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Effective treatment and immunoprophylaxis of viral respiratory infections with neutralizing monoclonal antibodies (mAbs) require maintaining inhibitory concentrations of mAbs at the airway surface. While engineered mAbs with increased affinity to the neonatal Fc receptor (FcRn) are increasingly employed, little is known how increased affinity of Fc to FcRn influences basal-to-apical transepithelial transport (transcytosis) of mAbs across the airway epithelium. To investigate this, we utilized a model of well-differentiated human airway epithelium (WD-HAE) that exhibited robust FcRn expression, and measured the transepithelial transport of a mAb against SARS-CoV-2 Spike protein (CR3022) with either wildtype IgG 1 -Fc or Fc modified with YTE or LS mutations known to increase affinity for FcRn. Despite the marked differences in the affinity of these CR3022 variants for FcRn, we did not find substantial differences in basal-to-apical transport reflective of systemic dosing, or apical-to-basal transport reflective of inhaled dosing, compared to the transport of wildtype IgG 1 -Fc. These results suggest increasing FcRn affinity may only have limited influence over transcytosis rates of systemically dosed mAbs across the human airway epithelium over short time scales. Over longer time scales, the elevated circulating levels of mAbs with greater FcRn affinity, due to more effective FcRn-mediated recycling, may better resupply mAb into the respiratory tract, leading to more effective extended immunoprophylaxis., Competing Interests: Authors LZ, MP, and KW were employed by the company ZabBio. Author SL is founder of Mucommune, LLC and currently serves as its interim CEO. Author SL is also founder of Inhalon Biopharma, Inc, and currently serves as its CSO as well as on its Board of Director and Scientific Advisory Board. Author SL has equity interests in both Mucommune and Inhalon Biopharma; Author SL’s relationships with Mucommune and Inhalon are subject to certain restrictions under university policy. The terms of these arrangements are managed by UNC-CH in accordance with its conflict-of-interest policies. Author SL was inventor of intellectual property that has been licensed to Inhalon Biopharma. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Togami, Wolf, Olson, Card, Shen, Schaefer, Okuda, Zeitlin, Pauly, Whaley, Pickles and Lai.)

Advanced glycation end-products (AGEs) stochastically accrue in skeletal muscle and on collagen over an individual's lifespan, stiffening the muscle and modifying the stem cell (MuSC) microenvironment while promoting proinflammatory, antiregenerative signaling via the receptor for advanced glycation end-products (RAGEs). In the present study, a novel in vitro model was developed of this phenomenon by cross linking a 3-D collagen scaffold with AGEs and investigating how myoblasts responded to such an environment. Briefly, collagen scaffolds were incubated with d-ribose (0, 25, 40, 100, or 250 mM) for 5 days at 37°C. C2C12 immortalized mouse myoblasts were grown on the scaffolds for 6 days in growth conditions for proliferation, and 12 days for differentiation and fusion. Human primary myoblasts were also used to confirm the C2C12 data. AGEs aberrantly extended the DNA production stage of C2C12s (but not in human primary myoblasts) which is known to delay differentiation in myogenesis, and this effect was prevented by RAGE inhibition. Furthermore, the differentiation and fusion of myoblasts were disrupted by AGEs, which were associated with reductions in integrins and suppression of RAGE. The addition of S100b (RAGE agonist) recovered the differentiation and fusion of myoblasts, and the addition of RAGE inhibitors (FPS-ZM1 and Azeliragon) inhibited the differentiation and fusion of myoblasts. Our results provide novel insights into the role of the AGE-RAGE axis in skeletal muscle aging, and future work is warranted on the potential application of S100b as a proregenerative factor in aged skeletal muscle. NEW & NOTEWORTHY Collagen cross-linked by advanced glycation end-products (AGEs) induced myoblast proliferation but prevented differentiation, myotube formation, and RAGE upregulation. RAGE inhibition occluded AGE-induced myoblast proliferation, while the delivery of S100b, a RAGE ligand, recovered fusion deficits.

