Distinctive enchondromatosis with spine abnormality,regressive lesions,short stature,and coxa vara: Importance of long‐term follow‐up

We report a girl with a unique type of enchondromatosis observed from birth to puberty. Radiographic abnormalities documented at the age of 14 months included distinctive spondylometaphyseal enchondromatous types of lesions with minimal involvement of the short tubular and flat bones. Follow‐up radiographic examinations documented progressive coxa vara and hypoplasia/dysplasia of the left ulna. At puberty, the short tubular bones appeared normal. There was marked regression of the flat bone, rib, and spinal lesions. This case shows the importance of long‐term observation of unclassified forms of skeletal dysplasia. © 2001 Wiley‐Liss, Inc.     

Expansile bone lesions in a three‐generation family

We report on a three‐generation family with “expansile” bone lesions of the distal radius and ulna, cortical thickening of the proximal long bones, and pathologic fractures. The differential diagnosis of expansile bone lesions includes isolated bone cysts and tumors, such as enchondromas and fibrous dysplasia; familial expansile osteolysis; and the genochondromatoses. Our patients have findings most similar to the genochondromatoses; however, the distribution of the lesions and the accompanying manifestations may be evidence for a unique genetic condition in this family. Am. J. Med. Genet. 82:1–5, 1999. © 1999 Wiley‐Liss, Inc.     

Enchondromatosis: insights on the different subtypes

Enchondromatosis is a rare, heterogeneous skeletal disorder in which patients have multiple enchondromas. Enchondromas are benign hyaline cartilage forming tumors in the medulla of metaphyseal bone. The disorder manifests itself early in childhood without any significant gender bias. Enchondromatosis encompasses several different subtypes of which Ollier disease and Maffucci syndrome are most common, while the other subtypes (metachondromatosis, genochondromatosis, spondyloenchondrodysplasia, dysspondyloenchondromatosis and cheirospondyloenchondromatosis) are extremely rare. Most subtypes are non-hereditary, while some are autosomal dominant or recessive. The gene(s) causing the different enchondromatosis syndromes are largely unknown. They should be distinguished and adequately diagnosed, not only to guide therapeutic decisions and genetic counseling, but also with respect to research into their etiology. For a longtime enchondromas have been considered a developmental disorder caused by the failure of normal endochondral bone formation. With the identification of genetic abnormalities in enchondromas however, they were being thought of as neoplasms. Active hedgehog signaling is reported to be important for enchondroma development and PTH1R mutations have been identified in ∼10% of Ollier patients. One can therefore speculate that the gene(s) causing the different enchondromatosis subtypes are involved in hedgehog/PTH1R growth plate signaling. Adequate distinction within future studies will shed light on whether these subtypes are different ends of a spectrum caused by a single gene, or that they represent truely different diseases. We therefore review the available clinical information for all enchondromatosis subtypes and discuss the little molecular data available hinting towards their cause.     

Absence of IHH and retention of PTHrP signalling in enchondromas and central chondrosarcomas

Enchondromas and conventional central chondrosarcomas are, respectively, benign and malignant hyaline cartilage-forming tumours that originate in the medulla of bone. In order to gain a better understanding of the molecular process underlying malignant transformation of enchondroma, and to investigate whether there is a biological difference between conventional central cartilaginous tumours and those of enchondromatosis or with phalangeal localization, a series of 64 enchondromas (phalanx, n = 21; enchondromatosis, n = 15) and 89 chondrosarcomas (phalanx, n = 17; enchondromatosis, n = 13) was collected. Indian Hedgehog (IHH)/parathyroid hormone related peptide (PTHrP) signalling, an important pathway in chondrocyte proliferation and differentiation within the normal growth plate, was studied by immunohistochemical analysis of the expression of PTHrP, PTHR1, Bcl-2, p21, cyclin D1, and cyclin E. Quantitative real-time PCR for IHH, PTCH, SMO, and GLI2 was performed on a subset of tumours. The data show that IHH signalling is absent in enchondromas and central chondrosarcomas, while PTHrP signalling is active. There was no difference in the expression of any of the molecules between 35 enchondromas and 26 grade I central chondrosarcomas, indicating that PTHrP signalling is not important in malignant transformation of enchondroma. Higher expression of PTHR1 and Bcl-2 was associated with increasing histological grade in chondrosarcoma, suggesting involvement in tumour progression. No difference was found between samples from enchondromatosis patients and solitary cases, suggesting no difference in PTHrP signalling. A small subset of phalangeal chondrosarcomas demonstrated down-regulation of PTHrP, which may be related to its more indolent clinical behaviour. Thus, in both enchondromas and central chondrosarcomas, PTHrP signalling is active and independent of IHH signalling, irrespective of the presence or absence of enchondromatosis.     

