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PubMed2026

Potential impact of NUCB2 genetic variants with the clinicopathological characteristics of prostate cancer.

The most prevalent illness in men is prostate cancer, which risk increases with age and obesity. The precursor NUCB2 gene produces the adipokine nesfatin-1, which was first found in hypothalamic neurons. It is currently unclear how NUCB2 polymorphisms, cancer-promoting lifestyle factors, and prostate cancer are related. We investigated the relationship between clinicopathological features and 4 NUCB2 gene polymorphisms in prostate cancer when compared to healthy individuals. Compared with the wild-type T/T genotype, carriage of at least one G allele (T/G or G/G genotypes) at the NUCB2 SNP rs10766383 was linked with a declined risk of clinical T3+T4 stage, pathologic T3+T4 stage, and perineural invasion. In addition, the TG/GG genotypes at rs10766383 were also associated to a lower risk of clinical T3+T4 stage and perineural invasion in patients with biochemical recurrence. Importantly, GTEx data indicated that the wild-type TT homozygous genotype was linked with markedly higher NUCB2 levels compared to the GG allele of variant rs10766383 variant in mucosa and whole blood tissues. Thus, the NUCB2 SNP rs10766383 may play a protective function against prostate cancer progression.

Humans↗
PubMed2026

ER proteostasis failure in HYOU1 deficiency alters B cells, neutrophils, and interferon signalling.

Hypoxia upregulated 1 (HYOU1) is a stress-inducible ER chaperone. We investigated 2 unrelated patients carrying biallelic HYOU1 variants and presenting with primary immunodeficiency. Patient 1, homozygous for p.Pro444His, displayed failure to thrive, hypoglycemia, B cell lymphopenia, and neutropenia. Patient 2, compound heterozygous for p.Arg262Gln and p.Pro757_Glu758insAla, exhibited recurrent infections, enteropathy, and hypogammaglobulinemia. In Patient 1, while HYOU1 transcription was preserved, the protein was severely reduced. Tunicamycin treatment of dermal fibroblasts showed a blunted unfolded protein response and defective induction of ER stress-responsive genes. Immunophenotyping showed near-absence of circulating B cells, and single-cell RNA sequencing of bone marrow identified an arrest at the pro-B cell stage. Neutrophils displayed hypogranulation and dysregulated IFN- and apoptosis-associated transcriptional signatures, unresponsive to G-CSF. HYOU1 deficiency hence results in ER stress-induced proteostasis failure that simultaneously impairs adaptive immunity through B cell developmental arrest and innate immunity through neutrophil dysfunction and IFN pathway imbalance. This work expands the spectrum of HYOU1 deficiency and further identifies ER proteostasis as a central determinant of immune homeostasis.

Journal Article↗
PubMed2000

Survival analysis for recurrent event data: an application to childhood infectious diseases.

Many extensions of survival models based on the Cox proportional hazards approach have been proposed to handle clustered or multiple event data. Of particular note are five Cox-based models for recurrent event data: Andersen and Gill (AG); Wei, Lin and Weissfeld (WLW); Prentice, Williams and Peterson, total time (PWP-CP) and gap time (PWP-GT); and Lee, Wei and Amato (LWA). Some authors have compared these models by observing differences that arise from fitting the models to real and simulated data. However, no attempt has been made to systematically identify the components of the models that are appropriate for recurrent event data. We propose a systematic way of characterizing such Cox-based models using four key components: risk intervals; baseline hazard; risk set, and correlation adjustment. From the definitions of risk interval and risk set there are conceptually seven such Cox-based models that are permissible, five of which are those previously identified. The two new variant models are termed the 'total time - restricted' (TT-R) and 'gap time - unrestricted' (GT-UR) models. The aim of the paper is to determine which models are appropriate for recurrent event data using the key components. The models are fitted to simulated data sets and to a data set of childhood recurrent infectious diseases. The LWA model is not appropriate for recurrent event data because it allows a subject to be at risk several times for the same event. The WLW model overestimates treatment effect and is not recommended. We conclude that PWP-GT and TT-R are useful models for analysing recurrent event data, providing answers to slightly different research questions. Further, applying a robust variance to any of these models does not adequately account for within-subject correlation.