Background: Bisphosphonates limit resorption by inhibiting osteoclast formation and activation. They are removed during preparation of demineralized bone matrix (DBM) particles, but it is not known if osteogenesis and incorporation of mineralized bone allografts from patients treated with oral bisphosphonates are affected in vivo., Methods: Human block allografts from 3 bisphosphonate-treated donors and 3 age and sex-matched control donors who had not received bisphosphonates were obtained (Musculoskeletal Transplant Foundation); one-half from each donor was demineralized. In the first study, 3 × 2-mm mineralized and demineralized cylindrical grafts were implanted bilaterally in the femoral metaphysis of 56 rats. In the second study, samples from each group were pooled, prepared as particles, and implanted bilaterally in the femoral marrow canal of 24 rats. Osseointegration, defined as native bone in contact with allograft, was assessed at 10 weeks by micro-computed tomography (CT) and histomorphometry., Results: Micro-CT showed greater bone volume in sites treated with demineralized samples compared with the control mineralized and bisphosphonate-exposed mineralized samples. More new bone was generated along the cortical-endosteal interface compared with mineralized samples. Histology showed significantly less new bone in contact with the mineralized bisphosphonate-exposed allograft (10.4%) compared with mineralized samples that did not receive bisphosphonates (22.8%) and demineralized samples (31.7% and 42.8%). A gap was observed between native bone and allograft in the bisphosphonate-exposed mineralized samples (0.50 mm 2 ). The gap area was significantly greater compared with mineralized samples that did not receive bisphosphonates (0.16 mm 2 ) and demineralized samples (0.10 and 0.03 mm 2 )., Conclusions: Mineralized allografts were osseointegrated, but not remodeled or replaced by living bone, preventing full regeneration of the bone defect. Prior treatment of the donor with bisphosphonates affected osteogenesis, preventing osteointegration and remodeling of the allograft into the regenerating bone., Clinical Relevance: Clinical use of mineralized allografts from patients who had received bisphosphonate therapy needs to be evaluated; in this animal model, such grafts were not integrated into the host bone or remodeled, and full regeneration of the bone defects was prevented., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article ( http://links.lww.com/JBJS/H183 )., (Copyright © 2022 by The Journal of Bone and Joint Surgery, Incorporated.)

Transfection of chondrocytes with microRNA-451(miR-451), present in growth zone cartilage of the growth plate, upregulates production of enzymes association with extracellular matrix degradation. miR-451 is also present in articular cartilage and exacerbates IL-1β effects in articular chondrocytes. Moreover, when osteoarthritis (OA) was induced in Sprague Dawley rats via bilateral anterior cruciate ligament transection (ACLT), miR-451 expression was increased in OA cartilage compared to control, suggesting its inhibition might be used to prevent or treat OA. To examine the prophylactic and therapeutic potential of inhibiting miR-451, we evaluated treatment with miR-451 power inhibitor (451-PI) at the onset of joint trauma and treatment after OA had developed. The prophylactic animal cohort received twice-weekly intra-articular injections of either 451-PI or a negative control (NC-PI) beginning on post-surgical day 3. OA was allowed to develop for 24 days in the therapeutic cohort before beginning injections. All rats were killed on day 45. Micro-CT, histomorphometrics, OARSI scoring, and muscle force testing were performed on samples. 451-PI mitigated OA progression compared to NC-PI limbs in the prophylactic cohort based on histomorphometric analysis and OARSI scoring, but no differences were detected by micro-CT. 451-PI treatment beginning 24 days post-surgery was not able to reduce OA severity. Prophylactic administration of 451-PI mitigates OA progression in a post-trauma ACLT rat model supporting its potential to prevent OA development following an ACLT injury clinically., (© 2022. The Author(s).)

Volumetric muscle loss (VML) is the acute loss of muscle mass due to trauma. Such injuries occur primarily in the extremities and are debilitating, as there is no clinical treatment to restore muscle function. Pro-inflammatory advanced glycation end-products (AGEs) and the soluble receptor for advanced glycation end-products (RAGE) are known to increase in acute trauma patient's serum and are correlated with increased injury severity. However, it is unclear whether AGEs and RAGE increase in muscle post-trauma. To test this, we used decellularized muscle matrix (DMM), a pro-myogenic, non-immunogenic extracellular matrix biomaterial derived from skeletal muscle. We delivered adipose-derived stromal cells (ASCs) and primary myoblasts to support myogenesis and immunomodulation (N = 8 rats/group). DMM non-seeded and seeded grafts were compared to empty defect and sham controls. Then, 56 days after surgery muscle force was assessed, histology characterized, and protein levels for AGEs, RAGE, p38 MAPK, and myosin heavy chains were measured. Overall, our data showed improved muscle regeneration in ASC-treated injury sites and a regulation of RAGE and p38 MAPK signaling, while myoblast-treated injuries resulted in minor improvements. Taken together, these results suggested that ASCs combined with DMM provides a pro-myogenic microenvironment with immunomodulatory capabilities and indicates further exploration of RAGE signaling in VML.

Advanced age causes skeletal muscle to undergo deleterious changes including muscle atrophy, fast-to-slow muscle fiber transition, and an increase in collagenous material that culminates in the age-dependent muscle wasting disease known as sarcopenia. Advanced glycation end-products (AGEs) non-enzymatically accumulate on the muscular collagens in old age via the Maillard reaction, potentiating the accumulation of intramuscular collagen and stiffening the microenvironment through collagen cross-linking. This review contextualizes known aspects of skeletal muscle extracellular matrix (ECM) aging, especially the role of collagens and AGE cross-linking, and underpins the motor nerve's role in this aging process. Specific directions for future research are also discussed, with the understudied role of AGEs in skeletal muscle aging highlighted. Despite more than a half century of research, the role that intramuscular collagen aggregation and cross-linking plays in sarcopenia is well accepted yet not well integrated with current knowledge of AGE's effects on muscle physiology. Furthermore, the possible impact that motor nerve aging has on intramuscular cross-linking and muscular AGE levels is posited.

