A multi-center retrospective cohort study defines the spectrum of kidney pathology in Coronavirus 2019 Disease (COVID-19).

Kidney failure is common in patients with Coronavirus Disease-19 (COVID-19), resulting in increased morbidity and mortality. In an international collaboration, 284 kidney biopsies were evaluated to improve understanding of kidney disease in COVID-19. Diagnoses were compared to five years of 63,575 native biopsies prior to the pandemic and 13,955 allograft biopsies to identify diseases that have increased in patients with COVID-19. Genotyping for APOL1 G1 and G2 alleles was performed in 107 African American and Hispanic patients. Immunohistochemistry for SARS-CoV-2 was utilized to assess direct viral infection in 273 cases along with clinical information at the time of biopsy. The leading indication for native biopsy was acute kidney injury (45.4%), followed by proteinuria with or without concurrent acute kidney injury (42.6%). There were more African American patients (44.6%) than patients of other ethnicities. The most common diagnosis in native biopsies was collapsing glomerulopathy (25.8%), which was associated with high-risk APOL1 genotypes in 91.7% of cases. Compared to the five-year biopsy database, the frequency of myoglobin cast nephropathy and proliferative glomerulonephritis with monoclonal IgG deposits was also increased in patients with COVID-19 (3.3% and 1.7%, respectively), while there was a reduced frequency of chronic conditions (including diabetes mellitus, IgA nephropathy, and arterionephrosclerosis) as the primary diagnosis. In transplants, the leading indication was acute kidney injury (86.4%), for which rejection was the predominant diagnosis (61.4%). Direct SARS-CoV-2 viral infection was not identified. Thus, our multi-center large case series identified kidney diseases that disproportionately affect patients with COVID-19 and demonstrated a high frequency of APOL1 high-risk genotypes within this group, with no evidence of direct viral infection within the kidney.

Transforming Growth Factor Beta Receptor 3 (TGFBR3)-Associated Membranous Nephropathy.

Background: Membranous lupus nephritis (MLN) comprises 10%-15% of lupus nephritis and increases morbidity and mortality of patients with SLE through complications of nephrotic syndrome and chronic kidney failure. Identification of the target antigens in MLN may enable noninvasive monitoring of disease activity, inform treatment decisions, and aid in prognostication, as is now possible for idiopathic MN caused by antibodies against the phospholipase A2 receptor. Here, we show evidence for type III TGF-ß receptor (TGFBR3) as a novel biomarker expressed in a subset of patients with MLN. Methods: Mass spectrometry was used for protein discovery through enrichment of glomerular proteins by laser capture microdissection and through elution of immune complexes within MLN biopsy specimens. Colocalization with IgG within glomerular immune deposits from patients and disease controls was evaluated by confocal microscopy. Immunostaining of consecutive case series was used to determine the overall frequency in MN and MLN. Results: TGFBR3 was found to be enriched in glomeruli and coimmunoprecipitated with IgG within a subset of MLN biopsy specimens by mass spectrometry. Staining of consecutive MN cases without clinical evidence of SLE did not show TGFBR3 expression (zero of 104), but showed a 6% prevalence in MLN (11 of 199 cases). TGFBR3 colocalized with IgG along the glomerular basement membranes in TGFBR3-associated MN, but not in controls. Conclusions: Positive staining for TGFBR3 within glomerular immune deposits represents a distinct form of MN, substantially enriched in MLN. A diagnosis of TGFBR3-associated MN can alert the clinician to search for an underlying autoimmune disease.

Cerebral amyloid angiopathy-related inflammation: A potentially reversible cause of dementia with characteristic imaging findings.

