GPATCH8 modulates mutant SF3B1 mis-splicing and pathogenicity in hematologic malignancies.

Mutations in the RNA splicing factor gene SF3B1 are common across hematologic and solid cancers and result in widespread alterations in splicing, yet there is currently no therapeutic means to correct this mis-splicing. Here, we utilize synthetic introns uniquely responsive to mutant SF3B1 to identify trans factors required for aberrant mutant SF3B1 splicing activity. This revealed the G-patch domain-containing protein GPATCH8 as required for mutant SF3B1-induced splicing alterations and impaired hematopoiesis. GPATCH8 is involved in quality control of branchpoint selection, interacts with the RNA helicase DHX15, and functionally opposes SURP and G-patch domain containing 1 (SUGP1), a G-patch protein recently implicated in SF3B1-mutant diseases. Silencing of GPATCH8 corrected one-third of mutant SF3B1-dependent splicing defects and was sufficient to improve dysfunctional hematopoiesis in SF3B1-mutant mice and primary human progenitors. These data identify GPATCH8 as a novel splicing factor required for mis-splicing by mutant SF3B1 and highlight the therapeutic impact of correcting aberrant splicing in SF3B1-mutant cancers.

Antileishmanial effects of Crotalaria spectabilis Roth aqueous extracts on Leishmania amazonensis.

Fifteen polar extracts from leaf, seed, pod, stem, flower and root of Crotalaria spectabilis were prepared using aqueous systems, based on the principles of green chemistry, and showed different protease inhibitor (PI) activities on trypsin, papain, pepsin and the extracellular L. amazonensis serine protease (LSPIII). The most pronounced inhibitory effect on LSPIII was observed in leaf (CS-P), root, stem, flower (CS-FPVPP) and pod (CS-VA) extracts. Crotalaria extracts exhibited low cytotoxicity on macrophages; however, they decreased the viability of L. amazonensis promastigotes and amastigotes, as observed in leaf (CS-AE, CS-P, CS-T and CS-PVPP), seed (CS-ST), flower and root (CS-RA) extracts. CS-P was chosen to study PI and secondary metabolites and a 10-12 kDa protein, analyzed by mass spectrometry, was identified as a serine PI homologous with papaya latex serine PI. Glycosylated flavonoids, such as quercetins, vitexin and tricin were the major secondary metabolites of CS-P. The presence of PIs in C. spectabilis is a new finding, especially in other organs than seeds since PIs have been reported only in seed legumes. Besides, this is the first report of antileishmanial activity of C. spectabilis extracts and the identification of serine polypeptide PI and glycosylated flavonoids from leaf.

Oral pentamidine-loaded poly(d,l-lactic-co-glycolic) acid nanoparticles: an alternative approach for leishmaniasis treatment.

Leishmaniasis is a group of diseases caused by a protozoa parasite from one of over 20 Leishmania species. Depending on the tissues infected, these diseases are classified as cutaneous, mucocutaneous and visceral leishmaniasis. For the treatment of leishmaniasis refractory to antimony-based drugs, pentamidine (PTM) is a molecule of great interest. However, PTM displays poor bioavailability through oral routes due to its two strongly basic amidine moieties, which restricts its administration by a parenteral route and limits its clinical use. Among various approaches, nanotechnology-based drug delivery systems (nano-DDS) have potential to overcome the challenges associated with PTM oral administration. Here, we present the development of PTM-loaded PLGA nanoparticles (NPs) with a focus on the characterization of their physicochemical properties and potential application as an oral treatment of leishmaniasis. NPs were prepared by a double emulsion methodology. The physicochemical properties were characterized through the mean particle size, polydispersity index (PdI), zeta potential, entrapment efficiency, yield process, drug loading, morphology, in vitro drug release and in vivo pharmacological activity. The PTM-loaded PLGA NPs presented with a size of 263 ± 5 nm (PdI = 0.17 ± 0.02), an almost neutral charge (-3.2 ± 0.8 mV) and an efficiency for PTM entrapment of 91.5%. The release profile, based on PTM dissolution, could be best described by a zero-order model, followed by a drug diffusion profile that fit to the Higuchi model. In addition, in vivo assay showed the efficacy of orally given PTM-loaded PLGA NPs (0.4 mg kg-1) in infected BALB/c mice, with significant reduction of organ weight and parasite load in spleen (p-value < 0.05). This work successfully reported the oral use of PTM-loaded NPs, with a high potential for the treatment of visceral leishmaniasis, opening a new perspective to utilization of this drug in clinical practice.

