Age-dependent formation of TMEM106B amyloid filaments in human brains.

Many age-dependent neurodegenerative diseases, such as Alzheimer's and Parkinson's, are characterized by abundant inclusions of amyloid filaments. Filamentous inclusions of the proteins tau, amyloid-ß, α-synuclein and transactive response DNA-binding protein (TARDBP; also known as TDP-43) are the most common1,2. Here we used structure determination by cryogenic electron microscopy to show that residues 120-254 of the lysosomal type II transmembrane protein 106B (TMEM106B) also form amyloid filaments in human brains. We determined the structures of TMEM106B filaments from a number of brain regions of 22 individuals with abundant amyloid deposits, including those resulting from sporadic and inherited tauopathies, amyloid-ß amyloidoses, synucleinopathies and TDP-43 proteinopathies, as well as from the frontal cortex of 3 individuals with normal neurology and no or only a few amyloid deposits. We observed three TMEM106B folds, with no clear relationships between folds and diseases. TMEM106B filaments correlated with the presence of a 29-kDa sarkosyl-insoluble fragment and globular cytoplasmic inclusions, as detected by an antibody specific to the carboxy-terminal region of TMEM106B. The identification of TMEM106B filaments in the brains of older, but not younger, individuals with normal neurology indicates that they form in an age-dependent manner.

Cryo-EM structures of amyloid-ß filaments with the Arctic mutation (E22G) from human and mouse brains.

The Arctic mutation, encoding E693G in the amyloid precursor protein (APP) gene [E22G in amyloid-ß (Aß)], causes dominantly inherited Alzheimer's disease. Here, we report the high-resolution cryo-EM structures of Aß filaments from the frontal cortex of a previously described case (AßPParc1) with the Arctic mutation. Most filaments consist of two pairs of non-identical protofilaments that comprise residues V12-V40 (human Arctic fold A) and E11-G37 (human Arctic fold B). They have a substructure (residues F20-G37) in common with the folds of type I and type II Aß42. When compared to the structures of wild-type Aß42 filaments, there are subtle conformational changes in the human Arctic folds, because of the lack of a side chain at G22, which may strengthen hydrogen bonding between mutant Aß molecules and promote filament formation. A minority of Aß42 filaments of type II was also present, as were tau paired helical filaments. In addition, we report the cryo-EM structures of Aß filaments with the Arctic mutation from mouse knock-in line AppNL-G-F. Most filaments are made of two identical mutant protofilaments that extend from D1 to G37 (AppNL-G-F murine Arctic fold). In a minority of filaments, two dimeric folds pack against each other in an anti-parallel fashion. The AppNL-G-F murine Arctic fold differs from the human Arctic folds, but shares some substructure.

When does subliminal affective image priming influence the ability of schizophrenic patients to perceive face emotions?

BACKGROUND: Deficits in face emotion perception are among the most pervasive aspects of schizophrenia impairments which strongly affects interpersonal communication and social skills. MATERIAL AND METHODS: Schizophrenic patients (PSZ) and healthy control subjects (HCS) performed 2 psychophysical tasks. One, the SAFFIMAP test, was designed to determine the impact of subliminally presented affective or neutral images on the accuracy of face-expression (angry or neutral) perception. In the second test, FEP, subjects saw pictures of face-expression and were asked to rate them as angry, happy, or neutral. The following clinical scales were used to determine the acute symptoms in PSZ: Positive and Negative Syndrome (PANSS), Young Mania Rating (YMRS), Hamilton Depression (HAM-D), and Hamilton Anxiety (HAM-A). RESULTS: On the SAFFIMAP test, different from the HCS group, the PSZ group tended to categorize the neutral expression of test faces as angry and their response to the test-face expression was not influenced by the affective content of the primes. In PSZ, the PANSS-positive score was significantly correlated with correct perception of angry faces for aggressive or pleasant primes. YMRS scores were strongly correlated with PSZ's tendency to recognize angry face expressions when the prime was a pleasant or a neutral image. The HAM-D score was positively correlated with categorizing the test-faces as neutral, regardless of the affective content of the prime or of the test-face expression (angry or neutral). CONCLUSIONS: Despite its exploratory nature, this study provides the first evidence that conscious perception and categorization of facial emotions (neutral or angry) in PSZ is directly affected by their positive or negative symptoms of the disease as defined by their individual scores on the clinical diagnostic scales.

