A Thyrotoxicosis Surprise: Jod-Basedow Phenomenon Following IV Contrast Administration.

Jod-Basedow phenomenon (JBP) is a rare thyrotoxic condition due to increased exogenous iodine exposure, also known as iodine-induced hyperthyroidism (IIH). Historically JBP was typically seen in iodine-deficient patients when exposed to increased amounts of iodine. However, in today's era, the most common cause of JBP is exposure to iodinated contrast media commonly used in various radiological examinations and interventional procedures, resulting in massive iodine exposure. Patients with normal thyroid function usually experience no ill effects. There has been increasing use of iodinated contrast in imaging and procedures over recent decades. Deposition of iodine in the thyroid in a person with normal functioning thyroid glands would usually be autoregulated and inhibited by the Wolff Chaikoff effect. However, a small albeit a significant portion of patients, particularly those with pre-existing thyroid conditions, can escape this auto-regulatory effect and be subject to life-threatening conditions, such as arrhythmias, heart failure, pulmonary arterial hypertension, cerebrovascular and pulmonary embolism, and cardiomyopathy. We present a case of a 59-year-old female with pre-existing goiter who presented with altered mentation and seizures, requiring endotracheal intubation for airway protection. She underwent a CT angiogram of the head and neck for a suspected stroke, receiving iodinated IV contrast in the process. Thyroid function tests on admission showed a thyroid-stimulating hormone (TSH) of 0.974 mIU/L (reference range 0.465-4.650 mIU/L) and free T4 of 0.46 ng/dL (reference range 0.75-2.19 ng/dL). The ensuing ICU course was complicated by thyrotoxicosis eight days after contrast administration with a surge of free T4 from 0.46 ng/dL on admission to 4.07 ng/dL and a TSH suppression to <0.015 mIU/L. She subsequently required three sessions of emergent plasmapheresis to remove excess free T4 before undergoing partial thyroidectomy and cardiac catheterization. Iodine-induced hyperthyroidism solidifies the need for awareness of a potential JBP following contrast administration, especially in an aging population and undiagnosed thyroid conditions, and timely diagnosis and intervention can greatly influence outcomes.

Biomarkers and novel therapeutic approaches for diffuse large B-cell lymphoma in the era of precision medicine.

Despite the great efforts for better treatment options for diffuse large B-cell lymphoma (DLBCL) (most common form of non-Hodgkin lymphoma, NHL) to treat and prevent relapse, it continues to be a challenge. Here, we present an overview of DLBCL and address the diagnostic assays and molecular techniques used in its diagnosis, role of biomarkers in detection, treatment of early and advanced stage DLBCL, and novel drug regimens. We discuss the significant biomarkers that have emerged as essential tools for stratifying patients according to risk factors and for providing insights into the use of more targeted and individualized therapeutics. We discuss techniques such as gene expression studies, including next-generation sequencing, which have enabled a more understanding of the complex pathogenesis of DLBCL and have helped determine molecular targets for novel therapeutic agents. We examine current treatment approaches, outline the findings of completed clinical trials, and provide updates for ongoing clinical trials. We highlight clinical trials relevant to the significant fraction of DLBCL patients who present with complex cases marked by high relapse rates. Supported by an increased understanding of targetable pathways in DLBCL, clinical trials involving specialized combination therapies are bringing us within reach the promise of an effective cure to DLBCL using precision medicine. Optimization of therapy remains a crucial objective, with the end goal being a balance between high survival rates through targeted and personalized treatment while reducing adverse effects in DLBCL patients of all subsets.

Outcomes of Community-Based Systematic Screening of Household Contacts of Patients with Multidrug-Resistant Tuberculosis in Myanmar.

Screening of household contacts of patients with multidrug-resistant tuberculosis (MDR-TB) is a crucial active TB case-finding intervention. Before 2016, this intervention had not been implemented in Myanmar, a country with a high MDR-TB burden. In 2016, a community-based screening of household contacts of MDR-TB patients using a systematic TB-screening algorithm (symptom screening and chest radiography followed by sputum smear microscopy and Xpert-MTB/RIF assays) was implemented in 33 townships in Myanmar. We assessed the implementation of this intervention, how well the screening algorithm was followed, and the yield of active TB. Data collected between April 2016 and March 2017 were analyzed using logistic and log-binomial regression. Of 620 household contacts of 210 MDR-TB patients enrolled for screening, 620 (100%) underwent TB symptom screening and 505 (81%) underwent chest radiography. Of 240 (39%) symptomatic household contacts, 71 (30%) were not further screened according to the algorithm. Children aged <15 years were less likely to follow the algorithm. Twenty-four contacts were diagnosed with active TB, including two rifampicin- resistant cases (yield of active TB = 3.9%, 95% CI: 2.3%-6.5%). The highest yield was found among children aged <5 years (10.0%, 95% CI: 3.6%-24.7%). Household contact screening should be strengthened, continued, and scaled up for all MDR-TB patients in Myanmar.