Decellularized tissues are biocompatible materials that engraft well, but the age of their source has not been explored for clinical translation. Advanced glycation end products (AGEs) are chemical cross-links that accrue on skeletal muscle collagen in old age, stiffening the matrix and increasing inflammation. Whether decellularized biomaterials derived from aged muscle would suffer from increased AGE collagen cross-links is unknown. We characterized gastrocnemii of 1-, 2-, and 20-month-old C57BL/6J mice before and after decellularization to determine age-dependent changes to collagen stiffness and AGE cross-linking. Total and soluble collagen was measured to assess if age-dependent increases in collagen and cross-linking persisted in decellularized muscle matrix (DMM). Stiffness of aged DMM was determined using atomic force microscopy. AGE levels and the effect of an AGE cross-link breaker, ALT-711, were tested in DMM samples. Our results show that age-dependent increases in collagen amount, cross-linking, and general stiffness were observed in DMM. Notably, we measured increased AGE-specific cross-links within old muscle, and observed that old DMM retained AGE cross-links using ALT-711 to reduce AGE levels. In conclusion, deleterious age-dependent modifications to collagen are present in DMM from old muscle, implying that age matters when sourcing skeletal muscle extracellular matrix as a biomaterial.

As the landscape of melanomagenesis becomes better refined through increasingly detailed schema grounded in distinct clinicopathologic-molecular pathways, the stepwise process and variations of molecular nevogenesis have largely remained elusive. Herein, we present a series of 8 melanocytic nevi in patients ranging from 40 to 74 years of age (median: 59.5 y), which demonstrated a reproducible constellation of histomorphologic features as well as a copy number gain of the long arm of chromosome 15 (15q). The most characteristic histologic feature was sclerosis with maturation at the base of the lesion. All cases demonstrated a dome-shaped configuration and epidermal acanthosis with hyperpigmentation. However, the cytologic features ranged in their appearances from that of a banal nevus with ovoid nuclei, inconspicuous nucleoli, and minimal cytoplasm to enlarged, epithelioid forms with central nucleoli and abundant cytoplasm. No lesions showed staining with BRAF V600E or NRAS Q61R immunohistochemistry. Single-nucleotide polymorphism-based chromosome microarray analysis revealed a monoaberrant 15q gain in all cases. The histology was sufficiently distinctive in the initial 6 cases encountered to allow for prospective identification of 2 additional cases harboring a 15q gain. The clinical follow-up did not reveal recurrence in any case. Although adverse outcomes were not observed in our cohort, future studies are needed to more adequately characterize the clinical and biological behavior of these lesions., Competing Interests: Conflicts of Interest and Source of Funding: Data presented in this manuscript was in part generated through CGAT in the Department of Pathology and Laboratory Medicine at Dartmouth-Hitchcock Medical Center, and the Norris Cotton Cancer Center (NCI Cancer Support Grant #5P30CA023108-37). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: The authors declare no conflict of interest.

Products developed for skeletal muscle regeneration frequently incorporate allogeneic and xenogeneic materials to elicit a regenerative response to heal skeletal muscle wounds. To avoid graft rejection in preclinical studies, immunodeficient rodents are used. Whether the immunodeficiency alters the host response to the material in skeletal muscle has not been studied. In this study, we hypothesized that an allogeneic acellular skeletal muscle grafts implanted in an immunodeficient rat (RNU, Foxn1 -deficient) would exhibit better new muscle fiber formation compared to grafts implanted in immunocompetent Sprague Dawley (SD) rats. Decellularized SD skeletal muscle matrix (DMM) was implanted in the gastrocnemius (N = 8 rats/group). 56 days after surgery, animal gait was examined and animals were euthanized. Muscle force was assessed and fiber number as well as immune cell infiltrate was measured by histomorphometry and immunohistochemistry. Animal gait and percent recovery of muscle force were unchanged in both groups, but newly regenerated muscle fibers increased in RNU rats. Macrophage staining for CD68 was higher in RNU rats than in SD rats. These data show differences in muscle regeneration between animal models using the same biomaterial treatment, but these differences could not be ascribed to the immune response. Overall, our data provide awareness that more studies are needed to understand how host responses to biomaterials differ based on the animal model used.

Cutaneous metastases by solid malignancies often signify advanced disease and portend severely limited survival. Appropriate diagnosis of these lesions is particularly hampered when they closely resemble primary cutaneous tumors. In this article, we present two diagnostically challenging cases of metastatic lesions to the scalp bearing striking histologic resemblance to primary cutaneous neoplasms. One case of a metastatic urothelial carcinoma showed epidermotropism as well as histologic and immunohistochemical features virtually indistinguishable from those of a poorly differentiated squamous cell carcinoma. Next generation sequencing was performed on both the primary urothelial carcinoma and scalp malignancy revealing an identical BRAF p. S467L somatic mutation, confirming the diagnosis. Another case of metastatic renal cell carcinoma showed clinical and histomorphologic features highly reminiscent of a pyogenic granuloma. These cases demonstrate the potential of metastatic lesions to assume a myriad array of innocuous disguises and underscore the vigilance required to avoid misdiagnosis. In addition, we highlight the emerging role of molecular strategies in resolving these problematic cases.