Increase in Tau Pathology in P290S Mapt Knock-In Mice Crossed with App NL-G-F Mice.

Alzheimer's Disease (AD) is characterized by the pathologic assembly of amyloid ß (Aß) peptide, which deposits into extracellular plaques, and tau, which accumulates in intraneuronal inclusions. To investigate the link between Aß and tau pathologies, experimental models featuring both pathologies are needed. We developed a mouse model featuring both tau and Aß pathologies by knocking the P290S mutation into murine Mapt and crossing these Mapt P290S knock-in (KI) mice with the App NL-G-F KI line. Mapt P290S KI mice developed a small number of tau inclusions, which increased with age. The amount of tau pathology was significantly larger in App NL-G-F xMapt P290S KI mice from 18 months of age onward. Tau pathology was higher in limbic areas, including hippocampus, amygdala, and piriform/entorhinal cortex. We also observed AT100-positive and Gallyas-Braak-silver-positive dystrophic neurites containing assembled filamentous tau, as visualized by in situ electron microscopy. Using a cell-based tau seeding assay, we showed that Sarkosyl-insoluble brain extracts from both 18-month-old Mapt P290S KI and App NL-G-F xMapt P290S KI mice were seed competent, with brain extracts from double-KI mice seeding significantly more than those from the Mapt P290S KI mice. Finally, we showed that App NL-G-F xMapt P290S KI mice had neurodegeneration in the piriform cortex from 18 months of age. We suggest that App NL-G-F xMapt P290S KI mice provide a good model for studying the interactions of aggregation-prone tau, Aß, neuritic plaques, neurodegeneration, and aging.

Cryo-EM structures of amyloid-ß 42 filaments from human brains.

Filament assembly of amyloid-ß peptides ending at residue 42 (Aß42) is a central event in Alzheimer's disease. Here, we report the cryo­electron microscopy (cryo-EM) structures of Aß42 filaments from human brains. Two structurally related S-shaped protofilament folds give rise to two types of filaments. Type I filaments were found mostly in the brains of individuals with sporadic Alzheimer's disease, and type II filaments were found in individuals with familial Alzheimer's disease and other conditions. The structures of Aß42 filaments from the brain differ from those of filaments assembled in vitro. By contrast, in AppNL-F knock-in mice, Aß42 deposits were made of type II filaments. Knowledge of Aß42 filament structures from human brains may lead to the development of inhibitors of assembly and improved imaging agents.

A California Cancer Registry Analysis of Urothelial and Non-urothelial Bladder Cancer Subtypes: Epidemiology, Treatment, and Survival.

INTRODUCTION: We evaluated epidemiologic trends and survival for bladder cancer histologic subtypes in California patients by comparing urothelial carcinoma of the bladder (UCB) and non-urothelial subtypes including squamous cell carcinoma (SCC), adenocarcinoma (ADC), and small-cell carcinoma (SmCC). MATERIALS AND METHODS: The California Cancer Registry (CCR) was queried for incident bladder cancer cases from 1988 to 2012. Epidemiologic trends based on tumor histology were described. The primary outcome was disease-specific survival (DSS). Kaplan-Meier and multivariable Cox regression survival analyses were performed. RESULTS: A total of 72,452 bladder cancer cases (66,260 UCB, 1390 SCC, 587 ADC, 370 SmCC, and 3845 other) were included. The median age was 72 years (range, 18-109 years). ADC was more common in younger patients. Male:female ratios varied among cancer types (3.1:1 in UCB, 2.9:1 in SmCC, 1.6:1 in ADC, and 0.9:1 in SCC). Most non-urothelial cases (> 60%) presented at advanced stages, whereas most UCB cases (80.6%) were localized. Kaplan-Meier analysis revealed the best 5-year DSS and overall survival (OS) in UCB, whereas the worst outcomes were seen with SCC and SmCC (P < .0001). Multivariable analysis controlling for age, gender, tumor stage, and grade demonstrated that non-urothelial histologic subtypes were associated with significantly worse DSS compared with UCB (SCC hazard ratio [HR], 2.612; SmCC HR, 1.641; and ADC HR, 1.459; P < .0001). CONCLUSIONS: Non-urothelial bladder cancers have worse oncologic outcomes than UCB in California patients. SCC and SmCC are associated with the worst DSS based on univariable and multivariable analyses.