BACKGROUND AND PURPOSE: Cerebral amyloid angiopathy with inflammation (CAA-I) is a less well-recognized clinically and radiologically distinct subtype of CAA. We aim to describe the imaging manifestations of this uncommon entity. MATERIALS AND METHODS: A retrospective review of the medical records and imaging database yielded 9 patients with clinical and radiological findings compatible with CAA-I. The neurological findings at presentation, MRI findings including the presence of white matter involvement, mass effect, microhemorrhages and contrast enhancement, treatment provided and outcome were evaluated. Brain biopsy specimens, when available were also reviewed. RESULTS: All patients presented with subacute cognitive decline. In all 9 patients, confluent white matter lesions with mass effect were observed. Eight out of 9 patients demonstrated foci of microhemorrhage, while in 1, the microhemorrhages appeared 12 weeks after the initial examination. No significant parenchymal or meningeal enhancement was present in any patient. In 4 patients, brain biopsy was consistent with CAA-I. Immunosuppressive therapy was initiated in all patients, leading to full recovery in 5. CONCLUSION: CAA-I is characterized by the subacute onset of dementia, a distinct pattern of confluent white matter signal abnormality with mass effect and response to immunosuppressive therapy. Prompt recognition may help obviate brain biopsy and initiation of treatment.

Dexamethasone administration during definitive radiation and temozolomide renders a poor prognosis in a retrospective analysis of newly diagnosed glioblastoma patients.

BACKGROUND: Dexamethasone (DXM) is commonly used in the management of cerebral edema in patients diagnosed with glioblastoma multiforme (GBM). Bevacizumab (BEV) is FDA-approved for the progression or recurrence of GBM but has not been shown to improve survival when given for newly diagnosed patients concurrently with radiation (RT) and temozolomide (TMZ). Both DXM and BEV reduce cerebral edema, however, DXM has been shown to induce cytokine cascades which could interfere with cytotoxic therapy. We investigated whether DXM would reduce survival of GBM patients in the setting of concurrent TMZ and BEV administration. METHODS: We reviewed the treatment of all 73 patients with GBM who received definitive therapy at our institution from 2005 to 2013 with RT (60 Gy) delivered with concurrent daily TMZ (75 mg/m(2)). Of these, 34 patients also were treated with concurrent BEV (10 mg/kg every two weeks). Patients received adjuvant therapy (TMZ or TMZ/Bev) until either progression, discontinuation due to toxicity, or 12 months after radiation completion. All patients who had GBM progression with TMZ were offered BEV for salvage therapy, with 19 (56 %) receiving BEV. RESULTS: With a median follow-up of 15.6 months, 67 (91.8 %) patients were deceased. The OS for the entire cohort was 15.9 months, while the PFS was 7.7 months. The extent of resection was a prognostic indicator for OS (p = .0044). The median survival following gross tumor resection (GTR) was 22.5 months, subtotal resection (STR) was 14.9 months, and biopsy was 12.1 months. The addition of BEV to TMZ with RT was borderline significantly associated with increased PFS (9.4 vs. 5.1 months, p = 0.0574) although was not significantly associated with OS (18.1 vs. 15.3 months respectively, p = 0.3064). In patients receiving TMZ, DXM use concurrent with RT was a poor prognostic indicator of both OS (12.7 vs. 22.6 months, p = 0.003) and PFS (3.6 vs. 8.4 months, p <0.0001). DXM did not reduce OS in patients who received TMZ and BEV concurrently with RT (22.9 vs 22.8 months, p = 0.4818). On multivariable analysis, DXM use predicted an unfavorable OS hazard ratio (HR) = 1.72, p = 0.045). CONCLUSIONS: Our results with TMZ, BEV, and RT are similar to previous studies in terms of PFS and OS. DXM use during RT with concurrent TMZ correlated with reduced OS and PFS unless BEV was administered.

BAP1 protein loss by immunohistochemistry: a potentially useful tool for prognostic prediction in patients with uveal melanoma.

