Diabetic Ketoacidosis Associated with Sodium-Glucose Cotransporter 2 Inhibitors: Clinical and Biochemical Characteristics of 29 Cases.

Objective: To describe the clinical and biochemical characteristics of all reported cases of DKA associated with SGLT2 inhibitor use in patients with type 2 diabetes mellitus and to identify potential risk factors. Design: A retrospective case series was conducted between March 2013 and August 2019 using an electronic medical record search algorithm. Results: 25 patients met the criteria for DKA associated with SGLT2i use (total of 29 cases), 15 were female, average age was 54.24 years, and mean diabetes duration was 8.76 years. The majority of the patients (23 patients) had no history of prior DKA. Average blood glucose concentrations at presentation were 298.9 ± 152.7 mg/dl. Interestingly, nearly half of the episodes (14) met the criteria of euglycemic DKA (glucose <250 mg/dl). Average anion gap values were 26.59 ± 6.15 mg/dl, bicarbonate values were 11.14 ± 5.57 mg/dl, and pH values were 7.16 ± 0.12. All had positive serum and urine ketones. The most common presenting symptoms were nausea, vomiting (18 cases), and abdominal pain (10 cases). Common precipitants were poor oral intake (18 cases) and infection (10 cases). A variety of drugs were prescribed along with an SGLT2i, and 11 of the patients were using insulin. None of the cases were fatal. Comparison between euglycemic DKA and hyperglycemic DKA did not identify any significant difference. A major limitation factor of the study was the lack of control group or comparison to other antiglycemic agents to assess the relative risk. Conclusions: The majority of SGLT2i-associated DKA cases occurred in patients with T2DM without prior episodes of DKA. The most common presenting symptoms were nausea, vomiting, and abdominal pain, while poor food intake and infection were the main precipitants. Clinicians should consider the possibility of DKA in SGLT2i-treated patients presenting with these symptoms, even in absence of marked hyperglycemia.

PAR-1 and PAR-2 Expression Is Enhanced in Inflamed Odontoblast Cells.

Protease-activated receptors (PARs) are G protein-coupled receptors, which are activated by proteolytical cleavage of the amino-terminus and act as sensors for extracellular proteases. We hypothesized that PAR-1 and PAR-2 can be modulated by inflammatory stimulus in human dental pulp cells. PAR-1 and PAR-2 gene expression in human pulp tissue and MDPC-23 cells were analyzed by quantitative polymerase chain reaction. Monoclonal PAR-1 and PAR-2 antibodies were used to investigate the cellular expression of these receptors using Western blot, flow cytometry, and confocal microscopy in MDPC-23 cells. Immunofluorescence assays of human intact and carious teeth were performed to assess the presence of PAR-1 and PAR-2 in the dentin-pulp complex. The results show for the first time that human odontoblasts and MDPC-23 cells constitutively express PAR-1 and PAR-2. PAR-2 activation increased significantly the messenger RNA expression of matrix metalloproteinase (MMP)-2, MMP-9, MMP-13, and MMP-14 in MDPC-23 cells ( P < 0.05), while the expression of these enzymes decreased significantly in the PAR-1 agonist group ( P < 0.05). The high-performance liquid chromatography and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry analysis showed the presence of MMP-13 activity cleaving PAR-1 at specific, noncanonical site TLDPRS42↓F43LL in human dental pulp tissues. Also, we detected a presence of a trypsin-like activity cleaving PAR-2 at canonical site SKGR20↓S21LIGRL in pulp tissues. Confocal microscopy analysis of human dentin-pulp complex showed intense positive staining of PAR-1 and PAR-2 in the odontoblast processes in dentinal tubules of carious teeth compared to intact ones. The present results support the hypothesis of activation of the upregulated PAR-1 and PAR-2 by endogenous proteases abundant during the inflammatory response in dentin-pulp complex.

Coupling of vinculin to F-actin demands Syndecan-4 proteoglycan.

