Disseminated cryptococcosis in a patient with nephrotic syndrome

Disseminated cryptococcosis mainly occurs in patients with impaired cell mediated immunity. We present a case of disseminated cryptococcosis in a non-HIV patient with nephrotic syndrome who never received immunosuppression. Cultures of bone marrow aspirate, cerebrospinal fluid analysis and histology of skin lesions were all consistent with Cryptococcus neoformans infection. Treatment with amphotericin B followed by fluconazole was successful and in the course of two months when, the skin nodules disappeared.     

Simultaneous inhibition of aberrant cancer kinome using rationally designed polymer-protein core-shell nanomedicine

Simultaneous inhibition of deregulated cancer kinome using rationally designed nanomedicine is an advanced therapeutic approach. Herein, we have developed a polymer-protein core-shell nanomedicine to inhibit critically aberrant pro-survival kinases (mTOR, MAPK and STAT5) in primitive (CD34⁺/CD38^?) Acute Myeloid Leukemia (AML) cells. The nanomedicine consists of poly-lactide-co-glycolide core (~ 250 nm) loaded with mTOR inhibitor, everolimus, and albumin shell (~ 25 nm thick) loaded with MAPK/STAT5 inhibitor, sorafenib and the whole construct was surface conjugated with monoclonal antibody against CD33 receptor overexpressed in AML. Electron microscopy confirmed formation of core-shell nanostructure (~ 290 nm) and flow cytometry and confocal studies showed enhanced cellular uptake of targeted nanomedicine. Simultaneous inhibition of critical kinases causing synergistic lethality against leukemic cells, without affecting healthy blood cells, was demonstrated using immunoblotting, cytotoxicity and apoptosis assays. This cell receptor plus multi-kinase targeted core-shell nanomedicine was found better specific and tolerable compared to current clinical regime of cytarabine and daunorubicin.From the Clinical EditorThese authors demonstrate simultaneous inhibition of critical kinases causing synergistic lethality against leukemic cells, without affecting healthy blood cells by using rationally designed polymer-protein core-shell nanomedicine, provoding an advanced method to eliminate cancer cells, with the hope of future therapeutic use.     

Phylogenic analysis of the M genes of influenza viruses isolated from free-flying water birds from their Northern Territory to Hokkaido, Japan

During 2000-2007, 218 influenza viruses of 28 different combinations of HA (H1-H13) and NA (N1-N9) subtypes were isolated from fecal samples of free-flying water birds at two distant lakes in Hokkaido, Japan. Phylogenic analysis of the matrix (M) genes of 67 strains, selected on the basis of their subtype combinations, revealed that A/duck/Hokkaido/W95/2006 (H10N8) was a reassortant whose M gene belonged to North American non-gull-avian and the other seven genes to Eurasian non-gull-avian lineages. The M genes of other 65 strains belonged to Eurasian non-gull-avian and the one to Eurasian-gull lineages. The M genes of 65 strains were grouped into three different sublineages, indicating that influenza viruses circulating in different populations of free-flying water birds have evolved independently in nature.     

Cinnamic aldehydes affect hydrolytic enzyme secretion and morphogenesis in oral Candida isolates

Effect of cinnamaldehyde (CD), 4-hydroxy-3-methoxy cinnamaldehyde (HMCD) and 3,5-dimethoxy-4-hydroxy cinnamaldehyde (HDMCD) on growth and virulence factors of standard (Candida albicans 90028) and 26 oral isolates of C. albicans has been investigated. Growth was significantly inhibited by all three compounds in both solid and liquid medium, no systematic difference was observed between various isolates. MIC₉₀ ranged from 125 to 450 μg/ml for CD, 100–250 μg/ml for HMCD and 62.5–125 μg/ml for HDMCD. All oral isolates were found to be proteinase and phospholipase secretors, both proteinase and phospholipase secretion was significantly inhibited by all the three tested molecules. No systematic difference in secretion or its inhibition was observed between standard and oral isolates as also between various isolates. Average drop in proteinase and phospholipase secretion caused by ½ MIC of CD was 33% and 28%, HMCD; 46% and 44%, HDMCD; 59% and 54%. The standard strain and all the 26 oral isolates displayed morphogenesis under triggering experimental conditions; no difference was seen between standard and various isolates. In the absence of test compounds hyphae development at 300 min was 83% for standard strain whereas average hyphae development for oral isolates was 85%. Average hyphal transition was suppressed by all tested compounds. At ½ MIC concentration at 300 min average hyphal transition of standard and oral isolates was CD; 49% and 57%, HMCD; 45% and 38%, HDMCD; 5% and 5%. Average haemolytic activity of the three tested compounds varied from 10 to 15% at their highest MIC compared to 20% shown by fluconazole at typical MIC of 30 μg/ml.     