Purpose : Fasanella-Servat operation (FSO) was previously reported to be associated with post-operative dry eyes due to accessory lacrimal gland resection during the surgery.We performed a retrospective, cohort study to determine the frequency of lacrimal tissue resection during FSO and its correlation with post-operative eye dryness and keratopathy. Methods : Review of all patients who underwent FSO at New York-Presbyterian Weill Cornell Hospital over a two-year period (2013-2015). Patients were included only if they had adequate histopathological specimens of the resected tissue obtained during surgery. Outcomes included the study of the pathological specimen for the presence of lacrimal tissue; Post-operative dry eye symptoms and pre- and post-operative corneal epitheliopathy. Results : 46 patients with a total of 58 eyelid resections were studied.Eight eyelids (13.7%) were found to have lacrimal tissue present in the pathology specimens.Postoperatively, nine patients reported some symptoms of dry eye and new-onset keratopathy was noted in four eyes (6.8%), only one of which had lacrimal tissue present in histopathology specimen obtained from surgery. Discussion : Previous studies found lacrimal tissue present in up to 43% of specimens resected during FSO. Our data found a lower rate of lacrimal tissue resection during FSO, and did not find an association between lacrimal tissue resection and post-operative dryness or epitheliopathy. Conclusion : Our study is one of few to examine histopathological resections from the FSO.We found that lacrimal tissue is not frequently resected during FSO, and when it is resected, there is no increased incidence of post-operative dryness or keratopathy.

T cell lymphoproliferative disorders that arise in the skin are mainly derived from post thymic T cells most commonly of CD4 subset. Human CD4 positive T cells are dynamic exhibiting phenotypic and functional malleability. For example, with repetitive antigen exposure most commonly associated with age, CD4 positive T cells acquire a cytotoxic phenotype. The authors present four cases characterized by cutaneous infiltrates of cytotoxic CD30 negative CD4 positive T cells in the skin; three cases were forms of malignant lymphoma other than mycosis fungoides and one case was a reactive lymphomatoid photodermatosis associated with underlying collagen vascular disease. The three patients with lymphoma were adult men, two above 50 years of age and all with disseminated cutaneous disease. One of these patients whose biopsy showed a large cell morphology succumbed to the disease while one patient with localized disease responded to local radiation. In all three cases there was a nodular and diffuse pan-dermal infiltrate which was predominated by non-cerebriform atypical lymphocytes ranging from small to intermediate sized cells in two cases to a large cell dominant morphology in one case. The biopsies showed some degree of epidermotropism, and in one case it was striking. Neoplastic cells were positive for CD4, and at least one cytotoxic protein (i.e. granzyme and/or TIA). CD56, CD57 or CD30 were negative. In addition, CD28, the naïve T cell marker, was negative. Based on the few cases reported herein, one might suggest that the prognosis mirrors that seen in other forms of cutaneous T cell lymphoma with mature small cell dominant infiltrates exhibiting an indolent pattern while a CD30 negative large cell T cell lymphoma would be expected to demonstrate an aggressive clinical course., (Copyright © 2018. Published by Elsevier Inc.)

Impact Statement: Recombinant human bone morphogenetic protein 2 (rhBMP-2) delivery from collagen sponges for bone formation is an important clinical example of growth factors in tissue engineering. Side effects from rhBMP-2 burst release and rapid collagen resorption have led to investigation of alternative carriers. Here, keratin carriers with tunable erosion rates were formulated by varying disulfide crosslinking via ratios of oxidatively (keratose) to reductively (kerateine) extracted keratin. In vitro rhBMP-2 bioactivity increased with kerateine content, reaching levels greater than with collagen. Heterotopic bone formation in a mouse model depended on the keratin formulation, highlighting the importance of the growth factor carrier.