Acute Disease↗
PubMed1997

[Recurrent syncope without angina: an uncommon presentation of coronary spasm].

We report the case of a 64-year-old patient admitted for repetitive syncope as an isolated clinical manifestation probably due to coronary artery spasm. The patient had no history of previous cardiac disease, and was studied because of two nonspecific syncopes. Long-term electrocardiographic monitoring showed many episodes of transient ST segment elevation, associated with premature ventricular beats and runs of ventricular tachycardia. Coronary angiography during ergonovine infusion was performed to confirm the diagnosis. We discuss the incidence of coronary spasm provoking syncope and the need to establish a correct diagnosis in order to administer an effective therapy to the patient.

Angina Pectoris, Variant↗
PubMed1992

Successful treatment of recurrent hepatic Candida infection with fluconazole after chemotherapy for acute leukemia: a case report.

Hepatic candidiasis represents an increasingly difficult problem in immunocompromised patients. It has been recognized as a variant of disseminated candidiasis after a period of neutropenia. Establishment of diagnosis is difficult since liver biopsy as well as culture may be negative, in spite of the presence of fungus. Hepatic lesions are generally not detectable by ultrasound examination or computed tomography until the neutrophil count has returned to normal. The aim of this case report is to describe the problems related to the diagnosis and treatment of hepatic candidiasis following chemotherapy for acute leukemia. The report also provides further evidence that fluconazole, a new broad-spectrum antifungal drug, can be safely and effectively used for the long-term treatment of deep-seated hepatic candidiasis.

Adult↗
PubMedDate not supplied

Desmoplastic melanoma: a clinico-pathological review.

Desmoplastic Melanoma (DM) represents a rare histological variant of melanoma. It has been described in isolated case reports as a cutaneous tumour with a high incidence of local recurrence and nodal metastases, requiring early aggressive surgery. However, overall clinical experience of the tumour is limited. 13 patients with DMM seen over a 20 year period were reviewed. The mean age at presentation was 67 years (range 34-87), and 2/3 of the lesions were in the head and neck. Tumour thickness averaged 5.78 mm (Breslow). 7 patients developed recurrence, 4 as regional nodes, and 3 as skin nodules. Four of these patients developed disseminated disease, of whom 3 died. The mean time to first recurrence was 26 months and mean follow-up time in the review was 40 months (range 3-141 months).

Adult↗
PubMed2026

Targeted sequencing reveals a distinct genetic alteration landscape in oral multiple primary squamous cell carcinomas.

OBJECTIVE: Oral multiple primary cancers (MPCs) are associated with poor clinical outcomes, yet their genomic characteristics remain insufficiently understood. DESIGN: Fifty-four formalin-fixed paraffin-embedded (FFPE) tumor samples from 30 patients with oral MPCs were analyzed using high-depth targeted sequencing of a customized 14-gene panel derived from prior whole-exome sequencing data. Detected alterations were analyzed after removal of synonymous mutations. RESULTS: Non-silent genomic alterations were identified in 59.3% (32/54) of samples, involving 19 patients. A total of 70 variant loci across 13 genes were detected. AKAP13 was the most frequently mutated gene at both the sample (22.2%, 12/54), with recurrent mutations observed across multiple patients. In contrast, TP53 mutations occurred at a substantially lower frequency (11.1%, 6/54). Marked inter- and intra-patient mutational heterogeneity was observed. CONCLUSIONS: FFPE-based targeted sequencing enabled an initial characterization of genomic alterations in oral MPCs. Recurrent alterations in AKAP13, GLI2, JMJD1C, and DNAH8, together with the relatively low frequency of TP53 alterations, identify candidate genomic features for further investigation and provide a basis for future studies of the molecular basis of oral MPCs.

Humans↗
PubMed2006

[Imaging in adult chronic otitis].

