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1.
Acta Radiol Open ; 9(8): 2058460120942789, 2020 Aug.
Article in English | MEDLINE | ID: mdl-32913666

ABSTRACT

In the latest World Health Organization classification of brain tumors, gliomatosis cerebri has been redefined to varying subsets of diffuse gliomas; however, the term is still used to describe gliomas with infiltrative growth into three or more cerebral lobes. These tumors are frequently misdiagnosed and difficult to treat due to their atypical presentation using structural imaging modalities including computed tomography and T1/T2-weighted magnetic resonance imaging (MRI). In this retrospective case series, we compared clinical MRI to amino acid positron emission tomography (PET) to assess the potential value of PET in the assessment of the extent of tumor involvement and in monitoring disease progression. We report the clinical course and serial multimodal imaging findings of four patients. Each patient presented at varying points in disease progression with widespread glioma brain involvement and was evaluated at least once by amino acid PET using alpha-[11C]methyl-L-tryptophan ([11C]-AMT). Increased uptake of [11C]-AMT was detected in a subset of non-enhancing brain lesions and detected tumor invasion before MRI signs of tumor in some regions. Increased uptake of [11C]-AMT was also detected in tumorous regions not detected by perfusion MRI or MR spectroscopy. Metabolic response to treatment was also observed in two patients. Overall, these data are consistent with and expand upon previous reports using other amino acid PET tracers in gliomatosis and show the potential added value of this imaging modality to clinical MRI in the detection and monitoring of these diffusely infiltrative tumors.

2.
Am J Physiol Heart Circ Physiol ; 319(2): H306-H319, 2020 08 01.
Article in English | MEDLINE | ID: mdl-32618513

ABSTRACT

Dilated cardiomyopathy (DCM) is clinically characterized by dilated ventricular cavities and reduced ejection fraction, leading to heart failure and increased thromboembolic risk. Mutations in thin-filament regulatory proteins can cause DCM and have been shown in vitro to reduce contractility and myofilament Ca2+-affinity. In this work we have studied the functional consequences of mutations in cardiac troponin T (R131W), cardiac troponin I (K36Q) and α-tropomyosin (E40K) using adenovirally transduced isolated guinea pig left ventricular cardiomyocytes. We find significantly reduced fractional shortening with reduced systolic Ca2+. Contraction and Ca2+ reuptake times were slowed, which contrast with some findings in murine models of myofilament Ca2+ desensitization. We also observe increased sarcoplasmic reticulum (SR) Ca2+ load and smaller fractional SR Ca2+ release. This corresponds to a reduction in SR Ca2+-ATPase activity and increase in sodium-calcium exchanger activity. We also observe dephosphorylation and nuclear translocation of the nuclear factor of activated T cells (NFAT), with concordant RAC-α-serine/threonine protein kinase (Akt) phosphorylation but no change to extracellular signal-regulated kinase activation in chronically paced cardiomyocytes expressing DCM mutations. These changes in Ca2+ handling and signaling are common to all three mutations, indicating an analogous pathway of disease pathogenesis in thin-filament sarcomeric DCM. Previous work has shown that changes to myofilament Ca2+ sensitivity caused by DCM mutations are qualitatively opposite from hypertrophic cardiomyopathy (HCM) mutations in the same genes. However, we find several common pathways such as increased relaxation times and NFAT activation that are also hallmarks of HCM. This suggests more complex intracellular signaling underpinning DCM, driven by the primary mutation.NEW & NOTEWORTHY Dilated cardiomyopathy (DCM) is a frequently occurring cardiac disorder with a degree of genetic inheritance. We have found that DCM mutations in proteins that regulate the contractile machinery cause alterations to contraction, calcium-handling, and some new signaling pathways that provide stimuli for disease development. We have used guinea pig cells that recapitulate human calcium-handling and introduced the mutations using adenovirus gene transduction to look at the initial triggers of disease before remodeling.