Interleukin-12 family members and type I interferons in Th17-mediated inflammatory disorders

Cytokines produced by antigen-presenting cells govern the fate of helper T-cell responses. Herein, we review the impact of interleukin (IL)-23 and IL-27 on the outcome of T-helper (Th) 17 cell responses and discuss their impact in the pathogenesis of T-cell-mediated inflammatory disorders of autoimmune or allergic origin. We then discuss how type I interferons might influence the course of autoimmune diseases by tipping the balance between IL-12 family members.     

Cytogenetic studies of human T-cell leukemia virus type I carriers. A family study

Recently, the chromosome 14q11 anomaly has been reported to be specific to adult T-cell leukemia (ATL), and this anomaly has also been confirmed in the preleukemic state of adult T-cell leukemia (pre-ATL) patients. Because the cytogenetic abnormality at the stage of human T-cell leukemia virus type I (HTLV-I) carrier remains uncertain, we performed cytogenetic studies of lymphocytes stimulated with phytohemagglutinin in three HTLV-I carriers and three non-HTLV-I carriers in an ATL family. As a result, in three HTLV-I carriers, four of 311 cells examined (1.3%) had chromosome 14q11 anomaly. However, in three non-HTLV-I carriers, none of 260 cells examined had chromosome 14q11 anomaly. These results suggest that chromosome 14q11 anomaly is already present at the stage of HTLV-I carrier and seems to be an important cytogenetic clue to the pathogenesis of ATL.     

Lack of common haplotype among four family members with late-onset Kaposi's sarcoma

Kaposi's sarcoma is associated with an increased frequency of HLA-DR5. The hypothesized model of a susceptibility gene in linkage disequilibrium with DR5 may be tested by haplotype analysis in familial Kaposi's sarcoma. Our finding of no common haplotype among afflicted members of a family provides evidence against the hypothesized linkage.     

Guadalajara camptodactyly syndrome type I. A corroborative family

Three sibs, two girls aged 18 and 9 years, and a 7-year-old boy, were found to have Guadalajara camptodactyly syndrome type I (GCSI). They had intrauterine growth retardation, dwarfism, peculiar facial appearance, camptodactyly and skeletal anomalies. Comparison with other camptodactyly syndromes led to the conclusion that the patients had the same disorder as the two first reported patients with GCSI. The clinical and radiological concordance in the five patients permits further delineation of GCSI and corroboration of its autosomal recessive inheritance.     

Genochondromatosis type II: report of a new patient and further delineation of the phenotype

Enchondromas are common intraosseous usually benign cartilaginous tumors that develop in close proximity to growth plate cartilage. Genochondromatosis is a familial skeletal condition with autosomal dominant inheritance pattern. Genochondromatosis type I is a skeletal disorder characterized by symmetrical chondromatosis with characteristic localization: clavicle, upper end of humerus, and lower end of femur. The condition shows a benign course and is clearly different from metachondromatosis, generalized enchondromatosis, and spondyloenchondrodysplasia. In contrast, genochondromatosis type II is characterized by normal clavicles, but metaphyseal involvement of the hands, feet, knees, and wrists. To date, one family has been described with two affected individuals and possibly a second one with seven affected individuals. We report here on a boy with radiographic features of genochondromatosis type II. This report confirms that this disorder represents a separate clinical entity distinguishable for genochondromatosis type I. In addition, this report confirms the benign course of this rare disorder and will help accurate genetic counseling.     