Establishment and Benefits of a Normal Pressure Hydrocephalus Support Group on Patient Education and Experience.

INTRODUCTION: Normal pressure hydrocephalus (NPH) is a debilitating, neurological condition that can lead to mental deterioration. With the diagnosis and treatment of NPH constantly evolving and its symptoms worsening with age, education for patients and their families is crucial. In this study, we aim to explore the potential educational benefits of a physician-led NPH support group. METHODS: Between December 2015 and November 2018, six semiannual NPH support group meetings were held for patients and their families. Attendees, ages 20-90, completed a Likert scale-based survey designed to assess the support group's educational benefits using the following primary outcome variables: (1) subjective knowledge, (2) perceived utility/efficacy, and (3) patient satisfaction. RESULTS: Our survey data suggests that patients and their family members agree on the efficacy of the support group in learning about NPH. They felt that the support group served its purpose and improved their comfort/knowledge regarding NPH. There was consensus about sustaining and maintaining the support group for the future. Of 65 survey responses, the composite average score of questions pertaining to subjective knowledge, perceived utility/efficacy, and patient satisfaction was 4.5 out of 5.0. CONCLUSION: We demonstrated that support groups are effective in educating the adult NPH population and their family/friends about NPH onset and treatment. Enhanced educational awareness for patients and families can help patients cope with their neurological condition and improve patient adherence to follow-up and physician recommendations.

Racial and Socioeconomic Disparities in Bladder Cancer Survival: Analysis of the California Cancer Registry.

PURPOSE: To examine the California Cancer Registry (CCR) for bladder cancer survival disparities based on race, socioeconomic status (SES), and insurance in California patients. PATIENTS AND METHODS: The CCR was queried for bladder cancer cases in California from 1988 to 2012. The primary outcome was disease-specific survival (DSS), defined as the time interval from date of diagnosis to date of death from bladder cancer. Survival analyses were performed to determine the prognostic significance of racial and socioeconomic factors. RESULTS: A total of 72,452 cases were included (74.5% men, 25.5% women). The median age was 72 years (range, 18-109 years). The racial distribution among the patients was 81% white, 3.8% black, 8.8% Hispanic, 5.2% Asian, and 1.2% from other races. In black patients, tumors presented more frequently with advanced stage and high grade. Medicaid patients tended to be younger and had more advanced-stage, higher-grade tumors compared to patients with Medicare or managed care (P < .0001). Kaplan-Meier analysis demonstrated significantly poorer 5-year DSS in black, low SES, and Medicaid patients (P < .0001). When controlling for stage, grade, age, and gender, multivariate analysis revealed that black race (DSS hazard ratio = 1.295; 95% confidence interval, 1.212-1.384), low SES (DSS hazard ratio = 1.325; 95% confidence interval, 1.259-1.395), and Medicaid insurance (DSS hazard ratio = 1.349; 95% confidence interval, 1.246-1.460) were independent prognostic factors (P < .0001). CONCLUSION: An analysis of the CCR demonstrated that black race, low SES, and Medicaid insurance portend poorer DSS. These findings reflect a multifaceted socioeconomic and public health conundrum, and efforts to reduce inequalities should be pursued.

Implementation of an Interactive Tablet-based Educational Intervention in the Neurotrauma Clinic: A 1-year Retrospective Analysis.