BACKGROUND: Uveal melanoma is the most common primary malignant intraocular tumour in adults. Recently, biallelic inactivation of the BAP1 gene was shown to be associated with increased risk of metastasis in patients with uveal melanoma. Immunohistochemical (IHC) assessment of BAP1 protein loss has been shown to be an excellent surrogate for biallelic inactivation of BAP1. In this pilot study, we investigated whether loss of BAP1 expression by IHC is associated with prognosis in uveal melanoma patients. METHODS: We retrieved clinical data, reviewed pathological slides, and performed IHC for BAP1 in 40 primary uveal melanomas. Tumour cell type was classified as: spindle (>90% spindle cells); epithelioid (>90% epithelioid cells); or mixed. BAP1 expression was scored as diffuse (nuclear staining in >90% of tumour cells), heterogenous (nuclear staining in <90% of tumour cells), or absent (no nuclear staining). We analysed associations of BAP1 expression with clinical and pathological parameters, and with overall survival. RESULTS: Tumours were obtained from 20 males and 20 females, with a median age of 60 years (range 31-81 years). Tumour cell types were: epithelioid (n=7, 18%), mixed (n=20, 50%), and spindled (n=13, 33%). BAP1 expression was absent in 23 (58%) tumours, heterogenous in seven (18%) tumours, and diffuse in 10 (25%) tumours. Absent BAP1 expression was more frequently seen in epithelioid/mixed cell tumours (19/27, 70%) than was heterogenous (3/27, 11%) or diffuse (5/27, 19%) expression; the corresponding figures for spindle cell tumours were 4/13 (31%), 4/13 (31%) and 5/13 (38%), respectively (p=0.057). Factors associated with improved survival were diffuse or heterogenous BAP1 expression (compared with absent expression, p=0.03) and age less than 60 years (p=0.049). CONCLUSION: Analysis of BAP1 protein expression using immunohistochemistry may serve as a rapid and cost-effective means of identifying uveal melanoma patients with aggressive disease, who can then be managed appropriately.

Diagnosis and treatment of chordoma.

Chordoma is a primary bone cancer arising on the midline from the skull base to the sacrum. Diagnosis is often delayed because of insidious onset and nonspecific symptoms. Chordomas appear histologically low-grade but are highly invasive and often recur locally. Management centers primarily on radical en bloc surgical resection when possible. Radiation therapy using protons and/or photons is often necessary because complete resection is seldom possible due to critical location and invasion of the cancer cells into surrounding structures. No approved medical therapy exists. The high rate of recurrence is reflected by a median survival of 6 to 7 years. This article reviews the clinical management of chordoma and discusses ongoing research in the field.

Spindle cell rhabdomyosarcoma of the neck with t(6;8) translocation: report of a case and literature review.

Spindle cell rhabdomyosarcoma is an uncommon subtype of embryonal rhabdomyosarcoma. Found almost exclusively in children, these tumors are classically located in the paratesticular and head and neck regions. Morphologically these lesions can resemble several other benign or malignant soft-tissue spindle cell lesions, especially smooth muscle or myofibroblastic tumors, and thus immunohistochemical staining is often needed to prove skeletal muscle differentiation. Although there is extensive literature reporting the genetics of embryonal rhabdomyosarcoma, little is reported specific to the spindle cell subtype. Below we present the case of a 7-month-old male presenting with a large posterior neck mass that was diagnosed as spindle cell rhabdomyosarcoma. Karyotype evaluation revealed a t(6;8) (p12;q11.2) chromosomal translocation within the lesion. We review the histologic and immunohistochemical diagnosis of these tumors and discuss the genetics of rhabdomyoscarcomas.

Update on molecular findings, management and outcome in low-grade gliomas.

