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PubMed2003

Diagnostic single nucleotide polymorphism analysis of factor V Leiden and prothrombin 20210G > A. A comparison of the Nanogen Eelectronic Microarray with restriction enzyme digestion and the Roche LightCycler.

Genetic thrombosis risk factors include a sequence variant in the prothrombin gene (20210G > A) and factor V Leiden (1691G > A). These single nucleotide polymorphisms can be diagnosed with restriction fragment length polymorphism (RFLP) analysis, fluorescent genotyping on the LightCycler (Roche Diagnostics, Indianapolis, IN), and microarray-based testing on the novel NanoChip electronic microarray (NanoChip Molecular Biology Workstation, Nanogen, San Diego, CA). We compared these methods for accuracy, time to results, throughput, and interpretation. Results from 789 of 800 individual amplicons analyzed on the NanoChip were in complete agreement with the other assays. Eleven were "no calls" (uninterpreted by the NanoChip system) resulting from failed polymerase chain reaction amplifications. Although the NanoChip System, when used in a low-throughput setting, requires more overall time than the LightCycler, it is nearly equivalent per genotyping call. Owing to minimal sample handling, assay results are more reliable on the NanoChip platform and on the LightCycler than with RFLP. The NanoChip assay is reliable and may be especially valuable to laboratories with a large volume of thrombophilia test requests.

Factor V↗

PubMed1975

The management of pathological grief.

Earlier descriptions of pathological grief are reviewed. From the study of recently bereaved widows major forms of pathological grief are outlined. These are suppressed or inhibited grief and distorted grief, including forms with extreme anger or extreme guilt. Other grief variants are noted. The management of pathological grief is outlined; specifically the encouragement of the expression of suppressed affects especially sadness, anger and guilt; as well as the going over of memories and feelings to do with the lost relationship. Consideration is given to: the establishment of the therapeutic contract; the specific exploration of the response to the death and the pre-existing relationship; resistances; interpretation of defences; assessment of progress of mourning; social network factors; termination; and transference and counter-transference.

Affective Symptoms↗

PubMed2005

[Miller-Fisher syndrome].

BACKGROUND: Miller-Fisher syndrome is characterised by the clinical triad of ophthalmoplegia, ataxia and areflexia and is considered a variant form of Guillain-Barré syndrome. In western countries the incidence is reported to be approximately 1-5% that of Guillain-Barré syndrome. Approximately 90% of patients have antibodies against the ganglioside GQ1b, which is of diagnostic and pathogenic importance. MATERIAL AND METHODS: We present two patients with Miller-Fisher syndrome and describe clinical features and possible mechanisms of GQ1b antibodies. RESULTS AND INTERPRETATION: Both patients presented with the classical triad of symptoms and GQ1b antibodies after upper respiratory tract infections. One of the patients had a more severe form with additional bulbar signs and was treated with plasma exchange. Both made almost complete recoveries within a few months.

Aged↗

PubMedDate not supplied

Osteomyelitis of the ischiopubic synchondrosis.

Infection of the ischiopubic synchondrosis (IPS) is a diagnostic dilemma. This article reviews four such cases. All patients complained of ipsilateral groin pain, were febrile, and had elevated erythrocyte sedimentation rates. Initial radiographs were interpreted as normal but later showed increasingly lucent zones at the IPS. Radionuclide bone scans demonstrated diffusely increased uptake in the vicinity of the IPS. This contrasts with the discrete pattern seen with a normal IPS. Blood cultures were positive. Satisfactory outcomes were obtained with conservative treatment. Clinical presentation, laboratory results, radiographs, and bone scans must be correlated to distinguish this syndrome from a "normal radiologic variant".

Anti-Bacterial Agents↗

PubMed2002

Diagnosis of "follicular neoplasm": a gray zone in thyroid fine-needle aspiration cytology.