Subject(s)
Calcium Signaling , Cardiomyopathy, Dilated/genetics , Microfilament Proteins/genetics , Mutation , Myocardial Contraction , Myocytes, Cardiac/enzymology , NFATC Transcription Factors/metabolism , Oncogene Protein v-akt/metabolism , Ventricular Function, Left , Animals , Cardiomyopathy, Dilated/metabolism , Cardiomyopathy, Dilated/physiopathology , Cardiomyopathy, Hypertrophic/genetics , Cardiomyopathy, Hypertrophic/metabolism , Cardiomyopathy, Hypertrophic/physiopathology , Cells, Cultured , Genetic Predisposition to Disease , Guinea Pigs , Male , Microfilament Proteins/metabolism , Phenotype , Sarcoplasmic Reticulum/metabolism , Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism , Sodium-Calcium Exchanger/metabolism , Tropomyosin/genetics , Tropomyosin/metabolism , Troponin I/genetics , Troponin I/metabolism , Troponin T/genetics , Troponin T/metabolism
3.
Cureus ; 11(6): e4979, 2019 Jun 23.
Article in English | MEDLINE | ID: mdl-31467813

ABSTRACT

Spontaneous coronary artery dissection (SCAD) is thought to be a rare condition that is hard to predict due to the lack of easily identifiable warning signs. We report the case of a 49-year-old woman with a locally advanced Stage IIIB anal squamous cell carcinoma who presented with chest pain and a positive stress test, ST elevations in her inferior echocardiogram leads, and induced chest pain with exercise without heart perfusion defects. Coronary catheterization revealed a right coronary artery dissection, which led to the diagnosis of SCAD. Our patient was diagnosed while undergoing a combination treatment of fluorouracil (5-FU), mitomycin, and pelvic radiotherapy. We reviewed the current literature and update the etiologies that have been proposed since the publication of this case report.

4.
Circ Res ; 124(8): 1228-1239, 2019 04 12.
Article in English | MEDLINE | ID: mdl-30732532

ABSTRACT

RATIONALE: Subcellular Ca2+ indicators have yet to be developed for the myofilament where disease mutation or small molecules may alter contractility through myofilament Ca2+ sensitivity. Here, we develop and characterize genetically encoded Ca2+ indicators restricted to the myofilament to directly visualize Ca2+ changes in the sarcomere. OBJECTIVE: To produce and validate myofilament-restricted Ca2+ imaging probes in an adenoviral transduction adult cardiomyocyte model using drugs that alter myofilament function (MYK-461, omecamtiv mecarbil, and levosimendan) or following cotransduction of 2 established hypertrophic cardiomyopathy disease-causing mutants (cTnT [Troponin T] R92Q and cTnI [Troponin I] R145G) that alter myofilament Ca2+ handling. METHODS AND RESULTS: When expressed in adult ventricular cardiomyocytes RGECO-TnT (Troponin T)/TnI (Troponin I) sensors localize correctly to the sarcomere without contractile impairment. Both sensors report cyclical changes in fluorescence in paced cardiomyocytes with reduced Ca2+ on and increased Ca2+ off rates compared with unconjugated RGECO. RGECO-TnT/TnI revealed changes to localized Ca2+ handling conferred by MYK-461 and levosimendan, including an increase in Ca2+ binding rates with both levosimendan and MYK-461 not detected by an unrestricted protein sensor. Coadenoviral transduction of RGECO-TnT/TnI with hypertrophic cardiomyopathy causing thin filament mutants showed that the mutations increase myofilament [Ca2+] in systole, lengthen time to peak systolic [Ca2+], and delay [Ca2+] release. This contrasts with the effect of the same mutations on cytoplasmic Ca2+, when measured using unrestricted RGECO where changes to peak systolic Ca2+ are inconsistent between the 2 mutations. These data contrast with previous findings using chemical dyes that show no alteration of [Ca2+] transient amplitude or time to peak Ca2+. CONCLUSIONS: RGECO-TnT/TnI are functionally equivalent. They visualize Ca2+ within the myofilament and reveal unrecognized aspects of small molecule and disease-associated mutations in living cells.


