Nonsclerotic Lichen Sclerosus of Vulva: A Clinicopathologic Analysis.

The International Society of the Study of Vulvovaginal Diseases (ISSVD) recently defined nonsclerotic lichen sclerosus (NSLS) as a scenario wherein the clinical findings are consistent with lichen sclerosus (LS), but no microscopic evidence of dermal sclerosis is found and recognized 4 histologic subcategories. Herein, we present an institutional experience with NSLS, with an emphasis on frequency, application of the ISSVD categories in routine practice, and clinicopathologic correlation. The authors reviewed clinical and pathologic findings for consecutive vulvar biopsies in which LS was a clinical and/or pathologic consideration. Cases were classified as classical/sclerotic LS (CLS), NSLS (per ISSVD criteria), and "unclassified," the latter of which were cases not classifiable as NSLS or CLS, despite a clinical impression or LS or LS being a significant clinical consideration (ie, "clinical LS"). In clinical LS cases, CLS and NSLS were diagnosed histologically in 61% (182/298) and 15% (44/298), respectively, whereas the remainder were histologically unclassified. The latter group was microscopically heterogeneous, devoid of a consistent pathologic profile, and generally showed absence, focality, minimality, ambiguity, or infrequency of features that would have allowed their categorization into one of the NSLS categories. Among the 4 categories for the categorizable NSLS cases, the "lichenoid dermatitis" pattern (61.4%) was the commonest, followed by dermal fibrosis with acanthosis (22.7%), dermal fibrosis without acanthosis (9.1%), and hypertrophic lichenoid dermatitis (6.8%). The clinical response rates to topical therapies for the NSLS and unclassified groups were 71% and 62%, respectively (P=0.4). Our findings highlight the significance of clinicopathologic correlation in the diagnosis of NSLS. In the setting of clinical LS, some histologic evidence to support that impression is found in most cases when the ISSVD system for diagnosis and classification of biopsies is applied. However, a subset of clinical LS cases are not pathologically classifiable as either CLS or any of the NSLS categories; these display nonspecific histologic features and require future study.

B3 thymoma mimicking poorly differentiated thyroid carcinoma: Diagnostic pitfalls of anterior mediastinal mass fine needle aspiration.

B3 thymoma is a rare malignant type of thymic epithelial neoplasm found in the anterior mediastinum. Diagnosis of thymoma from fine needle aspiration (FNA) can be challenging due to the infrequency of sampling and its morphologic overlap with other entities such as squamous cell carcinoma, lymphoma or thyroid carcinoma. We report a case of B3 thymoma mimicking poorly differentiated thyroid carcinoma. We present its diagnostic pitfalls on cytology specimens, especially where it concerns identifying the correct location of the lesion, discuss the differential diagnosis, and correlation with the corresponding surgical resection specimen. A neck computed tomography angiogram (CTA) revealed a partially calcified 2.1 cm mass inferior to the left thyroid lobe in a 51 yr old woman being evaluated for stroke/TIA symptoms. She was referred for evaluation of the lesion. On the initial FNA and core needle biopsy, the lesion showed high-grade epithelioid cells with abundant lymphocytic infiltration and occasional necrosis, and was diagnosed as a high-grade carcinoma, favored to represent a poorly differentiated thyroid carcinoma considering the location on imaging. The patient subsequently underwent total thyroidectomy, central neck dissection, and thymectomy. Final surgical pathologic diagnosis indicated a type B3 thymoma. Due to the infrequency of sampling, thymoma poses a diagnostic challenge on preoperative FNA or core needle biopsy. Herein, we present a case of B3 thymoma with a preoperative cytologic specimen that consisted of hyperchromatic sheets of epithelioid tumor cells with a background of lymphocytes without definitive follicular cells or colloid. The core needle biopsy and cell block material showed abundant necrosis, intermixed lymphocytes and neoplastic epithelial cells with strong positive staining for pan-keratin and p40. The cytology and core needle biopsy material were interpreted as representing a probable thyroid neoplasm and raised a broad differential including anaplastic thyroid carcinoma, poorly differentiated thyroid carcinoma with squamous features, metastatic squamous carcinoma, and metastatic carcinoma to a lymph node. The final surgical resection specimen showed a B3 type-thymoma.

Littoral macroinvertebrate communities of alpine lakes along an elevational gradient (Hohe Tauern National Park, Austria).