Interdigitating dendritic cell sarcoma (IDS) is a rare form of hematologic malignancy associated with an aggressive clinical course. Only 4 prior cases have been described as originating in the skin. We encountered two male patients ages 47 and 61years of age who presented with solitary cutaneous neoplasms diagnosed as IDS. Histologic exam showed a coalescing nested and multinodular proliferation of large pleomorphic epithelioid cells. In one case an initial diagnosis of melanoma was rendered. A recurrence 8months later was then interpreted as a primary cutaneous IDS. This patient died of widespread metastatic disease within 2years from his initial surgery. The other patient has recently undergone wide excision and radiation without any recurrence or metastatic disease during this short follow up time period. Both patients had a tumor exhibiting the same phenotypic profile comprising leukocyte common antigen, SOX10, S100, CD68, and CD163 positivity. In reviewing the 4 other reported cases, there is a similar older male predominance (mean age of 58years) although women affected were significantly younger (mean age of 28years); there was a predilection for the proximal extremities and the face. Patients treated with excision only developed recurrent disease with one patient subsequently dying of metastatic disease. Primary cutaneous IDS is a highly aggressive hematologic malignancy that has many overlapping features with poorly differentiated epithelioid and spindle cell melanoma including SOX10 staining. An aggressive treatment protocol at the beginning could optimize patient survival., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Primary cutaneous CD4+ small/medium sized pleomorphic T-cell lymphoma (SMPTCL) is unique among the peripheral T-cell lymphomas because of its indolent nature, typically presenting as a solitary nodule or plaque in the head and neck area of middle-aged and older adults. Recent studies have suggested a follicular helper cell origin for these lesions., Materials and Methods: A retrospective review was conducted on all cases of SMPTCL diagnosed between 2008 and 2017. The goal of our study was to better categorize the clinical, pathologic and molecular features of cases of SMPTCL showing a significant degree of CD30 neoplastic large cell infiltration., Results: Fifteen patients (10 male, 5 female) were encountered (age 33-86years at presentation). All lesions were solitary and the head and neck region was the most common area of involvement (7 cases). Surgical excision alone was performed in 6 cases and was supplemented with radiation in 5 cases. Disease recurrence did not occur. Spontaneous regression following biopsy was reported and two patients had a history compatible with lymphomatoid papulosis. All cases showed pathologic features characteristic of SMPTCL. Additionally, there were many larger CD30+ T-cells occupying 15-30% of the infiltrate. Monoclonality was demonstrated in 5 of 10 cases in which clonality studies were performed., Conclusion: CD30 positivity amidst large neoplastic T-cells is not uncommon in SMPTCL. The extent of CD30 positivity in SMPTCL needs to be defined further along with its association with other forms of CD30+ lymphoproliferative disease including its potential categorization as a form of endogenous CD30+ lymphoproliferative disease., (Copyright © 2017. Published by Elsevier Inc.)

Introduction: Lymphomatoid drug reactions are atypical T cell cutaneous lymphocytic infiltrates induced by pharmacological therapy. Due to phenotypic abnormalities, clonality, and their close clinical and morphologic resemblance to T cell lymphomas, these eruptions have been categorized as drug-associated reversible granulomatous T cell dyscrasias., Design: A total of 20 cases were encountered in which a diagnosis of CD30 lymphomatoid drug reaction was rendered., Results: There were 11 women and 9 men ranging from 31 to 86 years of age presenting with a sudden onset often generalized cutaneous papular eruption. Two patients had vasculitic lesions. In all cases, a positive drug history was elicited and in most the initiation of the drug was temporally associated with the cutaneous eruption. Among the implicated drugs were statins (6 cases), immunomodulators (4 cases), ACE inhibitors (3 cases), antibiotics (3 cases), chemotherapy agents (3 cases), and antidepressants (1 case). Biopsies demonstrated a similar morphology, namely a superficial angiocentric lymphocytic infiltrate containing many immunoblasts. Tissue eosinophilia, interface dermatitis, and supervening eczematous changes in the overlying epidermis were observed in most cases. In all cases, the angiocentric infiltrate was highlighted by CD3, CD30, and CD4. Cytotoxic protein granule expression or monoclonality was not observed. In all cases, there was improvement or complete regression of the eruption upon drug modulation., Conclusion: The CD30 positive lymphomatoid angiocentric drug reaction poses a diagnostic challenge because of its close resemblance to type A lymphomatoid papulosis and potential confusion with a peripheral T cell lymphoma with large cell transformation.