Subject(s)
Calcium/metabolism , Cardiomyopathy, Hypertrophic/genetics , Mutation , Myocytes, Cardiac/metabolism , Myofibrils/metabolism , Sarcomeres/metabolism , Adenosine Triphosphatases/antagonists & inhibitors , Adenosine Triphosphatases/metabolism , Adenoviridae , Animals , Benzylamines/pharmacology , Cardiomyopathy, Hypertrophic/metabolism , Guinea Pigs , In Vitro Techniques , Male , Myofibrils/drug effects , Myosins/drug effects , Myosins/metabolism , Simendan/pharmacology , Transduction, Genetic/methods , Troponin I/genetics , Troponin I/metabolism , Troponin T/genetics , Troponin T/metabolism , Uracil/analogs & derivatives , Uracil/pharmacology , Urea/analogs & derivatives , Urea/pharmacology
5.
J Biol Chem ; 293(27): 10487-10499, 2018 07 06.
Article in English | MEDLINE | ID: mdl-29760186

ABSTRACT

Mutations in thin filament regulatory proteins that cause hypertrophic cardiomyopathy (HCM) increase myofilament Ca2+ sensitivity. Mouse models exhibit increased Ca2+ buffering and arrhythmias, and we hypothesized that these changes are primary effects of the mutations (independent of compensatory changes) and that increased Ca2+ buffering and altered Ca2+ handling contribute to HCM pathogenesis via activation of Ca2+-dependent signaling. Here, we determined the primary effects of HCM mutations on intracellular Ca2+ handling and Ca2+-dependent signaling in a model system possessing Ca2+-handling mechanisms and contractile protein isoforms closely mirroring the human environment in the absence of potentially confounding remodeling. Using adenovirus, we expressed HCM-causing variants of human troponin-T, troponin-I, and α-tropomyosin (R92Q, R145G, and D175N, respectively) in isolated guinea pig left ventricular cardiomyocytes. After 48 h, each variant had localized to the I-band and comprised ∼50% of the total protein. HCM mutations significantly lowered the Kd of Ca2+ binding, resulting in higher Ca2+ buffering of mutant cardiomyocytes. We observed increased diastolic [Ca2+] and slowed Ca2+ reuptake, coupled with a significant decrease in basal sarcomere length and slowed relaxation. HCM mutant cells had higher sodium/calcium exchanger activity, sarcoplasmic reticulum Ca2+ load, and sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) activity driven by Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of phospholamban. The ryanodine receptor (RyR) leak/load relationship was also increased, driven by CaMKII-mediated RyR phosphorylation. Altered Ca2+ homeostasis also increased signaling via both calcineurin/NFAT and extracellular signal-regulated kinase pathways. Altered myofilament Ca2+ buffering is the primary initiator of signaling cascades, indicating that directly targeting myofilament Ca2+ sensitivity provides an attractive therapeutic approach in HCM.


Subject(s)
Calcium Signaling , Calcium/metabolism , Cardiomyopathy, Hypertrophic/pathology , Mutation , Tropomyosin/genetics , Troponin I/genetics , Troponin T/genetics , Animals , Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Cardiomyopathy, Hypertrophic/genetics , Cardiomyopathy, Hypertrophic/metabolism , Cells, Cultured , Guinea Pigs , Humans , Myofibrils/metabolism , Myofibrils/pathology , Phosphorylation , Sarcomeres/metabolism , Sarcoplasmic Reticulum/metabolism , Sarcoplasmic Reticulum Calcium-Transporting ATPases/genetics , Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism , Tropomyosin/metabolism , Troponin I/metabolism , Troponin T/metabolism
6.
J Vasc Surg ; 63(2): 355-61, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26506934