Leishmanicidal Activity of Withanolides from Aureliana Fasciculata var. Fasciculata.

Leishmaniasis is the generic denomination to the neglected diseases caused by more than 20 species of protozoa belonging to the genus Leishmania. The toxic and parenteral-delivered pentavalent antimonials remain to be the first-line treatment. However, all the current used drugs have restrictions. The species Aureliana fasciculata (Vell.) Sendtner var. fasciculata is a native Brazilian species parsimoniously studied on a chemical point of view. In this study, the antileishmanial activity of A. fasciculata was evaluated. Among the evaluated samples of the leaves, the dichloromethane partition (AFfDi) showed the more pronounced activity, with IC50 1.85 µg/ml against promastigotes of L. amazonensis. From AFfDi, two active withanolides were isolated, the Aurelianolides A and B, with IC50 7.61 µM and 7.94 µM, respectively. The withanolides also proved to be active against the clinically important form, the intracellular amastigote, with IC50 2.25 µM and 6.43 µM for Aurelianolides A and B, respectively. Furthermore, withanolides showed results for in silico parameters of absorption, distribution, metabolism, excretion, and toxicity (ADMET) similar to miltefosine, the reference drug, and were predicted as good oral drugs, with the advantage of not being hepatotoxic. These results suggest that these compounds can be useful as scaffolds for planning drug design.

Biology of Psorophora albigenu Under Laboratory Conditions.

The present study investigates the effect of multiple immersions on Psorophora albigenu eggs and their development cycle under laboratory conditions. Engorged Ps. albigenu specimens were captured in January 2011 around the Transpantaneira Park Road, Mato Grosso, Brazil, using CO2-baited Centers for Disease Control and Prevention light traps. Psorophora albigenu eggs (n = 1274) were subjected to immersion, with a hatching rate between 49% and 73%. The Williams average showed a peak of 29% hatched eggs in the 3rd immersion; after 4-5 immersions, the effect of additional immersions was generally negligible. The average cycle for both males and females was 5.68 ± 1.00 days. This short development time from the egg stage to adult emergence followed the pattern seen in other species of the genus Psorophora.

Enhancing Dementia Knowledge and Self-Efficacy of In-Home Supportive Services Caregivers Through Online Training.

California's In-Home Supportive Services (IHSS) program provides vital home care to low-income consumers, some of whom live with Alzheimer's disease or related dementias (ADRD). Yet, most IHSS caregivers receive little or no training in dementia care. We present preliminary descriptive results of the IHSS + ADRD Training Project, a 10-week, competency-based, dementia training program, delivered online, for IHSS caregivers, in Alameda County. Increase in dementia knowledge and self-efficacy at training completion supports the importance of continuing and expanding this work.

Systematic evaluation of AML-associated antigens identifies anti-U5 SNRNP200 therapeutic antibodies for the treatment of acute myeloid leukemia.

