Clindamycin-Benzoyl Peroxide Gel Compared with Clindamycin Lotion for Hidradenitis Suppurativa: A Randomized Controlled Assessor-Blinded Intra-Patient Pilot Study.

BACKGROUND: Antibiotic resistance is a major concern, especially in hidradenitis suppurativa (HS). However, antibiotics form a cornerstone in its treatment. Topical clindamycin is known to cause bacterial resistance but is still advised as monotherapy for the treatment of mild to moderate HS. METHODS: This is a randomized, controlled, assessor-blinded, intra-patient pilot trial to compare the clinical efficacy of clindamycin-benzoyl peroxide gel with clindamycin lotion in patients with mild to moderate HS. Two contralateral body sites were randomized for treatment in each patient. The primary outcome was the difference in the International Hidradenitis Suppurativa Severity Score (IHS4) between the two groups after 12 weeks. Secondary objectives were feasibility of the intra-patient design, efficacy within treatment groups, effect on HS pain, HS itch, patient satisfaction, antibiotic resistance, and the prolonged efficacy after 16 weeks. RESULTS: Ten patients were included, resulting in two groups of 10 treated body sites. No significant differences were found between the two groups for all measurements after 12 or 16 weeks, while both therapies led to an improvement in the IHS4, pain, and itch scores. A significant decrease was observed in the IHS4 for both the clindamycin lotion (-1.5; p < 0.05) and the clindamycin-benzoyl peroxide gel (-2; p < 0.01) after 16 weeks, and the pain scores were reduced from 7 to 2.5, p < 0.01 and 6.5 to 3, p = 0.03, respectively. Using the IHS4-55, we identified 50% of patients as responders in both groups after 12 weeks. The intra-patient design, however, unexpectedly appeared to hinder the inclusion of patients. CONCLUSION: Clindamycin-benzoyl peroxide gel showed favorable clinical efficacy results, similar to clindamycin lotion, suggesting that it could replace clindamycin lotion in the treatment of mild to moderate HS and to prevent antibiotic resistance. A larger controlled trial is needed to validate these results.

Validity and Reliability of Two Digital Wound Measurement Tools after Surgery in Patients with Hidradenitis Suppurativa.

BACKGROUND: After excision surgery in patients with hidradenitis suppurativa (HS), wounds are usually left open for secondary intention healing. To evaluate wound healing, reliable wound measurement is important. However, digital wound measurement tools for measuring the surface area are validated for small wounds located on flat or mildly convex body surfaces in studies, often powered inadequately. Up until now, a validated digital measurement tool to accurately measure wounds on all body surfaces, including the intertriginous areas, was not available. OBJECTIVES: The aim of this study was to validate two digital wound measurement tools for the measurement of the surface area of larger and concave wounds, using surgical wounds in patients with HS. METHODS: This prospective observational validation study included consecutive patients with HS undergoing excision surgery in the Department of Dermatology of the Erasmus University Medical Center, Rotterdam. Wound measurements using a ruler, the tracing method, the inSight® 3-dimensional (3D) device, and the ImitoWound app were performed by three investigators. The intraclass correlation coefficients (ICCs) for concurrent validity and the intra- and inter-rater reliability were analyzed. The standard error of measurement (SEm) and minimal detectable change were calculated, and Bland-Altman plots were constructed to determine the limits of agreement. RESULTS: Twenty patients with a total of 52 wounds were included. The wounds had a mean surface of 18.7 cm2. The inSight® 3D device showed an ICC of 0.987 for concurrent validity, 0.998 for intra-rater reliability, and 0.997 for inter-rater reliability. The ICCs from the ImitoWound application were 0.974, 0.978, and 0.964 for concurrent validity, intra-rater reliability, and inter-rater reliability, respectively. The SEms for intra- and inter-rater reliability were 0.95 cm2 and 1.11 cm2 for the inSight® 3D device and 3.33 cm2 and 3.51 cm2 for the ImitoWound app, respectively. CONCLUSION: Both the inSight® 3D device and the ImitoWound app demonstrated excellent concurrent validity and reliability for the surface measurements of concave wound, enabling these tools to be used reliably in clinical research and daily practice. Furthermore, it paves the way for broader application, such as telemonitoring of wound care at home.

Ex Vivo and In Vivo Evaluation of Dodecaborate-Based Clusters Encapsulated in Ferumoxytol Nanoparticles.