ABSTRACT

OBJECTIVE: This study was undertaken to analyze the occurrence of postoperative urinary retention (POUR) after carotid endarterectomy (CEA) and determine whether there are any associated modifiable risk factors. CEA was chosen to minimize the confounding effects of known risk factors for POUR, including immobilization, regional and severe pain, and neuroaxial anesthesia. METHODS: This was a retrospective record review of 186 male patients undergoing CEA between 2007 and 2011. Demographic, comorbidities, and operative characteristics were compared. Continuous variables are reported as median and interquartile range (IQR) and categoric variables as frequencies and proportions. Pearson χ(2) or Mann-Whitney U tests compared categoric and continuous variables, respectively. Logistic regression was used to examine univariate and multivariate odds of POUR. Multivariate analysis controlled for known predictors of urinary retention. Association with other complications was examined with the Pearson correlation coefficient. RESULTS: POUR occurred in 34 patients (18.3%). Median age and history of urinary tract infection (UTI) were significantly associated with POUR: median age was 73.0 years (IQR, 67-80 years) for those with POUR vs 69.5 years (IQR, 63-76 years) for those without (P = .047); 17.6% of patients with a history of UTI developed POUR vs 5.9% without (P = .023). These findings persisted on multivariate analysis controlling for known predictors of POUR (body mass index, history of diabetes, benign prostate hyperplasia, and prior prostate surgery): median age (odds ratio, 1.05; 95% confidence interval, 1-1.1) and history of UTI (odds ratio, 4.16; 95% confidence interval, 1.23-14.05; P = .022). The occurrence of POUR was significantly correlated with postoperative UTI: 18.8% with POUR vs 0.7% without (Pearson r = 0.369; P < .001). CONCLUSIONS: POUR requiring bladder catheterization after CEA predisposes patients to postoperative UTI and is more common in older patients and those with a history of UTI. CEA patients lack inherent risk factors for POUR and would be a useful population for prospective studies involving POUR.


Subject(s)
Carotid Artery Diseases/surgery , Endarterectomy, Carotid/adverse effects , Urinary Retention/etiology , Urinary Tract Infections/complications , Age Factors , Aged , Aged, 80 and over , Carotid Artery Diseases/diagnosis , Chi-Square Distribution , Humans , Logistic Models , Male , Multivariate Analysis , Odds Ratio , Retrospective Studies , Risk Assessment , Risk Factors , Time Factors , Treatment Outcome , Urinary Catheterization , Urinary Retention/diagnosis , Urinary Retention/therapy
7.
Biomark Insights ; 9: 77-84, 2014.
Article in English | MEDLINE | ID: mdl-25232277

ABSTRACT

FAS-associated protein with death domain (FADD) is a major adaptor protein involved in extrinsic apoptosis, embryogenesis, and lymphocyte homeostasis. Although abnormalities of the FADD/death receptor apoptotic pathways have been established in tumorigenesis, fewer studies have analyzed the expression and role of phosphorylated FADD (pFADD). Our identification of FADD as a lymphoma-associated autoantigen in T-cell lymphoma patients raises the possibility that pFADD, with its correlation with cell cycle, may possess role(s) in human T-cell lymphoma development. This immunohistochemical study investigated pFADD protein expression in a range of normal tissues and lymphomas, particularly T-cell lymphomas that require improved therapies. Whereas pFADD was expressed only in scattered normal T cells, it was detected at high levels in T-cell lymphomas (eg, 84% anaplastic large cell lymphoma and 65% peripheral T cell lymphomas, not otherwise specified). The increased expression of pFADD supports further study of its clinical relevance and role in lymphomagenesis, highlighting phosphorylation of FADD as a potential therapeutic target.

8.
Int J Gynecol Cancer ; 24(1): 97-101, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24264358

ABSTRACT

OBJECTIVES: This study aimed to determine the impact of tumor grade on patterns of recurrence and survival end points in patients with endometrioid carcinoma 2009 International Federation of Gynecology and Obstetrics stages I-II. METHODS: We identified 949 patients who underwent hysterectomy between 1988 and 2011. Patients were divided into 3 groups based on tumor grade. Kaplan-Meier plots were generated for each group for recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS). RESULTS: Median follow-up was 52 months. Median age was 60 years. All patients underwent total abdominal hysterectomy and salpingo-oophorectomy. Eighty percent of patients underwent lymph node dissection, 83% had peritoneal cytology. There were 76 (8%) patients who developed tumor recurrence. Tumor recurrence rates were significantly higher in patients with grade 3 tumors compared to grade 1 (P = 0.006). Additionally, patients with grade 3 tumors developed significantly more frequent distant metastases compared to patients with grade 1 (P = 0.002). Five-year RFS for the patients with grade 1, 2, and 3 were 95%, 82%, and 68%, respectively (P = <0.001). Five-year DSS was 99%, 93%, and 79%, respectively (P = <0.001). Five-year OS was 89%, 84%, and 63%, respectively (P = <0.001). Lymphovascular space involvement and grade were significant independent predictors of RFS and DSS. For OS age, lymphovascular space involvement, grade, and body mass index were significant predictors. CONCLUSIONS: International Federation of Gynecology and Obstetrics grade is a strong predictor of clinical survival end points in women with early-stage endometrioid carcinoma. The pattern of recurrence in patients with grade 3 tumors is mainly distant rather than locoregional. Further studies incorporating systemic therapy in the adjuvant settings in these patients are warranted.


