Efficacy of Mepliex® Ag Versus Xeroform® As A Split-Thickness Skin Graft Donor Site Dressing: Bad Habits Die Hard.

Autografting with split-thickness skin grafts (STSG) remains an essential procedure in burn and reconstructive surgery. The process of harvesting STSG, however, leaves behind a donor site, an exposed area of partial-thickness dermis left to heal by secondary intention. There has yet to be a consensus amongst surgeons regarding optimal management of the donor site. The ideal donor site dressing is one that allows for expeditious healing while minimizing pain and infection. Despite numerous studies demonstrating the superiority of moist wound healing, many surgeons continue to treat STSG donor sites dry, with petroleum-based gauze. In this study, two burn centers performed a retrospective review of burn patients whose STSG donor sites were treated with either Xeroform® or Mepilex® Ag dressings. Infections were documented and in a subgroup analysis of patients, postoperative pain scores were noted and total opiate usage during hospitalization was calculated. Analysis revealed an overall infection rate of 1.2% in the Mepilex® Ag group and 11.4% in the Xeroform® group (p<0.0001). Patients with Xeroform® donor site dressings had increased odds of donor site infection (OR=10.8, p=0.002). In subgroup analysis, there were no significant differences in maximum pain scores between Mepilex® Ag and Xeroform® groups, nor were there differences in opiate usage. STSG donor sites dressed with silver foam dressings have a lower rate of donor site infection relative to those dressed with petroleum-based gauze. Moist donor site dressings such as foam dressings (including Mepilex® Ag) should be the standard of care in STSG donor site wound care.

La greffes de peau mince (GPM) demeure une procédure essentielle dans la chirurgie de brûlure et de reconstruction. La zone donneuse de greffe (ZDG) représente une perte de substance cutanée superficielle, cicatrisant spontanément. Il n'y a pas de consensus concernant la prise en charge optimale de la ZDG. Le pansement idéal de la ZDG doit promouvoir la cicatrisation et réduire la douleur ainsi que le risque infectieux. Malgré les nombreuses publications montrant l'intérêt d'un environnement humide pour la cicatrisation, de nombreux chirurgiens réalisent des pansements secs vaselinés. Cette étude rétrospective effectuée dans 2 CTB compare les pansements de ZDG réalisés au Xéroform® ou au Mepilex Ag®. Les infections ont été documentées et, dans un sous-groupe, les scores de douleur et la consommation d'opiacés au long de l'hospitalisation ont été notés. Les taux d'infection sont de 1,2% dans le groupe Mepilex Ag® et 11,4% avec Xéroform® (p<0,0001). Le risque d'infection de la ZDG est augmenté (OR 10,8 ; p = 0,002) en cas d'utilisation de Xéroform®. Il n'y avait pas de différence de douleur et de consommation d'opiacés entre les 2 groupes. Les ZDG recouvertes d'un pansement hydrocellulaire imprégné d'argent s'infectent moins que celles traitées avec une gaze imprégnée de vaseline. L'utilisation sur les ZDG d'un pansement humide comme une mousse hydrocellulaire (par exemple Mepilex Ag®) devrait devenir la norme.

A pathogenic role for myelin-specific CD8(+) T cells in a model for multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) characterized by plaques of infiltrating CD4(+) and CD8(+) T cells. Studies of MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS, focus on the contribution of CD4(+) myelin-specific T cells. The role of CD8(+) myelin-specific T cells in mediating EAE or MS has not been described previously. Here, we demonstrate that myelin-specific CD8(+) T cells induce severe CNS autoimmunity in mice. The pathology and clinical symptoms in CD8(+) T cell-mediated CNS autoimmunity demonstrate similarities to MS not seen in myelin-specific CD4(+) T cell-mediated EAE. These data suggest that myelin-specific CD8(+) T cells could function as effector cells in the pathogenesis of MS.

In situ tolerance within the central nervous system as a mechanism for preventing autoimmunity.