Syndecans are heparan sulfate proteoglycans characterized as transmembrane receptors that act cooperatively with the cell surface and extracellular matrix proteins. Syn4 knockdown was performed in order to address its role in endothelial cells (EC) behavior. Normal EC and shRNA-Syn4-EC cells were studied comparatively using complementary confocal, super-resolution and non-linear microscopic techniques. Confocal and super-resolution microscopy revealed that Syn4 knockdown alters the level and arrangement of essential proteins for focal adhesion, evidenced by the decoupling of vinculin from F-actin filaments. Furthermore, Syn4 knockdown alters the actin network leading to filopodial protrusions connected by VE-cadherin-rich junction. shRNA-Syn4-EC showed reduced adhesion and increased migration. Also, Syn4 silencing alters cell cycle as well as cell proliferation. Moreover, the ability of EC to form tube-like structures in matrigel is reduced when Syn4 is silenced. Together, the results suggest a mechanism in which Syndecan-4 acts as a central mediator that bridges fibronectin, integrin and intracellular components (actin and vinculin) and once silenced, the cytoskeleton protein network is disrupted. Ultimately, the results highlight Syn4 relevance for balanced cell behavior.

Anti-Leishmania titers and positive skin tests in patients cured of kala-azar

Visceral leishmaniasis (VL), also known as kala-azar, is an important public health problem. If not treated, virtually all clinically symptomatic patients die within months. The diagnosis is based on the Montenegro skin test (MST) and anti-Leishmania titers. Nevertheless, the time required for cured individuals living in a leishmaniasis-endemic area to present a positive skin test and negative anti-Leishmania serology is known. To determine the cellular and humoral immune response profile in relation to different times post-VL cure, a cross-sectional study was conducted on subjects from a kala-azar endemic area in Paço do Lumiar, MA, Brazil, on the basis of 1995-2005 notifications reported by the National Health Foundation/Regional Coordination of Maranhão. We visited cured individuals with a history of VL within the last 10 years. Seventy-four subjects (30 females) ranging in age from 1 to 44 years were included, all of them symptom free at the time of the study. A cellular immune response was observed in 73 (98.6 percent) subjects, whereas no significant antibody titers were detected by indirect immunofluorescence (IIF) in the sera of 69 (93.2 percent) cases. Ten years post-cure, 39 (52 percent) subjects had a positive MST and negative IIF reaction, while in one subject the skin and anti-Leishmania serology tests were negative. Two other subjects were positive in both tests 1 year after cure. These data suggest that a cellular immune response may still be present in subjects cured of VL regardless of post-cure time, and that the parasite persists in the host after clinical cure of the disease. This would explain the persistence of significant Leishmania sp antibody titers in some subjects after treatment.

Anti-Leishmania titers and positive skin tests in patients cured of kala-azar.

Visceral leishmaniasis (VL), also known as kala-azar, is an important public health problem. If not treated, virtually all clinically symptomatic patients die within months. The diagnosis is based on the Montenegro skin test (MST) and anti-Leishmania titers. Nevertheless, the time required for cured individuals living in a leishmaniasis-endemic area to present a positive skin test and negative anti-Leishmania serology is known. To determine the cellular and humoral immune response profile in relation to different times post-VL cure, a cross-sectional study was conducted on subjects from a kala-azar endemic area in Paço do Lumiar, MA, Brazil, on the basis of 1995-2005 notifications reported by the National Health Foundation/Regional Coordination of Maranhão. We visited cured individuals with a history of VL within the last 10 years. Seventy-four subjects (30 females) ranging in age from 1 to 44 years were included, all of them symptom free at the time of the study. A cellular immune response was observed in 73 (98.6%) subjects, whereas no significant antibody titers were detected by indirect immunofluorescence (IIF) in the sera of 69 (93.2%) cases. Ten years post-cure, 39 (52%) subjects had a positive MST and negative IIF reaction, while in one subject the skin and anti-Leishmania serology tests were negative. Two other subjects were positive in both tests 1 year after cure. These data suggest that a cellular immune response may still be present in subjects cured of VL regardless of post-cure time, and that the parasite persists in the host after clinical cure of the disease. This would explain the persistence of significant Leishmania sp antibody titers in some subjects after treatment.

Leishmaniosevisceral (calazar) na Ilha de São Luís, Maranhão, Brasil: evolução e perspectivas / Visceral leishmaniasis (kala-azar) on Ilha de São Luís, Maranhão. Brazil: its evolution and outlook

Leishmaniose visceral (calazar) entrou definitivamente como nosologia importante do Estado do Maranhão, Brasil, a partir de 1982. Desde então, vários autores têm trabalhado o tema do ponto de vista de relatos. No entanto, a parte de diagnóstico, tratamento e controle de cura percorreram caminhos difíceis e sempre preocupou os que estudam a doença que se instalou na Ilha de São Luís a partir da desestabilização dos ecótopos da Lutzomya longipalpis, o transmissor mais importante. Após 1993 a constatação de casos com má resposta ao antimoniato-n-metil glucamina (Glucantime®) veio se somar às outras preucupações. O estudo atual mostra como o Sistema Único de Saúde, através dos seus serviços, atua no controle da doença e conclui sobre a existência de refratariedade ao Glucantime® o que impõe maior vigilância no diagnóstico, tratamento e controle de cura dos pacientes.

