Absence of Toxemia in Clostridioides difficile Infection: Results from Ultrasensitive Toxin Assay of Serum

Digestive Diseases and Sciences - Clostridioides difficile infection (CDI) is caused by Toxins A and B, secreted from pathogenic strains of C. difficle. This infection can vary greatly in symptom...     

Impact of revised triage to improve throughput in an ED with limited traditional fast track population

Background

Emergency department (ED) crowding is associated with patient safety concerns, increased patients left without being seen (LWBS), low patient satisfaction, and lost ED revenue. The objective was to measure the impact of a revised triage process on ED throughput.

Synthetic and partially-purified adenylate cyclase-stimulating proteins from tumors associated with humoral hypercalcemia of malignancy inhibit phosphate transport in a PTH-responsive renal cell line

Hypophosphatemia and hyperphosphaturia characteristically occur in patients with humoral hypercalcemia of malignancy (HHM). To determine if a tumor product causes these abnormalities in phosphate metabolism, rather than, for example, hypercalcemia, we investigated the effect of partially-purified adenylate cyclase-stimulating activity (ACSA) from human and animal HHM-associated tumors on sodium-dependent phosphate transport (Na PiT) in a PTH-responsive renal epithelial cell line. Thirty minute exposure to 7 X 10(-10) MbPTH (1-34) equivalents of ACSA from the human and animal tumors, reduced NaPiT by 20% and 14%, respectively. We also recently isolated an adenylate cyclase-stimulating protein (hACSP) from two human tumors associated with HHM and identified a cDNA clone for this protein which encodes a 141 amino-acid peptide. Based on the deduced amino-acid sequence, we synthesized tyr36 (1-36) hACSP. This synthetic peptide induced a 22% decrease in the initial rate of NaPiT by the epithelial monolayer. Its inhibitory activity was roughly equipotent to that of bPTH (1-34). We conclude that the ACSP derived from HHM-associated tumors decreases phosphate transport in renal epithelial cells. This peptide appears to play a key role in mediating the changes in phosphate metabolism in this syndrome.     

The Timothy syndrome mutation differentially affects voltage- and calcium-dependent inactivation of CaV1.2 L-type calcium channels

Calcium entry into excitable cells is an important physiological signal, supported by and highly sensitive to the activity of voltage-gated Ca²⁺ channels. After membrane depolarization, Ca²⁺ channels first open but then undergo various forms of negative feedback regulation including voltage- and calcium-dependent inactivation (VDI and CDI, respectively). Inactivation of Ca²⁺ channel activity is perturbed in a rare yet devastating disorder known as Timothy syndrome (TS), whose features include autism or autism spectrum disorder along with severe cardiac arrhythmia and developmental abnormalities. Most cases of TS arise from a sporadic single nucleotide change that generates a mutation (G406R) in the pore-forming subunit of the L-type Ca²⁺ channel Ca_V1.2. We found that the TS mutation powerfully and selectively slows VDI while sparing or possibly speeding the kinetics of CDI. The deceleration of VDI was observed when the L-type channels were expressed with β₁ subunits prominent in brain, as well as β₂ subunits of importance for the heart. Dissociation of VDI and CDI was further substantiated by measurements of Ca²⁺ channel gating currents and by analysis of another channel mutation (I1624A) that hastens VDI, acting upstream of the step involving Gly⁴⁰⁶. As highlighted by the TS mutation, CDI does not proceed to completeness but levels off at ≈50%, consistent with a change in gating modes and not an absorbing inactivation process. Thus, the TS mutation offers a unique perspective on mechanisms of inactivation as well as a promising starting point for exploring the underlying pathophysiology of autism.     

Understanding and harnessing the graft-versus-leukaemia effect

The graft-versus-leukaemia (GVL) effect is a central component of the stem cell allograft's ability to cure haematological malignancies. The GVL effect is mediated by donor-derived natural killer cells and T lymphocytes, which have distinct mechanisms of recognizing and targeting the recipient's malignant cells. After transplantation the cytokine milieu is favourable to the early establishment of a GVL effect, but the need to prevent graft-versus-host disease limits the full potential of this process. Clinical studies have identified some critical components of the transplant preparation, donor selection, stem cell source (peripheral blood versus bone marrow) and post-transplant management that can be manipulated to optimize the GVL effect. However, further developments focusing on the selective depletion of unwanted alloreactivity with preservation of GVL effects, and the use of vaccines or the adoptive transfer of leukaemia-specific lymphocytes, will be required to enhance the GVL effect to reliably eradicate more resistant leukaemias.     

The bioavailability of benorylate in hot beverages.

It has been recommended that benorylate may be administered with hot beverages to overcome the problem of its relative unpalatability. Urine salicylate recovery used as a measure of bioavailability in 20 normal subjects has shown that hot coffee has no significant effect on drug availability from the orally administered suspension.