Multiple sclerosis (MS) is believed to be an autoimmune disease in which autoreactive T cells infiltrate the central nervous system (CNS). Animal models of MS have shown that CNS-specific T cells are present in the peripheral T cell repertoire of healthy mice and cause autoimmune disease only when they are activated by immunization. T cell entry into the CNS is thought to require some form of peripheral activation because the blood-brain barrier prohibits trafficking of this tissue by naive cells. We report here that naive T cells can traffic to the CNS without prior activation. Comparable numbers of T cells are found in the CNS of both healthy recombinase activating gene (Rag)(-/)- T cell receptor (TCR) transgenic mice and nontransgenic mice even when the transgenic TCR is specific for a CNS antigen. Transgenic T cells isolated from the CNS that are specific for non-CNS antigens are phenotypically naive and proliferate robustly to antigenic stimulation in vitro. Strikingly, transgenic T cells isolated from the CNS that are specific for myelin basic protein (MBP) are also primarily phenotypically naive but are unresponsive to antigenic stimulation in vitro. Mononuclear cells from the CNS of MBP TCR transgenic but not nontransgenic mice can suppress the response of peripheral MBP-specific T cells in vitro. These results indicate that naive MBP-specific T cells can traffic to the CNS but do not trigger autoimmunity because they undergo tolerance induction in situ.

Immunoglobulin heavy-chain enhancer requires one or more tissue-specific factors.

Enhancer sequences are regulatory regions that greatly increase transcription of certain eukaryotic genes. An immunoglobulin heavy-chain variable gene segment is moved from a region lacking enhancer activity to a position adjacent to the known heavy-chain enhancer early in B-cell maturation. In lymphoid cells, the heavy-chain and SV40 enhancers bind a common factor essential for enhancer function. In contrast, fibroblast cells contain a functionally distinct factor that is used by the SV40 but not by the heavy-chain enhancer. The existence of different factors in these cells may explain the previously described lymphoid cell specificity of the heavy-chain enhancer.

T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis.

Encounters with antigen can stimulate T cells to become activated and proliferate, become nonresponsive to antigen, or to die. T cell death was shown to be a physiological response to interleukin-2-stimulated cell cycling and T cell receptor reengagement at high antigen doses. This feedback regulatory mechanism attenuates the immune response by deleting a portion of newly dividing, antigen-reactive T cells. This mechanism deleted autoreactive T cells and abrogated the clinical and pathological signs of autoimmune encephalomyelitis in mice after repetitive administration of myelin basic protein.

Satisfaction with life after burn: A Burn Model System National Database Study.

OBJECTIVES: While mortality rates after burn are low, physical and psychosocial impairments are common. Clinical research is focusing on reducing morbidity and optimizing quality of life. This study examines self-reported Satisfaction With Life Scale scores in a longitudinal, multicenter cohort of survivors of major burns. Risk factors associated with Satisfaction With Life Scale scores are identified. METHODS: Data from the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR) Burn Model System (BMS) database for burn survivors greater than 9 years of age, from 1994 to 2014, were analyzed. Demographic and medical data were collected on each subject. The primary outcome measures were the individual items and total Satisfaction With Life Scale (SWLS) scores at time of hospital discharge (pre-burn recall period) and 6, 12, and 24 months after burn. The SWLS is a validated 5-item instrument with items rated on a 1-7 Likert scale. The differences in scores over time were determined and scores for burn survivors were also compared to a non-burn, healthy population. Step-wise regression analysis was performed to determine predictors of SWLS scores at different time intervals. RESULTS: The SWLS was completed at time of discharge (1129 patients), 6 months after burn (1231 patients), 12 months after burn (1123 patients), and 24 months after burn (959 patients). There were no statistically significant differences between these groups in terms of medical or injury demographics. The majority of the population was Caucasian (62.9%) and male (72.6%), with a mean TBSA burned of 22.3%. Mean total SWLS scores for burn survivors were unchanged and significantly below that of a non-burn population at all examined time points after burn. Although the mean SWLS score was unchanged over time, a large number of subjects demonstrated improvement or decrement of at least one SWLS category. Gender, TBSA burned, LOS, and school status were associated with SWLS scores at 6 months; scores at 12 months were associated with LOS, school status, and amputation; scores at 24 months were associated with LOS, school status, and drug abuse. CONCLUSIONS: In this large, longitudinal, multicenter cohort of burn survivors, satisfaction with life after burn was consistently lower than that of non-burn norms. Furthermore mean SWLS scores did not improve over the two-year follow-up period. This study demonstrates the need for continued efforts to improve patient-centered long term satisfaction with life after burn.