Alpine lakes support unique communities which may respond with great sensitivity to climate change. Thus, an understanding of the drivers of the structure of communities inhabiting alpine lakes is important to predict potential changes in the future. To this end, we sampled benthic macroinvertebrate communities and measured environmental variables (water temperature, dissolved oxygen, conductivity, pH, nitrate, turbidity, blue-green algal phycocyanin, chlorophyll-a) as well as structural parameters (habitat type, lake size, maximum depth) in 28 lakes within Hohe Tauern National Park, Austria, between altitudes of 2,000 and 2,700 m a.s.l. The most abundant macroinvertebrate taxa that we found were Chironomidae and Oligochaeta. Individuals of Coleoptera, Diptera, Hemiptera, Plecoptera, Trichoptera, Tricladida, Trombidiformes, Veneroida were found across the lakes and determined to family level. Oligochaeta were not determined further. Generalized linear modeling and permanova were used to identify the impact of measured parameters on macroinvertebrate communities. We found that where rocky habitats dominated the lake littoral, total macroinvertebrate abundance and family richness were lower while the ratio of Ephemeroptera, Plecoptera and Trichoptera (EPT) was higher. Zoo- and phytoplankton densities were measured in a subset of lakes but were not closely associated with macroinvertebrate abundance or family richness. With increasing elevation, macroinvertebrate abundances in small and medium-sized lakes increased while they decreased in large lakes, with a clear shift in community composition (based on families). Our results show that habitat parameters (lake size, habitat type) have a major influence on benthic macroinvertebrate community structure whereas elevation itself did not show any significant effects on communities. However, even habitat parameters are likely to change under climate change scenarios (e.g. via increased erosion) and this may affect alpine lake macroinvertebrates.

Nonmass enhancement lesions of the breast on core needle biopsy: outcomes, frequency of malignancy, and pathologic findings.

Nonmass enhancement (NME) on breast magnetic resonance imaging (MRI) is defined as an area whose internal enhancement characteristics can be distinguished from the normal surrounding breast parenchyma, without an associated mass in the Breast Imaging Reporting and Data System lexicon. In this study, we evaluated the pathologic correlates of NME lesions of the breast identified on MRI at our institution, including the frequency of atypical or malignant lesions in the core needle biopsies (CNBs), performed after such a radiologic finding. A retrospective study was performed on all CNBs performed for NME on breast MRI between 2010 and 2019. A total of 443 biopsies from 411 patients were identified, comprising 5.5% of all CNBs over the study period. The pathologic diagnoses were benign in the majority of the biopsies (68.0%), whereas 11.5% and 20.5% of the cases were atypical and malignant lesions, respectively. Of the malignant cases, 69.2% were ductal carcinoma in situ (DCIS) and 30.8% were invasive carcinomas. The most common invasive cancer was invasive ductal carcinoma (50%), followed by invasive lobular carcinoma (39.3%). NME identified on breast MRI carried a significant (32%) risk of atypia and malignancy in our cohort, which confirms that biopsy evaluation of these lesions is warranted. DCIS was the most commonly identified malignancy. Notably, among invasive cancers, invasive lobular carcinoma was identified at a substantially higher frequency that would be expected for that histotype.

Distance dependent shedding of IL-6R.

Proteolytic processing of membrane proteins by A disintegrin and metalloprotease-17 (ADAM17) is a key regulatory step in many physiological and pathophysiological processes. This so-called shedding is essential for development, regeneration and immune defense. An uncontrolled ADAM17 activity promotes cancer development, chronic inflammation and autoimmune diseases. Consequently, the ADAM17 activity is tightly regulated. As a final trigger for the shedding event a phosphatidylserine (PS) flip to the outer leaflet of the cell membrane was recently described. PS interacts with the extracellular part of ADAM17, which results in the shedding event by shifting the catalytic domain towards the membrane close to the cleavage sites within ADAM17 substrates. Our data indicate that the intrinsic proteolytic activity of the catalytic domain is prerequisite for the shedding activity and constantly present. However, the accessibility for substrate cleavage sites is controlled on several levels. In this report, we demonstrate that the positioning of the catalytic domain towards the cleavage sites is a crucial part of the shedding process. This finding contributes to the understanding of the complex and multilayered regulation of ADAM17 at the cell surface.

KDEL Receptor 1 Contributes to Cell Surface Association of Protein Disulfide Isomerases.

