Squamoid eccrine ductal carcinoma: clinical, histological and immunohistochemical features.

Squamoid eccrine ductal carcinoma (SEDC) is a cutaneous adnexal malignancy that is histologically challenging to distinguish from squamous cell carcinoma. We report three cases of this rare entity and review the present literature regarding clinical, histological, and immunohistochemical features. Patients presented with a single nodule or plaque lesion on their back and temple. The shave biopsies for Patient A and C were interpreted as SEDC. Patient B's initial shave biopsy was interpreted as probable surface of squamous cell carcinoma, and subsequent excision revealed SEDC. Ductal differentiation was confirmed by positive expression of epithelial membrane antigen and carcinoembryonic antigen immunostains in all three patients. Review of the 67 previously reported cases emphasizes the importance of diagnosing SEDC accurately and promptly given its potential for distant metastasis and mortality. Perineural or lymphatic invasion is associated with higher rate of recurrence or metastasis. There should be high pathologic suspicion for SEDC in an elderly patient presenting with a palpable lesion, even if located outside of the head and neck area, particularly when there is suggestion of ductal differentiation in a sample of a squamous neoplasm.

Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.

Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43-depleted human iPSC-derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43-depleted human iPSC-derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43-depleted human iPSC-derived neurons were predictive of cryptic exons expressed in postmortem brain tissue from patients with TDP-43 proteinopathy. These cryptic exons produced transcript variants that generated de novo proteins. We found that the inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Last, we showed that 18 de novo peptides across 13 genes were present in CSF samples from patients with ALS/FTD spectrum disorders. The demonstration of cryptic exon translation suggests new mechanisms for ALS/FTD pathophysiology downstream of TDP-43 dysfunction and may provide a potential strategy to assay TDP-43 function in patient CSF.

ALSUntangled #73: Lion's Mane.

Lion's Mane (Hericium erinaceus) has historically been used as traditional medicine in Asia and Europe for its potential benefits in fighting infection and cancer. It has gained interest in the neurodegenerative disease field because of its mechanisms of action; these include anti-inflammation, neuroprotection, and promoting neurite growth demonstrated in various cell and animal models. A very small, double-blind, placebo-controlled trial in patients with mild cognitive impairment showed a temporary improvement in cognitive function; this finding has yet to be replicated. However, there have been no studies in ALS cell or animal models or in humans with ALS. Lion's Mane appears safe and inexpensive when consumed in powder or capsule, but one anaphylactic case was reported after a patient consumed fresh Lion's Mane mushroom. Currently, we do not have enough information to support the use of Lion's Mane for treating ALS. We support further research in ALS disease models and clinical trials to study its efficacy.

Common Variants Near ZIC1 and ZIC4 in Autopsy-Confirmed Multiple System Atrophy.

BACKGROUND: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. OBJECTIVE: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. METHODS: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). RESULTS: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10-6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). INTERPRETATION: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Genome-wide association study and functional validation implicates JADE1 in tauopathy.

Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-ß (Aß) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aß toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.

Looking backward to move forward: a meta-analysis of stem cell therapy in amyotrophic lateral sclerosis.

Transplantation of several types of stem cells (SC) for the treatment of amyotrophic lateral sclerosis (ALS) has been evaluated in numerous Phase I/II clinical trials with inconclusive results. Here, we conducted a meta-analysis to systematically assess the outcome of SC therapy trials which report the evolution of each patient before and after cell administration. In this way, we aimed to determine the effect of the SC intervention despite individual heterogeneity in disease progression. We identified 670 references by electronic search and 90 full-text studies were evaluated according to the eligibility criteria. Eleven studies were included comprising 220 cell-treated patients who received mesenchymal (M) SC (n = 152), neural (N) SC (n = 57), or mononuclear cells (MNC: CD34, CD117, and CD133 positive cells) (n = 11). Our analyses indicate that whereas intrathecal injection of mesenchymal stromal cells appears to have a transient positive effect on clinical progression, as measured by the ALS functional rating score, there was a worsening of respiratory function measured by forced vital capacity after all interventions. Based on current evidence, we conclude that optimal cell product and route of administration need to be determined in properly controlled preclinical models before further advancing into ALS patients. In addition, in-depth understanding of disease mechanisms in subsets of patients will help tailoring SC therapy to specific targets and increase the likelihood of improving outcomes.