The thyroid fine-needle aspiration (FNA) diagnosis of "follicular neoplasm" does not differentiate between a benign and malignant tumor. Often cases diagnosed as "follicular or Hürthle-cell neoplasm" undergo surgical excision for further characterization. The aim of this study was to identify clinical features that may help in predicting malignancy in patients with an FNA diagnosis of follicular neoplasm. One hundred eighty-four cases in 167 patients were diagnosed as "follicular neoplasm" among 1,024 thyroid FNA evaluated with on-site interpretation from 1998-2000. The cases were evaluated for the following variables: histologic diagnosis, age, sex, and size of the nodule. One hundred thirty-nine patients were female, and 28 were male (age range, 23-80 yr). Among 122 patients (67%) undergoing surgical excision (lobectomy, 96; total thyroidectomy, 26), malignancy was identified in 37 cases (31%). Nonpapillary (follicular/Hürthle) carcinoma was diagnosed in 11 (9%), follicular variant of papillary carcinoma in 25, and medullary carcinoma in 1 case. The risk of malignancy was greater in males (47% vs. 29%, P < 0.0004) than females, in nodules measuring 3 cm or more (55% vs. 23%, P < 0.0001), than in nodules measuring less than 3 cm, and in patients 40 or more yr old (20% vs. 10%, P = 0.0001) than in patients younger than 40 years. The diagnosis "follicular neoplasm" is indeterminate, and the majority of cases (70% in the current study) are benign. However, clinical features, including gender, nodule size, and age, can be a part of the decision analysis in selecting patients for surgery.

Adenoma, Oxyphilic↗

PubMed2004

Comparative proteomic analysis of de-N-glycosylated serum from hepatitis B carriers reveals polypeptides that correlate with disease status.

Analysis of the polypeptide profile in tissues, cells, and sera by high-resolution two-dimensional (2-D) gel electrophoresis offers promise in the identification of biomarkers that correlate with disease. However, sera contain many polypeptides bearing N-linked glycosylation that can complicate interpretation. Therefore, we tested the possibility that de-N-glycosylation of the polypeptides present in human serum would result in a simplification of serum proteome profiles. Briefly, polypeptides present in human serum were left untreated or subjected to de-N-glycosylation by incubation with PNGase F and resolved by high-resolution 2-D gel electrophoresis. De-N-glycosylation reduced the number of glycoform variants, enhanced the resolution of many polypeptides and allowed other polypeptides to become visible. As an initial test of concept, clinically relevant serum samples from individuals with or without diagnosis of hepatocellular carcinoma were compared. Several polypeptides, apparent only after de-N-glycosylation, were shown to correlate with disease. Although the results are preliminary and the identities of all the putative biomarkers not yet known, the data suggest that de-N-glycosylation offers a method to enhance the resolution of serum polypeptide profiles and has value in comparative proteomic studies.

Amyloid↗

PubMed1995

Endoscopic approach to pancreas divisum.

Pancreas divisum has been claimed to be a harmless congenital variant or to occasionally cause acute relapsing pancreatitis (ARP), chronic pancreatitis (CP), or a chronic abdominal pain (CAP) syndrome. Both surgical and endoscopic approaches to accessory papilla decompression have been promulgated and widely disparate results reported in the literature. We retrospectively reviewed a five-year experience with dorsal pancreatic duct decompression at our institution utilizing a variety of endotherapeutic techniques. Data collected included procedural complications; patient interpretation of pre- and posttherapy pain, frequency, and intensity graded on an analog pain scale; frequency of hospitalization; and patient perception of "global" improvement to endotherapy. At a mean follow-up of 20 months, there was a statistically significant decrease in pancreatitis incidence in 15 patients with ARP (P = 0.016) and 19 patients with CP (P = 0.025). The frequency and intensity of chronic pain was also significantly improved (P < 0.001) in the latter group. In contrast, only one of five patients with CAP and normal dorsal pancreatography and secretin tests experienced global improvement, and there was no improvement utilizing an analog pain scale (P = 0.262) in the group as a whole. There was a 20% incidence of mild procedure or subsequent stent-related pancreatitis and an 11.5% accessory papilla restenosis rate. It is concluded that a subset of carefully selected patients with pancreas divisum may respond to endotherapy but that long-term follow-up will be required to define its ultimate place in the management of symptomatic patients with this anomaly.