Background: Rapid cooling at procurement after cross-clamping has been the cornerstone of organ preservation. NanoICE is a new form of ice that has emerged in the food industry and is providing more efficient cooling and preservation than regular ice. We hypothesize that the use of NanoICE will accelerate the cooling process of the allograft and will be able to maintain a steady low temperature without causing any significant histologic damage., Methods: In this randomized pilot study, 14 pigs were used to study the liver core/surface cooling in a non-survival organ procurement operation. Animals were randomly assigned to 1 of 2 groups, each arm involving 7 pigs: (1) crushed-iced normal saline cooling method (control group) and (2) NanoICE cooling method (study group). Surface and core temperatures were measured with temperature probes, and liver biopsies were obtained before cross-clamping and 15 hours after preservation to assess for any evidence and degree of freezing injury., Results: NanoICE was able to reduce and sustain lower core temperatures at 30 minutes, 60 minutes, and 15 hours, compared with crushed ice. The degree of histologic damage (reflecting cold injury) at 15 hours after flushing was not significantly different between the 2 methods., Conclusions: NanoICE cools the deeper liver parenchyma more quickly and sustains a cooler temperature than regular crushed ice without causing significantly histologic damage. Future research should focus on whether the effect of NanoICE has any impact on graft function and survival., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Negative immunoregulatory checkpoints impede effective immune responses to tumor and reduce the action of anticancer agents. One such example is programmed death marker-1 (PD-1), an inhibitory signaling receptor expressed on activated and regulatory T-cells. PD-1 expression was reported in a few reports, but the expression profile of PD-1 and mycosis fungoides (MF) remains largely to be characterized., Design: In this study, skin biopsies from 42 prelymphomatous T-cell dyscrasias (CLD), 9 Sezary's syndrome (SS), 103 MF, and 20 CD30+ lymphoproliferative diseases (LPD) were examined for PD-1 expression using immunohistochemistry., Results: PD-1 staining was observed amidst many neoplastic T-cells in 6/9(66.7%) and 62/103 (60.2%) cases of SS and MF respectively, while only 6/42 (14.3%) cases of CLD and 0/20 (0%) cases of CD30+ LPD (P<0.001). Three cases are from same patients representing different stages of disease evolution from CLD to MF and SS with a corresponding enrichment of PD-1 positivity. In all cases there was variable staining of PD-1 amidst macrophages. There was no correlation with disease progression among MF cases. Twenty cases of CD30+ LPD did not show any PD-1 positivity., Conclusion: PD-1 seems to correlate with disease progression in epitheliotropic T cell dyscrasias ranging from minimal staining in prelymphomatous dyscrasias to significant staining in MF, likely reflecting the effects of PD-1 on inhibiting tumor surveillance regulatory T cell populations. PD-1 was consistently expressed in MF while it was consistently negative in primary CD30+ LPD, suggesting the possibility of using PD-1 as a means of distinguishing CD30+ MF from primary cutaneous ALCL., (Copyright © 2017. Published by Elsevier Inc.)

Aggressive extracutaneous B-cell lymphomas span the various stages of B-cell ontogeny and include B-cell lymphoblastic lymphoma, Burkitt lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma. Diffuse large B-cell lymphomas represent the most common histologic subtype of non-Hodgkin lymphomas, comprising 30% of adult non-Hodgkin lymphomas in the United States. A distinctive form of diffuse large B-cell lymphoma is the double-hit lymphoma, with most cases exhibiting a combined MYC and BCL2 rearrangement, leading some hematopathologists to propose the term MYC/BCL2 lymphoma. More recently, MYC rearrangement with multiple copies/gain of BCL2 or multiple copies/gain of MYC with a BCL2 rearrangement have been described and exhibit a very similar clinical course to conventional double-hit lymphomas. We report the seventh case of diffuse large B-cell lymphoma exhibiting this distinct cytogenetic abnormality and the first reported case in the skin. The patient's clinical course was aggressive, succumbing to disease 18 months after his initial presentation.

Hodgkin lymphoma (HL), although a common hematopoietic malignancy, presents as a primary cutaneous form in extraordinarily rare instances. In this study, we present a remarkable case of a 76-year-old woman with a history of bony metastatic breast cancer who developed multiple subcutaneous nodules on the left neck and scalp. A biopsy revealed the histological and immunohistochemical findings of classic HL. She was treated with systemic chemotherapy and quickly achieved disease remission. Five months later, she was alive and without evidence of lymphoma, consistent with our understanding of primary cutaneous HL as an indolent variant of HL.

Posttransplant lymphoproliferative disorders define an important form of lymphoproliferative disease causally linked with a state of iatrogenic immune dysregulation inherent to the posttransplant setting. Most posttransplant lymphoproliferative disorders are in the context of Epstein-Barr virus-associated B-cell lymphoproliferative disease, most notably diffuse large-cell B-cell lymphoma. A less common variant falls under the rubric of posttransplant T-cell lymphoproliferative disease, which is largely unrelated to Epstein-Barr virus infection. Anaplastic large-cell lymphoma (ALCL) is the most recognized form of posttransplant T-cell lymphoproliferative disease. Although the 6p25.3 translocation is seen in a variety of B-cell lymphoproliferative disorders, this particular translocation in the spectrum of T-cell lymphoproliferative disease is a fairly specific finding pointing toward a diagnosis of primary cutaneous ALCL and a rare subset of lymphomatoid papulosis. This translocation in the peripheral T-cell lymphoma setting serves as a favorable prognostic predictor. We report a case of an 81-year-old heart transplant recipient who developed an expansile neck mass 17 years after his heart transplant. A diagnosis of cutaneous ALCL was subsequently made with cytogenetic analysis yielding the 6p25.3 translocation. The characteristic biphasic morphology of a small-cell epidermotropic neoplastic cell populace in concert with a dermal based large-cell infiltrate characteristic for those cases of ALCL harboring this translocation was seen. After excision of the nodule, his azathioprine was withheld. He is currently alive and well without evidence of disease.