Subject(s)
Carcinoma, Endometrioid/pathology , Endometrial Neoplasms/pathology , Genitalia, Female/pathology , Neoplasm Recurrence, Local/pathology , Adult , Aged , Aged, 80 and over , Carcinoma, Endometrioid/mortality , Endometrial Neoplasms/mortality , Female , Humans , Michigan/epidemiology , Middle Aged , Neoplasm Grading , Neoplasm Metastasis , Neoplasm Recurrence, Local/epidemiology , Retrospective Studies
9.
Anticancer Res ; 33(2): 619-24, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23393357

ABSTRACT

BACKGROUND: Baby boomers (BB) entering retirement represent a significant burden on medical resources. The unique lifestyle characteristics engendered by the BB may lead to different endometrial cancer characteristics that bear understanding. We sought to characterize BB with endometrioid carcinoma after hysterectomy and compare the results to those of prior to the baby boomers (PB). PATIENTS AND METHODS: After reviewing our prospectively maintained database of 1,450 patients with endometrial cancer, we identified 595 patients who underwent hysterectomy for 1988 International Federation of Gynecologic Oncology (FIGO) stage I-II uterine endometrioid carcinomas, who were born between 1926 and 1964. Their medical records were reviewed in this Institutional review board (IRB)-approved study. Patients with non-endometrioid carcinoma and those who received preoperative therapy were excluded. Patients were defined as BB (born 1946-1964) or PB (born in 1926-1945). The two groups were compared regarding patients' demographics, tumor characteristics and survival. Following a univariate analysis, multivariable modeling was carried out using Cox regression analysis. RESULTS: All patients underwent hysterectomy with a minimum of two years' follow-up. There were 234 patients (39%) in the BB group and 361 patients (61%) in the PB group. Median follow-up for the study cohort was 56 months. BB had higher body mass index (p=0.027), lower tumor grade (p=0.002), earlier FIGO stage (p=0.023), higher number of dissected lymph nodes (p=0.008), less lymphvascular space involvement (p=<0.034), less utilization of adjuvant therapy (p=<0.001), and younger age at diagnosis (p=0.002). However, there was no significant difference found between the BB and PB in regards to local control, disease-specific survival and overall survival. For the study cohort, FIGO stage and tumor grade were independent predictors of recurrence-free and disease-specific survival. There was a trend towards shorter overall survival for the PB women (p=0.063). CONCLUSION: Although tumor characteristics were more favorable in the BB group of women, local control and survival end-points were not statistically different compared to those of the PB group. As more BB are diagnosed with endometrial carcinoma, further research is warranted to further elucidate the characteristic differences in endometrial carcinoma, if any, in this generation.


Subject(s)
Endometrial Neoplasms/epidemiology , Uterine Neoplasms/epidemiology , Aged , Aged, 80 and over , Cohort Studies , Disease-Free Survival , Endometrial Neoplasms/pathology , Endometrial Neoplasms/therapy , Female , Humans , Kaplan-Meier Estimate , Middle Aged , Neoplasm Staging , Proportional Hazards Models , Uterine Neoplasms/pathology , Uterine Neoplasms/therapy
10.
J Proteomics ; 75(17): 5279-92, 2012 Sep 18.
Article in English | MEDLINE | ID: mdl-22732457