Nature of transposon-mediated high-level gentamicin resistance in Enterococcus faecalis isolated in the United Kingdom

Forty-two high-level gentamicin-resistant (MIC > 1000 mg/L) strains of Enterococcus faecalis, isolated from diverse geographical locations throughout the UK between 1993 and 1995, were studied to identify the nature of the high-level gentamicin-resistant determinants and the possibility of these determinants being associated with a transposon. High-level gentamicin resistance was attributed to the synthesis of the bifunctional (AAC6'-APH2") aminoglycoside-modifying enzyme. The aac6'-aph2" gene, which was present on a 70 kb plasmid in all 42 isolates, could be transferred by conjugation in association with the 70 kb plasmid in 39 of the isolates studied. In three E. faecalis isolates, however, the high-level gentamicin resistance was transferable independent of the 70 kb plasmid, suggesting the presence of a conjugative transposon. Long-PCR studies showed that all 42 clinical isolates harboured a transposon similar to Tn5281, originally identified in E. faecalis strain HH22 isolated in the USA. Restriction endonuclease and Southern hybridization analysis of the UK transposon showed that it is closely related to the high-level gentamicin resistance-conferring transposon Tn5281. However, the UK transposon lacks the HaeIII site identified in Tn5281. Pulsed-field gel electrophoresis analysis identified seven different patterns. Further studies with nine restriction endonucleases showed that the aac6'-aph2" gene was associated with nine different plasmid types in E. faecalis.     

Metabolic clustering of risk factors: evaluation of Triglyceride-glucose index (TyG index) for evaluation of insulin resistance

Background

Metabolic syndrome over the years have structured definitions to classify an individual with the disease. Literature review suggests insulin résistance is hallmark of these metabolic clustering. While measuring insulin resistance directly or indirectly remains technically difficult in general practice, along with multiple stability issues for insulin, various indirect measures have been suggested by authorities. Fasting triglycerides-glucose (TyG) index is one such marker, which is recently been suggested as a useful diagnostic marker to predict metabolic syndrome. However, limited data is available on the subject with almost no literature from our region on the subject.

Objective

1. To correlate TyG index with insulin resistance, anthropometric indices, small dense LDLc, HbA1c and nephropathy. 2. To evaluate TyG index as a marker to diagnose metabolic syndrome in comparison to other available markers.

Design-cross-sectional analysis

Place and duration of study-From Jun-2016 to July-2017 at PSS HAFEEZ hospital Islamabad.

Subjects and methods

From a finally selected sample size of 227 male and female subjects we evaluated their anthropometric data, HbA1c, lipid profile including calculated sdLDLc, urine albumin creatinine raito(UACR) and insulin resistance (HOMAIR). TyG index was calculated using formula of Simental-Mendía LE et al. Aforementioned parameters were correlated with TyG index, differences between subjects with and without metabolic syndrome were calculated using Independent sample t-test. Finally ROC curve analysis was carried out to measure AUC for candidate parameters including TyG Index for comparison.

Results

TyG index in comparison to other markers like fasting triglycerides, HOMAIR, HDLc and non-HDLc demonstrated higher positive linear correlation with BMI, atherogenic dyslipidemia (sdLDLc), nephropathy (UACR), HbA1c and insulin resistance. TyG index showed significant differences between various markers among subjects with and without metabolic syndrome as per IDF criteria. AUC (Area Under Curve) demonstrated highest AUC for TyG as [(0.764, 95% CI 0.700–0.828, p-value?≤?0.001)] followed by fasting triglycerides [(0.724, 95% CI 0.656–0.791, p-value?≤?0.001)], sdLDLc [(0.695, 95% CI 0.626–0.763, p-value?≤?0.001)], fasting plasma glucose [(0.686, 95% CI 0.616–0.756, p-value?≤?0.001)], Non-HDLc [(0.640, 95% CI 0.626–0.763, p-value?≤?0.001)] and HOMAIR [(0.619, 95% CI 0.545–0.694, p-value?≤?0.001)].

Conclusion

TyG index, having the highest AUC in comparison to fasting glucose, triglycerides, sdLDLc, non-HDLc and HOMAIR can act as better marker for diagnosing metabolic syndrome.

     

Influence of single‐nucleotide polymorphisms in the IFNG towards susceptibility to tuberculosis in a Pakistani population

Tuberculosis (TB) is a global issue as one‐third of the population worldwide is considered to be infected. TB has become a critical public health problem as a result of increasing drug resistance, which poses a challenge to current control strategies. Similar to environmental factors, genetic makeup of the host equally contributes to disease onset. We performed genotypic analysis to examine the relationship between IFNG and TB onset and drug resistance in a Pakistani population comprising 689 subjects. Notable differences were observed in the IFNG polymorphism (+874T/A) between the case and control groups. The frequency of the wild‐type genotype (TT) in the controls (43.2%) was significantly higher than in the cases (25.3%) (odds ratio [OR] = 0.77, p < 0.0001), while the mutant genotype frequency (AA) (38.57%) in the cases was significantly higher than in the controls (22.6%) (OR = 1.46, p < 0.0001). The heterozygous genotype frequency (TA) did not significantly differ between the control and case groups. Compared with the controls, the variant allele (A) was approximately twice as frequent in the cases. Females and older people have a higher chance of disease development. Finally, the IFNG (+874T/A) polymorphism was not associated with drug sensitivity or resistance. However, a genotypic polymorphism of IFNG (+874T/A) was significantly associated with susceptibility to TB, and the T allele conferred protection against TB. Additional studies involving larger cohorts are needed to further explore this relationship between genetics and disease vulnerability.