Cytodiagnosis of Ollier's disease: A case report

Ollier's disease is a rare nonhereditary condition where patients present with multiple enchondromas involving usually the small bones of the hands and feet. We report the case of a 17‐year‐old girl who presented with multiple osteolytic lesions involving almost all phalanges of both her hands. Fine‐needle aspiration cytology (FNAC) was performed from her left index finger. Smears showed mostly chondroid matrix with singly scattered cells showing binucleation and mild atypia at places. A diagnosis of enchondroma was offered in view of the cytologic and radiological findings. The dysplastic cartilage in Ollier's disease may show features similar to well differentiated chondrosarcoma. It is important not to overdiagnose such cases with atypia as low grade chondrosarcomas. Radiological appearances must be taken into account. FNAC is helpful as an outpatient diagnostic procedure when it obviates surgical intervention as most lesions tend to regress asthe skeleton matures. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

Adult hypophosphatasia without apparent skeletal disease: “odontohypophosphatasia“ in four heterozygote members of a family

Summary Twenty members of a family with adult hypophosphatasia were examined clinically and biochemically. Severe caries causing early loss of permanent teeth was the only clinical symptom which could be attributed to hypophosphatasia. None of them had a history of defective bone mineralization, rachitic skeletal alterations, and recurrent pseudofractures or fractures. An iliac crest bone biopsy of the proposita showed a normal finding corresponding to the age of the patient.Four family members in two subsequent generations were affected, thus suggesting an autosomal dominant inheritance. Their serum and leukocyte alkaline phosphatases were reduced. The phosphoethanolamine (PEA) excretion in the urine was increased to a level which suggests a heterozygote state. The serum alkaline phosphatase activity could be ascribed to the liver isoenzyme fraction. This was shown by polyacrylamide electrophoresis, by inhibition studies with organ-specific inhibitors, heat inactivation, inhibition by antibodies, and treatment with neuraminidase.The proposita had an unexplained, diffuse fatty infiltration of the liver. Thus, not only alterations of bone but also of liver metabolism in hypophosphatasia should be considered.The variety of adult hypophosphatasia described in this paper is characterized by the lack of severe bone abnormalities, the apparently autosomal dominant inheritance, and the reduction of bone and intestinal isoenzyme in the serum. Our study suggests that hypophosphatasia is a heterogenous disorder which includes both severe and clinically mild forms.     

Identification of four new members of the internalin multigene family of Listeria monocytogenes EGD.

Listeria monocytogenes is a bacterial pathogen that is able to invade nonphagocytic cells. Two surface proteins, internalin, the inlA gene product, and InlB, play important roles in the entry into cultured mammalian cells. These proteins also have extensive sequence similarities. Previously, Southern hybridization predicted the existence of an internalin multigene family. Recently, InlC, a secreted protein of 30 kDa homologous to InlA and InlB, was identified. In this work, we identified and characterized four new members of the internalin multigene family, inlC2, inlD, inlE, and inlF which encode proteins of 548, 567, 499, and 821 amino acids respectively. inlC2, inlD, and inlE are contiguous on the chromosome of L. monocytogenes EGD, whereas inlF is located in a different chromosomal region. These four inl gene products display the principal features of internalin, namely, a signal sequence, two regions of repeats (or LRR and B repeats), and a putative cell wall anchor sequence containing the sorting motif LPXTG. The four inl genes were maximally expressed albeit at a low level during early exponential growth in bacterial medium at 37 degrees C. The role of these inl genes in L. monocytogenes invasion was assessed by constructing isogenic chromosomal deletion mutants and testing them for entry into various nonphagocytic cells. Unexpectedly, the inlC2, inlD, inlE, and inlF null mutants were not affected for entry into any of the cell lines tested, raising the possibility that these genes are needed for an aspect of pathogenicity other than invasion. The identity of such an aspect remains to be determined.     