BACKGROUND/AIMS: Endoplasmic reticulum (ER)-resident proteins with a C-terminal KDEL ERretention sequence are captured in the Golgi apparatus by KDEL receptors (KDELRs). The binding of such proteins to these receptors induces their retrograde transport. Nevertheless, some KDEL proteins, such as Protein Disulfide Isomerases (PDIs), are found at the cell surface. PDIs target disulfide bridges in the extracellular domains of proteins, such as integrins or A Disintegrin And Metalloprotease 17 (ADAM17) leading to changes in the structure and function of these molecules. Integrins become activated and ADAM17 inactivated upon disulfide isomerization. The way that PDIs escape from retrograde transport and reach the plasma membrane remains far from clear. Various mechanisms might exist, depending on whether a local cell surface association or a more global secretion is required. METHODS: To get a more detailed insight in the transport of PDIs to the cell surface, methods such as cell surface biotinylation, flow cytometric analysis, immunoprecipitation, fluorescence microscopy as well as labeling of cells with fluorescence labled recombinant PDIA6 was performed. RESULTS: Here, we show that the C-terminal KDEL ER retention sequence is sufficient to prevent secretion of PDIA6 into the extracellular space but is mandatory for its association with the cell surface. The cell surface trafficking of PDIA1, PDIA3, and PDIA6 is dependent on KDELR1, which travels in a dynamic manner to the cell surface. This transport is assumed to result in PDI cell surface association, which differs from PDI inducible secretion into the extracellular space. Distinct PDIs differ in their trafficking properties. Endogenous KDELR1, detectable at the cell surface, might be involved not only in the transport of cell-surface-associated PDIs, but also in their retrieval and internalization from the extracellular space. CONCLUSION: Beside their ER retention motive PDIs travel to the cell surface. Here they target different proteins to render their function. To escape the ER PDIs travel via various pathways. One of them depends on the KDELR1, which can transport its target to the cell surface, where it is to be expected to release its cargo in close vicinity to its target molecules. Hence, the KDEL sequence is needed for cell surface association of PDIs, such as PDIA6.

GRP78 protects a disintegrin and metalloprotease 17 against protein-disulfide isomerase A6 catalyzed inactivation.

The shedding of ectodomains is a crucial mechanism in many physiological and pathological events. A disintegrin and metalloprotease-17 (ADAM17) is a key sheddase involved in essential processes, such as development, regeneration, and immune defense. ADAM17 exists in two conformations which differ in their disulfide connection in the membrane-proximal domain (MPD). Protein-disulfide isomerases (PDIs) on the cell surface convert the open MPD into a rigid closed form, which corresponds to inactive ADAM17. ADAM17 is expressed in its open activatable form in the endoplasmic reticulum (ER) and consequently must be protected against ER-resident PDI activity. Here, we show that the chaperone 78-kDa glucose-regulated protein (GRP78) protects the MPD against PDI-dependent disulfide-bond isomerization by binding to this domain and, thereby, preventing ADAM17 inhibition.

Recalcitrant genital papules.

This patient was initially told he had genital warts, but the appearance of the lesions, and the presence of a rash on his trunk and extremities, suggested another diagnosis.

Pearls and pitfalls: Autoimmune lymphoproliferative syndrome and autoimmune lymphoproliferative syndrome-like disease.

A case of autoimmune lymphoproliferative syndrome (ALPS) was presented, followed by a discussion of the clinical characteristics, pathophysiology, diagnosis, and management of this disease. Clinical pearls and pitfalls are emphasized for the use of the practicing allergist and the fellow in-training. The diagnosis of ALPS was guided by published criteria. A careful history and workup were needed to exclude other possible etiologies for the patient's symptoms and physical findings. ALPS often carries significant morbidity and is best managed through a multidisciplinary approach.

Subhepatic Sterile Abscess 10 Years After Laparoscopic Cholecystectomy.

We present a case of a large, sterile, subhepatic abdominal wall abscess secondary to foreign body reaction to dropped gallstones during laparoscopic cholecystectomy performed 10 years ago. Dropped gallstones are common complications of laparoscopic cholecystectomy, but they rarely result in abscess formation. When abscesses do occur, they may present a few months to a few years after surgery. It is important to recognize dropped gallstones as an etiology for subhepatic abscess in patients with history of laparoscopic cholecystectomy.