Individuals with conversion disorder have neurologic symptoms that are not identified by an underlying organic cause. Often the symptoms manifest as gait disturbances. The modified gait abnormality rating scale (GARS-M) may be useful for quantifying gait abnormalities in these individuals. The purpose of this study was to examine the reliability, responsiveness and concurrent validity of GARS-M scores in individuals with conversion disorder. Data from 27 individuals who completed a rehabilitation program were included in this study. Pre- and post-intervention videos were obtained and walking speed was measured. Five examiners independently evaluated gait performance according to the GARS-M criteria. Inter- and intrarater reliability of GARS-M scores were estimated with intraclass correlation coefficients (ICCs). Responsiveness was estimated with the minimum detectable change (MDC). Pre- to post-treatment changes in GARS-M scores were analyzed with a dependent t-test. The correlation between GARS-M scores and walking speed was analyzed to assess concurrent validity. GARS-M scores were quantified with good-to-excellent inter- (ICC = 0.878) and intrarater reliability (ICC = 0.989). The MDC was 2 points. Mean GARS-M scores decreased from 7 ± 5 at baseline to 1 ± 2 at discharge (t26 = 7.411, p < 0.001) and 85% of patients improved beyond the MDC. Furthermore, GARS-M scores and walking speed measurements were moderately correlated (r = -0.582, p = 0.004), indicating that the GARS-M has acceptable concurrent validity. Our findings provide evidence that the GARS-M scores are reliable, valid and responsive for quantifying gait abnormalities in patients with conversion disorder. GARS-M scores provide objective measures upon which treatment effects can be assessed., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Nicotine has an antinociceptive effect in animal models. The analgesic effect in humans has been examined, but studies have had mixed results. A proposed etiology is variability in chronic nicotine exposure because of differences in tobacco smoking rates and second-hand smoke exposure. In this study, we examined the postoperative analgesic effect of a transdermal nicotine patch in smokers in a parallel design to a previous study in nonsmokers., Methods: We conducted a randomized, double-blind, prospective, placebo-controlled trial of 28 patients undergoing abdominal or pelvic surgery who required patient-controlled analgesia and an overnight hospital stay. Before anesthetic induction, a transdermal nicotine patch was applied (0, 5, 10, or 15 mg). The primary outcome variable was postoperative pain reported over the first hour and over the next 5 days using a standard numerical rating scale. Secondary outcome variables were pain medication use, hemodynamic values, nausea, and sedation., Results: Patients treated with nicotine reported higher pain scores than those treated with placebo over the first hour after surgery (P < 0.01, average numerical rating scale increase = 0.67) and there was no difference between groups in the subsequent 5 days (P > 0.05). There was no significant dose effect. Diastolic blood pressure in the first hour was higher in the placebo group compared with the nicotine-treated group (P < 0.01, average increase = 11 mm Hg). There was no difference in nausea or sedation., Conclusions: Transdermal nicotine, 5-15 mg, failed to relieve postoperative pain or reduce opioid use in smokers.

The use of donation after cardiac death (DCD) donor hepatic allografts is becoming more widespread; however, there have been published reports of increased graft failure from specific complications associated with this type of allograft. The complication of ischemic cholangiopathy (IC) has been reported to occur more frequently after the use of DCD hepatic allografts. We report the results of 52 liver transplants from DCD donors and the factors that influenced the development of IC. We conducted a retrospective review of all DCD and donation after brain death (DBD) donor liver recipients from September 2003 through December 2006 at a single institution. Survival and complication rates were compared between the 2 groups. The Cox proportional hazards model was then used to identify recipient and donor factors that predict the development of IC in the DCD group. There was no difference in 1-year patient or graft survival rates between the 2 groups. There was no incidence of primary nonfunction from the DCD allografts. Hepatic artery complications and anastomotic bile duct complications were comparable in the 2 groups. There was, however, an increased risk for the development of IC in the DCD group (13.7% versus 1%, P = 0.001). Donor weight >100 kg and total ischemia times > or =9 hours, in donors older than 50 years of age, predicted the development of IC in the DCD group. In conclusion, there is a higher incidence of IC in recipients receiving DCD donor livers; however, patient and graft outcomes with DCD donors remain comparable to those with DBD donors. Careful donor selection may improve utilization of these grafts.

Introduction: We report a technique for extending the distal aorta to facilitate the transplantation of en bloc horseshoe kidneys., Technical Considerations: En bloc horseshoe kidneys can be transplanted by a technique that is analogous to the en bloc transplantation of small pediatric kidneys. However, the horseshoe kidney's isthmus prevents ascent of the kidney, and the fused lower poles stay below the level of the inferior mesenteric artery. Therefore, the distal aorta is behind the isthmus. Extending the distal aorta produces adequate vessel length to simplify en bloc transplantation of horseshoe kidneys. The extra aortic length is obtained by spatulating the distal common iliac arteries on their medial surfaces and bringing them together as a "pair of pants" for about 1.5 cm. This produces an arterial conduit that branches into the left and right common iliac arteries and then rejoins at the distal aorta. The aortic extension produces a useable vascular conduit that can be anastomosed to the recipient's external iliac artery. The distal inferior vena cava is anastomosed to the external iliac vein. We used this technique in 1 patient. The transplanted kidney made urine promptly and was providing normal function with a serum creatinine of 1.1 mg/dL., Conclusions: It is preferable to transplant some horseshoe kidneys en bloc using the distal aorta and inferior vena cava for vascular anastomoses. This technique extends the distal aorta and provides adequate vessel length to facilitate en bloc transplantation.

