Skin Necrosis Distal to a Rapid Infusion Catheter: Understanding Possible Complications of Large-bore Vascular Access Devices.

Rapid infusion catheters (RICs) allow expedient conversion of peripheral intravenous (PIV) catheters to peripheral sheaths; however, little is known about potential complications. In this case, a 64-year-old male polytrauma patient had a 20-gauge PIV catheter in the right cephalic vein upsized to an 8.5 French (Fr) RIC without incident during an arrest with pulseless electrical activity (PEA). On RIC post-placement day two, the patient developed edema and ecchymosis extending from the right dorsal mid-hand to the antecubital fossa, just distal to the RIC insertion point. Compartments were soft; the volar surface (including an arterial line location), fingers, and upper arm were normal. The RIC flushed and returned blood appropriately. Ultrasound revealed a noncompressible cephalic vein either related to the catheter or thrombosis, and imaging of the hand showed an ulnar styloid fracture and a minimally displaced triquetral fracture. The RIC was removed immediately. Over the next week, the areas of ecchymosis developed bullae and then sloughed, leaving open wounds extending into the dermis. The patient later expired from unrelated causes. The area and timing of the skin necrosis were highly suspicious for a catheter-associated complication, despite the presence of the arterial line and small distal fractures. The necrosis was potentially due to thrombosis of the superficial venous outflow system, leading to congestion and skin compromise, but we found no similar reports. Alternatively, the catheter may have ruptured the vein and caused a gravity-dependent ecchymosis, but the volar surface was not impacted, and the catheter was functioning properly. The RIC may also have encroached on the arterial space, decreasing flow, but we would have expected distal hand changes. The only published reports we could find on RIC complications involved a lost guide wire, fragmentation of a catheter during placement, and a case of compartment syndrome, raising the question of whether skin necrosis is truly a rare event or simply underreported with the RIC. Although the exact causal relationship remains unknown in our case, RICs should be removed as soon as possible after immediate stabilization

Rho-associated kinase signalling and the cancer microenvironment: novel biological implications and therapeutic opportunities

The Rho/ROCK pathway is involved in numerous pivotal cellular processes that have made it an area of intense study in cancer medicine, however, Rho-associated coiled-coil containing protein kinase (ROCK) inhibitors are yet to make an appearance in the clinical cancer setting. Their performance as an anti-cancer therapy has been varied in pre-clinical studies, however, they have been shown to be effective vasodilators in the treatment of hypertension and post-ischaemic stroke vasospasm. This review addresses the various roles the Rho/ROCK pathway plays in angiogenesis, tumour vascular tone and reciprocal feedback from the tumour microenvironment and explores the potential utility of ROCK inhibitors as effective vascular normalising agents. ROCK inhibitors may potentially enhance the delivery and efficacy of chemotherapy agents and improve the effectiveness of radiotherapy. As such, repurposing of these agents as adjuncts to standard treatments may significantly improve outcomes for patients with cancer. A deeper understanding of the controlled and dynamic regulation of the key components of the Rho pathway may lead to effective use of the Rho/ROCK inhibitors in the clinical management of cancer

Allosteric p97 inhibitors can overcome resistance to ATP-competitive p97 inhibitors for potential anti-cancer therapy

A major challenge of targeted cancer therapy is the selection for drug‐resistant mutations in tumor cells leading to loss of treatment effectiveness. p97/VCP is a central regulator of protein homeostasis and a promising anti‐cancer target because of its vital role in cell growth and survival. One ATP‐competitive p97 inhibitor, CB‐5083, has entered clinical trials. Selective pressure on HCT116 cells treated with CB‐5083 identified 5 different resistant mutants. Identification of p97 inhibitors with different mechanisms of action would offer the potential to overcome this class of resistance mutations. Our results demonstrate that two CB‐5083 resistant p97 mutants, N660K and T688A, were also resistant to several other ATP‐competitive p97 inhibitors, whereas inhibition by two allosteric p97 inhibitors NMS‐873 and UPCDC‐30245 were unaffected by these mutations. We also established a CB‐5083 resistant cell line that harbors a new p97 double mutation (D649A/T688A). While CB‐5083, NMS‐873, and UPCDC‐30245 all effectively inhibited proliferation of the parental HCT116 cell line, NMS‐873 and UPCDC‐30245 were 30‐fold more potent than CB‐5083 in inhibiting the CB‐5083 resistant D649A/T688A double mutant. Our results suggest that allosteric p97 inhibitors are promising alternatives when resistance to ATP‐competitive p97 inhibitors arises during anti‐cancer treatment

Thin Fisher Zeroes

Biskup et al. [Phys. Rev. Lett. 84 (2000) 4794] have recently suggested that the loci of partition function zeroes can profitably be regarded as phase boundaries in the complex temperature or field planes. We obtain the Fisher zeroes for Ising and Potts models on non-planar (``thin'') regular random graphs using this approach, and note that the locus of Fisher zeroes on a Bethe lattice is identical to the corresponding random graph. Since the number of states appears as a parameter in the Potts solution the limiting locus of chromatic zeroes is also accessible.Comment: 10 pages, 4 figure

The AFF4 scaffold binds human P-TEFb adjacent to HIV Tat.

Human positive transcription elongation factor b (P-TEFb) phosphorylates RNA polymerase II and regulatory proteins to trigger elongation of many gene transcripts. The HIV-1 Tat protein selectively recruits P-TEFb as part of a super elongation complex (SEC) organized on a flexible AFF1 or AFF4 scaffold. To understand this specificity and determine if scaffold binding alters P-TEFb conformation, we determined the structure of a tripartite complex containing the recognition regions of P-TEFb and AFF4. AFF4 meanders over the surface of the P-TEFb cyclin T1 (CycT1) subunit but makes no stable contacts with the CDK9 kinase subunit. Interface mutations reduced CycT1 binding and AFF4-dependent transcription. AFF4 is positioned to make unexpected direct contacts with HIV Tat, and Tat enhances P-TEFb affinity for AFF4. These studies define the mechanism of scaffold recognition by P-TEFb and reveal an unanticipated intersubunit pocket on the AFF4 SEC that potentially represents a target for therapeutic intervention against HIV/AIDS. DOI:http://dx.doi.org/10.7554/eLife.00327.001

Optimal trading strategies vs. a statistical adversary

Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 1994.Includes bibliographical references (leaves 47-50).by Andrew Chou.M.S

Static replication of exotic options

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 1997.Includes bibliographical references (p. 103-106).by Andrew Chou.Ph.D

The error term in counting prime pairs

We relate the size of the error term in the Hardy-Littlewood conjectured formula for the number of prime pairs to the $L^{1}$ norm of an exponential sum over the primes formed with the von Mangoldt function.Comment: 21 pages, 3 figures, and 1 tabl