Visceral leishmaniasis (kala-azar) was definitively an important disease of the state of Maranhão, Brasil since 1982. Since of then, many authors have been working with this topic in spite of reports. Nevertheless, the aspects of diagnosis, treatment an control of cure went through still hard worried the authors have been studying the disease, that came at São Luís Island since of the destabilization of the ecotopes of Lutzomya longipalpis, most important sandflies bites. After 1993 the constatation of cases with bad response to pentavalent antimonial (Glucantime) comes to add the other worries. This actual trial accost the disease and conclude about an existence of failures to Glucantime being important to have much vigilance in the diagnosis, treatment and control of cure of the patients.

[Visceral leishmaniasis (kala-azar) on Ilha de São Luís, Maranhão. Brazil: its evolution and outlook]. / Leishmaniosevisceral (calazar) na Ilha de São Luís, Maranhão, Brasil: evolução e perspectivas.

Visceral leishmaniasis (kala-azar) was definitively an important disease of the state of Maranhão, Brasil since 1982. Since of then, many authors have been working with this topic in spite of reports. Nevertheless, the aspects of diagnosis, treatment an control of cure went through still hard worried the authors have been studying the disease, that came at São Luís Island since of the destabilization of the ecotopes of Lutzomya longipalpis, most important sandflies bites. After 1993 the constatation of cases with bad response to pentavalent antimonial (Glucantime) comes to add the other worries. This actual trial accost the disease and conclude about an existence of failures to Glucantime being important to have much vigilance in the diagnosis, treatment and control of cure of the patients.

[The epidemiological determinant aspects in the maintenance of visceral leishmaniasis in the state of Maranhão, Brazil]. / Aspectos epidemiológicos determinantes na manutenção da leishmaniose visceral no Estado do Maranhão--Brasil.

The authors analysed the visceral leishmaniasis (VL) aspects in the state of Maranhão, Brazil, from 1982 to 1993. The disease happens to occur predominantly in São Luís Island (MA) and during the epidemic period, town of São Luís was pointed out as the main endemic area. The greatest frequency of cases occurred in 1993, despite the use of insecticide and dogs control. There was predominance of age between 0- to 4-year-old population with 58.04% of cases. Neither the human disease nor the rainfall index had significant seasonal variation. However they were correlated moderately, with high number of cases after the period of great precipitation of rain. After this study, the data obtained will allow a better control of the disease, despite some factors such as: the urbanization, localization and dynamic of transmission in endemic areas in the Maranhão state.

[Visceral leishmaniasis in the State of Maranhão, Brazil: evolution of an epidemic]. / Leishmaniose visceral no estado do Maranhão, Brasil: a evolução de uma epidemia.

The authors provide a brief report on the historical evolution of visceral leishmaniasis in the State of Maranhão, Brazil, evaluating possible factors for growth of the disease in the State and control measures by the Brazilian Ministry of Health to integrate health services into the maintenance of control programs.

Leishmaniose visceral e sindrome da imunodeficiencia adquirida (SIDA): relato de um caso / Visceral leishmaniais and acquired immunodeficiency syndrome (AIDS) : case report

Os autores descrevem um caso de associacao de leishmaniose visceral, SIDA e provavel tuberculose disseminada. Discutem a possibilidade de associacao desta protozoonose e infeccao pelo virus da Imunodeficiencia Adquirida (VIH) principalmente pelo aumento de prevalencia de infeccao pelo VIH em areas endemicas para o calazar. A presenca de imunodepressao pelo VIH possibilita manifestacoes de agentes oportunistas muitas vezes associados e relacionados com as endemias prevalentes nestas regioes de subdesenvolvimento.

[Visceral leishmaniasis and acquired immunodeficiency syndrome (AIDS). Report of a case]. / Leishmaniose visceral e síndrome da imunodeficiência adquirida (SIDA). Relato de um caso.

This is a case report that describe an association of AIDS, visceral leishmaniasis and probable disseminated tuberculosis. Due to the spread of AIDS in developing areas worldwide this association would be more frequently, seen on subjects from endemic areas where this protozoonosis is prevalent. More than one opportunistic infection related with the endemic diseases of the developing regions can be associated with those immunocompromised patients.