BACKGROUND: Traumatic Brain Injury (TBI) is a devastating and widely prevalent cause of death and disability in the United States. Educational interventions integrated into neurosurgical neurotrauma clinics can facilitate patient education and optimize the clinical encounter. Interactive educational modalities may enhance knowledge acquisition and patient satisfaction, however, no description of implementing such a program has been presented in the literature. The implementation of an interactive iBook-based educational intervention in an outpatient neurotrauma clinic is discussed. METHODS: Concussion and TBI iBooks and surveys were created. Then, a retrospective chart review and data analysis of 202 consecutive patients and family members presenting to the neurotrauma clinic was conducted. The participants completed a presurvey, reviewed an interactive iBook, and then completed a post-survey to test interim knowledge improvement. RESULTS: We discuss the process and problems encountered when creating the iBooks and implementing them in a clinical setting. Between August 1, 2015 and August 1, 2016, 93 patients (46%) and 109 (54%) family members participated in the study, for a total of 202 participants. 104 subjects reviewed a concussion iBook, and 98 subjects reviewed a TBI iBook, depending on their medical condition. Significant improvements in self-reported knowledge measures were demonstrated. Participants ranged in age from 10 to 90 years, with a mean of 45 years. The male to female ratio was 1.104:1. CONCLUSIONS: Interactive iBooks were readily implemented into a neurotrauma clinic. Improvements in self-reported knowledge measures and strong preference for the interactive iBook were attributed to the efficacy of the educational intervention. Examples of how interactive iBooks may be a useful adjunct in the education of head injury patients and their families in the neurotrauma setting are presented.

Interactive eBooks in educating patients and their families about head injury regardless of age.

OBJECTIVES: Traumatic Brain Injury (TBI) is a common and debilitating injury that is particularly prevalent in patients over 60. Given the influence of head injury on dementia (and vice versa), and the increased likelihood of ground-level falls, elderly patients are vulnerable to TBI. Educational interventions can increase knowledge and influence preventative activity to decrease the likelihood of further TBI. We sought to determine the efficacy of interactive tablet-based educational interventions in elderly patients on self-reported knowledge. PATIENTS AND METHODS: Patients and family members, ages 20-90, presenting to a NeuroTrauma clinic completed a pre-survey to assess baseline TBI or concussion knowledge, depending on their diagnosis. Participants then received an interactive electronic book (eBook), or a text-based pamphlet with identical information, and completed a post-survey to test interim knowledge improvement. RESULTS: All participants (n=180), regardless of age, had significantly higher post-survey scores (p<0.01, 95% CI). Elderly participants who received the eBook (n=39) scored lower than their younger counterparts despite higher pre-survey scores (p<0.01, 95% CI). All participants who received the eBook (n=20, 90) significantly improved on the post-survey (p<0.01, 95% CI) when compared to participants who received the paper pamphlets (n=10, 31). All participants significantly preferred the eBook (p<0.01, 95% CI). CONCLUSIONS: We demonstrated that interactive educational interventions are effective in the elderly TBI population. Enhanced educational awareness in the elderly population, especially patients at risk or with prior TBI, may prevent further head injury by educating patients on the importance of avoiding further head injury and taking precautionary measures to decrease the likelihood of further injury.

Price variation in the most commonly prescribed ear drops in Southern California.