Low-grade infiltrating gliomas in adults include diffuse astrocytoma, oligoastrocytoma and oligodendroglioma. The current gold standard diagnosis of these tumors relies on histological classification; however, emerging molecular abnormalities discovered in these tumors are playing an increasingly prominent part in the process of tumor diagnosis and, consequently, patient management. The frequency and clinical importance of tumor protein p53 (TP53) abnormalities, deletions involving chromosomes 1p and 19q, O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, abnormalities in the PTEN tumor suppressor gene and the BRAF oncogene, and isocitrate dehydrogenase (IDH) mutations have become better defined. Molecular markers have not, historically, had an important role in determining the course of treatment for patients with low-grade gliomas, but ongoing phase III clinical trials incorporate 1p deletion or 1p19q codeletion status-and future trials plan to incorporate MGMT promoter methylation status-as stratification factors. Future trials will need to incorporate IDH mutational status in addition to these factors. Ultimately, molecular marker assessment will, hopefully, improve the accuracy of tumor diagnosis and enhance the effectiveness of treatment to achieve improved patient outcomes.

WT1 is not a reliable marker to distinguish reactive from neoplastic astrocyte populations in the central nervous system.

A diagnostic difficulty in neuropathology practice is distinguishing reactive from neoplastic astrocyte populations. This is particularly true in small biopsy samples that lack evidence of increased cellularity or mitotic activity, microvascular proliferation, or necrosis. We performed the current study to validate the previously reported finding that in the central nervous system, the expression of WT1 is limited to neoplastic astrocytes. We retrospectively studied WT1 protein expression by immunohistochemistry (IHC) in 100 formalin-fixed, paraffin-embedded brain tissue samples consisting of 3 normal control tissues, 44 cases of reactive gliosis, 49 gliomas and 4 lesions suspicious for glioma. In normal human cortex, WT1 staining was restricted to vascular endothelium. Most cases of reactive gliosis (82%) showed at least focal WT1 positivity, and analysis of specimens with electrode monitoring lesions showed an inverse relationship between WT1 expression intensity and the number of days from electrode placement to tissue resection. All glioma samples (100%) and all cases suspicious for glioma (100%) showed at least focal WT1 positivity. Our results likely differ from those in the prior report because of differences in tissue fixation and IHC methodology. Thus, our findings indicate that WT1 expression alone is not a reliable feature to distinguish reactive from neoplastic astrocytes.

Clinical and pathological characteristics of brain metastasis resected after failed radiosurgery.

OBJECTIVE: This study evaluates the tumor histopathology and clinical characteristics of patients who underwent resection of their brain metastasis after failed gamma knife radiosurgery. METHODS: This study was a retrospective review from a prospective database. A total of 1200 brain metastases in 912 patients were treated by gamma knife radiosurgery during a 7-year period. Fifteen patients (1.6% of patients, 1.2% of all brain metastases) underwent resective surgery for either presumed tumor progression (6 patients) or worsening neurological symptoms associated with increased mass effect (9 patients). Radiographic imaging, radiosurgical and surgical treatment parameters, histopathological findings, and long-term outcomes were reviewed for all patients. RESULTS: The mean age at the time of radiosurgery was 57 years (age range, 32-65 years). Initial pathological diagnoses included metastatic non-small cell lung carcinoma in 8 patients (53%), melanoma in 4 patients (27%), renal cell carcinoma in 2 patients (13%), and squamous cell carcinoma of the tongue in 1 patient (7%). The mean time interval between radiosurgery and surgical extirpation was 8.5 months (range, 3 weeks to 34 months). The mean treatment volume for the resected lesion at the time of radiosurgery was 4.4 cm(3) (range, 0.6-8.4 cm(3)). The mean dose to the tumor margin was 21Gy (range, 18-24 Gy). In addition to the 15 tumors that were eventually resected, a total of 32 other metastases were treated synchronously, with a 78% control rate. The mean volume immediately before surgery for the 15 resected lesions was 7.5 cm(3) (range, 3.8-10.2 cm(3)). Histological findings after radiosurgery varied from case to case and included viable tumor, necrotic tumor, vascular hyalinization, hemosiderin-laden macrophages, reactive gliosis in surrounding brain tissue, and an elevated MIB-1 proliferation index in cases with viable tumor. The mean survival for patients in whom viable tumor was identified (9.4 months) was significantly lower than that of patients in whom only necrosis was seen (15.1 months; Fisher's exact test, P < 0.05). CONCLUSION: Radiation necrosis and tumor radioresistance are the most common causes precipitating a need for surgical resection after radiosurgery in patients with brain metastasis.