Abdominal Pain↗

PubMed2006

Phosphaturic mesenchymal tumor (mixed connective tissue variant): a case report with spectral analysis.

We present a further case of a rare mesenchymal neoplasm termed phosphaturic mesenchymal tumor (mixed connective tissue variant). The patient was a 42-year-old man with a long history of osteomalacia of unknown etiology with pathological bone fracture, abnormality of parathyroid glands, kyphosis, scoliosis, and spondylosis. Laboratory investigation disclosed hypophosphatemia, elevated serum alkaline phosphatase activity, and normal serum calcium level. The patient had a soft tissue mass in the right inguinal area, measuring 11 x 6 x 5 cm, which was previously interpreted as a calcified hematoma on sonography. The tumor was surgically removed. Grossly, the tumor was well circumscribed, unencapsulated, and had soft to dense consistency. The cut surface had a variegated appearance due to the presence of large hemorrhagic areas admixed with foci of grey-yellow tissue. Histologically, the tumor was composed of primitive mesenchymal cells, osteoclast-like cells, and cells showing myofibroblastic features without cytologic atypia. There were a well developed vascular network, microcystic areas, and poorly formed cartilaginous foci. Unusual and hitherto unpublished prominent features were flower-like, slate-gray crystals, widespread hemosiderin deposits and large areas of hemorrhages, with the latter comprising approximately 60% of the tumor. A spectral analysis indicated that chemically, the crystals mainly consisted of calcium phosphate and sodium nitrate.

Adult↗

PubMed2001

The antiphospholipid syndrome and infection.

Infectious agents have been implicated in the induction of antiphospholipid (aPL) antibodies and the development of the antiphospholipid syndrome (APS). This review focuses on the types of aPL antibodies detected in infections and addresses whether these antibodies are of clinical importance in patients with infections. Hepatitis C virus (HCV) infection is given special attention because this virus has the propensity to induce various autoimmune phenomena. Several aspects are emphasized that should be considered carefully when interpreting results. Most of the published data agree that thrombophilia is not observed in patients with infections (including HCV) because aPL antibodies are mostly the natural or nonpathogenic type. Thus, we do not recommend routinely testing for HCV in patients with APS. However, not all infection-associated aPL antibodies are cofactor independent. For instance, infections are increasingly recognized as a major precipitating condition of the catastrophic variant of APS, perhaps via mechanisms of molecular mimicry. Therefore, it may be possible to prevent this devastating evolution if the infectious process is promptly recognized and exhaustively treated.

Adult↗

PubMed2005

Identification of a splicing enhancer in MLH1 using COMPARE, a new assay for determination of relative RNA splicing efficiencies.

Exonic splicing enhancers (ESEs) are sequences that facilitate recognition of splice sites and prevent exon-skipping. Because ESEs are often embedded within protein-coding sequences, alterations in them can also often be interpreted as nonsense, missense or silent mutations. To correctly interpret exonic mutations and their roles in diseases, it is important to develop strategies that identify ESE mutations. Potential ESEs can be found computationally in many exons but it has proven difficult to predict whether a given mutation will have effects on splicing based on sequence alone. Here, we describe a flexible in vitro method that can be used to functionally compare the effects of multiple sequence variants on ESE activity in a single in vitro splicing reaction. We have applied this method in parallel with conventional splicing assays to test for a splicing enhancer in exon 17 of the human MLH1 gene. Point mutations associated with hereditary non-polyposis colorectal cancer (HNPCC) have previously been found to correlate with exon-skipping in both lymphocytes and tumors from patients. We show that sequences from this exon can replace an ESE from the mouse IgM gene to support RNA splicing in HeLa nuclear extracts. ESE activity was reduced by HNPCC point mutations in codon 659, indicating that their primary effect is on splicing. Surprisingly, the strongest enhancer function mapped to a different region of the exon upstream of this codon. Together, our results indicate that HNPCC point mutations in codon 659 affect an auxillary element that augments the enhancer function to ensure exon inclusion.