Chronic otitis media (COM) can be divided into two subtypes: COM with cholesteatoma (including precholesteatomatous states) is an aggressive form of otitis. Surgical treatment is mandatory because of the risk for labyrinthine or cerebromeningeal complications. CT is very important in the preoperative work-up (extension of cholesteatoma, anatomic variants). In patients who have undergone middle ear surgery, CT and presently MRI play an increasing role in the detection of recurrent or relapsing cholesteatoma. COM without cholesteatoma does not have an osteolytic potential, but may leave auditive sequelae that in selected cases may warrant surgical treatment to improve hearing. CT is useful in the etiological work-up of patients with severe hypoacusis. CT also plays an important role in cases of surgical failure, to detect a dislocation of the ossiculoplasty or impairment of the middle ear caused by fluid effusion. The objective of this paper is to specify the indications, the results and the limits of pre- and postoperative imaging in COM.

Adult↗
PubMed2005

Shared promiscuous activities and evolutionary features in various members of the amidohydrolase superfamily.

The amidohydrolase superfamily comprises hundreds of hydrolytic enzymes of the (beta/alpha)8 barrel fold with mono- or binuclear active-site metal centers, and a diverse spectrum of substrates and reactions. Promiscuous activities, or cross-reactivities, between different members of the same superfamily may provide important hints regarding evolutionary and mechanistic relationships. We examined three members: dihydroorotase (DHO), phosphotriesterase (PTE), and PTE-homology protein (PHP). Of particular interest are PTE, which is thought to have evolved within the last several decades, and PHP, an amidohydrolase superfamily member of unknown function, and the closest known homologue of PTE. We found a diverse and partially overlapping pattern of promiscuous activities in these enzymes, including a significant lactonase activity in PTE, esterase activities in both PTE and PHP, and a weak PTE activity in DHO. Directed evolution was applied to improve the promiscuous esterase activities of PTE and PHP. Remarkably, the most recurrent mutation increasing esterase activity in PTE, or PHP, maps to the same location in their superposed 3D structures. The evolved variants also exhibit newly acquired promiscuous activities that were not selected for, including very weak, yet measurable, paraoxonase activity in PHP. Our results illustrate the mechanistic, structural, and evolutionary links between these enzymes, and highlight the importance of studying laboratory evolution intermediates that might resemble node intermediates along the evolutionary pathways leading to the divergence of enzyme superfamilies.

Amidohydrolases↗
PubMed2001

Mott cell tumor of the stomach with Helicobacter pylori infection.

A plasma cell tumor of the stomach with unusual histology is reported. Macroscopically, the tumor formed two ulcers in the gastric body, and microscopic examination revealed proliferation of plasma cells producing immunoglobulin G kappa monotypic immunoglobulin, with metastatic infiltration in some perigastric lymph nodes. Most of these plasma cells had various-sized Russell bodies in the cytoplasm; hence the tumor may be called Mott cell tumor. The Russell bodies showed a strong affinity to concanavalin A by lectin immunohistochemistry, compared with those in reactive Mott cells. In addition, Helicobacter pylori (H. pylori) infection was proved by Gimenez stain and immunohistochemistry. The mixture of some centrocyte-like cells and presence of reactive lymph follicles with follicular colonization by tumor cells suggest that this lesion may be a variant of mucosa-associated lymphoid tissue lymphoma in association with H. pylori infection. The patient has shown no evidence of recurrence of the tumor after 11 years of follow up.

Antigens, Bacterial↗
PubMed2000

Herlitz junctional epidermolysis bullosa: novel and recurrent mutations in the LAMB3 gene and the population carrier frequency.

Herlitz junctional epidermolysis bullosa is a heritable bullous disease caused by mutations found primarily in the b3 chain of laminin 5 (LAMB3). In this study, we examined the LAMB3 gene for mutations in 22 Herlitz junctional epidermolysis bullosa families, and identified 15 distinct mutations, eight of them previously unreported, bringing the total number of distinct Herlitz junctional epidermolysis bullosa mutations in LAMB3 to 35. Examination of the mutation database revealed several recurrent mutations that have been reported, as well as six previously unreported. All recurrent mutations may be readily detected by polymerase chain reaction of genomic DNA and restriction endonuclease digestion. Mutation screening and prenatal diagnosis of families at risk may be expedited by molecular testing for these recurrent mutations prior to screening the entire gene. Finally, the U.S. population carrier risk for Herlitz junctional epidermolysis bullosa and all variants of junctional epidermolysis bullosa was calculated to be one in 781 and one in 350, respectively, while the overall epidermolysis bullosa carrier frequency was calculated to be one in 113. These data allow accurate testing, counseling, and risk calculation for nuclear families, as well as extended family members at risk for junctional epidermolysis bullosa.