Patients with MDR-TB on domiciliary care in programmatic settings in Myanmar: Effect of a support package on preventing early deaths.

BACKGROUND: The community-based MDR-TB care (CBMDR-TBC) project was implemented in 2015 by The Union in collaboration with national TB programme (NTP) in 33 townships of upper Myanmar to improve treatment outcomes among patients with MDR-TB registered under NTP. They received community-based support through the project staff, in addition to the routine domiciliary care provided by NTP staff. Each project township had a project nurse exclusively for MDR-TB and a community volunteer who provided evening directly observed therapy (in addition to morning directly observed therapy by NTP). OBJECTIVES: To determine the effect of CBMDR-TBC project on death and unfavourable outcomes during the intensive phase of MDR-TB treatment. METHODS: In this cohort study involving record review, all patients diagnosed with MDR-TB between January 2015 and June 2016 in project townships and initiated on treatment till 31 Dec 2016 were included. CBMDR-TBC status was categorized as "receiving support" if project initiation in patient's township was before treatment initiation, "receiving partial support" if project initiation was after treatment initiation, and "not receiving support" if project initiation was after intensive phase treatment outcome declaration. Time to event analysis (censored on 10 April 2017) and cox regression was done. RESULTS: Of 261 patients initiated on treatment, death and unfavourable outcomes were accounted for 13% and 21% among "receiving support (n = 163)", 3% and 24% among "receiving partial support (n = 75)" and 13% and 26% among "not receiving support (n = 23)" respectively. After adjusting for other potential confounders, the association between CBMDR-TBC and unfavourable outcomes was not statistically significant. However, when compared to "not receiving support", those "receiving support" and "receiving partial support" had 20% [aHR (0.95 CI: 0.8 (0.2-3.1)] and 90% lower hazard [aHR (0.95 CI: 0.1 (0.02-0.9)] of death, respectively. This was intriguing. Implementation of CBMDR-TBC coincided with implementation of decentralized MDR-TB centers at district level. Hence, patients that would have generally not accessed MDR-TB treatment before decentralization also started receiving treatment and were also included under CBMDR-TBC "received support" group. These patients could possibly be expected to sicker at treatment initiation than patients in other CBMDR-TBC groups. This could be the possible reason for nullifying the effect of CBMDR-TBC in "receiving support" group and therefore similar survival was found when compared to "not receiving support". CONCLUSION: CBMDR-TBC may prevent early deaths and has a scope for expansion to other townships of Myanmar and implications for NTPs globally. However, future studies should consider including data on extent of sickness at treatment initiation and patient level support received under CBMDR-TBC.

Cholesterol modulates cell signaling and protein networking by specifically interacting with PDZ domain-containing scaffold proteins.

Cholesterol is known to modulate the physical properties of cell membranes, but its direct involvement in cellular signaling has not been thoroughly investigated. Here we show that cholesterol specifically binds many PDZ domains found in scaffold proteins, including the N-terminal PDZ domain of NHERF1/EBP50. This modular domain has a cholesterol-binding site topologically distinct from its canonical protein-binding site and serves as a dual-specificity domain that bridges the membrane and juxta-membrane signaling complexes. Disruption of the cholesterol-binding activity of NHERF1 largely abrogates its dynamic co-localization with and activation of cystic fibrosis transmembrane conductance regulator, one of its binding partners in the plasma membrane of mammalian cells. At least seven more PDZ domains from other scaffold proteins also bind cholesterol and have cholesterol-binding sites, suggesting that cholesterol modulates cell signaling through direct interactions with these scaffold proteins. This mechanism may provide an alternative explanation for the formation of signaling platforms in cholesterol-rich membrane domains.

Genome-wide functional annotation of dual-specificity protein- and lipid-binding modules that regulate protein interactions.