Despite recent advances in the treatment of acute myeloid leukemia (AML), there has been limited success in targeting surface antigens in AML, in part due to shared expression across malignant and normal cells. Here, high-density immunophenotyping of AML coupled with proteogenomics identified unique expression of a variety of antigens, including the RNA helicase U5 snRNP200, on the surface of AML cells but not on normal hematopoietic precursors and skewed Fc receptor distribution in the AML immune microenvironment. Cell membrane localization of U5 snRNP200 was linked to surface expression of the Fcγ receptor IIIA (FcγIIIA, also known as CD32A) and correlated with expression of interferon-regulated immune response genes. Anti-U5 snRNP200 antibodies engaging activating Fcγ receptors were efficacious across immunocompetent AML models and were augmented by combination with azacitidine. These data provide a roadmap of AML-associated antigens with Fc receptor distribution in AML and highlight the potential for targeting the AML cell surface using Fc-optimized therapeutics.

Tissue expression of TGF-ß1 in uterine cervical samples from HIV/AIDS patients.

Case-control study based on the immunohistochemistry for TGF-ß1 evaluation of cervical samples obtained from two groups of women: CIN/HIV- and CIN/HIV+. Eleven women infected with HIV and with a histopathological diagnosis of CIN were included. The control group consisted of 12 patients with CIN. Cervical tissue samples obtained from all patients were submitted to histopathology and semiquantitative analysis of immunostaining for TGF-ß1 protein. In addition, the peripheral CD4+ cell count and viral load were evaluated in HIV + patients. Tissue expression of the cytokine was higher in the CIN/HIV+ group compared to control (p = 0.0023). In addition, higher TGF-ß1 expression was observed in higher grade cervical lesions in the two groups. There was a trend toward a direct correlation between peripheral CD4+ T cell count and tissue TGF-ß1, and toward an inverse correlation between viral load and cytokine expression. Thus, TGF-ß1 was more marked in situations in which cervical lesions are known to present a more aggressive behavior, suggesting that this cytokine is involved in the pathogenesis of tumor growth in these lesions. Tissue expression of TGF-ß1 is increased in cervical samples from HIV-infected women with CIN.

Study of the proteolytic activity of the tropical legume Crotalaria spectabilis.

The characterization of legume proteases contributes to the understanding of the physiology of plants and their interaction with the environment. Thirteen extracts from various parts of Crotalaria spectabilis were made using different extraction systems. The highest protein content was found in seeds, and the most pronounced proteolytic activity was observed in leaf extracts, with an optimal pH value in the alkaline range. Proteases in extracts from roots, stems, and flowers were active in various pH ranges. Proteases in all extracts were maximally active between 30 degrees C and 60 degrees C and were thermostable (24 h, 60 degrees C). Hemoglobin, bovine serum albumin, casein, and gelatin were hydrolyzed by C. spectabilis extracts in different ways. The highest serine protease activity was found in leaves. Seeds contained high levels of serine proteases and low levels of cysteine proteases. Flowers, roots, and stems contained different levels of serine, aspartic, and metalloproteases, respectively. The proteolytic activities in extracts were modulated by cations and oxidants to various degrees. C. spectabilis proteases are differentially expressed in distinctive organs, and their stability against heat and oxidants makes this plant an important source of stable proteases.

Extracorporeal Membrane Oxygenation After Norwood Surgery in Patients With Hypoplastic Left Heart Syndrome: A Retrospective Single-Center Cohort Study From Brazil.