Stathmin-2: adding another piece to the puzzle of TDP-43 proteinopathies and neurodegeneration.

Cytoplasmic aggregated proteins are a common neuropathological feature of neurodegenerative diseases. Cytoplasmic mislocalization and aggregation of TAR-DNA binding protein 43 (TDP-43) is found in the majority of patients with amyotrophic lateral sclerosis (ALS) and in approximately 50% of patients dying of frontotemporal lobar degeneration (FTLD). In this issue of the JCI, Prudencio, Humphrey, Pickles, and colleagues investigated the relationship of TDP-43 pathology with the loss of stathmin-2 (STMN2), an essential protein for axonal growth and maintenance. Comparing genetic, cellular, and neuropathological data from patients with TDP-43 proteinopathies (ALS, ALS-frontotemporal dementia [ALS-FTD], and FTLD-TDP-43 [FTLD-TDP]) with data from patients with non-TDP-related neurodegenerations, they demonstrate a direct relationship between TDP-43 pathology and STMN2 reduction. Loss of the normal transcription suppressor function of TDP-43 allowed transcription of an early termination cryptic axon, resulting in truncated, nonfunctional mRNA. The authors suggest that measurement of truncated STMN2 mRNA could be a biomarker for discerning TDP proteinopathies from other pathologies.

Flexible ureterorenoscopy to treat upper urinary tract stones in children.

Development of surgical expertise and technology has affected the way renal tract stones are treated. Our hypothesis was that flexible ureteroscopy (FURS) for upper tract stones in children produces good results. Our outcomes were reviewed. A retrospective case note review was performed for children with upper tract calculi who were treated by FURS. There were 56 stone episodes in 36 patients. Median age was 10.6 years. Stones were 3-23 mm (median 8 mm); 64.3% had multiple calculi. Median follow-up was for 17.1 months. After the first FURS there was stone clearance in 42/56 (75%). Although there were no immediate complications, two required re-admission; one with stent symptoms, the other with urinary infection. A second FURS was performed in 11, bringing the cumulative clearance to 89%, although this was often done as "another look" before stent removal. There was no statistically significant difference in stone clearance after first FURS for those with single stones (81.0%) compared to those with multiple stones (72.2%). Clearance rates of more than 70% after first FURS were achieved with stones of up to 17 mm. Unexpected disease was found and treated during FURS in 9 (16.1%) children. FURS is safe in children and good clearance rates are achieved. Multiple stones at different sites may be treated during the same treatment. In addition, FURS allows diagnosis and treatment of unexpected problems.

Extra-Anatomic Stents in Ureteric Obstruction: Our Experience.

OBJECTIVES: To present our experience of the Detour extra-anatomic stent (EAS; Porges-Coloplast, Denmark) to bypass ureteric obstruction. Use of the EAS is indicated in patients with complex ureteric strictures or malignant disease, where long-term nephrostomy drainage is undesirable. MATERIALS AND METHODS: Between December 2001 and October 2017, 20 Detour EAS were implanted into 13 patients. The primary indication was ureteric obstruction or injury secondary to metastatic malignancy, or from treatment for malignancy. Five patients required bilateral EAS, with two patients having bilateral EAS following initial unilateral insertion. In 11 patients, the stent was inserted into their bladder, with 2 diverted into a double-barreled stoma. The mean age at the time of implantation was 64 years (range: 50-83 years), and the median follow-up was 12 months (range: 1.5-42 months). RESULTS: Four patients required stent revision for urinary leaks, and two developed recurrent urinary tract infections in their stent requiring intravenous antibiotics. All EAS continued to drain successfully following treatment or revision. One patient died due to complications from dislodgement of the stent, leading to laparotomy and intra-abdominal sepsis. Seven patients died due to progression of metastatic malignant disease, and the Detour EAS was functioning in all seven at time of death. The remaining five patients are well with functioning Detour EAS. CONCLUSIONS: The Detour EAS system provides a suitable alternative option for urinary diversion, affording a good quality of life to carefully selected patients with multiple comorbidities and malignant disease.

Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort.