OBJECTIVES/HYPOTHESIS: To evaluate the variability and discrepancies among the most commonly prescribed ear drops sold at pharmacies in southern California. STUDY DESIGN: Prospective study evaluating 11 commonly used ear drops to treat otologic disorders. METHODS: Randomly selected drug stores in three major counties in Southern California (Los Angeles, Orange, and San Diego) were included. Mean, range, minimum, and maximum prices for each drug were calculated and analyzed. The median income of pharmacy ZIP code was also cross-referenced. RESULTS: Data were collected from 108 pharmacies. The mean prices are noted for each of the individual drugs: Cortisporin (brand) 10 mL, $82.70; neomycin, polymyxin B sulfates, and hydrocortisone (Cortisporin-generic) 10 mL, $34.70; ofloxacin (generic) 10 mL, $99.95; sulfacetamide (generic) 15 mL, $40.18; Ciprodex (brand) 7.5 mL, $194.44; Cipro HC (brand) 10 mL, $233.32; Vosol (brand) 15 mL, $120.75; acetic acid (Vosol-generic) 10 mL, $116.55; VosolHC (brand) 10 mL, $204.14; acetic acid/aluminum acetate (Domeboro-generic) 60 mL, $22.91; and Tobradex (brand) 5 mL, $166.47. CONCLUSIONS: There is significant variability among the prices of ear drops across Southern Californian pharmacies, which can be a financial burden to patients paying out of pocket or with high deductibles. A state-mandated, publically accessible report of drug prices may help decrease variability and cost by promoting competition among pharmacies. Price negotiations by governmental payers may assist in reducing prices. In the treatment of otologic disorders, clinicians can help reduce costs for patients by prescribing generic ear drop medications and cheaper alternatives when clinically appropriate. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:1780-1784, 2017.

Smartphone-Enabled Otoscopy in Neurotology/Otology.

Objective A smartphone-enabled otoscope (SEO) can capture tympanic membrane (TM) images. We sought to compare a SEO to microscopic otoscopy in the detection and evaluation of TM pathology in an otology/neurotology practice. Study Design Prospective single-site study in adults presenting over a 3-month period. Setting Neurotology clinic within a tertiary care academic medical center. Subjects and Methods Following consent, 57 patients underwent a medical and microscopic ear examination. Afterward, clinicians photographed bilateral TMs using a SEO. A second "blinded" neurotologist received a SEO-acquired image of each TM and a brief patient history. Our primary end point was identification of TM pathology (or lack thereof) and the blinded neurotologists' corresponding diagnosis. Secondary end points included patient-reported SEO comfort levels. Results A single SEO-acquired TM image and brief patient history resulted in correct diagnosis of 96% (23/24) of normal TMs and identification of 100% (33/33) of microscope-confirmed abnormal TMs. When pathology was identified by the "blinded" physician, the diagnosis was identical to that made by the primary treating physician 82% (27/33) of the time. On patient surveys, 93% (53/57) of patients felt "very comfortable" with SEO utilization, and 88% (50/57) reported viewing acquired images was "very useful" in understanding their condition. Conclusion A SEO is 96% specific in identifying normal TMs and 100% sensitive in identifying pathology. Its 97% positive predictive value and small false-positive rate makes it a useful screening tool. Furthermore, patients are receptive to this technology and felt comfortable with its utilization in a health care or possible telemedicine setting.

Interactive iBook-Based Patient Education in a NeuroTrauma Clinic.

BACKGROUND: Traumatic brain injury (TBI) is a leading cause of death and disability in the United States. Educational interventions may alleviate the burden of TBI for patients and their families. Interactive modalities that involve engagement with the educational material may enhance patient knowledge acquisition when compared to static text-based educational material. OBJECTIVE: To determine the effects of educational interventions in the outpatient setting on self-reported patient knowledge, with a focus on iPad-based (Apple, Cupertino, California) interactive modules. METHODS: Patients and family members presenting to a NeuroTrauma clinic at a tertiary care academic medical center completed a presurvey assessing baseline knowledge of TBI or concussion, depending on the diagnosis. Subjects then received either an interactive iBook (Apple) on TBI or concussion, or an informative pamphlet with identical information in text format. Subjects then completed a postsurvey prior to seeing the neurosurgeon. RESULTS: All subjects (n = 152) significantly improved on self-reported knowledge measures following administration of either an iBook (Apple) or pamphlet (P < .01, 95% confidence interval [CI]). Subjects receiving the iBook (n = 122) performed significantly better on the postsurvey (P < .01, 95% CI), despite equivalent presurvey scores, when compared to those receiving pamphlets (n = 30). Lastly, patients preferred the iBook to pamphlets (P < .01, 95% CI). CONCLUSION: Educational interventions in the outpatient NeuroTrauma setting led to significant improvement in self-reported measures of patient and family knowledge. This improved understanding may increase compliance with the neurosurgeon's recommendations and may help reduce the potential anxiety and complications that arise following a TBI.