Overexpression of specific cysteine peptidases confers pathogenicity to a nonpathogenic Entamoeba histolytica clone.

Cysteine peptidases (CPs) of Entamoeba histolytica are considered to be important pathogenicity factors. Previous studies have found that under standard axenic culture conditions, only four (ehcp-a1, ehcp-a2, ehcp-a5, and ehcp-a7) out of 35 papain-like ehcp genes present in the E. histolytica genome are expressed at high levels. Little is known about the expression of CPs in E. histolytica during amoebic liver abscess (ALA) formation. In the current study, a quantitative real-time PCR assay was developed to determine the expression of the various ehcp genes during ALA formation in animal models. Increased expression of four ehcp genes (ehcp-a3, -a4, -a10, and -c13) was detected in the gerbil and mouse models. Increased expression of another three ehcp genes (ehcp-a5, -a6, and -a7) was detected in the mouse model only, and two other ehcp genes (ehcp-b8 and -b9) showed increased expression in the gerbil model only. Trophozoites of the nonpathogenic E. histolytica HM-1:IMSS clone A1, which was unable to induce ALAs, were transfected with vectors enabling overexpression of those CPs that are expressed at high levels under culture conditions or during ALA formation. Interestingly, overexpression of ehcp-b8, -b9, and -c13 restored the pathogenic phenotype of the nonpathogenic clone A1 whereas overexpression of various other peptidase genes had no effect on the pathogenicity of this clone.

Controlled treadmill exercise eliminates chondroid deposits and restores tensile properties in a new murine tendinopathy model.

Tendinopathy is a widespread and disabling condition characterized by collagen fiber disruption and accumulation of a glycosaminoglycan-rich chondroid matrix. Recent clinical reports have illustrated the potential of mechanical loading (exercise) therapies to successfully treat chronic tendinopathies. We have developed a new murine tendinopathy model which requires a single injection of TGF-ß1 into the Achilles tendon midsubstance followed by normal cage activity for 2 weeks. At this time, tendon maximum stress showed a dramatic (66%) reduction relative to that of normal controls and this persisted at four weeks. Loss of material properties was accompanied by abundant chondroid cells within the tendon (closely resembling the changes observed in human samples obtained intra-operatively) and increased expression of Acan, Col1a1, Col2a1, Col3a1, Fn1 and Mmp3. Mice subjected to two weeks of daily treadmill exercise following TGF-ß1 injection showed a similar reduction in tendon material properties as the caged group. However, in mice subjected to 4 weeks of treadmill exercise, tendon maximum stress values were similar to those of naive controls. Tendons from the mice exercised for 4 weeks showed essentially no chondroid cells and the expression of Acan, Col1a1, Col2a1, Col3a1, and Mmp3 was significantly reduced relative to the 4-week cage group. This technically simple murine tendinopathy model is highly amenable to detailed mechanistic and translational studies of the biomechanical and cell biological pathways, that could be targeted to enhance healing of tendinopathy.

Colonic diffuse large B-cell lymphoma in a liver transplant patient with historically very low tacrolimus levels.

Posttransplant lymphoproliferative disorders (PTLDs) comprise a wide spectrum of hematologic malignancies that are found increasingly in orthotopic liver transplant (OLT) patients given the rising frequency of these surgeries and their long-term success. PTLDs are highly correlated with both the Epstein-Barr virus (EBV) infection and the degree of immunosuppression involved. Herein is reported a case of a 53-year-old male with successfully treated hepatitis C virus genotype 4 and hepatocellular carcinoma who underwent OLT and developed symptoms of weakness and poor appetite 4 years later while on tacrolimus 3 mg b.i.d. with historically very low plasma levels. He was found to be anemic and colonoscopy revealed a 4.5 cm cecal diffuse large B-cell lymphoma (DLBCL). Further workup revealed mesenteric lymph node enlargement consistent and nodal DLBCL dissemination. He was treated with cyclophosphamide-hydroxyldaunorubicin-oncovin-prednisone-rituximab (CHOP-R) chemotherapy and his tacrolimus dose was lowered. Additionally, he manifested PTLD-associated cryoglobulinemia leading to acute kidney injury. After a prolonged hospitalization he was discharged with close followup.

Neural crest deletion of Dlx3 leads to major dentin defects through down-regulation of Dspp.