Adaptor Proteins, Signal Transducing↗

PubMed2026

Comparing genome-wide significant and chemosensory variants as instruments for dietary patterns in Mendelian randomization.

BACKGROUND: Diet is a modifiable risk factor for cardiometabolic disease, yet establishing causality remains challenging. Mendelian randomization (MR) leverages genetic variants as instrumental variables (IVs) to enable causal inference. METHOD: Using two-sample MR, we assessed the causal effects of four principal component-derived dietary patterns (DPs)-Unhealthy, Healthy, Meat-based, Pescatarian-on cardiometabolic outcomes including body mass index, coronary artery disease, blood lipids, blood pressures, type 2 diabetes, fasting glucose and insulin, and glycated haemoglobin. Two sets of IVs were employed: conventional genome-wide significant variants associated with each DP, filtered for pleiotropy and directionality; and biologically informed variants in chemosensory receptor genes, given the role of taste and smell perception in food choice. RESULTS: Using conventional IVs, the Pescatarian DP was associated with reduced fasting insulin (βIVW = -0.10 pmol/L per SD increase in the Pescatarian DP score, 95% confidence interval -0.15, -0.04; P = 1.19 × 10-3), surviving multiple sensitivity analyses. Associations between the Unhealthy DP and elevated blood pressure and glycated haemoglobin should be interpreted cautiously; one of the two filtered IVs was strongly associated with caffeine intake, limiting the attribution of these findings to the DP itself. Chemosensory Receptor IVs yielded null findings, reflecting insufficient power. CONCLUSION: Evidence for causal effects of DPs on cardiometabolic traits was limited, with the strongest support for a protective effect of the Pescatarian DP on fasting insulin. Chemosensory IVs demonstrated limited utility for DPs, likely reflecting the heterogeneous and complex sensory profiles of overall diets. Future efforts should consider guideline-based dietary indices to facilitate interpretability and translation.

Humans↗

PubMed1979

Hen fluorescein-labeled gonococcal lipopolysaccharide antibody in the delayed fluorescent antibody technique for the confirmation of Neisseria gonorrhoeae.

A fluorescent antibody reagent (termed anti-LPS conjugate) was prepared from sera obtained from hens immunized with gonococcal R-type lipopolysaccharide. The reagent was absorbed with Formalin-treated cells of Neisseria meningitidis. The anti-LPS conjugate gave uniform brilliant staining of Neisseria gonorrhoeae with little background fluorescence, thus making interpretation and reading of fluorescence simple. The conjugate did not significantly stain cultures of N. meningitidis, Neisseria lactamica, nonpathogenic Neisseria species, or other gram-negative bacteria. Several preparations of the conjugate provided the same specificity and reproducibility of staining. The anti-LPS conjugate was compared with Difco Laboratories fluorescent antibody conjugate for staining of N. gonorrhoeae. Both conjugates stained cells of the light and dark variants of gonococcal colony types 1 and 2, as well as cells of colony types 3 and 4. When used for the confirmation of N. gonorrhoeae, the anti-LPS and Difco conjugates stained 426 of 431 (98.8%) and 210 of 213 (98.6%) of the gonococcal cultures, respectively. Absorption of the anti-LPS conjugate with R-type lipopolysaccharide removed the staining of gonococci. However, absorption of Difco conjugate with R-type lipopolysaccharide did not remove the staining of gonococci, suggesting that the majority of fluorescein-labeled antibody present in the Difco conjugate is directed to gonococcal cell surface components other than lipopolysaccharide. The results of this study indicate that fluorescein-labeled gonococcal lipopolysaccharide antibody should be a reliable fluorescent antibody reagent for the confirmation of N. gonorrhoeae.