The expression of molecular chaperone HSP90 and IL-6 in patients with systemic lupus erythematosus.

To explore the expression and clinical significance of molecular chaperone heat shock protein 90 (HSP90) in peripheral blood mononuclear cells (PBMC) and plasma level of interleukin-6 (IL-6) in patients with systemic lupus erythematosus (SLE), HSP90 was detected in PBMC by Western blot assay and the plasma level of IL-6 was measured by ELISA in 38 SLE patients and 20 normal controls. The correlation analysis was performed between the SLE disease activity index (SLE-DAI) and the expression of HSP90 and IL-6. The results showed that there was increased expression of HSP90 in the SLE patients. The active SLE group exhibited higher HSP90 levels (0.82+/-0.10) than the inactive SLE group (0.54+/-0.09) (P<0.01). The expression of HSP90 in normal control group (0.37+/-0.11) showed significant statistical difference as compared to both the inactive and active SLE groups (P<0.01, P<0.01, respectively). The plasma level of IL-6 exhibited a significant increase in both the inactive and active SLE groups (28.99+/-1.74 pg/mL, 44.58+/-9.15 pg/mL, respectively) compared with normal control group (P<0.01, P<0.01, respectively). The expression of HSP90 and IL-6 in SLE patients showed significant positive correlation with SLEDAI scoring (r=0.80, P<0.01: r= 0.74, P<0.01, respectively). In addition, there was a positive correlation between the level of IL-6 and HSP90 in SLE patients (r=0.86, P<0.01). The increased expression of molecular chaperone HSP90 and IL-6 may play an important role in the pathogenesis of SLE by regulating autoimmunity.

Evaluation of an iPhone Otoscope in a Neurotrauma Clinic and as an Adjunct to Neurosurgical Education.

INTRODUCTION: CellScope®, an iPhone-enabled otoscope, was introduced into the neurotrauma clinic at an American College of Surgeons certified Level I trauma center. CellScope is an innovative tool that digitally improves optical clarity of the tympanic membrane, providing the acquisition of HIPPA compliant images. We compared the CellScope to the traditional otoscope in teaching medical students, neurosurgery physician assistants, and neurosurgery residents. In addition, the utility of this device in a neurotrauma clinic was specifically examined because of the high frequency of otologic symptoms after head trauma. METHOD: CellScope examination of the tympanic membranes was introduced as a standard/routine part of the exam of neurotrauma patients. We retrospectively reviewed the clinic charts of the NeuroTrauma patients during a three-month time period to determine if their otologic symptoms correlated with any CellScope visualized abnormalities. Medical students, P.A.s, residents, and attendings were surveyed before and after using CellScope to assess their comfort and skill in completing an otological exam, as well as their opinion on the utility of CellScope in their medical training. RESULTS: 18 medical professionals were surveyed before and after the use of CellScope. Surveys were graded on a 1-5 scale and indicated a greater preference for the CellScope (4.7/5.0) versus the otoscope (3.16/5.0). Similarly, there was a preference for the CellScope for medical education (4.7/5.0 versus 2.78/5.0). Finally, surveys showed a greater preference for CellScope in identifying abnormal pathology. The overall score showed a 49% increased preference for CellScope over the traditional otoscope. Six previously undiagnosed abnormalities of the tympanic membrane were identified in a total of 27 neurotrauma patients using CellScope. CONCLUSION: The visualization of the tympanic membrane is an important part of the physical examination of the neurotrauma patient. Smartphone-enabled medical instruments like CellScope may facilitate and remove barriers to routine implementation of this part of the physical examination.

Emerging techniques for evaluation of the hemodynamics of intracranial vascular pathology.

