The importance of genus Candida in human samples

Microbiology is a rapidly changing field. As new researches and experiences broaden our knowledge, changes in the approach to diagnosis and therapy have become necessary and appropriate. Recommended dosage of drugs, method and duration of administration, as well as contraindications to use, evolve over time all drugs. Over the last 2 decades, Candida species have emerged as causes of substantial morbidity and mortality in hospitalized individuals. Isolation of Candida from blood or other sterile sites, excluding the urinary tract, defines invasive candidiasis. Candida species are currently the fourth most common cause of bloodstream infections (that is, candidemia) in U.S. hospitals and occur primarily in the intensive care unit (ICU), where candidemia is recognized in up to 1% of patients and where deep-seated Candida infections are recognized in an additional 1 to 2% of patients. Despite the introduction of newer anti-Candida agents, invasive candidiasis continues to have an attributable mortality rate of 40 to 49%; excess ICU and hospital stays of 12.7 days and 15.5 days, respectively, and increased care costs. Postmortem studies suggest that death rates related to invasive candidiasis might, in fact, be higher than those described because of undiagnosed and therefore untreated infection. The diagnosis of invasive candidiasis remains challenging for both clinicians and microbiologists. Reasons for missed diagnoses include nonspecific risk factors and clinical manifestations, low sensitivity of microbiological culture techniques, and unavailability of deep tissue cultures because of risks associated with the invasive procedures used to obtain them. Thus, a substantial proportion of invasive candidiasis in patients in the ICU is assumed to be undiagnosed and untreated. Yet even when invasive candidiasis is diagnosed, culture diagnosis delays treatment for 2 to 3 days, which contributes to mortality. Interventions that do not rely on a specific diagnosis and are implemented early in the course of Candida infection (that is, empirical therapy) or before Candida infection occurs (that is, prophylaxis) might improve patient survival and may be warranted. Selective and nonselective administration of anti-Candida prophylaxis is practiced in some ICUs. Several trials have tested this, but results were limited by low statistical power and choice of outcomes. Thus, the role of anti-Candida prophylaxis for patients in the ICU remains controversial. Initiating anti-Candida therapy for patients in the ICU who have suspected infection but have not responded to antibacterial therapy (empirical therapy) is practiced in some hospitals. This practice, however, remains a subject of considerable debate. These patients are perceived to be at higher risk from invasive candidiasis and therefore are likely to benefit from empirical therapy. Nonetheless, empirical anti-Candida therapies have not been evaluated in a randomized trial and would share shortcomings that are similar to those described for prophylactic strategies. Current treatment guidelines by the Infectious Diseases Society of America (IDSA) do not specify whether empirical anti-Candida therapy should be provided to immunocompetent patients. If such therapy is given, IDSA recommends that its use should be limited to patients with Candida colonization in multiple sites, patients with several other risk factors, and patients with no uncorrected causes of fever. Without data from clinical trials, determining an optimal anti-Candida strategy for patients in the ICU is challenging. Identifying such a strategy can help guide clinicians in choosing adequate therapy and may improve patient outcomes. In our study, we developed a decision analytic model to evaluate the cost-effectiveness of empirical anti-Candida therapy given to high-risk patients in the ICU, defined as those with altered temperature (fever or hypothermia) or unexplained hypotension despite 3 days of antibacterial therapy in the ICU

Bile Acid Synthesis: From Nature to the Chemical Modification and Synthesis and Their Applications as Drugs and Nutrients