A 58 year old woman with a corpus callosum nodule at autopsy.

Intracranial lipomas are uncommon benign mesenchymal tumors, found usually near or at the midline. The existence of such intracranial tumors has been documented in the literature in only over 200 cases. Although usually asymptomatic, they can sometimes trigger neurological symptoms, specifically epileptic seizures. We describe the incidental finding of a lipoma of the corpus callosum at autopsy in a 58 year-old woman with a history of seizures, and provide a concise review of the pertinent literature with respect to this entity.

Bilateral massive retinal gliosis associated with retinopathy of prematurity.

Massive retinal gliosis (MRG) is a rare, benign intraocular condition that may develop in association with long-standing eye conditions including chronic inflammation, vascular disorders, glaucoma, trauma, or congenital abnormalities. It is thought to represent a nonneoplastic reactive tissue response to retinal injury. Here, we describe an unusual case of bilateral MRG in association with retinopathy of prematurity. To our knowledge, this may be the first report of such an occurrence. The differential diagnosis of MRG is discussed with specific emphasis on its relationship to vasoproliferative tumor of the retina and presumed acquired retinal hemangiomas. In addition, we hypothesize that MRG, vasoproliferative tumor of the retina, and presumed acquired retinal hemangiomas may represent different phenotypes along a spectrum of the same disease process.

p63 Expression in olfactory neuroblastoma and other small cell tumors of the sinonasal tract.

Olfactory neuroblastoma (ONB) is a rare neoplasm of the head and neck region that is included in the differential diagnosis of other sinonasal tract malignancies. We studied the usefulness of using p63 as an aid in the diagnosis of ONB and other tumors of the sinonasal region. The specimens were 14 ONBs; 4 nasopharyngeal carcinomas (NPCs), nonkeratinizing subtype; 2 NPCs, undifferentiated subtype; 10 sinonasal undifferentiated carcinomas (SNUCs); 7 malignant melanomas; and 2 extranodal natural killer (NK)/T-cell lymphomas. We observed p63 expression in 5 ONBs (36%), 4 nonkeratinizing NPCs (100%), 1 undifferentiated NPC (50%), 2 SNUCs (20%); 0 malignant melanomas (0%); and 1 extranodal NK/T-cell lymphoma (50%). While all cases of NPC with positive staining for p63 showed strong and diffuse immunoreactivity, the ONB, SNUC, and lymphoma cases with positive immunoreactivity showed only focal staining for p63. No p63 expression was observed in malignant melanoma. We think p63 is a useful marker to help distinguish nonkeratinizing or undifferentiated NPC subtypes from various sinonasal tract malignancies. In particular, p63 helps distinguish nonkeratinizing and undifferentiated NPC subtypes from SNUC.

The cytologic features of sinonasal undifferentiated carcinoma and olfactory neuroblastoma.

Sinonasal undifferentiated carcinoma (SNUC) is a rare, aggressive malignancy of the sinonasal tract. Olfactory neuroblastoma (ONB) is an uncommon neuroectodermal tumor of the superior nasal cavity. Upon examining these lesions, a broad differential diagnosis of poorly differentiated round cell tumors must be considered. The cytologic features of SNUC and ONB have been rarely reported. We searched our cytology files for cases of SNUC and ONB and assessed the following: cellularity, architecture, cytoplasm, cell size, nuclear contours, nucleoli, chromatin, anisonucleosis/anisocytosis, mitotic activity, background, and nuclear crush. Seven cases of SNUC produced hypercellular smears with a single-cell-predominant pattern. Cells were intermediate-sized with irregular nuclear contours and small nucleoli. Nuclear crush and mitotic figures were noted. The background exhibited naked nuclei and karyorrhectic debris. Of 7 cases, 6 (86%) exhibited vacuoles or extracellular lumina. The 10 cases of ONB exhibited cellularity, cellular arrangement, and chromatin similar to SNUC. In contrast, ONBs demonstrated fibrillary cytoplasm and smooth nuclear contours; mitotic figures were generally absent. Homer Wright rosettes were encountered in 9 cases (90%). We believe that in the appropriate clinical context, a specific cytologic diagnosis should be possible.