Host-guest interactions represent a growing research area with recent work demonstrating the ability to chemically manipulate both host molecules as well as guest molecules to vary the type and strength of bonding. Much less is known about the interactions of the guest molecules and hybrid materials containing similar chemical features to typical macrocyclic hosts. This work uses in vitro and in vivo kinetic analyses to investigate the interaction of closo-dodecahydrododecaborate derivatives with ferumoxytol, an iron oxide nanoparticle with a carboxylated dextran coating. We find that several boron cluster derivatives can become encapsulated into ferumoxytol, and the lack of pH dependence in these interactions suggests that ion pairing, hydrophobic/hydrophilic interaction, and hydrogen bonding are not the driving force for encapsulation in this system. Biodistribution experiments in BALB/c mice show that this system is nontoxic at the reported dosage and demonstrate that encapsulation of dodecaborate-based clusters in ferumoxytol can alter the biodistribution of the guest molecules.

Similarities in the immunoglobulin response and VH gene usage in rhesus monkeys and humans exposed to porcine hepatocytes.

BACKGROUND: The use of porcine cells and organs as a source of xenografts for human patients would vastly increase the donor pool; however, both humans and Old World primates vigorously reject pig tissues due to xenoantibodies that react with the polysaccharide galactose alpha (1,3) galactose (alphaGal) present on the surface of many porcine cells. We previously examined the xenoantibody response in patients exposed to porcine hepatocytes via treatment(s) with bioartficial liver devices (BALs), composed of porcine cells in a support matrix. We determined that xenoantibodies in BAL-treated patients are predominantly directed at porcine alphaGal carbohydrate epitopes, and are encoded by a small number of germline heavy chain variable region (VH) immunoglobulin genes. The studies described in this manuscript were designed to identify whether the xenoantibody responses and the IgVH genes encoding antibodies to porcine hepatocytes in non-human primates used as preclinical models are similar to those in humans. Adult non-immunosuppressed rhesus monkeys (Macaca mulatta) were injected intra-portally with porcine hepatocytes or heterotopically transplanted with a porcine liver lobe. Peripheral blood leukocytes and serum were obtained prior to and at multiple time points after exposure, and the immune response was characterized, using ELISA to evaluate the levels and specificities of circulating xenoantibodies, and the production of cDNA libraries to determine the genes used by B cells to encode those antibodies. RESULTS: Xenoantibodies produced following exposure to isolated hepatocytes and solid organ liver grafts were predominantly encoded by genes in the VH3 family, with a minor contribution from the VH4 family. Immunoglobulin heavy-chain gene (VH) cDNA library screening and gene sequencing of IgM libraries identified the genes as most closely-related to the IGHV3-11 and IGHV4-59 germline progenitors. One of the genes most similar to IGHV3-11, VH3-11cyno, has not been previously identified, and encodes xenoantibodies at later time points post-transplant. Sequencing of IgG clones revealed increased usage of the monkey germline progenitor most similar to human IGHV3-11 and the onset of mutations. CONCLUSION: The small number of IGVH genes encoding xenoantibodies to porcine hepatocytes in non-human primates and humans is highly conserved. Rhesus monkeys are an appropriate preclinical model for testing novel reagents such as those developed using structure-based drug design to target and deplete antibodies to porcine xenografts.

Comparison of 2-Ethyl-Cyanoacrylate and 2-Butyl-Cyanoacrylate for Use on the Calvaria of CD1 Mice.

Short-chain cyanoacrylates (SCCA), such as ethyl-2-cyanoacrylate (KrazyGlue, Aron Alpha, Columbus, OH) are commonly used as commercial fast-acting glues. Although once used in clinical medicine as skin adhesives, these products caused tissue toxicity and thus their use in live tissue was discontinued. SCCA were replaced by longer-chain versions (LCCA), such as butyl-cyanoacrylate (Vetbond, 3M, St Paul, Minnesota), which were found to be less toxic than the short-chain formulations. Some researchers prefer to use SCCA due to the belief that they create a stronger bond than do the longer-chain counterparts. In survival surgeries, we compared the bone thickness, bone necrosis, fibrosis, inflammation, and bone regeneration in the calvaria of control (naïve), surgery-only, SCCA-treated, and LCCA-treated mice (n = 20 per group). At 1 and 14 d after surgery, all mice except those treated with SCCA showed statistically similar bone measurements to those of the naive control group. The SCCA group had significantly less bone regeneration than did all other groups. These results suggest that the application of SCCA causes bone damage resulting in the loss of bone regeneration. This finding may assist investigators in choosing a tissue glue for their studies and may support the IACUC in advocating the use of pharmaceutical-grade tissue glues.

A transgenic mouse strain with antigen-specific T cells (RAG1KO/sf/OVA) demonstrates that the scurfy (sf) mutation causes a defect in T-cell tolerization.