Animals↗

PubMed1978

The cellular origin of chemically induced tumours.

Tumours were induced by chemical carcinogens in chimaeric mice made by the amalgamation of two embryos each producing a different electrophoretic variant of the enzyme glucose phosphate isomerase. Although, in these chimaeras, the smallest samples of normal tissue that could be analysed almost invariably contained both isoenzymes, almost all the tumours contained only one. An analysis of the size of the clones that formed the chimaeric epidermis permitted the conclusion that the epidermal tumours produced could not have risen from more than 8 cells; and the most probable interpretation of the data is that these tumours were clonal growths.

Animals↗

PubMed2003

[Genetic aspects of migraine].

BACKGROUND, MATERIAL AND METHODS: On the basis of studies identified by Medline and PubMed searches, this review focuses on the genetics of migraine. RESULTS: Compared to the general population, first-degree relatives of probands with migraine without aura (MO) have a two-fold risk of MO, whereas first-degree relatives of probands with migraine with aura (MA) have a four-fold increased risk of MA. Population-based family and twin studies have shown that migraines with or without aura have a multifactorial inheritance. In patients with familial hemiplegic migraine, a rare variant, a mutated gene encoding a subunit of a brain-specific calcium channel in cell membranes has been found (CACNA1A). This gene may be of importance in the common forms of migraine in a few families and, at least in part, migraine may be a genetically determined channelopathy. However, migraine has also been linked to other genes with other functions, which makes the picture less clear. INTERPRETATION: It is to be hoped that in the next few years much more will be known about the molecular genetic mechanisms of migraines with and without aura. No gene is as yet defined.

Genetic Predisposition to Disease↗

PubMed1990

The effect of chemotherapy on the in vivo frequency of glycophorin A 'null' variant erythrocytes.

A human in vivo somatic cell assay based on the enumeration of variant erythrocytes lacking expression of an allelic form of the cell-surface sialoglycoprotein, glycophorin A, was applied to the study of blood samples from patients obtained prior to, during, and following chemotherapy for malignant disease in order to determine the effect of mutagenic chemical agents on the frequency of variant cells. In 22 patients assayed prior to therapy, the mean variant cell frequency was 11.9 per million, which was not significantly different from that observed in healthy controls. In an initial cross-sectional survey, blood samples were obtained at various times during and after therapy from 30 patients diagnosed with a variety of malignancies who were treated with one or more known mutagenic agents including adriamycin, bleomycin, cis-platinum, cyclophosphamide, dacarbazine, etoposide, lomustine, mechlorethamine, melphalan, mitomycin C, and procarbazine. Significant elevations in the mean frequency of variant cells over pre-therapy and normal levels were observed in samples obtained during and after therapy. In a time-series study, 14 breast cancer patients treated with CAF (cyclophosphamide, adriamycin, 5-fluorouracil), CMF (cyclophosphamide, methotrexate, 5-fluorouracil), or VMF (vinblastine, methotrexate, 5-fluorouracil) adjuvant chemotherapy were sampled repeatedly during and after therapy. For the CAF and CMF patients an increase in the frequency of variant cells was observed with a lag in the appearance of induced variants after initiation of therapy; variant frequencies gradually increased during therapy reaching a maximum at or shortly after the end of therapy, then declined to near pre-therapy levels within 6 months. The maximum level of induced variants ranged from 2- to 7-fold over pre-therapy or normal levels depending on the combination of agents used. The breast cancer patients treated with both adriamycin and cyclophosphamide showed consistent elevations in the frequency of variant cells; patients treated only with cyclophosphamide showed lower and more variable elevations. The data demonstrate that mutagenic chemotherapy agents induce elevated levels of glycophorin A variant erythrocytes consistent with the hypothesis that variant cells result from somatic mutation. The elevations in variant cells were transient, suggesting that these agents primarily affect the rapidly cycling committed erythroid cell population.