ABSTRACT

Characterising tumour-associated antigens (TAAs) not only represents an important approach to the identification of new diagnostic/prognostic markers, but can also provide information on disease processes and additional potential therapeutic targets. Preliminary screening of a protein macroarray, containing more than 12,000 different proteins, with sera from anaplastic lymphoma kinase (ALK)-negative and ALK-positive anaplastic large cell lymphoma (ALCL) patients identified ribonuclease and tumour suppressor protein Ribonuclease T2 (RNASET2), phosphatase lipid phosphate phosphatase-related protein type 3 (LPPR3) and apoptotic adaptor molecule Fas-associating protein (FADD) as ALK-negative ALCL-associated TAAs. Further validation of these observations was confirmed using the ALCL sera in reverse ELISAs. The circulating anti-RNASET2 autoantibodies present in ALCL patients' sera also recognised eukaryotically expressed RNASET2 protein. RNASET2 expression was then investigated in normal tissues and in lymphomas to explore its clinical potential. RNASET2 protein and mRNA levels showed highest expression in the spleen, leucocytes and pancreas. RNASET2 protein expression was not restricted to ALK-negative ALCL (81%), being expressed in ALK-positive ALCL (65%) as well as in a number of other lymphomas. The immunological recognition of RNASET2, its expression in ALCL and other lymphomas together with its known tumourigenic properties suggest that further studies on this autoantigen are warranted.


Subject(s)
Lymphoma, Large-Cell, Anaplastic/metabolism , Protein Array Analysis , Ribonucleases/metabolism , Ribonucleases/physiology , Tumor Suppressor Proteins/metabolism , Tumor Suppressor Proteins/physiology , Animals , Autoantigens/analysis , Autoantigens/metabolism , Case-Control Studies , Cell Line, Tumor , Female , Humans , Lymphoma, Large-Cell, Anaplastic/pathology , Male , Mice , Middle Aged , Ribonucleases/analysis , Tissue Distribution , Tumor Suppressor Proteins/analysis , Validation Studies as Topic
11.
Endocrinology ; 151(7): 3169-80, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20427481

ABSTRACT

Nesfatin-1 is a recently identified anorexigenic peptide derived from its precursor protein, nonesterified fatty acid/nucleobindin 2 (NUCB2). Although the hypothalamus is pivotal for the maintenance of energy homeostasis, adipose tissue plays an important role in the integration of metabolic activity and energy balance by communicating with peripheral organs and the brain via adipokines. Currently no data exist on nesfatin-1 expression, regulation, and secretion in adipose tissue. We therefore investigated NUCB2/nesfatin-1 gene and protein expression in human and murine adipose tissue depots. Additionally, the effects of insulin, dexamethasone, and inflammatory cytokines and the impact of food deprivation and obesity on nesfatin-1 expression were studied by quantitative RT-PCR and Western blotting. We present data showing NUCB2 mRNA (P < 0.001), nesfatin-1 intracellular protein (P < 0.001), and secretion (P < 0.01) were significantly higher in sc adipose tissue compared with other depots. Also, nesfatin-1 protein expression was significantly increased in high-fat-fed mice (P < 0.01) and reduced under food deprivation (P < 0.01) compared with controls. Stimulation of sc adipose tissue explants with inflammatory cytokines (TNFalpha and IL-6), insulin, and dexamethasone resulted in a marked increase in intracellular nesfatin-1 levels. Furthermore, we present evidence that the secretion of nesfatin-1 into the culture media was dramatically increased during the differentiation of 3T3-L1 preadipocytes into adipocytes (P < 0.001) and after treatments with TNF-alpha, IL-6, insulin, and dexamethasone (P < 0.01). In addition, circulating nesfatin-1 levels were higher in high-fat-fed mice (P < 0.05) and showed positive correlation with body mass index in human. We report that nesfatin-1 is a novel depot specific adipokine preferentially produced by sc tissue, with obesity- and food deprivation-regulated expression.