Unusual presentation of an adult intramedullary spinal teratoma with diplomyelia.

BACKGROUND: Spinal teratomas are rare lesions. The authors present an intramedullary spinal teratoma associated with diplomyelia. CASE DESCRIPTION: This 34-year-old female patient presented with right lower extremity weakness, left lower extremity sensory deficit, and urinary retention. Magnetic resonance imaging showed a focally expansile, intramedullary lesion at L1-2 levels with exophytic component, which was located at the apex of diplomyelia separating the cord into equal hemicords and low-lying spinal cord ending at L3 level. Intraoperative electrophysiologic monitoring was used. Tumor was composed of both intramedullary solid/cystic parts and exophytic fatty infiltrated tissue. There was diplomyelia located caudal to intramedullary lesion and harboring an exophytic lobule at the junction of the nondiplomyelic and the diplomyelic cord. A complete removal was not accomplished because of presence of functional neural tissue within the exophytic component of the lesion. Histopathological examination revealed a mature teratoma. This is the fourth intramedullary teratoma associated with SCM to be reported in the literature. CONCLUSIONS: Teratomas should be taken into consideration in differential diagnosis of intramedullary lesions associated with SCM. Neuroimaging is helpful, but definitive diagnosis is done by histopathological examination. Radical resection should be the aim; however, excision should be tailored according to intraoperative electrophysiologic monitoring. A truly intramedullary teratoma and an exophytic midline fatty infiltrated tissue bisecting spinal cord is another unique feature of the present case that supports the dysembryogenic origin of spinal teratomas.

Fatal encephalitis in a patient with refractory celiac disease presenting with myorhythmia and carpal spasm.

We report the case of a woman with refractory celiac disease who developed abnormal spontaneous movements of the extremities and face consistent with myorhythmia. Investigation led to a diagnosis of encephalitis, confirmed by postmortem examination. The movements were likely caused by nonparaneoplastic encephalitis associated with refractory celiac disease. Etiologic and diagnostic considerations and treatment options are discussed.

Primary disseminated leptomeningeal oligodendroglioma with 1p deletion. Case report.

The authors report the case of a 2-year-old boy with a primary, diffuse leptomeningeal oligodendroglioma in which the deletion of chromosome arm lp was identified by performing a fluorescence in situ hybridization (FISH) analysis. This previously healthy child initially presented with malaise, anorexia, nausea, vomiting, and macrocephaly. Imaging studies confirmed the presence of hydrocephalus, and a ventriculoperitoneal shunt was placed. The postoperative course was complicated by emesis, continued weight loss, and numerous seizurelike episodes. A contrast-enhanced magnetic resonance imaging study performed approximately 10 weeks postoperatively showed diffuse leptomeningeal thickening and enhancement without evidence of an intraparenchymal mass lesion. A right frontal lobe brain biopsy revealed a hypercellular proliferation of small oligodendroglioma-like cells, which occupied the leptomeninges diffusely and spared the underlying cortical gray matter. The tumor cells displayed prominent perinuclear clearing and had evenly spaced, uniformly round nuclei. Occasional mitotic figures were observed. Background vessels were thin and delicate, and there was no evidence of necrosis. The tumor cells showed strong immunoreactivity for S100 protein; the results of immunohistochemical staining were negative for glial fibrillary acidic protein, vimentin, epithelial membrane antigen, NeuN, and synaptophysin. The deletion of lp was demonstrated by FISH analysis; lq, 19p, and 19q were intact. This appears to be the first reported case of a primary diffuse leptomeningeal oligodendroglioma in which a lp deletion was identified.

