A Comparison of Single Dimension and Volume Measurements in the Risk Stratification of Pancreatic Cystic Lesions.

The incidence of pancreatic cystic lesions (PCLs) has been rising due to improvements in imaging. Of these, intraductal papillary mucinous neoplasms (IPMNs) are the most common and are thought to contribute to almost 20% of pancreatic adenocarcinomas. All major society guidelines for the management of IPMNs use size defined by maximum diameter as the primary determinant of whether surveillance or surgical resection is recommended. However, there is no consensus on how these measurements should be obtained or whether a single imaging modality is superior. Furthermore, the largest diameter may fail to capture the complexity of PCLs, as most are not perfectly spherical. This article reviews current PCL measurement techniques in CT, MRI, and EUS and posits volume as a possible alternative to the largest diameter.

The Effects of Growth Hormone on Nerve Regeneration and Alloimmunity in Vascularized Composite Allotransplantation.

BACKGROUND: Poor outcomes in functional recovery following upper extremity transplantation are largely due to denervation-induced muscle atrophy that occurs during the prolonged period of nerve regeneration. Growth hormone (GH) has well-established trophic effects on neurons, myocytes, and Schwann cells and represents a promising therapeutic approach to address this challenge. This study sought to confirm the positive effects of GH treatment on nerve regeneration and functional recovery and to evaluate the effects of GH treatment on the immune response in the setting of vascularized composite allotransplantation. METHODS: Rats underwent orthotopic forelimb transplantation across a full MHC-mismatch and received either porcine-derived growth hormone or no treatment (n=18 per group). Functional recovery was measured using electrically-stimulated grip strength testing. Animals were monitored for clinical and subclinical signs of rejection. RESULTS: Neuromuscular junction reinnervation and grip strength were improved in GH-treated animals (p=0.005; p=0.08). No statistically significant differences were seen in muscle atrophy, degree of myelination, axon diameter, and axon counts between groups. The rates of clinical and histological rejection did not significantly differ among groups. CONCLUSIONS: Our findings alleviate concern for increased risk of transplant rejection during GH therapy and therefore support the translation of growth hormone as a therapeutic method to promote improved functional recovery in upper extremity transplantation.

Sustained IGF-1 delivery ameliorates effects of chronic denervation and improves functional recovery after peripheral nerve injury and repair.

Functional recovery following peripheral nerve injury is limited by progressive atrophy of denervated muscle and Schwann cells (SCs) that occurs during the long regenerative period prior to end-organ reinnervation. Insulin-like growth factor 1 (IGF-1) is a potent mitogen with well-described trophic and anti-apoptotic effects on neurons, myocytes, and SCs. Achieving sustained, targeted delivery of small protein therapeutics remains a challenge. We hypothesized that a novel nanoparticle (NP) delivery system can provide controlled release of bioactive IGF-1 targeted to denervated muscle and nerve tissue to achieve improved motor recovery through amelioration of denervation-induced muscle atrophy and SC senescence and enhanced axonal regeneration. Biodegradable NPs with encapsulated IGF-1/dextran sulfate polyelectrolyte complexes were formulated using a flash nanoprecipitation method to preserve IGF-1 bioactivity and maximize encapsulation efficiencies. Under optimized conditions, uniform PEG-b-PCL NPs were generated with an encapsulation efficiency of 88.4%, loading level of 14.2%, and a near-zero-order release of bioactive IGF-1 for more than 20 days in vitro. The effects of locally delivered IGF-1 NPs on denervated muscle and SCs were assessed in a rat median nerve transection-without- repair model. The effects of IGF-1 NPs on axonal regeneration, muscle atrophy, reinnervation, and recovery of motor function were assessed in a model in which chronic denervation is induced prior to nerve repair. IGF-1 NP treatment resulted in significantly greater recovery of forepaw grip strength, decreased denervation-induced muscle atrophy, decreased SC senescence, and improved neuromuscular reinnervation.

The Effects of a Porcine Extracellular Matrix Nerve Wrap as an Adjunct to Primary Epineurial Repair.