Initiation and regulation of CNS autoimmunity.

Our studies addressed the questions of how self-reactive T cells escape tolerance and what stimuli cause these T cells to initiate autoimmune responses. We employed experimental allergic encephalomyelitis (EAE) as an animal model of multiple sclerosis (MS). Endogenous expression of myelin basic protein (MBP) induces tolerance in T cells that recognize one region of MBP, whereas T cells specific for a different region escape tolerance. Triggers of disease induction were investigated in a T-cell receptor (TCR) transgenic model in which the majority of T cells recognize the MBP epitope that does not induce tolerance. EAE occurs spontaneously in this model and the incidence of disease depends on microbial exposure. EAE can also be actively induced by immunization with MBP peptide accompanied by injection of pertussis toxin as well as by administration of pertussis toxin alone. Immunization with MBP peptide without pertussis toxin, however, stimulates the transgenic T cells, but the activated T cells do not accumulate in the central nervous system (CNS) or induce EAE. Our studies suggest that initiation of autoimmune disease involves complex interactions between the neuroendocrine system as well as the innate and specific immune systems.

Microsurgery in the burn population - a review of the literature.

The management of patients suffering from burn injury poses unique challenges for the reconstructive surgeon, both in the acute and delayed settings. Once resuscitative measures are optimized and hemodynamic stability is achieved, early burn debridement and coverage is performed. Traditionally, this consists of excision of devitalized tissue and subsequent coverage using split thickness skin grafts. However, in certain instances, and depending on the extent and nature of the burn injury, skin grafting (or even local tissue rearrangement) may not be a reasonable option. in these cases, free tissue transfer may provide a viable reconstructive alternative. While free flap reconstruction is rare in burn surgery, particularly in the acute setting, burn injuries that expose vital structures, such as tendon, nerve, bone, or deep vessels, require robust flap coverage. in the delayed setting, unsightly scar formation and contracture often occurs secondary to skin graft coverage. These significant patient morbidities are often amenable to free tissue transfer as well. This review article discusses the indications, applications, and problems with free flap surgery for burn injuries in both the acute and delayed setting, and summarizes the available literature on microsurgical free tissue transfer for burn management.

La prise en charge des patients atteints de brûlures pose des défis uniques pour le chirurgien de reconstruction, à la fois dans les cadres aigus et retardés. Une fois les mesures de réanimation sont optimisés et la stabilité hémodynamique est obtenue, il faut faire le débridement précoce et la couverture de la brûlure. Traditionnellement, il s'agit de l'excision des tissus dévitalisés et la couverture par division ultérieure en utilisant des greffes de peau partielle épaisse. Cependant, dans certains cas, et en fonction des dimensions et la nature de la brûlure, une greffe de peau n'est pas toujours une option raisonnable. Dans ces cas, le transfert de tissu libre peut fournir une alternative viable. Alors que la reconstruction de lambeau libre est rare dans la chirurgie des brûlures, en particulier dans le cadre aiguë, les brûlures qui exposent les structures vitales, telles que les tendons, nerfs, os, ou les vaisseaux profonds, nécessitent une couverture robuste. Dans le cadre retardé, la formation de cicatrices inesthétiques et de contractures se produit fréquemment secondaire à une couverture de greffe de peau. Souvent ces morbidités importantes sont aussi prêtent au transfert de tissu libre. Cet article de revue discute les indications, les applications, et des problèmes avec la chirurgie de lambeau libre pour des brûlures dans les cadres aigus et retardés. Cet article résume aussi la littérature disponible sur la microchirurgie du transfert de tissu libre pour la prise en charge des brûlures.

Model genomes: the benefits of analysing homologous human and mouse sequences.

The human genome initiative has provided the motivating force for launching sequencing projects suitable for testing various DNA-sequencing strategies, as well as motivating the development of mapping and sequencing technologies. In addition to projects targeting selected regions of the human genome, other projects are based on model organisms such as yeast, nematode and mouse. The sequencing of homologous regions of human and mouse genomes is a new approach to genome analysis, and is providing insights into gene evolution, function and regulation which could not be determined so easily from the analysis of just one species.