Adolescent↗

PubMed1998

The gene encoding the alpha1A-voltage-dependent calcium channel (CACN1A4) is not a candidate for causing common subtypes of idiopathic generalized epilepsy.

Mutations in the gene encoding the alpha1A-calcium channel subunit play a causative role in the epileptogenesis of absence seizures in tottering mutant mice. The present family-based association and non-parametric linkage study tested the hypothesis that allelic variants of the homologous human gene (CACN1A4) confer susceptibility to common subtypes of idiopathic generalized epilepsy (IGE). An expressed polymorphic CAG trinucleotide repeat in the 3' end of the CACN1A4 gene was assessed in 70 families ascertained through members with either childhood (CAE) and juvenile absence epilepsy (JAE), or juvenile myoclonic epilepsy (JME). Our association analysis using the haplotype-based haplotype relative risk statistic provided no evidence for an allelic association of the CAG repeat polymorphism with either IGE, or CAE and JAE, or JME. We found no relation between the CAG repeat length and susceptibility neither to IGE, nor to CAE and JAE, nor to JME. Non-parametric linkage analysis revealed no evidence for linkage of IGE traits with the CACN1A4 locus in 42 families of patients with either CAE or JAE. A weak trend towards an excess of allele sharing (identity by descent) among family members affected by an IGE was obtained in 26 families of JME patients (Z[NPL] = 1.25 at theta = 0.000, p = 0.057). Taken together, we found no statistically significant evidence that genetic variants of the CACN1A4 gene play a causative role in the pathogenesis of common subtypes of IGE in humans.

Alleles↗

PubMed1984

Signet ring carcinoma of the pancreas, a rare variant with very high CEA values. Immunohistologic comparison with adenocarcinoma.

Signet ring carcinoma of the pancreas is rare. We report a case which was remarkable for (1) diffuse, infiltrating growth which suggested chronic pancreatitis at laparotomy, and (2) an associated very high circulating carcinoembryonic antigen (CEA) level of 6400 ng/ml. The case report and autopsy are presented. Twelve other cases of pancreatic adenocarcinoma (non-signet ring) are compared with the signet ring carcinoma with respect to CEA staining and circulating levels. We conclude immunocytochemical staining of biopsy tissue for CEA is a useful adjunct in the interpretation of circulating CEA levels in pancreatic carcinoma.

Adenocarcinoma↗

PubMed1992

Molecular and structural basis of hemagglutination in mengovirus.

The molecular and structural basis of mengovirus hemagglutination (HA) was investigated by the comparison of nucleotide sequences of the entire capsid coding regions of an HA+ variant, two HA- mutants, 205 and 280, and two HA+ revertants of 205. The mutants were selected after acridine mutagenesis of mengovirus-37A, a heat-stable and HA+ variant that is neurotropic in mice. HA+ revertants of mutant 205 were isolated from brain tissue of mice inoculated with mutant 205. The nucleotide sequences were determined by consensus RNA sequencing using genomic RNA templates from purified virions. Two nucleotide differences were observed in the VP1 coding region of the RNA genomes of mutants 205 and 280 in comparison to the RNA sequences of 37A and the revertants. Interpretation of these data predict substitutions of two consecutive amino acids at residues 1231 (K to R) and 1232 (P to S) of VP1 which form part of the H-I loop of VP1 found at the icosahedral fivefold axis. Analysis of the amino acid substitutions in the context of the three-dimensional structure of the mengovirus-M capsid indicated that hemagglutination most likely involves residues found at the icosahedral fivefold axis and probably does not involve the residues that form the putative cellular receptor binding site (the "pit"). Eleven amino acid differences were observed between the structural proteins of mengovirus-M and 37A, five in VP1, three in VP2, and three in VP3.

Amino Acid Sequence↗