Alleles↗
PubMed1981

Gene duplication and transposition linked to antigenic variation in Trypanosoma brucei.

DNA sequence complementary to Trypanosoma brucei mRNAs coding for the synthesis of the variant-specific antigens AnTat 1.1 and AnTat 1.8 have been cloned and characterized. These sequences have been used as probes to analyze the corresponding genes in the nuclear DNA. The two genes seem to be represented in several (three to six) copies, some of which are incomplete. Transcription of one or the other of these two genes is linked to a genetic rearrangement implying duplication and transposition of the "basic" coding sequence. There is probably one additional copy of each gene, and it seems to be complete. The 3' end of each cloned sequence contains, within a 300-base-pair fragment, a genetic element that seems to be repeated and widely distributed in the genome. This repetitive sequence is variant specific. The expression-linked copy of the gene is lost in the culture (procyclic) form of the trypanosome, where the synthesis of variant-specific antigens is shut down. Comparison of two different cloned populations expressing the same serotype (AnTat 1) showed that the recurrence of a given antigenic type may be accompanied by the production of the same additional copy.

Animals↗
PubMed1992

Common lesions of the oral mucosa. A guide to diseases of the lips, cheeks, tongue, and gingivae.

Canker sores and cold sores are common, relatively banal diseases of the oral mucosa and lips, occurring most often in young persons. Some otherwise healthy patients may have a more severe variant, such as major aphthous ulcers, recurring lesions of aphthous stomatitis, or acute herpetic gingivostomatitis. Other patients may present with severe recurrent herpes simplex labialis or chronic oral candidiasis, and in these patients an immunodeficiency state must be considered.

Cheek↗
PubMedDate not supplied

Identification of Prevotella in pedal osteomyelitis of a diabetic patient.

Osteomyelitis in a diabetic patient with a nonhealing foot ulcer, multiple medical conditions, and recurrent hospitalization for antibiotic therapy was found to be associated with gram-negative bacteria Prevotella melanginoganica and Prevotella melaninoganica hemagglutinating variant. Those organisms were identified due to the morphologically distinct features in electron microscopy and sequencing of the genes after Polymerase chain reaction amplification from the pathological material. The bacteria invaded the bone and resided in osteocyte, osteoblast, and endothelial cells. The bacteria are usually associated with periodontal plaques, causing inflammation and destruction of gingival tissue and resorption of the alveolar bone. This is the first ultrastructural and molecular study of a diabetic bone lesion with anaerobic bacterial infection.

Bacteroidaceae Infections↗
PubMed1997

A site-directed Staphylococcus aureus hemB mutant is a small-colony variant which persists intracellularly.

Although small-colony variants (SCVs) of Staphylococcus aureus have been recognized for many years, this phenotype has only recently been related to persistent and recurrent infections. Clinical S. aureus SCVs are frequently auxotrophic for menadione or hemin, two compounds involved in the biosynthesis of the electron transport chain elements menaquinone and cytochromes, respectively. While this observation as well as other biochemical characteristics of SCVs suggests a link between electron-transport-defective strains and persistent infections, the strains examined thus far have been genetically undefined SCVs. Therefore, we generated a stable mutant in electron transport by interrupting one of the hemin biosynthetic genes, hemB, in S. aureus by inserting an ermB cassette into hemB. We isolated a hemB mutant, due to homologous recombination, by growth at a nonpermissive temperature and selection for erythromycin resistance. This mutant showed typical characteristics of clinical SCVs, such as slow growth, decreased pigment formation, low coagulase activity, reduced hemolytic activity, and resistance to aminoglycosides. Additionally, the mutant was able to persist within cultured endothelial cells due to decreased alpha-toxin production. Northern and Western blot analyses showed that expression of alpha-toxin and that of protein A were markedly reduced, at both the mRNA and the protein level. The SCV phenotype of the hemB mutant was reversed by growth with hemin or by complementation with intact hemB. Hence, a defect in the electron transport system allows S. aureus SCVs to resist aminoglycosides and persist intracellularly.