Rag-1-dependent cells are necessary for 1,25-dihydroxyvitamin D(3) prevention of experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is a demyelinating disease involving genetic and environmental risk factors. Geographic, genetic, and biological evidence suggests that one environmental risk factor may be lack of vitamin D. Here, we investigated how 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) inhibits experimental autoimmune encephalomyelitis (EAE), an MS model. The experiments used adoptive transfer of TCR-transgenic (TCR1) cells specific for myelin basic protein (MBP) peptide into unprimed recipients. When unprimed TCR1 splenocytes were transferred, and the recipients were immunized with peptide, the mock-treated mice developed EAE, but the 1,25-(OH)(2)D(3)-treated recipients remained disease-free. Both groups had TCR1 T cells that proliferated in response to MBP Ac1-11 and produced IFN-gamma but not IL-4 in the lymph node. In the central nervous system (CNS), the mock-treated mice had activated TCR1 T cells that produced IFN-gamma but not IL-4, while the 1,25-(OH)(2)D(3)-treated mice had TCR1 T cells with a non-activated phenotype that did not produce IFN-gamma or IL-4. When activated TCR1 T cells producing IFN-gamma were transferred into unprimed mice, the mock-treated and the 1,25-(OH)(2)D(3)-treated recipients developed EAE. Likewise, the 1,25-(OH)(2)D(3) did not inhibit Th1 cell IFN-gamma production or promote Th2 cell genesis or IL-4 production in vitro. Finally, the 1,25-(OH)(2)D(3) inhibited EAE in MBP-specific TCR-transgenic mice that were Rag-1(+), but not in animals that were Rag-1-null. Together, these data refute the hypothesis that the hormone inhibits Th1 cell genesis or function directly or through an action on antigen-presenting cells, or promotes Th2 cell genesis or function. Instead, the evidence supports a model wherein the 1,25-(OH)(2)D(3) acts through a Rag-1-dependent cell to limit the occurrence of activated, autoreactive T cells in the CNS.

Scanning electron microscopy and X-ray diffraction studies in the analysis of medical materials: Gore-Tex versus braided polyester tape for repair of the incompetent cervix.

Cathodoluminescence in the scanning electron microscope and roentgenogram diffraction studies were applied to the analysis of two different medical materials used in cervical cerclage, the treatment of cervical incompetence. Braided polyester tape or Gore-Tex was used as suture material and was analyzed both before and after use in cerclage of the cervix. Results of SEM and X-ray diffraction studies showed distinct differences between the two materials, with the Gore-Tex demonstrating a superior morphological integrity and a decreased likelihood of phagocyte adhesion. These results correlated well with the clinical observations, which also showed Gore-Tex to be a superior medical material.

Sulfur mustard gas exposure: case report and review of the literature.

This report describes a case of burn injury following exposure to sulfur mustard, a chemical agent used in war. A review of the diagnostic characteristics, clinical manifestations, and therapeutic measures used to treat this uncommon, yet extremely toxic, entity is presented. The aim of this report is to highlight the importance of considering this diagnosis in any war victim, especially during these unfortunate times of rising terrorist activities.

Ce rapport décrit un cas de brûlure suite à une exposition au gaz moutarde, un agent chimique utilisé dans la guerre. On présente un examen des caractéristiques de diagnostic, les manifestations cliniques et les mesures thérapeutiques utilisés pour traiter ce phénomène rare, mais extrêmement toxique. L'objectif de ce rapport est de mettre en évidence l'importance de considérer ce diagnostic dans toute victime de la guerre, surtout en ces temps malheureux de la hausse des activités terroristes.

Renal dysfunction in burns: a review.

Acute kidney injury (AKI), although rare, is a major complication of burn injury that commonly leads to mortality. It results from a complex interplay of various cellular and neuro-humoral changes affecting burn patients. Guidelines for the treatment of this entity are still not well defined; therefore, prevention and early diagnosis are key to avoid the unfavorable prognosis of AKI. These entail a comprehensive understanding of the global physiologic changes underlying the condition of burn patients and a judicious interpretation of their continuous homeostatic alterations. The aim of this review is to present the salient features in burn patient physiology that contribute to AKI. Strategies for identifying early AKI are presented. Finally, the different treatment modalities are revisited.

