (including endothelium-derived relaxing factor) are inhibitors of sympathetic neurotransmission to vascular smooth muscle and inhibit the efflux of norepinephrine from sympathetic nerves. Moreover, prostacyclin, papaverine, iloprost, and forskolin, compounds which stimulate the enzyme adenylate cyclase, and rolipram (neural specific) and milrinone, enoximone, and piroximone (muscle specific) inhibitors of Type III cAMP PDE and degradation of cAMP, do not inhibit nerve stimulation to most blood vessels. The data support the concept that cGMP may act as a negative feedback modulator of physiologic frequencies of sympathetic nerve activity to blood vessels. cAMP does not appear to modulate adrenergic neurotransmission to vascular smooth muscle at physiologic frequencies of neural stimulation.

Effect of race on expression of acquired immunodeficiency syndrome-associated nephropathy.

The prevalence of renal disease associated with the acquired immunodeficiency syndrome (AIDS) is unknown, but appears to vary in different regions. Centers in New York, NY, and Miami, Fla, have reported patients with renal disease complicating AIDS. These populations have included large proportions of black patients and intravenous drug abusers. Reports from San Francisco, Calif, have suggested the prevalence of renal disease complicating AIDS is low, but the population was composed primarily of white patients, with a low proportion of drug abusers. The George Washington University Medical Center was the site of treatment for 31.4% of the patients with AIDS in Washington, DC. This population was split roughly evenly between black and white patients. A retrospective survey of patients with both AIDS and renal disease revealed approximately two thirds of the patients were black, reflecting the demographics of the population with AIDS; 11% of patients had intravenous drug abuse as a risk factor for the development of AIDS; and 74% had acute renal failure. Of these patients, approximately equal proportions were black and white. Twenty-six percent of the population had chronic renal failure, but the overwhelming proportion were black. There were no differences between proportions of patients in age, sex, race, or risk factors in patients with acute renal failure and chronic renal failure, but there was a significant difference in the proportions of black and white patients with chronic renal failure. The reason for these differences is unknown, but differences in host responses to viral proteins, physiologic adaptations, or socioeconomic factors in these populations may play an important role in mediating the expression of renal disease in individual patients.

Inhibition of sympathetic neurotransmitter release by modulators of cyclic GMP in canine vascular smooth muscle.

The contractile response to neurally released norepinephrine (NE) from sympathetic nerve endings innervating vascular smooth muscle are inhibited by substances which raise either cyclic AMP and cyclic GMP concentrations in smooth muscle. However, cyclic AMP is believed to facilitate NE release from sympathetic nerves whereas the role of cyclic GMP in this process is undefined. We examined the effects of presumed modulation of the intraneuronal concentration of cyclic AMP and cyclic GMP on sympathetic neurotransmission to isolated canine mesenteric artery by measurement of the efflux of [2-14C]NE during transmural nerve stimulation (calcium dependent release of NE) and administration of tyramine (calcium independent release of NE) and measurement of the contractions to exogenous NE and tyramine. Stimulation of adenylate cyclase with forskolin, prostacyclin and iloprost, a stable prostacyclin analog, and inhibition of Type III cyclic AMP phosphodiesterase with neural specific rolipram, 'non-specific pelrinone and milrinone and isobutylmethylxanthine did not enhance the efflux of [2-14C]NE from sympathetic nerves innervating the blood vessels. Isoproterenol enhanced the efflux of [2-14C]NE. The effect was inhibited by propranolol but not affected by milrinone, amrinone or rolipram. Activators of guanylate cyclase (SIN-1a an active metabolic of molsidomine, nitroglycerin and sodium nitroprusside) and inhibitors of Type II cyclic GMP phosphodiesterase (M&B-22948 and verofyllin) inhibited the efflux of NE released by transmural nerve stimulation but not by tyramine. These data support the conclusion that cyclic GMP may be an inhibitory modulator of calcium and depolarization dependent NE release from sympathetic nerves, whereas neuronal cyclic AMP may not be a primary modulator of neurotransmission to vascular smooth muscle.