Aminoglycosides↗
PubMed2005

Phylodynamic analysis of human immunodeficiency virus type 1 in distinct brain compartments provides a model for the neuropathogenesis of AIDS.

"Phylodynamic" analysis combines various statistical procedures that can be used to correlate the epidemiological and evolutionary behavior of viral pathogens with the immune system of the host. We utilized this approach to examine human immunodeficiency virus type 1 (HIV-1) gp120 envelope DNA sequences (V1, V2, and V3) isolated from different brain compartments of a T-cell-depleted patient diagnosed with severe HIV-associated dementia at the time of death. In agreement with previous reports, phylogenetic analysis showed distinct virodemes but also revealed a significant amount of viral gene flow among different brain compartments. Local-molecular-clock analysis showed that HIV-1 meninges and temporal lobe subpopulations evolve about 30 and 100 times faster, respectively, than the other viral populations in the brain. However, maximum likelihood codon-based substitution models did not detect any site under significant positive selective pressure, and the main cause of HIV-1 genetic variation appeared to be random genetic drift. Therefore, the higher evolutionary rate in the meninges and temporal lobe could be due to an enhanced infection/expansion rate of macrophages as a consequence of the immune system failure. In conclusion, in this case study, viral infection in the brain progressed with a nonspecific genetic evolution, recurrent migration events, and an expansion of macrophage-tropic sequences. The data suggest that after immune failure newly produced viral variants, which would be rapidly cleared under normal conditions, begin to productively infect macrophages in a "self-amplifying" cycle of infection/inflammatory response that could be at the origin of HIV-associated dementia.

AIDS Dementia Complex↗
PubMed2005

Osteoplastic maxillotomy for treatment of neoplasms of the nasopharynx and infratemporal fossa.

Approaches to the infratemporal fossa and nasopharynx are difficult because of the anatomic complexity of these regions. We describe our experience with osteoplastic maxillotomy, with our own modifications, and evaluate oncological outcomes and postoperative quality of life. Ten patients underwent osteoplastic maxillotomy, 3 of whom had a diagnosis of malignancy, and 7 of whom had nasopharyngeal angiofibromas (NPAs). A Weber-Fergusson incision was made to develop facial flaps and preserve the vascularity of the maxilla. Osteotomies were performed through the facial aspects of the maxilla, on the orbital rims, and on the malar eminence for the medial variant of the procedure. The anterolateral variant involved descent of the temporalis muscle with preservation of the facial nerve, and a zygomatic osteotomy. Four craniotomies were done. Two patients had the medial variant of the procedure, and 8 had the anterolateral variant. The complications were transient and mild. The patients who had malignancies are alive with no disease, and there was 1 recurrence among the 7 patients with NPAs. We found excellent aesthetic results in 8 of the 10 patients, and no change in basic functions in 8 patients. Osteoplastic maxillotomy allows resection of massive NPAs with no significant bleeding. Resection of malignant lesions with good results is feasible.

Adolescent↗
PubMed2007

Gene-environment interactions in asthma: with apologies to William of Ockham.

Many environmental factors and a large number of genetic polymorphisms have been reported to be associated with asthma risk in different locales and at different ages. It seems that what we call asthma is a heterogeneous set of conditions for which the only common feature is recurrent airway obstruction that is at least partially responsive to usual asthma therapy. Recent studies in which environmental factors and genetic variants were studied concomitantly have suggested a potential unifying concept for the disease. It seems that asthma is a genetically mediated development dysregulation of diverse immune and airway responses to a variety of specific and nonspecific exposures. It thus seems improbable that most genetic variants associated with asthma influence the disease regardless of which environmental factors trigger it and at which lifetime phase they are present. More likely, the most important gene variants for asthma are polymorphisms that exert their influence on the network system controlling biological responses to asthma-related exposures.

Asthma↗