NIPA1 (nonimprinted in Prader-Willi/Angelman syndrome 1) mutations are known to cause hereditary spastic paraplegia type 6, a neurodegenerative disease that phenotypically overlaps to some extent with amyotrophic lateral sclerosis (ALS). Previously, a genomewide screen for copy number variants found an association with rare deletions in NIPA1 and ALS, and subsequent genetic analyses revealed that long (or expanded) polyalanine repeats in NIPA1 convey increased ALS susceptibility. We set out to perform a large-scale replication study to further investigate the role of NIPA1 polyalanine expansions with ALS, in which we characterized NIPA1 repeat size in an independent international cohort of 3955 patients with ALS and 2276 unaffected controls and combined our results with previous reports. Meta-analysis on a total of 6245 patients with ALS and 5051 controls showed an overall increased risk of ALS in those with expanded (>8) GCG repeat length (odds ratio = 1.50, p = 3.8×10-5). Together with previous reports, these findings provide evidence for an association of an expanded polyalanine repeat in NIPA1 and ALS.

Stem cell transplantation for amyotrophic lateral sclerosis.

PURPOSE OF REVIEW: This review analyses the recent efforts to develop therapeutics using transplantation of stem cells for amyotrophic lateral sclerosis (ALS). RECENT FINDINGS: Stem cells are considered as a potential therapeutic for a variety of neurodegenerative diseases, in an effort to either replace cells that are lost, or to enhance the survival of the remaining cells. In ALS, meaningful attempts to verify the safety and feasibility of many cell transplantation approaches have only recently been completed or are underway. Due to the complexities of reconstructing complete motor neuron circuits in adult patients, current approaches aim rather to prolong the survival and function of existing motor neurons through paracrine effects or production of new interneurons or astrocytes. Recent trials showed that autologous mesenchymal stem cells can be safely injected intrathecally, transiently enhancing growth factor concentrations and anti-inflammatory cytokines into the cerebrospinal fluid. Likewise, a small pilot study investigating safety of autologous transplantation of regulatory T-cells for immunomodulation was recently completed. Finally, early phase trials demonstrated safety of direct surgical transplantation of heterologous fetal-derived neural progenitor cells into the spinal cord of ALS patients, as an attempt to provide a lasting source of local trophic support for motor neurons. SUMMARY: With clinical trials recently demonstrating that stem cell transplantation can be safe and well tolerated in ALS, the field is positioned to complete pivotal controlled trials to determine efficacy.

Long-term Phase 1/2 intraspinal stem cell transplantation outcomes in ALS.

OBJECTIVE: Intraspinal human spinal cord-derived neural stem cell (HSSC) transplantation is a potential therapy for amyotrophic lateral sclerosis (ALS); however, previous trials lack controls. This post hoc analysis compared ambulatory limb-onset ALS participants in Phase 1 and 2 (Ph1/2) open-label intraspinal HSSC transplantation studies up to 3 years after transplant to matched participants in Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) and ceftriaxone datasets to provide required analyses to inform future clinical trial designs. METHODS: Survival, ALSFRS-R, and a composite statistic (ALS/SURV) combining survival and ALS Functional Rating Scale revised (ALSFRS-R) functional status were assessed for matched participant subsets: PRO-ACT n = 1108, Ph1/2 n = 21 and ceftriaxone n = 177, Ph1/2 n = 20. RESULTS: Survival did not differ significantly between cohorts: Ph1/2 median survival 4.7 years, 95% CI (1.2, ∞) versus PRO-ACT 2.3 years (1.9, 2.5), P = 1.0; Ph1/2 3.0 years (1.2, 5.6) versus ceftriaxone 2.3 years (1.8, 2.8), P = 0.88. Mean ALSFRS-R at 24 months significantly differed between Ph1/2 and both comparison cohorts (Ph1/2 30.1 ± 8.6 vs. PRO-ACT 24.0 ± 10.2, P = 0.048; Ph1/2 30.7 ± 8.8 vs. ceftriaxone 19.2 ± 9.5, P = 0.0023). Using ALS/SURV, median PRO-ACT and ceftriaxone participants died by 24 months, whereas median Ph1/2 participant ALSFRS-Rs were 23 (P = 0.0038) and 19 (P = 0.14) in PRO-ACT and ceftriaxone comparisons at 24 months, respectively, supporting improved functional outcomes in the Ph1/2 study. INTERPRETATION: Comparison of Ph1/2 studies to historical datasets revealed significantly improved survival and function using ALS/SURV versus PRO-ACT controls. While results are encouraging, comparison against historical populations demonstrate limitations in noncontrolled studies. These findings support continued evaluation of HSSC transplantation in ALS, support the benefit of control populations, and enable necessary power calculations to design a randomized, sham surgery-controlled efficacy study.

TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD.

The cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a common histopathological hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum (ALS/FTD). However, the composition of aggregates and their contribution to the disease process remain unknown. Here we used proximity-dependent biotin identification (BioID) to interrogate the interactome of detergent-insoluble TDP-43 aggregates and found them enriched for components of the nuclear pore complex and nucleocytoplasmic transport machinery. Aggregated and disease-linked mutant TDP-43 triggered the sequestration and/or mislocalization of nucleoporins and transport factors, and interfered with nuclear protein import and RNA export in mouse primary cortical neurons, human fibroblasts and induced pluripotent stem cell-derived neurons. Nuclear pore pathology is present in brain tissue in cases of sporadic ALS and those involving genetic mutations in TARDBP and C9orf72. Our data strongly implicate TDP-43-mediated nucleocytoplasmic transport defects as a common disease mechanism in ALS/FTD.

A fluorescent metal-sensor study provides evidence for iron transport by transcytosis in the intestinal epithelial cells.

Iron transport across the intestinal epithelium is facilitated by the divalent metal transporter 1 (DMT1) on the brush border membrane (BBM). The fluorescent metal sensor calcein, which is hydrophilic, membrane-impermeable and quenched by chelation with iron, was used to test our hypothesis that intestinal iron absorption is through the endocytic processes and is involved in a pathway where BBM-derived vesicles fuse with basolateral membrane (BLM)-derived vesicles. To monitor the flux of iron via transcytosis, Caco-2 cells were employed as a polarized cell layer in Transwell chambers. When calcein was added to the basal chamber along with apo-transferrin (apo-Tf), calcein rapidly underwent endocytosis and co-localized with apo-Tf. Calcein was quenched by adding an iron-ascorbate complex and then restored by adding 2,2'-dipyridyl into the apical chamber. These results were confirmed by live-cell imaging. When hemin from the apical surface and calcein from the basal chamber were added to the Caco-2 cells, internalization of DMT1 and quenching of calcein were not observed until 2 h later. These results indicated that absorbed hemin required processing before hemin-derived iron was available to BLM-derived vesicles. These studies suggest that iron is transported in Caco-2 cells by transcytosis with apical-derived vesicles that are fused to BLM-derived vesicles.

A Case of Cutaneous Leishmaniasis guyanensis Mimicking Otitis Externa.

Cutaneous leishmaniasis typically presents as a painless papule progressing to an ulcer or plaque. In this case study of the ear, the disease manifested as a small painful bump progressing into redness and swelling about the ear with purulent drainage. After multiple oral/intravenous antipseudomonal, antistaphylococcal, and antifungal treatments, there was no improvement. The skin progressed to an erythematous plaque and hemorrhagic ulcer; punch biopsy and speciation revealed Leishmaniasis guyanensis. The patient was switched to a seven-dose course of intravenous L-amphotericin B (visceral leishmaniasis protocol). Within 21 days, pain and edema resolved and the ulcers healed. Three-month follow-up demonstrated no recurrence. Further studies are needed to evaluate the use of L-amphotericin B in Leishmaniasis guyanensis.

Estimating the palliative effect of percutaneous endoscopic gastrostomy in an observational registry using principal stratification and generalized propensity scores.

Clinical disease registries offer a rich collection of valuable patient information but also pose challenges that require special care and attention in statistical analyses. The goal of this paper is to propose a statistical framework that allows for estimating the effect of surgical insertion of a percutaneous endogastrostomy (PEG) tube for patients living with amyotrophic lateral sclerosis (ALS) using data from a clinical registry. Although all ALS patients are informed about PEG, only some patients agree to the procedure which, leads to the potential for selection bias. Assessing the effect of PEG is further complicated by the aggressively fatal disease, such that time to death competes directly with both the opportunity to receive PEG and clinical outcome measurements. Our proposed methodology handles the "censoring by death" phenomenon through principal stratification and selection bias for PEG treatment through generalized propensity scores. We develop a fully Bayesian modeling approach to estimate the survivor average causal effect (SACE) of PEG on BMI, a surrogate outcome measure of nutrition and quality of life. The use of propensity score methods within the principal stratification framework demonstrates a significant and positive effect of PEG treatment, particularly when time of treatment is included in the treatment definition.