Emerging evidence indicates that membrane lipids regulate protein networking by directly interacting with protein-interaction domains (PIDs). As a pilot study to identify and functionally annodate lipid-binding PIDs on a genomic scale, we performed experimental and computational studies of PDZ domains. Characterization of 70 PDZ domains showed that ~40% had submicromolar membrane affinity. Using a computational model built from these data, we predicted the membrane-binding properties of 2,000 PDZ domains from 20 species. The accuracy of the prediction was experimentally validated for 26 PDZ domains. We also subdivided lipid-binding PDZ domains into three classes based on the interplay between membrane- and protein-binding sites. For different classes of PDZ domains, lipid binding regulates their protein interactions by different mechanisms. Functional studies of a PDZ domain protein, rhophilin 2, suggest that all classes of lipid-binding PDZ domains serve as genuine dual-specificity modules regulating protein interactions at the membrane under physiological conditions.

The PDZ2 domain of zonula occludens-1 and -2 is a phosphoinositide binding domain.

Zonula occludens proteins (ZO) are postsynaptic density protein-95 discs large-zonula occludens (PDZ) domain-containing proteins that play a fundamental role in the assembly of tight junctions and establishment of cell polarity. Here, we show that the second PDZ domain of ZO-1 and ZO-2 binds phosphoinositides (PtdInsP) and we identified critical residues involved in the interaction. Furthermore, peptide and PtdInsP binding of ZO PDZ2 domains are mutually exclusive. Although lipid binding does not seem to be required for plasma membrane localisation of ZO-1, phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P (2)) binding to the PDZ2 domain of ZO-2 regulates ZO-2 recruitment to nuclear speckles. Knockdown of ZO-2 expression disrupts speckle morphology, indicating that ZO-2 might play an active role in formation and stabilisation of these subnuclear structures. This study shows for the first time that ZO isoforms bind PtdInsPs and offers an alternative regulatory mechanism for the formation and stabilisation of protein complexes in the nucleus.

Mechanism of regulation of group IVA phospholipase A2 activity by Ser727 phosphorylation.

Although group IVA cytosolic phospholipase A(2) (cPLA(2)alpha) has been reported to be phosphorylated at multiple Ser residues, the mechanisms by which phosphorylation at different sites regulates cPLA(2)alpha activities are not fully understood. To explore the possibility that phosphorylation of Ser(727) modulates cellular protein-protein interactions, we measured the effect of Ser(727) mutations on the interaction of cPLA(2)alpha with a reported cPLA(2)alpha-binding protein, p11. In vitro activity assays and membrane binding measurements by surface plasmon resonance analysis showed that a heterotetramer (A2t) of p11 and annexin A2, but not p11 or annexin A2 alone, directly binds cPLA(2)alpha via Ser(727), which keeps the enzyme from binding the membrane and catalyzing the phospholipid hydrolysis. Phosphorylation of Ser(727) disrupts this inhibitory cPLA(2)alpha-A2t interaction, thereby activating cPLA(2)alpha. Subcellular translocation and activity measurements in HEK293 cells cotransfected with cPLA(2)alpha and p11 also showed that p11, in the form of A2t, inhibits cPLA(2)alpha by the same mechanism and that phosphorylation of Ser(727) activates cPLA(2)alpha by interfering with the inhibitory cPLA(2)alpha-A2t interaction. Collectively, these studies provide new insight into the regulatory mechanism of cPLA(2)alpha through Ser(727) phosphorylation.

Kazachstania siamensis sp. nov., an ascomycetous yeast species from forest soil in Thailand.

Two strains (S-34T and S-35) of a novel ascomycetous yeast species belonging to the genus Kazachstania were isolated from soil from a mixed deciduous forest in Amphoe Wang Nam Khiao, Nakhon Ratchasima Province, Thailand. The D1/D2 domains of the large-subunit rDNA sequences of the two strains were identical and also indicated a close relationship with respect to Kazachstania aquatica, Kazachstania unispora, Kazachstania aerobia, Kazachstania servazzii and Kazachstania solicola. The most closely related species, K. aquatica, has 14 nucleotide substitutions and three gaps in 566 nt. The phenotypic characteristics of the two strains were typical of those of members of the genus Kazachstania. These characteristics include the formation of a single globose ascospore in an unconjugated and persistent ascus, multilateral budding, the absence of arthrospores and ballistospores, the fermentation of glucose, the inability to assimilate nitrate, negative diazonium blue B and urease reactions, and the presence of ubiquinone Q-6. The novel strains can be distinguished from K. aquatica on the basis of a number of phenotypic characteristics and represent a novel species in the genus Kazachstania, for which the name Kazachstania siamensis sp. nov. is proposed. The type strain is S-34T (=CBS 10361T=NBRC 101968T=BCC 21230T).