Isothermal Microcalorimetry as a Quality by Design Tool to Determine Optimal Blending Sequences

This study was designed to assess the value of isothermal microcalorimetry (ITMC) as a quality by design (QbD) tool to optimize blending conditions during tablet preparation. Powder mixtures that contain microcrystalline cellulose (MCC), dibasic calcium phosphate dihydrate (DCPD), and prednisone were prepared as 1:1:1 ratios using different blending sequences. ITMC was used to monitor the thermal activity of the powder mixtures before and after each blending process. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) were performed on all final powder mixtures. Final powder mixtures were used to prepare tablets with 10 mg prednisone content, and dissolution tests were performed on all tablet formulations. Using ITMC, it was observed that the powder mixtures had different thermal activity depending on the blending sequences of the ingredients. All mixtures prepared by mixing prednisone with DCPD in the first stage were associated with relatively fast and significant heat exchange. In contrast, mixing prednisone with MCC in the first step resulted in slower heat exchange. Powder mixture with high thermal activity showed extra DSC peaks, and their dissolution was generally slower compared to the other tablets. Blending is considered as a critical parameter in tablet preparation. This study showed that ITMC is a simple and efficient tool to monitor solid-state reactions between excipients and prednisone depending on blending sequences. ITMC has the potential to be used in QbD approaches to optimize blending parameters for prednisone tablets.     

Fine-needle aspiration cytology and flow cytometric immunophenotyping in diagnosis and classification of non-Hodgkin lymphoma in comparison to histopathology

This prospective study aimed to compare the value of fine needle aspiration (FNA) cytology (FNAC) and flow cytometric immunophenotyping (FCI) with histopatopathology (HP) in the diagnosis and classification of non-Hodgkin lymphoma (NHL). Twenty-nine excised lymph nodes suspected of NHL were evaluated using FNAC, FCI, and HP. Specimens were divided into two equal parts; one for HP and the other for FNAC and FCI. Results were compared in terms of diagnosis (malignant, benign or reactive, and metastatic) and NHL class. With combined FNAC/FCI, 11 (37.9%) cases were diagnosed as NHL, 11 cases (37.9%) as reactive lymph node, six cases (20.6%) as Hodgkin's lymphoma, and one case (3.4%) as metastasis. HP revealed nine cases (31%) of NHL, five cases (17.2%) of reactive lymph nodes and all the diagnosed metastatic and Hodgkin's lymphoma. Considering histology as a gold standard method in diagnosis, the sensitivity, specificity, PPV and NPV of FNAC/FCI in differentiate malignant and benign lesion were 73.9%, 83.3%, 94.4%, and 45.5%, respectively and in differentiate NHL from others were 75%, 93.8%, 90%, and 83.3%, respectively. Cytology and HP in addition to FCI and HP are significantly different from determination of NHL lesions point of view (P = 0.001 and P < 0.0001, respectively). However, FCI can be considered as an adjunctive method for Cytology especially because Cytology is not competent enough to differentiate between benign lesions and Lymphoma. Additionally, FCI is shown to be an accurate method in classifying NHL.     

Pulmonary delivery of inhalable nanoparticles: dry powder inhalers

Pulmonary administration of inhalable nanoparticles (NPs) is an emerging area of interest. Dry powder inhalers may offer particular advantages for pulmonary administration of NPs. This article reviews research performed on the formulation of inhalable NPs as dry powder to achieve deep-lung deposition and enhance NP redispersibility. Moreover, the article summarizes up-to-date in vivo applications of inhalable NPs as dry powder inhalers.     

Estimation of diagnosis and prognosis in ET by assessment of CALR and JAK2<Superscript>V617F</Superscript> mutations and laboratory findings: a meta-analysis

Background

Essential thrombocythemia (ET) is a benign disease with slow progress in which thrombosis is a cause of mortality. JAK2^V617F and calreticulin (CALR) are the most frequent mutations in this disease. In this systematic review and meta-analysis, we compared the prevalence of JAK2^V617F and CALR mutations in ET and examined the incidence of thrombosis and other hematologic indices.

Methods

After choosing MeSH keywords, including essential thrombocythemia, JAK2^V617F, calreticulin, prognosis, and diagnosis, as well as searching Medline/PubMed and Scopus, 12 papers were selected. Data were pooled, and summary prevalence and OR were estimated using either a random-effects model or a fixed-effects model.

Results

The frequency of JAK2^V617F and CALR shows heterogeneity in Caucasian population [JAK2^V617 I ²% = 84.3, P < 0.001, 95% CI 0.56 (0.51–0.61)], [CALR I ²% = 96.1, P < 0.001, 95% CI 0.23 (0.15–0.31)]. The prevalence of JAK2^V617F and CALR was 0.57 (95% CI 0.53–0.61), I ²% = 79.3 and 0.22 (95% CI 0.16–0.27), I ²% = 94, respectively. JAK2^V617F positive ET was associated with increasing odds of thrombosis [OR 2.35 (95% CI 1.83–3.02), P < 0.001]. The incidence of splenomegaly was not statistically different between these two mutations. Hemoglobin, platelet, and WBC count did not affect the risk of thrombosis.