Subject(s)
Adipokines/genetics , Adipose Tissue/metabolism , Nerve Tissue Proteins/metabolism , Peptide Hormones/metabolism , 3T3-L1 Cells , Adipose Tissue/cytology , Adipose Tissue/drug effects , Animals , Blotting, Western , Calcium-Binding Proteins/genetics , Cell Differentiation/genetics , Cell Differentiation/physiology , Cells, Cultured , Cytokines/pharmacology , DNA-Binding Proteins/genetics , Dexamethasone/pharmacology , Dietary Fats/pharmacology , Enzyme-Linked Immunosorbent Assay , Humans , Immunohistochemistry , In Vitro Techniques , Insulin/pharmacology , Male , Mice , Mice, Inbred C57BL , Nerve Tissue Proteins/genetics , Nucleobindins , Obesity/blood , Obesity/metabolism , Peptide Hormones/blood , Peptide Hormones/genetics , Reverse Transcriptase Polymerase Chain Reaction
12.
Mol Cytogenet ; 3: 4, 2010 Feb 23.
Article in English | MEDLINE | ID: mdl-20178584

ABSTRACT

BACKGROUND: Down syndrome (DS), characterized by an extra free chromosome 21 is the most common genetic cause for congenital malformations and learning disability. It is well known that the extra chromosome 21 originates from the mother in more than 90% of cases, the incidence increases with maternal age and there is a high recurrence in young women. In a previous report we have presented data to indicate that maternal trisomy 21 (T21) ovarian mosaicism might provide the major causative factor underlying these patterns of DS inheritance. One important outstanding question concerns the reason why the extra chromosome 21 in DS rarely originates from the father, i.e. in less than 10% of T21 DS cases. We here report data indicating that one reason for this parental sex difference is a very much lower degree of fetal testicular in comparison to ovarian T21 mosaicism. RESULTS: We used fluorescence in situ hybridisation (FISH) with two chromosome 21-specific probes to determine the copy number of chromosome 21 in fetal testicular cell nuclei from four male fetuses, following termination of pregnancy for a non-medical/social reason at gestational age 14-19 weeks. The cells studied were selected on the basis of their morphology alone, pending immunological specification of the relevant cell types. We could not detect any indication of testicular T21 mosaicism in any of these four male fetuses, when analysing at least 2000 cells per case (range 2038-3971, total 11.842). This result is highly statistically significant (p < 0.001) in comparison to the average of 0.54% ovarian T21 mosaicism (range 0.20-0.88%) that we identified in eight female fetuses analysing a total of 12.634 cells, as documented in a previous report in this journal. CONCLUSION: Based on these observations we suggest that there is a significant sex difference in degrees of fetal germ line T21 mosaicism. Thus, it would appear that most female fetuses are T21 ovarian mosaics, while in sharp contrast most male fetuses may be either very low grade T21 testicular mosaics or they may be non-mosaics. We further propose that this sex difference in germ line T21 mosaicism may explain the much less frequent paternal origin of T21 DS than maternal. The mechanisms underlying the DS cases, where the extra chromosome 21 does originate from the father, remains unknown and further studies in this respect are required.

13.
Reproduction ; 139(1): 1-9, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19755486

ABSTRACT

We have recently documented that trisomy 21 mosaicism is common in human foetal ovaries. On the basis of this observation we propose that the maternal age effect in Down syndrome (DS) is caused by the differential behaviour of trisomy 21 in relation to disomy 21 oocytes during development from foetal life until ovulation in adulthood. In particular, we suggest that trisomy 21 oocytes, lagging behind those that are disomic, may escape the timed pruning of the seven million in foetal life to the 300-400 finally selected for ovulation. The net effect of this preferential elimination will be an accumulation of trisomy 21 oocytes in the ovarian reserve of older women. We here highlight the implications of this Oocyte Mosaicism Selection (OMS) model with respect to the prevalent view that the maternal age effect is complex, dependent on many different biological and environmental factors. We examine conclusions drawn from recent large-scale studies in families, tracing DNA markers along the length of chromosome 21q between parents and DS children, in comparison to the OMS model. We conclude that these family linkage data are equally compatible with the maternal age effect originating from the accumulation of trisomy 21 oocytes with advancing maternal age. One relatively straightforward way to get to grips with what is actually going on in this regard would be to compare incidence of trisomy 21 oocytes (and their pairing configurations) in foetal ovaries with that in oocytes at the meiosis I stage from adult women.