The scurfy (sf) murine mutation causes severe lymphoproliferation, which results in death of hemizygous males (sf/Y) by 22 to 26 days of age. The CD4+ T cells are crucial mediators of this disease. Recent publications have not only identified this mutation as the genetic equivalent of the human disease X-linked neonatal diabetes mellitus, enteropathy, and endocrinopathy syndrome, but also have indicated that the defective protein-scurfin-is a new forkhead/winged-helix protein with a frameshift mutation, resulting in a product without the functional forkhead. These results have lead to speculation that the scurfy gene acts by disrupting the T-cell tolerance mechanism, resulting in hyperresponsiveness and lack of down-regulation. The Rag1KO/sf/Y OVA strain, with virtually 100% of its CD4+ T cells reactive strictly to ovalbumin (OVA) peptide 323-339, is an excellent model for determination of the sf mutation's ability to disrupt tolerance. We hypothesized that Rag1KO/sf/OVA mice would not be tolerant to antigen at a dose that tolerizes control animals. We found that splenic cells from Rag1KO/sf/Y OVA mice injected with the same dose of OVA peptide that induces tolerance in cells from control mice proliferate in vitro in response to OVA peptide. These results are consistent with a defect in the pathway responsible for peripheral T-cell tolerization.

The xenoantibody response and immunoglobulin gene expression profile of cynomolgus monkeys transplanted with hDAF-transgenic porcine hearts.

BACKGROUND: Recent work has indicated a role for anti-Gal alpha 1-3Gal (Gal) and anti-non-Gal xenoantibodies in the primate humoral rejection response against human-decay accelerating factor (hDAF) transgenic pig organs. Our laboratory has shown that anti-porcine xenograft antibodies in humans and non-human primates are encoded by a small number of germline IgV(H) progenitors. In this study, we extended our analysis to identify the IgV(H) genes encoding xenoantibodies in immunosuppressed cynomolgus monkeys (Macaca fascicularis) transplanted with hDAF-transgenic pig organs. METHODS: Three immunosuppressed monkeys underwent heterotopic heart transplantation with hDAF porcine heart xenografts. Two of three animals were given GAS914, a poly-L-lysine derivative shown to bind to anti-Gal xenoantibodies and neutralize them. One animal rejected its heart at post-operative day (POD) 39; a second animal rejected the transplanted heart at POD 78. The third monkey was euthanized on POD 36 but the heart was not rejected. Peripheral blood leukocytes (PBL) and serum were obtained from each animal before and at multiple time points after transplantation. We analyzed the immune response by enzyme-linked immunosorbent assay (ELISA) to confirm whether anti-Gal or anti-non-Gal xenoantibodies were induced after graft placement. Immunoglobulin heavy-chain gene (V(H)) cDNA libraries were then produced and screened. We generated soluble single-chain antibodies (scFv) to establish the binding specificity of the cloned immunoglobulin genes. RESULTS: Despite immunosuppression, which included the use of the polymer GAS914, the two animals that rejected their hearts showed elevated levels of cytotoxic anti-pig red blood cell (RBC) antibodies and anti-pig aortic endothelial cell (PAEC) antibodies. The monkey that did not reject its graft showed a decline in serum anti-RBC, anti-PAEC, and anti-Gal xenoantibodies when compared with pre-transplant levels. A V(H)3 family gene with a high level of sequence similarity to an allele of V(H)3-11, designated V(H)3-11(cyno), was expressed at elevated levels in the monkey that was not given GAS914 and whose graft was not rejected until POD 78. IgM but not IgG xenoantibodies directed at N-acetyl lactosamine (a precursor of the Gal epitope) were also induced in this animal. We produced soluble scFv from this new gene to determine whether this antibody could bind to the Gal carbohydrate, and demonstrated that this protein was capable of blocking the binding of human serum xenoantibody to Gal oligosaccharide, as had previously been shown with human V(H)3-11 scFv. CONCLUSIONS: DAF-transgenic organs transplanted into cynomolgus monkeys induce anti-Gal and anti-non-Gal xenoantibody responses mediated by both IgM and IgG xenoantibodies. Anti-non-Gal xenoantibodies are induced at high levels in animals treated with GAS914. Antibodies that bind to the Gal carbohydrate and to N-acetyl lactosamine are induced in the absence of GAS914 treatment. The animal whose heart remained beating for 78 days demonstrated increased usage of an antibody encoded by a germline progenitor that is structurally related, but distinct from IGHV311. This antibody binds to the Gal carbohydrate but does not induce the rapid rejection of the xenograft when expressed at high levels as early as day 8 post-transplantation.