Background: Extracorporeal membrane oxygenation (ECMO) is increasingly being used to support patients after the repair of congenital heart disease. Objective: We report our experience with patients with a single functional ventricle who were supported by ECMO after the Norwood procedure, reviewing the outcomes and identifying risk factors for mortality in these patients. Methods: In this single-center retrospective cohort study, we enrolled 33 patients with hypoplastic left heart syndrome (HLHS) who received ECMO support after the Norwood procedure between January 2015 and December 2019. The independent variables evaluated in this study were demographic, anatomical, and those directly related to ECMO support (ECMO indication, local of initiation, time under support, and urinary output while on ECMO). The dependent variable was survival. A p < 0.05 was considered statistically significant. Results: The ECMO support was applied in 33 patients in a group of 120 patients submitted to Norwood procedure (28%). Aortic atresia was present in 72.7% of patients and mitral atresia in 51.5%. For 15% of patients, ECMO was initiated in the operating room; for all other patients, ECMO was initiated in the intensive care unit. The indications for ECMO in the cardiac intensive care unit were cardiac arrest in 22 (79%) of patients, low cardiac output state in 10 (18%), and arrhythmia in 1 patient (3%). The median time under support was 5 (2-25) days. The median follow-up time was 59 (4-150) days. Global survival to Norwood procedure was 90.9% during the 30-day follow-up, being 33.3% for those submitted to ECMO. Longer ECMO support (p = 0.004) was associated with a higher risk of death in the group submitted to ECMO. Conclusions: The mortality of patients with HLHS who received ECMO support after stage 1 palliation was high. Patients with low urine output were related to worse survival rates, and longer periods under ECMO support (more than 9 days of ECMO) were associated with 100% mortality. Earlier ECMO initiation before multiorgan damage may improve results.

Early Outcomes of the Norwood Procedure in a Reference Center in Brazil. / Resultados Precoces do Procedimento de Norwood em um Centro de Referência no Brasil.

BACKGROUND: Only two papers have addressed the early outcomes of patients with hypoplastic left heart syndrome (HLHS) undergoing the Norwood operation, in Brazil. OBJECTIVES: We evaluated patients with HLHS undergoing the first-stage Norwood operation in order to identify the predictive factors for early (within the first 30 days after surgery) and intermediate (from early survival up to the Glenn procedure) mortality. METHODS: Patients with HLHS undergoing the stage I Norwood procedure from January 2016 through April 2019, in our service, were enrolled. Demographic, anatomical, and surgical data were analyzed. Endpoints were early mortality (within the first 30 days after surgery), intermediate mortality (from early survival up to the Glenn procedure) and the need for postoperative ECMO support. Univariate and multivariate analyses were performed, and odds ratios, with 95% confidence intervals, were calculated. A p-value <0.05 was considered statistically significant. RESULTS: A total of 80 patients with HLHS underwent the stage I Norwood procedure. The 30-day survival rate was 91.3% and the intermediate survival rate 81.3%. Fourteen patients (17.5%) required ECMO support. Lower weight (p=0.033), aortic stenosis (vs aortic atresia; p=0.036), and the need for postoperative ECMO support (p=0.009) were independent predictive factors for 30-day mortality. Mitral valve stenosis (vs mitral valve atresia; p=0.041) was an independent predictive factor for intermediate mortality. CONCLUSION: The present study includes the largest Brazilian cohort of patients with HLHS undergoing the stage I Norwood procedure in the recent era. Our survival rates were comparable to the highest survival rates reported globally. Low body weight, aortic valve stenosis, and the need for postoperative ECMO support were independent predictors for 30-day mortality. Mitral valve stenosis was the only independent predictive factor for intermediate mortality.