Bile acids (BAs) are amphiphilic molecules with 24 carbon atoms and consist of a hydrophobic and a rigid steroid nucleus, to which are attached a hydrophilic hydroxyl group and a flexible acidic aliphatic side chain. The steroidal core of BAs constitutes a saturated cyclopentanoperhydrophenanthrene skeleton, consisting of three six-membered (A, B, and C) and one five-membered ring (D). Primary BAs are produced in the hepatocytes, while secondary BAs are formed by modifying the primary BAs in the intestinal lumen, i.e., by the reactions of 7α-dehydroxylation and deconjugation of cholic acid (CA) and chenodeoxycholic acid (CDCA). The most important secondary BAs are deoxycholic acid (DCA) and lithocholic acid (LCA). The BAs realize their effects through nuclear farnesoid X receptors (FXRs) and membrane TGR5 receptors. It has been found that BAs are also associated with other receptors such as the vitamin D receptor (VDR), from which the most significant ligand is calcitriol, as well as with pregnane X receptor (PXR) and potentially with the constitutive androstane receptor (CAR), whose ligands are numerous, structurally different xenobiotics that show greater affinity to BAs. The BAs as therapeutic agents (drugs) have the potential to produce beneficial effects in cases of sexually transmitted diseases, primary biliary cirrhosis (PBC), primary sclerosing cholangitis, gallstones, digestive tract diseases, cystic fibrosis, and cancer. Ursodeoxycholic acid (UDCA) was the only drug approved by the US Food and Drug Administration (FDA) for the treatment of PBC. In this paper, the different pathways of bile acid biosynthesis are explained as well as chemical modifications and the synthesis of different keto derivatives of BAs. Also, the effects of BAs on digestion of nutrients, their role as drugs, and, in particular, the emphasis on the hypoglycemic properties of 7α, 12α-dihydroxy−12–keto−5β-cholanic acid in the treatment of diabetes mellitus are examined in detail

Deoxycholic Acid as a Modifier of the Permeation of Gliclazide through the Blood Brain Barrier of a Rat

Major problem for diabetic patients represents damage of blood vessels and the oxidative stress of the brain cells due to increased concentration of free radicals and poor nutrition of brain cells. Gliclazide has antioxidative properties and poor blood brain barrier (BBB) penetration. Bile acids are known for their hypoglycemic effect and as promoters of drug penetration across biological membranes. Accordingly, the aim of this study is to investigate whether the bile acid (deoxycholic acid) can change the permeation of gliclazide, through the blood brain barrier of a rat model type-1 diabetes. Twenty-four male Wistar rats were randomly allocated to four groups, of which, two were given alloxan intraperitoneally (100 mg/kg) to induce diabetes. One diabetic group and one healthy group were given a bolus gliclazide intra-arterially (20 mg/kg), while the other two groups apart from gliclazide got deoxycholic acid (4 mg/kg) subcutaneously. Blood samples were collected 30, 60, 150, and 240 seconds after dose, brain tissues were immediately excised and blood glucose and gliclazide concentrations were measured. Penetration of gliclazide in groups without deoxycholic acid pretreatment was increased in diabetic animals compared to healthy animals. Also in both, the healthy and diabetic animals, deoxycholic acid increased the permeation of gliclazide through that in BBB

The Habsburg Imperial Army during the First half of the Thirty Years' War: Someaspects of Organization and Tactics

В статье рассматривается тактика имперской армии в первой половине Тридцатилетней войны, в тот момент, когда терции смогли одержать важную победу над протестантскими армиями в битве при Белой Горе. В работе показаны особенности построений имперских войск, их применение и взаимодействие на поле боя. В исследовании рассматривается влияние тактических решений на ход войны, а также роль Габсбургов в формировании и применении военных инноваций того времени, которые содействовали успеху армий императора и его союзников. Важными источниками при написании статьи стали испанские и немецкие военные трактаты, а также письма и воспоминания, в которых описываются либо ход сражения, либо особенности армий и их построений. Автор приходит к выводу, что тактика имперской армии в значительной степени способствовала победам терций над протестантскими формированиями в период с 1618 по 1632 гг., что открывает новые перспективы для исследования военной организации и тактики данного периода.The article examines the imperial army tactics in the first half of the Thirty Years’ War when seemingly outdated bulky formations called “thirds” were able to win a number of important victories over Protestant armies, most significant of which was the Battle of White Mountain. The paper shows the peculiarities of imperial formations, their use and interaction on the battlefield. The study examines the impact of tactical decisions on the course of the war, as well as the role of the Habsburgs in shaping and applying the military innovations of the time that contributed to the success of the armies of the emperor and his allies. Spanish and German military treatises, such as J. Wall-hause’s Kriegskunst zu Fuß and B. Barosso’s Teorica, practica, y exemplos, as well as letters and memoirs that describe either the course of the battle or the peculiarities of the armies and their formations, were important sources for the article. The author concludes that the tactics of the imperial army contributed significantly to the victories of the tercias over Protestant formations between 1618 and 1632, which opens up new perspectives for the study of the military organisation and tactics of this period

Probucol Release from Novel Multicompartmental Microcapsules for the Oral Targeted Delivery in Type 2 Diabetes