PURPOSE: Outcomes after end-to-end epineural suture repair remain poor. Nerve wraps have been advocated to improve regeneration across repair sites by potentially reducing axonal escape and scar ingrowth; however, limited evidence currently exists to support their use. METHODS: Forty Lewis rats underwent median nerve division and immediate repair. Half were repaired with epineural suturing alone, and the others underwent epineural suture repair with the addition of a nerve wrap. Motor recovery was measured using weekly grip strength and nerve conduction testing for 15 weeks. Histomorphometric analyses were performed to assess intraneural collagen deposition, cellular infiltration, and axonal organization at the repair site, as well as axonal regeneration and neuromuscular junction reinnervation distal to the repair site. RESULTS: The wrapped group demonstrated significantly less intraneural collagen deposition at 5 weeks. Axonal histomorphometry, cellular infiltration, neuromuscular junction reinnervation, and functional recovery did not differ between groups. CONCLUSIONS: Nerve wraps reduced collagen deposition within the coaptation; however, no differences were observed in axonal regeneration, neuromuscular junction reinnervation, or functional recovery. CLINICAL RELEVANCE: These findings suggest that extracellular matrix nerve wraps can attenuate scar deposition at the repair site. Any benefits that may exist with regards to axonal regeneration and functional recovery were not detected in our model.

Stimulated grip strength measurement: Validation of a novel method for functional assessment.

BACKGROUND: Reliable measurement of functional recovery is critical in translational peripheral nerve regeneration research. Behavioral functional assessments such as volitional grip strength testing (vGST) are limited by inherent behavioral variability. Isometric tetanic force testing (ITFT) is highly reliable but precludes serial measurements. Combining elements of vGST and ITFT, stimulated grip strength testing (sGST) involves percutaneous median nerve stimulation to elicit maximal tetanic contraction of digital flexors, thereby allowing for consistent measurement of maximal grip strength. METHODS: We measured side-to-side equivalence of force using sGST, vGST, and ITFT to determine relative reliability and repeatability. We also performed weekly force measurements following median nerve repair. RESULTS: sGST demonstrated greater reliability and inter-trial repeatability than vGST and similar reliability to ITFT, with the added benefit of serial measurements. CONCLUSIONS: sGST is a valid method for assessing functional recovery that addresses the limitations of the currently available modalities used in translational peripheral nerve regeneration research.

Allicin and derivates are cysteine protease inhibitors with antiparasitic activity.

Allicin and derivatives thereof inhibit the CAC1 cysteine proteases falcipain 2, rhodesain, cathepsin B and L in the low micromolar range. The structure-activity relationship revealed that only derivatives with primary carbon atom in vicinity to the thiosulfinate sulfur atom attacked by the active-site Cys residue are active against the target enzymes. Some compounds also show potent antiparasitic activity against Plasmodium falciparum and Trypanosoma brucei brucei.

Michael acceptor based antiplasmodial and antitrypanosomal cysteine protease inhibitors with unusual amino acids.

New peptidic Michael acceptor based cysteine protease inhibitors displaying antiparasitic activity were identified by testing a broad series of 45 compounds in total, containing Asn, Gln, or Phe. As target enzymes, falcipain-2 and -3 from P. falciparum and rhodesain from T. b. rhodesiense were used. In the case of the Asn/Gln containing compounds, the trityl-protected, diastereomeric E-configured vinylogous dipeptide esters 16 (Boc-(S)-Phg-(R/S)-vGln(Trt)-OEt) were discovered as most active inhibitors concerning both protease inhibition and antiparasitic acitivity, with inhibition constants in the submicromolar range. The compounds were shown to display time-dependent and competitive inhibition. In the case of the Phe containing compounds, the maleic acid derivatives 42 and 43 (BnO-Phe<--Mal-Phe-OBn, BnO-Phe<--Mal-Phe-Ala-OBn, Mal = maleic acid) displayed good inhibition of rhodesain as well as good antitrypanosomal activity, while the fumaric acid derived E-analogue 14 (BnO-Phe<--Fum-Phe-OBn) only displayed inhibition of the target enzymes but no antiparasitic activity. Inhibition by these Phe derivatives was shown to be time-independent and competitive.

Antimalarial and antitrypanosomal activity of a series of amide and sulfonamide derivatives of a 2,5-diaminobenzophenone.

Here, we describe a series of readily obtainable benzophenone derivatives with antimalarial and antitrypanosomal activity. The most active compounds display submicromolar activity against Plasmodium falciparum. Micromolar activity is obtained against Trypanosoma brucei. Main problem of the compounds is low selectivity. However, there are indications that separation of antimalarial and cytotoxic activity might by possible. In addition, some compounds inhibit human ABC transporter with nanomolar activity.