FUNDAMENTO: Apenas dois artigos abordam os resultados precoces de pacientes com síndrome do coração esquerdo hipoplásico (SHCE) submetidos à operação de Norwood, no Brasil. OBJETIVOS: Avaliamos pacientes com SHCE submetidos ao primeiro estágio da operação de Norwood para identificar os fatores preditivos de mortalidade precoce (nos primeiros 30 dias após a cirurgia) e intermediária (desde a sobrevida precoce até o procedimento de Glenn). MÉTODOS: Foram incluídos pacientes com SHCE submetidos em nosso serviço ao primeiro estágio da operação de Norwood de janeiro de 2016 a abril de 2019. Dados demográficos, anatômicos e cirúrgicos foram analisados. Os desfechos foram mortalidade precoce (nos primeiros 30 dias após a cirurgia), mortalidade intermediária (desde a sobrevida precoce até o procedimento de Glenn) e a necessidade de suporte pós-operatório com ECMO. Foram realizadas análises univariadas e multivariadas e calculados odds ratios, com intervalos de confiança de 95%. Um valor de p < 0,05 foi considerado estatisticamente significativo. RESULTADOS: Um total de 80 pacientes com SHCE foram submetidos ao primeiro estágio da operação de Norwood. A taxa de sobrevida em 30 dias foi de 91,3% e a taxa de sobrevida intermediária foi de 81,3%. Quatorze pacientes (17,5%) necessitaram de suporte com ECMO. Menor peso (p=0,033), estenose aórtica (vs atresia aórtica; p=0,036) e necessidade de suporte pós-operatório com ECMO (p=0,009) foram fatores preditivos independentes para mortalidade em 30 dias. A estenose da valva mitral ( vs atresia da valva mitral; p=0,041) foi um fator preditivo independente para mortalidade intermediária. CONCLUSÃO: O presente estudo inclui a maior coorte brasileira de pacientes com SHCE submetidos ao primeiro estágio da operação de Norwood na era recente. Nossas taxas de sobrevida foram comparáveis às mais altas taxas de sobrevida relatadas globalmente. Baixo peso corporal, estenose valvar aórtica e necessidade de suporte pós-operatório com ECMO foram preditores independentes para mortalidade em 30 dias. A estenose da valva mitral foi o único fator preditivo independente para mortalidade intermediária.

Efficacy of Spironolactone Treatment in Murine Models of Cutaneous and Visceral Leishmaniasis.

Translational studies involving the reuse and association of drugs are approaches that can result in higher success rates in the discovery and development of drugs for serious public health problems, including leishmaniasis. If we consider the number of pathogenic species in relation to therapeutic options, this arsenal is still small, and each drug possesses a disadvantage in terms of toxicity, efficacy, price, or treatment regimen. In the search for new drugs, we performed a drug screening of L. amazonensis promastigotes and intracellular amastigotes of fifty available drugs belonging to several classes according to their pharmacophoric group. Spironolactone, a potassium-sparing diuretic, proved to be the most promising drug candidate. After demonstrating the in vitro antileishmanial activity, we evaluated the efficacy on a murine experimental model with L. amazonensis and L. infantum. The treatment controlled the cutaneous lesion and reduced the parasite burden of L. amazonensis significantly, as effectively as meglumine antimoniate. The treatment of experimental visceral leishmaniasis was effective in reducing the parasite load on the main affected organs (spleen and liver) via high doses of spironolactone. The association between spironolactone and meglumine antimoniate promoted better control of the parasite load in the spleen and liver compared to the group treated with meglumine antimoniate alone. These results reveal a possible benefit of the concomitant use of spironolactone and meglumine antimoniate that should be studied more in depth for the future possibility of repositioning for leishmaniasis co-therapy.

Monocyclic Nitro-heteroaryl Nitrones with Dual Mechanism of Activation: Synthesis and Antileishmanial Activity.

5-Nitro-furan nitrones (1) and 5-nitro-thiophene nitrones (2) were synthesized in one step. Compounds 1a-c had the most potent leishmanicidal activity against intracellular amastigote forms of Leishmania amazonensis and L. infantum (from 0.019 to 2.76 µM), with excellent selectivity (from 39 to 5673). The comparison of the leishmanicidal activity in promastigotes of wild type L. donovani with those overexpressing nitroreductases NRT1 or NRT2 shows that 1a,b are activated by both, which could slow the development of resistance. Their redox potential (E redox) obtained by cyclic voltammetry (-0.67 and -0.62 V) shows that the reduction of the nitro group is modulated by the nitrone group. Oral administration of 1b to mice infected by L. infantum reduced the parasite load on the spleen by 76.6 and 95.0% with doses of 50 and 100 mg/kg, respectively, administered twice a day, for 5 days. In the liver, the parasite load suppression was above 75% with either treatment.

Biodiversity and influence of climatic factors on mosquitoes (Diptera: Culicidae) around the Peixe Angical hydroelectric scheme in the state of Tocantins, Brazil.