Subject(s)
Aging/genetics , Down Syndrome/genetics , Maternal Age , Mosaicism , Oocytes/growth & development , Ovary/embryology , Ovary/growth & development , Aging/physiology , Chromosomes, Human, Pair 21/genetics , Female , Genetic Linkage , Genetic Markers , Humans , Male , Models, Biological
14.
Mol Cytogenet ; 1: 21, 2008 Sep 18.
Article in English | MEDLINE | ID: mdl-18801168

ABSTRACT

BACKGROUND: Down syndrome, characterized by an extra chromosome 21 is the most common genetic cause for congenital malformations and learning disability. It is well known that the extra chromosome 21 most often originates from the mother, the incidence increases with maternal age, there may be aberrant maternal chromosome 21 recombination and there is a higher recurrence in young women. In spite of intensive efforts to understand the underlying reason(s) for these characteristics, the origin still remains unknown. We hypothesize that maternal trisomy 21 ovarian mosaicism might provide the major causative factor. RESULTS: We used fluorescence in situ hybridization (FISH) with two chromosome 21-specific probes to determine the copy number of chromosome 21 in ovarian cells from eight female foetuses at gestational age 14-22 weeks. All eight phenotypically normal female foetuses were found to be mosaics, containing ovarian cells with an extra chromosome 21. Trisomy 21 occurred with about the same frequency in cells that had entered meiosis as in pre-meiotic and ovarian mesenchymal stroma cells. CONCLUSION: We suggest that most normal female foetuses are trisomy 21 ovarian mosaics and the maternal age effect is caused by differential selection of these cells during foetal and postnatal development until ovulation. The exceptional occurrence of high-grade ovarian mosaicism may explain why some women have a child with Down syndrome already at young age as well as the associated increased incidence at subsequent conceptions. We also propose that our findings may explain the aberrant maternal recombination patterns previously found by family linkage analysis.

15.
Psychopharmacology (Berl) ; 171(4): 429-34, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14508636

ABSTRACT

RATIONALE: Although ethanol is known to influence, in humans, psychophysical measures of visual, auditory, and vestibular function, the influence of this drug on the ability to smell is not clear. OBJECTIVES: To evaluate, in eight men and eight women, the influences of ethanol ingestion on four well-validated measures of olfactory function: an ethanol odor detection threshold test, a phenyl ethyl alcohol odor detection threshold test, a 40-item smell identification test, and an odor discrimination/short-term odor memory test. METHODS: In this double-blind experiment, grape juice alone was administered prior to the olfactory tests on one test occasion, and a grape juice-vodka mixture, designed to produce blood levels of ethanol near the legal level of intoxication, on another. The order of the two drug conditions was counterbalanced, as was the order of the presentation of the olfactory tests. RESULTS: Ethanol ingestion markedly influenced the detection threshold for ethanol (all 16 subjects exhibited higher thresholds under the ethanol than under the non-ethanol condition) and had a significant, albeit small, influence on odor discrimination performance, as measured by the total number of correct responses independent of delay interval. Women performed significantly better than men on the latter measure. No influences of ethanol on odor identification, the phenyl ethyl alcohol detection threshold, or the delay interval (memory) component of the odor discrimination/memory test were observed. CONCLUSIONS: Alcohol ingestion markedly and selectively alters olfactory sensitivity to ethanol, perhaps via habituation processes, and may subtly influence some measures of odor discrimination.


Subject(s)
Discrimination, Psychological/drug effects , Ethanol/pharmacology , Smell/drug effects , Adult , Discrimination, Psychological/physiology , Double-Blind Method , Female , Humans , Male , Sensory Thresholds/drug effects , Sensory Thresholds/physiology , Sex Factors , Smell/physiology
16.
Ear Nose Throat J ; 82(3): 205-7, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12696242

ABSTRACT

We report a rare case of moderately differentiated neuroendocrine carcinoma of the larynx. We describe the clinical and pathologic findings relevant to this case, and we review the literature on the pathologic features of this malignancy. We also discuss treatment options.


Subject(s)
Laryngeal Neoplasms/pathology , Neuroendocrine Tumors/pathology , Adult , Female , Humans , Laryngeal Neoplasms/surgery , Neoplasm Invasiveness , Neuroendocrine Tumors/surgery
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