During development, Dlx3 is expressed in ectodermal appendages such as hair and teeth. Thus far, the evidence that Dlx3 plays a crucial role in tooth development comes from reports showing that autosomal dominant mutations in DLX3 result in severe enamel and dentin defects leading to abscesses and infections. However, the normal function of DLX3 in odontogenesis remains unknown. Here, we use a mouse model to demonstrate that the absence of Dlx3 in the neural crest results in major impairment of odontoblast differentiation and dentin production. Mutant mice develop brittle teeth with hypoplastic dentin and molars with an enlarged pulp chamber and underdeveloped roots. Using this mouse model, we found that dentin sialophosphoprotein (Dspp), a major component of the dentin matrix, is strongly down-regulated in odontoblasts lacking Dlx3. Using ChIP-seq, we further demonstrate the direct binding of Dlx3 to the Dspp promoter in vivo. Luciferase reporter assays determined that Dlx3 positively regulates Dspp expression. This establishes a regulatory pathway where the transcription factor Dlx3 is essential in dentin formation by directly regulating a crucial matrix protein.

Multifunctional, multichannel bridges that deliver neurotrophin encoding lentivirus for regeneration following spinal cord injury.

Therapeutic strategies following spinal cord injury must address the multiple barriers that limit regeneration. Multiple channel bridges have been developed that stabilize the injury following implantation and provide physical guidance for regenerating axons. These bridges have now been employed as a vehicle for localized delivery of lentivirus. Implantation of lentivirus loaded multiple channel bridges produced transgene expression that persisted for at least 4 weeks. Expression was maximal at the implant at the earliest time point, and decreased with increasing time of implantation, as well as rostral and caudal to the bridge. Immunohistochemical staining indicated transduction of macrophages, Schwann cells, fibroblasts, and astrocytes within the bridge and adjacent tissue. Subsequently, the delivery of lentivirus encoding the neurotrophic factors NT-3 or BDNF significantly increased the extent of axonal growth into the bridge relative to empty scaffolds. In addition to promoting axon growth, the induced expression of neurotrophic factors led to myelination of axons within the channels of the bridge, where the number of myelinated axons was significantly enhanced relative to control. Combining gene delivery with biomaterials to provide physical guidance and create a permissive environment can provide a platform to enhance axonal growth and promote regeneration.

Cholesterol in pregnancy: a review of knowns and unknowns.

Cholesterol forms part of every cell in the human body, and also helps make and metabolize hormones, bile acids and vitamin D. Human plasma cholesterol levels are determined by production in the liver and by dietary intake. Lipoproteins carry cholesterol around the body, and facilitate it crossing the placenta. Cholesterol is carefully monitored in the non-pregnant adult population, where its association with atherosclerosis and cardiovascular disease is well understood. Although it is known that cholesterol rises in pregnancy, at present it is not routinely measured or treated. The effects of maternal high cholesterol on pregnancy and on fetal development are not yet fully understood. However, a growing body of evidence from animal and human studies suggests adverse consequences of high cholesterol levels in pregnancy.

Diagnostic and therapeutic laparoscopy for stab wounds of the anterior abdomen.

BACKGROUND: At present, laparoscopy is used mainly as a diagnostic tool in patients with abdominal stab wounds. PATIENTS AND METHODS: Thirty-two hemodynamically stable patients with isolated stab wounds of the anterior abdomen, thought to be penetrating, were prospectively selected to undergo treatment via a laparoscopic approach. When possible, parenchymal wounds were coagulated or sealed, and wounds to the intestines were sutured or stapled. RESULTS: The results of laparoscopy were negative in 6 (18.8%) of the cases: nonpenetrating wounds in 4 cases and nonsignificant organ injury in 2 cases. A hemoperitoneum was identified in 13 (40.6%) of the cases, and significant organ injuries in 26 (81.3%) of the cases: stomach, 2; small bowel, 5; colon, 2; pancreas, 1; vascular injuries, 4; liver, 5; mesentery, 9. Laparoscopy was therapeutic in 20 (62.3%) of the cases. Conversion to open surgery was required in 6 (18.8%) of the cases. No injuries were missed, and no mortality occurred. Postoperative complications developed in 2 (6.2%) of the cases. The mean hospital stay was 4 days, with no late complications. CONCLUSIONS: Laparoscopy can avoid a number of unnecessary laparotomies and can treat most of the lesions found in hemodynamically stable patients with anterior abdominal stab wounds.