The influence of climatic factors on the seasonal frequency of mosquitoes (Diptera: Culicidae) at the Peixe Angical hydroelectric scheme (Tocantins, Brazil) was evaluated in the present paper. Mosquito surveys were conducted in the municipality of Peixe and in areas surrounding the reservoir in the municipalities of Paranã and São Salvador do Tocantins during two daytime periods (10 am-12 noon and 2 pm-4 pm) and two night-time periods (6 pm-8 pm and 6 pm-10 am) over 14 months. In total, 10,840 specimens from 42 species were captured, 84.5% of which belonged to the Culcinae. The most common species were Anopheles darlingi, Psorophora albipes and Sabethes chloropterus. The number of Culicidae specimens was higher in months with higher rainfall and air humidity than during the drier months. The large population of Ps. albipes and the presence of both An. darlingi (primary vector for human malaria parasites) and Haemagogus janthinomys (primary vector for yellow fever virus) are highlighted.

Immature mosquitoes of Serra do Mar park, Sao Paulo State, Brazil.

With the objective of providing knowledge about the natural habitat of mosquito larvae, we conducted a study on the culicid fauna and identified larval habitat types at 3 different locations in the Serra do Mar State Park, Brazil, over the 12 months of 1991. We collected 1,425 larvae belonging to 23 species, of which the most frequent were Culex iridescens, Culex spp., Limatus durhami, and Trichoprosopon pallidiventer. The mosquito larval habitats presenting the greatest densities of specimens were bamboo, bromeliads, rubber boots, and streams. We observed that the culicids used a variety of containers as larval habitats and bred under a diversity of ecological conditions. Most of the habitats were natural, formed by bamboo, bromeliads, streams, and depressions in the ground and in rocks, along with artificial habitats consisting of rubber boots and abandoned metal cans. Seven species occurred preferentially in the internodes of closed bamboo stems, 6 in internodes of open stems, and 4 in bromeliads.

Feeding patterns of Haemagogus capricornii and Haemagogus leucocelaenus (Diptera: Culicidae) in two Brazilian states (Rio de Janeiro and Goiás).

We present the identification of bloodfeeding sources of Haemagogus (Haemagogus) capricornii Lutz and Haemagogus (Conopostegus) leucocelaenus (Dyar & Shannon) (Diptera: Culicidae) from different regions of Brazil, as analyzed by precipitin tests. Anti-sera for bird, bovine, equine, human, opossum, and rodent were used. Two hundred one mosquitoes were examined (147 Hg. leucocelaenus and 54 Hg. capricornii), of which 177 reacted for some anti-serum. For Hg. leucocelaenus, 86 (68.3%) reacted to one blood source, 38 (30.2%) to two sources, and two (1.6%) to three sources; the combinations of bird + human (18.4%), bird + rodent (15.8%), and bird + marsupial (15.8%) were the most frequent. For Hg. capricornii, 34 (66.7%) reacted to one blood source; combinations bird + rodent (37.5%) and bird + marsupial (25%) were the most frequent combinations. Mosquito preference for bloodfeeding sources was different in these areas, possibly because of the availability of sources. This diversity of sources can have important epidemiological implications.

Influence of Climatic Factors On Psorophora (Janthinosoma) Albigenu In Pantanal Landscape, Mato Grosso State, Brazil.

In order to assess the influence of climatic variations in temperature, relative humidity, and rainfall upon the population density of Psorophora albigenu (Peryassú, 1908) in its natural habitat, samplings were carried out at different times of the year in Mato Grosso, Brazil. Mosquitoes were captured with the use of suction tubes and Shannon traps during 2 different periods of the day and 1 at night. A total of 2,637 Ps. albigenu specimens were captured, including 497 (18.8%) in March 2009, 1,240 (47.0%) in January 2010, and 484 (18.4%) in January 2011. These months represented 84.2% of this species occurrence during the collection period. November was the month of the lowest occurrence of the species, with only 10 (0.4%) specimens collected in 2009 and 8 (0.3%) specimens in 2010. The climatological variable that presented a linear correlation coefficient within the 95% confidence interval was rainfall, with a linear correlation indicator of 0.793, above the relevance factor of 0.708, showing a relationship between the frequency of Ps. albigenu and rainfall of the region.