Les lésions rénales aiguës (LRA) sont rares, mais elles constituent une complication majeure des brûlures qui mène souvent à la mortalité. Ces lésions sont provoquées par une interaction complexe de divers changements cellulaires et neurohumoraux qui affectent les patients brûlés. Les directives pour le traitement de ces patients ne sont pas encore bien définies et, par conséquent, la prévention et le diagnostic précoce sont essentiels pour éviter le pronostic défavorable des LRA. Cela nécessite une compréhension complète des changements physiologiques présents dans ces patients et une interprétation judicieuse de leurs continuelles altérations homéostatiques. Les Auteurs se sont proposé de présenter les principales caractéristiques de la physiologie du patient brûlé qui contribuent à ce type de lésion. Apres avoir discuté les stratégies pour identifier ces lésions en phase précoce, ils concluent avec une description des différentes modalités de traitement.

The role of a dedicated staff psychiatrist in modern burn centers.

Psychiatric disorders may be more common in burn-injured subjects than in the general population, and oftentimes contribute to the injury itself. Even in the absence of underlying psychiatric illnesses, burn patients may still benefit from a psychiatric evaluation during and after their hospitalization. In this regard, we included a dedicated psychiatry service in our multidisciplinary burn team. We review herein the course of burn patients that were offered psychiatric evaluation and highlight the benefits of such a program. We conducted an IRB-approved retrospective chart review of burn subjects admitted to our institution between June 15, 2009 and April 30, 2010 and identified 83 patients that were examined by our psychiatrist. Indications for consultation, history of psychiatric illness and substance abuse, as well as administered drugs, were recorded. Among the 83 evaluated patients, 48 (57.8%) had a preexisting psychiatric disorder and 36 (43.4%) suffered from substance abuse. The most common indications for consultation were pain (28.1%), alcohol dependence (25.8%), anxiety (24.7%), illicit drug abuse (16.8%), depression (15.7%), post-traumatic stress disorder (8.9%), and sleep disturbances (8.9%). Pharmacotherapy was initiated in 75 patients (90.3%). 31 (37.3%) had neither a psychiatric disorder nor a history of substance abuse, although 26 of them (83.9%) still received drugs for psychiatric conditions. The inclusion of a dedicated psychiatrist as part of our burn team has improved our comprehensive burn care. In the overwhelming majority of cases, even in the absence of preexisting psychiatric illnesses, consultation resulted in pharmacologic intervention and enhanced patient care.

Les troubles psychiatriques peuvent être plus fréquents chez les patients brûlés que dans la population générale, et contribuent souvent à la blessure elle-même. Même en l'absence de maladies psychiatriques sous-jacents, les patients brûlés peuvent encore bénéficier d'une évaluation psychiatrique pendant et après leur hospitalisation. À cet égard, nous avons inclus un service de psychiatrie dédié à notre équipe multidisciplinaire pour la gestion des brûlures. Nous examinons ici les cours de patients brûlés à qui une évaluation psychiatrique a été proposée et nous mettons en évidence les avantages d'un tel programme. Nous avons effectué un examen rétrospectif - approuvé par les CPP - des patients brûlés admis dans notre institution entre le 15 Juin 2009 et le 30 Avril, 2010, à partir de lequel nous avons identifié 83 patients qui ont été examinés par notre psychiatre. Nous avons enregistré les indications pour la consultation, les antécédents de maladie psychiatrique et la toxicomanie, ainsi que les médicaments administrés. Parmi les 83 patients évalués, 48 (57,8 %) avaient un trouble psychiatrique préexistante et 36 (43,4%) a souffert de l'abus de substances. Les indications les plus fréquentes de consultation étaient la douleur (28,1%), la dépendance à l'alcool (25,8%), l'anxiété (24,7%), l'abus de drogues illicites (16,8%), la dépression (15,7%), les troubles de stress post-traumatique (8,9%), et troubles du sommeil (8,9%). La pharmacothérapie a été instaurée dans 75 patients (90,3%). 31 (37,3%) ne présentaient pas de troubles psychiatriques ni une histoire d'abus de substance mais quand même 26 d'entre eux (83,9 %) ont reçu des médicaments pour des troubles psychiatriques. L'inclusion d'un psychiatre spécialisé dans le cadre de notre équipe a amélioré notre système complet de soins aux brulés. Dans l'écrasante majorité des cas, même en l'absence des maladies psychiatriques préexistantes, la consultation a donné lieu à une intervention pharmacologique et a amélioré les soins aux patients.