Advances in imaging modalities have improved the assessment of intracranial hemodynamics using non-invasive techniques. This review examines new imaging modalities and clinical applications of currently available techniques, describes pathophysiology and future directions in hemodynamic analysis of intracranial stenoses, aneurysms and arteriovenous malformations and explores how hemodynamic analysis may have prognostic value in predicting clinical outcomes and assist in risk stratification. The advent of new technologies such as pseudo-continuous arterial spin labeling, accelerated magnetic resonance angiography (MRA) techniques, 4D digital subtraction angiography, and improvements in clinically available techniques such as phase-contrast MRA may change the landscape of vascular imaging and modify current clinical practice guidelines.

Chromosome 13q neocentromeres: molecular cytogenetic characterization of three additional cases and clinical spectrum.

We report three new cases of chromosome 13 derived marker chromosomes, found in unrelated patients with dysmorphisms and/or developmental delay. Molecular cytogenetic analysis was performed using fluorescence in situ hybridization (FISH) with chromosome-specific painting probes, alpha satellite probes, and physically mapped probes from chromosome 13q, as well as comparative genomic hybridization (CGH). This analysis demonstrated that these markers consisted of inversion duplications of distal portions of chromosome 13q that have separated from the endogenous chromosome 13 centromere and contain no detectable alpha satellite DNA. The presence of a functional neocentromere on these marker chromosomes was confirmed by immunofluorescence with antibodies to centromere protein-C (CENP-C). The cytogenetic location of a neocentromere in band 13q32 was confirmed by simultaneous FISH with physically mapped YACs from 13q32 and immunofluorescence with anti-CENP-C. The addition of these three new cases brings the total number of described inv dup 13q neocentic chromosomes to 11, representing 21% (11/52) of the current overall total of 52 described cases of human neocentric chromosomes. This higher than expected frequency suggests that chromosome 13q may have an increased propensity for neocentromere formation. The clinical spectrum of all 11 cases is presented, representing a unique collection of polysomy for different portions of chromosome 13q without aneuploidies for additional chromosomal regions. The complexity and variability of the phenotypes seen in these patients does not support a simple reductionist view of phenotype/genotype correlation with polysomy for certain chromosomal regions.

Resection of a large benign pharyngo-oesophageal submucous mesenchymoma via laterocervical approach.

Two rare cases of benign submucosal pharyngo-oesophageal mesenchymoma are presented in this paper. One patient was treated by tumour removal via a combined thoracic and laterocervical approach and the other by resection through a laterocervical approach. The paper discusses the pathology and diagnosis of benign mesenchymomas. The authors suggest that for large tumours located in the pharynx and extending down the oesophagus without adhesion to the oesophageal wall, the laterocervical approach can avoid complications associated with the thoracic approach. The new technique caused less tissue damage and provided a quicker recovery and shorter hospitalization.

Cryptic out-of-frame translational initiation of TBCE rescues tubulin formation in compound heterozygous HRD.

Microtubules are indispensable dynamic structures that contribute to many essential biological functions. Assembly of the native alpha/beta tubulin heterodimer, the subunit that polymerizes to form microtubules, requires the participation of several molecular chaperones, namely prefoldin, the cytosolic chaperonin CCT, and a series of five tubulin-specific chaperones termed cofactors A-E (TBCA-E). Among these, TBCC, TBCD, and TBCE are essential in higher eukaryotes; they function together as a multimolecular machine that assembles quasinative CCT-generated alpha- and beta-tubulin polypeptides into new heterodimers. Deletion and truncation mutations in the gene encoding TBCE have been shown to cause the rare autosomal recessive syndrome known as HRD, a devastating disorder characterized by congenital hypoparathyroidism, mental retardation, facial dysmorphism, and extreme growth failure. Here we identify cryptic translational initiation at each of three out-of-frame AUG codons upstream of the genetic lesion as a unique mechanism that rescues a mutant HRD allele by producing a functional TBCE protein. Our data explain how afflicted individuals, who would otherwise lack the capacity to make functional TBCE, can survive and point to a limiting capacity to fold tubulin heterodimers de novo as a contributing factor to disease pathogenesis.