Kalilo plasmids are a family of four distinct members with individual global distributions across species

Kalilo is a linear 9-kb plasmid, isolated originally from Hawaiian strains of the heterothallic fungus Neurospora intermedia. Its properties include terminal inverted repeats, two ORFs coding for a presumptive DNA and an RNA polymerase, and the ability to cause senescence in its original host and in the closely related species Neurospora crassa. We have examined natural isolates alleged to contain plasmids homologous to kalilo. Most of these isolates do in fact contain plasmids with so close an identity to kalilo as to be certain relatives. We found a new case of kalilo in Neurospora tetrasperma from Moorea-Tahiti, and a new case of LA-kalilo (previously found only in N. tetrasperma) in N. crassa from Haiti. A previously unreported, substantially shorter, kalilo variant has been found in three geographically separate isolates of the heterothallic species Neurospora discreta. Therefore, if the previously reported kalilo variant from the genus Gelasinospora is included, in all there are four members of the kalilo plasmid family. The main differences between these plasmids are in the terminal inverted repeats (TIRs). The phylogeny of the TIR sequences is largely congruent with that of nuclear DNA in the species in which they are found, suggesting that the plasmids are related by vertical descent throughout the evolution of these species. However, there are two cases of a plasmid found in a heterothallic and a pseudohomothallic species in the same global area; these cases might have arisen from more recent horizontal transmission or introgression. Received: 14 July / 17 September 1999     

A direct interview family study of obsessive-compulsive disorder. I

BACKGROUND: This and the companion paper present two sequential family studies of obsessive-compulsive disorder (OCD) conducted by the same research group, but with different sampling and best-estimate procedures. In addition to providing further data on familial transmission of OCD, we used comparison of disparate findings (moderate, specific familial aggregation in this first study versus a stronger effect for other anxiety disorders than for OCD alone in the second) to examine possible effects of proband characteristics and informant data on outcome. METHOD: In this initial study we interviewed 179 first-degree relatives of 72 OCD probands and 112 relatives of 32 never mentally ill (NMI) controls. Informant data were obtained on an additional 126 relatives (total "combined" samples of 263 and 154 respectively). Analyses used best-estimate diagnoses made by consensus of two "blinded" senior clinicians who reviewed all diagnostic materials including proband informant data about relatives. RESULTS: Significantly higher risk for OCD but not other anxiety disorders was found in relatives of OCD probands compared to relatives of controls in both the directly interviewed and combined samples. There was no relationship between proband age at onset of OCD and strength of familial aggregation. CONCLUSIONS: These data indicate moderate familial aggregation of OCD, but do not support increased transmission by early onset probands, or a familial relationship between OCD and other anxiety disorders with the possible exception of generalized anxiety disorder.     

精神分裂症患者家属生活质量的对照研究

应用病例对照研究方法，对２０４例精神分裂症患者家属进行生活质量研究，结果发现，家属的家庭物质生活、生活事件、心理障碍、娱乐活动、生活满意度及情绪稳定性等均与对照组具有显著性差异，并且差异的范围及程度因家属角色的不同而不同，提示精神分裂症病人不同程度地影响了每个家庭成员的生活质量。     

Cleavage of caspase family members by granzyme B: a comparative study in vitro

The aspartase granzyme B is one of the major components of the granules involved in cell killing by cytotoxic T lymphocytes. Granzyme B has been shown to activate the apoptotic death pathway in the target cell, and this involves activation of members of the caspase (CASP) protein family. Therefore, activational cleavage of mouse (m) CASP proforms by granzyme B was examined in vitro. CASP can be subdivided in the CASP-1 (interleukin-1β-converting enzyme; ICE) subfamily, the CASP-2 (Ich1) subfamily, and the CASP-3 (CPP32) subfamily. Our results reveal that the proforms of the CASP-3 subfamily members mCASP-3 and mCASP-7 are hydrolyzed by granzyme B, while proforms of CASP-2 and CASP-1 subfamily members are not directly cleaved. Only one CASP-3 subfamily member, pro-mCASP-6, was not proteolytically cleaved by granzyme B. These results indicate that two members of the CASP-3 subfamily, but no others, become activated by granzyme B.     