Conclusions

Detection of CALR mutation is helpful for molecular diagnosis of ET patients as well as JAK2^V617F. Due to reduction of thrombosis in CALR-positive patients, it can be stated that such patients have less thrombotic disorders and better prognosis relative to patients bearing JAK2^V617F mutation. Therefore, detection of mutation in CALR and JAK2^V617F may contribute to diagnosis and prognosis of ET patients.

     

Progesterone receptors activation after acute cocaine administration

Cocaine modulates serum levels of progesterone in intact female and male rats, as well as in pregnant dams, and progesterone decreases or attenuates cocaine-induced behavioral and reward responses. It has been postulated that cocaine's modulation of serum progesterone levels may in turn alter progesterone receptor activity, thereby contributing to cocaine-induced alterations of neuronal functions and genomic regulations. To test this hypothesis, intact male rats received acute injections of saline or cocaine (15 or 30 mg/kg, dissolved in 0.9% saline, intraperitoneal). Progesterone serum levels, progesterone receptor (PR) protein levels, and PR-DNA binding complexes were measured in the striatum by radioimmunoassay, Western blot, and gel shift analyses, respectively. After injection of 15 mg/kg of cocaine, induction of progesterone serum levels was closely followed by an increase in receptor protein levels and DNA binding complexes. After injection of 30 mg/kg of cocaine, similar effects were observed along with an attenuation of receptor protein levels and DNA binding complexes at 60 min. Our results suggest that activation of progesterone receptors may be a mechanism by which cocaine mediates behavior through molecular alterations in the central nervous system.     

Cardiac Malformations in Fetuses of Gestational and Pre Gestational Diabetic Mothers

Objective

In this study we aimed to determine the prevalence of cardiac malformations in fetuses of Iranian diabetic mothers with pre-gestational and gestational diabetes mellitus (GDM) and to find the patterns of different cardiac malformations.

Methods

One-hundred and seventy diabetic pregnant women (68 preGDM and 102 GDM) (mean age: 32.17±4.8 years) and 85 healthy controls (mean age: 31.35±4.55 years) were recruited from September 2008 to July 2012. Fetal echocardiography was performed to assess cardiac malformation. In order to study major factors that may affect the results, a complete history was obtained.

Findings

Fetal echocardiography was performed at mean gestational age of 24.7±5.4 and 20.27±3.9 weeks in diabetic patients and control group, respectively. Fifteen (8.8%) fetuses of diabetic mothers were detected to have cardiac malformations compared with 1 (1.17%) fetus in control group (OR: 8.13, 95%CI: 1.1-62.61, P-value=0.02). Hypertrophic cardiomyopathy noted as the most common cardiac malformation occurred in 6 out of 15 (40%) fetuses, and was found significantly more common in pre-GDM compared to GDM group (7.4% vs 1%, P-value =0.04). Despite the higher incidence of cardiac malformation in pre-GDM compared to GDM group, the difference was not significant. Further, no significant association was observed between the variables including; parity, diabetic regimen, parents’ consanguinity, maternal history of hypertension or hypothyroidism and occurring cardiac malformations (P-value>0.05).

Conclusion

In this study we detected cardiac malformations in 8.8% of our diabetic referrals. The result of the present study shows that screening diabetic mothers for fetal cardiac malformations could be beneficial.     

Advances in serological,imaging techniques and molecular diagnosis of <Emphasis Type="Italic">Toxoplasma gondii</Emphasis> infection

Background

Toxoplasmosis is worldwide distributed zoonotic infection disease with medical importance in immunocompromised patients, pregnant women and congenitally infected newborns. Having basic information on the traditional and new developed methods is essential for general physicians and infectious disease specialists for choosing a suitable diagnostic approach for rapid and accurate diagnosis of the disease and, consequently, timely and effective treatment.

Methods

We conducted English literature searches in PubMed from 1989 to 2016 using relevant keywords and summarized the recent advances in diagnosis of toxoplasmosis.

Results

Enzyme-linked immunosorbent assay (ELISA) was most used method in past century. Recently advanced ELISA-based methods including chemiluminescence assays (CLIA), enzyme-linked fluorescence assay (ELFA), immunochromatographic test (ICT), serum IgG avidity test and immunosorbent agglutination assays (ISAGA) have shown high sensitivity and specificity. Recent studies using recombinant or chimeric antigens and multiepitope peptides method demonstrated very promising results to development of new strategies capable of discriminating recently acquired infections from chronic infection. Real-time PCR and loop-mediated isothermal amplification (LAMP) are two recently developed PCR-based methods with high sensitivity and specificity and could be useful to early diagnosis of infection. Computed tomography, magnetic resonance imaging, nuclear imaging and ultrasonography could be useful, although their results might be not specific alone.

Conclusion

This review provides a summary of recent developed methods and also attempts to improve their sensitivity for diagnosis of toxoplasmosis. Serology, molecular and imaging technologies each has their own advantages and limitations which can certainly achieve definitive diagnosis of toxoplasmosis by combining these diagnostic techniques.