Safety and efficacy of recanalization therapy in pediatric stroke: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Safety and efficacy of intravenous (IV) thrombolysis and endovascular therapy in children with acute ischemic stroke (AIS) are unknown to date. We aimed to review and synthesize currently available evidence on these acute recanalization therapies in pediatric stroke patients. METHODS: We performed a systematic review and meta-analysis of all available data on safety and efficacy of acute treatment including thrombolysis and endovascular therapy in pediatric AIS patients aged <18 years. We searched the electronic databases Medline and Cochrane Library for eligible studies published from the earliest date available until August 31, 2016. Safety outcomes included intracerebral hemorrhage (ICH) post-treatment and in-hospital mortality. Efficacy outcomes included functional outcome 3-6 months after index stroke. RESULTS: We identified 222 records, of which 3 studies with a total of 16,987 pediatric stroke patients met our eligibility criteria of whom 181 received IV thrombolysis. No data exists from randomized trials and no data is available on endovascular thrombectomy. Risk of any ICH was increased in children receiving thrombolysis (risk ratio = 3.48, 95%CI: 1.66-7.29; p = 0.001) compared with controls, with no evidence of heterogeneity (I2 = 0%). None of the included studies reported complete data on symptomatic ICH. In-hospital mortality was similar between pediatric stroke patients treated with thrombolysis and controls (risk ratio = 1.44, 95%CI: 0.39-5.40; p = 0.586), with evidence of heterogeneity (I2 = 62%). Efficacy of revascularization therapies could not be analyzed due to lack of outcome data. CONCLUSIONS: Our analyses demonstrate a substantial lack of data on efficacy and safety of acute recanalization therapies in children with AIS. PROSPERO REGISTRATION INFORMATION: URL: http://www.crd.york.ac.uk/PROSPERO. Unique identifier: CRD42016047140.

Impaired reduction of nocturnal systolic blood pressure and severity of diabetic retinopathy.

The aim of the present study was to evaluate the influence of elevated levels of nocturnal blood pressure (BP) on diabetic retinopathy (DR). A total of 88 diabetic hypertensive patients were divided according to the stage of DR. They underwent 24 h ambulatory BP monitoring and ophthalmological evaluation, and their average level of fasting blood glucose as well as their glycemic control index (percentage of fasting blood glucose higher than 11.2 mmol/L over the previous four years) were calculated. When diabetic patients with retinopathy (n=29) (group 1) were compared with patients without retinopathy (n=59) (group 2), a significant difference was observed in diabetes duration (124 months [range six to 460 months] versus 43 months [range six to 365 months], respectively; P<0.05). In addition, group 1 showed higher levels of nocturnal systolic BP (NSBP) (141 +/- 22 mmHg versus 132+/-18 mmHg; P<0.05). However, no significant differences were found between the two groups (group 1 and group 2) when diurnal pressoric levels were compared (diurnal systolic BP, 153+/-19 mmHg versus 146+/-19 mmHg, P not significant; and diurnal diastolic BP, 91+/-9 mmHg versus 91+/-13 mmHg, P not significant). DR correlated with diabetes duration (r=0.26; P<0.05) and with glycemic control index (r=0.24; P<0.01). Multivariate regression analysis showed NSBP to be an independent predictor of DR (r(2)=0.12; P<0.01). Moreover, patients with severe stages of DR (preproliferative, proliferative or macular edema) showed a lower decrease of NSBP than the other patients (3.9+/-6.0 mmHg versus 9.2+/-6.0 mmHg; P<0.05). The present study suggests that the absence of 24 h normal pressoric rhythm can interfere with the prevalence and severity of DR.