Predictors of one-year seizure remission--a clinicoradiological and electroencephalographic study

BACKGROUND and AIMS: In epileptic patients, the requirement of number of antiepileptic drug (AED) to achieve seizure remission may be different in different geographic location and races. This study aims at evaluating the requirement of AEDs for one-year seizure remission of Indian epileptic patients and their predictors with special reference to ring enhancing lesion. SUBJECTS and METHODS: Consecutive epileptic patients from neurology out patients department of a tertiary care center were included who completed one year follow up. Children < 12 years of age were excluded. A detailed history, neurological examination, CT scan and EEG were carried out. Patients were classified into idiopathic, symptomatic and cryptogenic epilepsy. Symptomatic epilepsies were further classified into patients with ring lesion and without it. Patients were prescribed appropriate AEDs, initially monotherapy then duo and later even more than 2 AEDs if seizures were not controlled. The relationship of various clinical, radiological and EEG changes with requirement of number of AEDs for seizure remission was compared employing Chi square test. RESULTS: There were 120 patients whose mean age was 26.8 (13-71) years and 34 females. 48(40%) patients were classified into idiopathic, 53(44%) symptomatic and 19(15.80%) cryptogenic. After commencement of AEDs, 90(75%) patients were seizure free at 1 year; 78(65%) on monotherapy, 12(10%) on duotherapy and none on more than 2 drugs. The frequency of remission was higher in idiopathic (79%) and symptomatic (79%) compared to cryptogenic (52%). The seizure remission and requirement of number of AEDs were related to type of epilepsy, seizure frequency, neurological deficit and EEG abnormality. Symptomatic patients in non-ring lesion group were younger, had more frequent seizure, neurological deficit and EEG abnormality than ring lesion. Seizure remission was better in patients with ring lesion (87%) compared to without it (44%). CONCLUSION: 75% epileptic patients had one year seizure remission; majority achieved on monotherapy, occasionally on duotherapy and none on more than 2 AEDs. Symptomatic epilepsy due to ring lesion had higher seizure remission rate followed by idiopathic. Cryptogenic epilepsy, frequent seizure, neurological deficit and EEG abnormalities were related to poor remission and requirement of more number of AEDs.     

Cytokines and chemokines in viral encephalitis: A clinicoradiological correlation

Japanese encephalitis (JE) is the commonest encephalitis in South East Asia associated with high morbidity and mortality. Neuronal injury is attributed to a number of proinflammatory cytokines. This study evaluates cerebrospinal fluid (CSF) cytokines and chemokines in encephalitis and correlates these with clinical and magnetic resonance imaging (MRI) findings. We examined 14 patients with encephalitis (8 JE, 1 dengue, 5 nonspecific encephalitis) and 10 healthy controls. CSF cytokines (IL-1β, IL-6, IL-10, IL-12p70, TNF-α, IL-8) and chemokines (IP-10, MCP-1, MIG, IL-8 and RANTES) were estimated using Cytometric Bead Array, compared with controls and were correlated with severity of encephalitis, radiological findings and presence of movement disorders. Median age of the patients was 25.5 (range 6–55 years); 6 had seizures, 10 movement disorders and 6 out of 11 had MRI abnormalities. The MRI abnormalities included thalamic involvement in 5, basal ganglia and mid brain in 3 each and cortical involvement in 2 patients. Both the patients with cortical involvement had seizures and 5 of the 10 patients with movement disorders had thalamic, basal ganglia and/or mid brain involvement. There was significant increase in IL-6 (p = 0.01), RANTES (p = 0.02) and IL-8 (p = 0.02) in encephalitis compared to controls but there was no difference in IL12p70, TNF-α, IL-10, IL-1β and MCP-1. Cytokines and chemokines did not correlate with severity of encephalitis, radiological changes and presence of movement disorders. CSF IL-6, IL-8 and RANTES were significantly higher in encephalitis patients compared to controls.     

B7家族成员的研究新进展

B7分子属免疫球蛋白超家族成员,表达于多种免疫细胞和非免疫细胞上.抗原提呈细胞表面的B7分子与T细胞上的相应受体结合可提供T细胞活化的第二信号,从而调节和控制T细胞的活化、增殖及免疫应答.B7家族成员在感染、肿瘤以及自身免疫性疾病等发病机制中起着关键作用.选择性阻断协同刺激分子有望能成为临床治疗这些疾病的一种新途径.近...