Follicular lymphoma of the dura: case report.

OBJECTIVE: We present an unusual dural-based follicular lymphoma with radiological and macroscopic features similar to a meningioma. The unusual location of this tumor and its distinction from meningioma, mucosa-associated lymphoid tissue-type marginal zone B-cell lymphoma of the dura, and intraparenchymal central nervous system lymphoma, dramatically alters the patient's postoperative treatment. The case illustrates the clinical, radiological, and histological relevance of this rare entity. CLINICAL PRESENTATION: A 41-year-old Caucasian man with chronic bifrontal headaches and a raised area over his left frontal cranium that persisted for 1 year presented to the emergency room with nausea and vomiting. His family reported that the patient demonstrated increased irritability and aggressive behavior. A computed tomographic scan revealed a large mass of the left frontal convexity with edema and mass effect. Magnetic resonance imaging scans showed a 5-cm homogeneously enhancing mass in the left posterior frontal lobe. INTERVENTION: Preoperatively, the patient underwent angiography and embolization of the tumor. The patient underwent gross total resection of tumor. The dural-based tumor invaded the cranium and scalp. Neuropathological findings were consistent with low-grade follicular lymphoma. The patient is currently undergoing radiation and chemotherapy. CONCLUSION: The current case represents the first report of extensive intracranial dural involvement by a follicular lymphoma that shows a classic immunophenotype by immunohistochemistry and flow cytometry. The case illustrates the clinical and radiographic similarities between dural-based lymphoma and meningioma. Distinguishing dural-based follicular lymphoma from mucosa-associated lymphoid tissue-type lymphoma and from intraparenchymal primary central nervous system lymphomas, which are more often large cell lymphomas with more aggressive biological behavior, is essential for proper clinical management.

Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy.

Myotonic dystrophy (DM1), the most common muscular dystrophy in adults, is caused by an expanded (CTG)n tract in the 3' UTR of the gene encoding myotonic dystrophy protein kinase (DMPK), which results in nuclear entrapment of the 'toxic' mutant RNA and interacting RNA-binding proteins (such as MBNL1) in ribonuclear inclusions. It is unclear if therapy aimed at eliminating the toxin would be beneficial. To address this, we generated transgenic mice expressing the DMPK 3' UTR as part of an inducible RNA transcript encoding green fluorescent protein (GFP). We were surprised to find that mice overexpressing a normal DMPK 3' UTR mRNA reproduced cardinal features of myotonic dystrophy, including myotonia, cardiac conduction abnormalities, histopathology and RNA splicing defects in the absence of detectable nuclear inclusions. However, we observed increased levels of CUG-binding protein (CUG-BP1) in skeletal muscle, as seen in individuals with DM1. Notably, these effects were reversible in both mature skeletal and cardiac muscles by silencing transgene expression. These results represent the first in vivo proof of principle for a therapeutic strategy for treatment of myotonic dystrophy by ablating or silencing expression of the toxic RNA molecules.

Evidence-based principles and practices in pathology: selected problem areas.

Contrary to the intuitive impression of most pathologists, there are still many areas in laboratory medicine where evidence-based medicine (EBM) principles are not applied. These include aspects of both anatomic and clinical pathology. Some non-EBM practices are perpetuated by clinical "consumers" of laboratory services, because of inadequate education, habit, or over-reliance on empirical factors. Other faulty procedures are pathologist-driven, with similar underpinnings. This overview considers several exemplary problem areas representing non-EBM practices in the hospital laboratory. Such examples include ideas and techniques centering on metastatic malignancies, "targeted" oncological therapy, analysis of surgical margins in the excision of neoplasms, general laboratory testing and data utilization, evaluation of selected coagulation defects, administration of blood products, and analysis of hepatic iron-overload syndromes. The concepts illustrating departures from EBM are discussed for each of those topics.