Tolerance and autoimmunity in TCR transgenic mice specific for myelin basic protein.

T-cell receptor (TCR) transgenic mice provide the ability to follow the maturation and fate of T cells specific for self-antigens in vivo. This technology represents a major breakthrough in the study of autoimmune diseases in which specific antigens have been implicated. Proteins expressed within the central nervous system are believed to be important autoantigens in multiple sclerosis. TCR transgenic models specific for myelin basic protein (MBP) allowed us to assess the role of tolerance in providing protection from T cells with this specificity. Our studies demonstrate that T cells specific for the immunodominant epitope of MBP do not undergo tolerance in vivo and that TCR transgenic mice are susceptible to spontaneous autoimmune disease. The susceptibility to spontaneous disease is dependent on exposure to microbial antigens. MBP TCR transgenic models expressing TCRs specific for the same epitope of MBP but utilizing different V alpha genes exhibit differing susceptibilities to spontaneous disease. These data support the idea that genetic and environmental differences play a role in susceptibility to autoimmunity. MBP TCR transgenic models are playing an important role in defining mechanisms by which infectious agents trigger autoimmune disease as well as defining mechanisms by which tolerance is induced to distinct epitopes within self-antigens.

Differential effects of alkylation of methionine residues on the activities of pituitary thyrotropin and lutropin.

Methionine residues of the alpha and beta subunits of bovine lutropin (LH) and bovine thyrotropin (TSH) have been specifically alkylated with iodoacetic acid. The alpha subunit has been modified so that two of the four methionines are quantitatively alkylated (residues 8 and 33, in agreement with studies by Cheng, K.-W. (1976) Biochem. J. 159, 71-77). Reassociation of the modified alpha subunit with unmodified LH-beta or thyrotropin (TSH)-beta resulted in reconstituted hormones which differed markedly in their respective biological activities. The alpha-modified TSH was fully active in both radioligand receptor and in vivo assays, while the alpha-modified LH, because of lowered affinity for receptor, lost approximately 70% of its activity in its radioligand receptor assay. This observation is the first to show that modification of the alpha subunit leads to a differential loss of activity in one glycoprotein hormone versus another. Circular dichorism studies revealed no changes in conformation; thus, the data strongly support, for LH, a direct interaction of the common subunit with receptor. Methionine 32 in TSH-beta can be modified with retention of full activity under conditions where methionines 8, 9, and 58 are not modified. In contrast, previous work on the modification of lysine 42 in LH-beta which lies in an analogous domain implicates that residue in receptor interaction (e.g. Liu, W.-K., Yang, K.-P., Nakagawa, Y., and Ward, D. N. (1974) J. Biol. Chem. 249, 5544-5550; Sairam, M. R., and Li, C.-H., (1975) ARch. Biochem. Biophys. 167, 534-539). These results further emphasize the probable importance of this domain in hormone specificity.

Separately expressed T cell receptor alpha and beta chain transgenes exert opposite effects on T cell differentiation and neoplastic transformation.

Two aspects of T cell differentiation in T cell receptor (TCR)-transgenic mice, the generation of an unusual population of CD4-CD8-TCR+ thymocytes and the absence of gamma delta cells, have been the focus of extensive investigation. To examine the basis for these phenomena, we investigated the effects of separate expression of a transgenic TCR alpha chain and a transgenic TCR beta chain on thymocyte differentiation. Our data indicate that expression of a transgenic TCR alpha chain causes thymocytes to differentiate into a CD4-CD8-TCR+ lineage at an early developmental stage, depleting the number of thymocytes that differentiate into the alpha beta lineage. Surprisingly, expression of the TCR alpha chain transgene is also associated with the development of T cell lymphosarcoma. In contrast, expression of the transgenic TCR beta chain causes immature T cells to accelerate differentiation into the alpha beta lineage and thus inhibits the generation of gamma delta cells. Our observations provide a model for understanding T cell differentiation in TCR-transgenic mice.