In previous studies, we developed and characterised multicompartmental microcapsules as a platform for the targeted oral delivery of lipophilic drugs in type 2 diabetes (T2D). We also designed a new microencapsulated formulation of probucol-sodium alginate (PB-SA), with good structural properties and excipient compatibility. The aim of this study was to examine the stability and pH-dependent targeted release of the microcapsules at various pH values and different temperatures. Microencapsulation was carried out using a Büchi-based microencapsulating system developed in our laboratory. Using SA polymer, two formulations were prepared: empty SA microcapsules (SA, control) and loaded SA microcapsules (PB-SA, test), at a constant ratio (1:30), respectively. Microcapsules were examined for drug content, zeta potential, size, morphology and swelling characteristics and PB release characteristics at pH 1.5, 3, 6 and 7.8. The production yield and microencapsulation efficiency were also determined. PB-SA microcapsules had 2.6 ± 0.25% PB content, and zeta potential of −66 ± 1.6%, suggesting good stability. They showed spherical and uniform morphology and significantly higher swelling at pH 7.8 at both 25 and 37°C (p < 0.05). The microcapsules showed multiphasic release properties at pH 7.8. The production yield and microencapsulation efficiency were high (85 ± 5 and 92 ± 2%, respectively). The PB-SA microcapsules exhibited distal gastrointestinal tract targeted delivery with a multiphasic release pattern and with good stability and uniformity. However, the release of PB from the microcapsules was not controlled, suggesting uneven distribution of the drug within the microcapsules

Microencapsulation as a novel delivery method for the potential antidiabetic drug, Probucol

Introduction: In previous studies, we successfully designed complex multicompartmental microcapsules as a platform for the oral targeted delivery of lipophilic drugs in type 2 diabetes (T2D). Probucol (PB) is an antihyperlipidemic and antioxidant drug with the potential to show benefits in T2D. We aimed to create a novel microencapsulated formulation of PB and to examine the shape, size, and chemical, thermal, and rheological properties of these microcapsules in vitro. Method: Microencapsulation was carried out using the Büchi-based microencapsulating system developed in our laboratory. Using the polymer, sodium alginate (SA), empty (control, SA) and loaded (test, PB-SA) microcapsules were prepared at a constant ratio (1:30). Complete characterizations of microcapsules, in terms of morphology, thermal profiles, dispersity, and spectral studies, were carried out in triplicate. Results: PB-SA microcapsules displayed uniform and homogeneous characteristics with an average diameter of 1 mm. The microcapsules exhibited pseudoplastic-thixotropic characteristics and showed no chemical interactions between the ingredients. These data were further supported by differential scanning calorimetric analysis and Fourier transform infrared spectral studies, suggesting microcapsule stability. Conclusion: The new PB-SA microcapsules have good structural properties and may be suitable for the oral delivery of PB in T2D. Further studies are required to examine the clinical efficacy and safety of PB in T2D

Novel artificial cell microencapsulation of a complex gliclazide-deoxycholic bile acid formulation: A Characterization Study

Gliclazide (G) is an antidiabetic drug commonly used in type 2 diabetes. It has extrapancreatic hypoglycemic effects, which makes it a good candidate in type 1 diabetes (T1D). In previous studies, we have shown that a gliclazide-bile acid mixture exerted a hypoglycemic effect in a rat model of T1D. We have also shown that a gliclazide-deoxycholic acid (G-DCA) mixture resulted in better G permeation in vivo, but did not produce a hypoglycemic effect. In this study, we aimed to develop a novel microencapsulated formulation of G-DCA with uniform structure, which has the potential to enhance G pharmacokinetic and pharmacodynamic effects in our rat model of T1D. We also aimed to examine the effect that DCA will have when formulated with our new G microcapsules, in terms of morphology, structure, and excipients’ compatibility. Microencapsulation was carried out using the Büchi-based microencapsulating system developed in our laboratory. Using sodium alginate (SA) polymer, both formulations were prepared: G-SA (control) at a ratio of 1:30, and G-DCA-SA (test) at a ratio of 1:3:30. Complete characterization of microcapsules was carried out. The new G-DCA-SA formulation was further optimized by the addition of DCA, exhibiting pseudoplastic-thixotropic rheological characteristics. The size of microcapsules remained similar after DCA addition, and these microcapsules showed no chemical interactions between the excipients. This was supported further by the spectral and microscopy studies, suggesting microcapsule stability. The new microencapsulated formulation has good structural properties and may be useful for the oral delivery of G in T1D