Over a period of ten months, five mice submitted to our service (the Pathology Section of the Veterinary Resources Program, Office of Research Services at the National Institutes of Health, Bethesda, Md.) were diagnosed with disseminated trichosporonosis. These mice had pyogranulomatous inflammation in multiple organs, including lung, liver, lymph nodes, salivary gland, and skin. Fungal elements in many of the lesions were identified, using special histochemical stains, and Trichosporon beigelii was obtained by use of culture of specimens at affected sites. This saprophytic fungus has caused disseminated disease in immunosuppressed humans. However, despite widespread use of immunosuppressed rodents in research, to the authors' knowledge, this organism had not previously been reported to cause spontaneous disseminated disease in laboratory mice. All affected mice had a genetically engineered defect in p47(phox), a critical component of the nicotinamide dinucleotide phosphate (NADPH) oxidase, the enzyme responsible for generating the phagocyte oxidative burst. These animals are used as a murine model of human chronic granulomatous disease. We discuss the lesions, differential diagnosis, identification of the organism, and the role of NADPH oxidase in protecting against disseminated trichosporonosis.

Background: Most clinical studies have shown that beta-adrenergic receptor antagonists improve long-term survival in heart failure patients. Bucindolol, a nonselective beta-receptor blocker, however, failed to reduce heart failure mortality in a recent large clinical trial. The reasons for this failure are not known. Bucindolol has partial agonist properties in rat myocardium, but whether it has agonist activity in human heart is controversial. To address this, we measured the ability of bucindolol to increase cAMP accumulation in human myocardium., Methods and Results: Myocardial strips ( approximately 1 mm(3)) obtained from rat and nonfailing human hearts were confirmed to be viable for > or = 48 hours in normoxic tissue culture by MTT assay and histology. Freshly isolated strips were exposed to beta-adrenergic antagonists and agonists and assayed for cAMP. In both rat and human strips, the full beta-adrenergic agonist isoproterenol raised cAMP levels by >2.5-fold at 15 minutes. Carvedilol and propranolol had no effect on basal cAMP levels, whereas metoprolol reduced basal cAMP by approximately 25%. In contrast, bucindolol and xamoterol increased cAMP levels in a concentration-dependent manner in both rat and human myocardium (maximum 1.64+/-0.25-fold and 2.00+/-0.27-fold over control, respectively, P<0.01 for human tissue)., Conclusions: Bucindolol exhibits approximately 60% of the beta-adrenergic agonist activity of xamoterol in normal human myocardial tissue.

Diagnostic Cytology Laboratory, Inc., has an outpatient Fine Needle Biopsy Clinic, which evaluated 7,487 fine-needle biopsies (FNB) from January 1989 to February 1992. Two hundred eighty-eight (3.8%) of these specimens were collected from patients 19 years old or younger and this represents the largest study of this population in the scientific literature. The majority of these specimens were obtained from palpable masses in the head and neck region [lymph nodes (58.3%), thyroid (7.6%), and salivary gland (5.2%)] while a smaller number were collected from miscellaneous soft tissue (18.8%) and breast masses (10.1%). Thirteen (4.5%) (from 12 patients) were diagnosed as malignant by FNB and 275 (95.5%) (264 patients) were benign by FNB. This benign:malignant ratio (22:1) is significantly higher than has been reported from tertiary care institutions and is a reflection of the difference of this outpatient population. Two hundred nine of 276 patients (75.7%) had adequate follow-up, including 137 (49.6%) patients followed by observation, 48 (17.4%) patients followed by surgical biopsy, and 24 (8.7%) patients followed by some other modality: imaging studies, flow cytometry, or treatment. There was a single false positive diagnosis (a pilomatrixoma) and one (1) false negative interpretation (a cystic acinic cell carcinoma) resulting in a diagnostic sensitivity of 92.3% and a specificity of 99.6%. The positive predictive value was 92.3%, the negative predictive value was 99.6%, and the test efficiency was 99.3%. The utility, cost-effectiveness and uniqueness of the clinic population is discussed.

Pertussis, one of the most communicable respiratory diseases, has a wide spectrum of severity, which generally decreases with age. Adults with waning immunity, who have subclinical pertussis, frequently infect nonimmunized or underimmunized children within the same household. High levels of pertussis activity persist, even in highly immunized populations. Infants less than 2 months of age have the highest attack rate and greatest morbidity and mortality. Serious complications include apnea, pneumonia, encephalopathy, and recurrence of coughing spasms with cyanosis. These complications further contribute to a protracted disease course in young infants. Although a decrease in the incidence of pertussis has occurred since the advent of active immunization in the United States, recent data show a striking resurgence in cases. Widespread transmission of disease, even in immunized individuals, and subclinical adult infection, which serves as a reservoir for disease in young infants, underscore the need for a more effective vaccine immunization strategy.