Analysis of the histologic features in the differential diagnosis of intrahepatic neonatal cholestasis

AIM： To compare the histologic features of the liver in intrahepatic neonatal cholestasis （IHNC） with infectious, genetic-endocrine-metabolic, and idiopathic etiologies. METHODS： Liver biopsies from 86 infants with IHNC were evaluated. The inclusion criteria consisted of jaundice beginning at 3 mo of age and a hepatic biop- sy during the 1st year of life. The following histologic features were evaluated： cholestasis, eosinophilia, giant cells, erythropoiesis, siderosis, portal fibrosis, and the presence of a septum. RESULTS： Based on the diagnosis, patients were classified into three groups： group 1 （infectious; n = 18）, group 2 （genetic-endocrine-metabolic; n = 18）, and group 3 （idiopathic; n = 50）. There were no significant differences with respect to the following variables： cholestasis, eosinophilia, giant cells, siderosis, portal fibrosis, and presence of a septum. A significant dif- ference was observed with respect to erythropoiesis, which was more severe in group 1 （Fisher＇s exact test, P = 0.016）. CONCLUSION： A significant difference was observed in IHNC of infectious etiology, in which erythropoiesis was more severe than that in genetic-endocrine-meta- bolic and idiopathic etiologies, whereas there were no significant differences among cholestasis, eosinophilia, giant cells, siderosis, portal fibrosis, and the presence of a septum.     

Abrogation of Microsatellite-instable Tumors Using a Highly Selective Suicide Gene/Prodrug Combination

A substantial fraction of sporadic and inherited colorectal and endometrial cancers in humans is deficient in DNA mismatch repair (MMR). These cancers are characterized by length alterations in ubiquitous simple sequence repeats, a phenotype called microsatellite instability. Here we have exploited this phenotype by developing a novel approach for the highly selective gene therapy of MMR-deficient tumors. To achieve this selectivity, we mutated the VP22FCU1 suicide gene by inserting an out-of-frame microsatellite within its coding region. We show that in a significant fraction of microsatellite-instable (MSI) cells carrying the mutated suicide gene, full-length protein becomes expressed within a few cell doublings, presumably resulting from a reverting frameshift within the inserted microsatellite. Treatment of these cells with the innocuous prodrug 5-fluorocytosine (5-FC) induces strong cytotoxicity and we demonstrate that this owes to multiple bystander effects conferred by the suicide gene/prodrug combination. In a mouse model, MMR-deficient tumors that contained the out-of-frame VP22FCU1 gene displayed strong remission after treatment with 5-FC, without any obvious adverse systemic effects to the mouse. By virtue of its high selectivity and potency, this conditional enzyme/prodrug combination may hold promise for the treatment or prevention of MMR-deficient cancer in humans.     

Young Malaysian children with lower respiratory tract infections show low incidence of chlamydial infection

Objective: The incidence of Chlamydia pneumoniae and Chlamydia trachomatis infection was studied among infants and young children admitted to hospital for the management of lower respiratory tract infections, over a 12 month period.
Methodology: Respiratory secretions were examined for chlamydiae by cell culture, enzyme-linked immunosorbent assay and polymerase chain reaction-enzyme immunoassay. Sera were tested by micro-immunofluorescence for chlamydial IgG, IgM and IgA. Other bacterial and viral pathogens were also looked for by standard cultural and serological methods.
Results: Of 87 patients aged 2 months-3 years, an aetiologic diagnosis was made in 41 (47.1%). C. pneumoniae and C. trachomatis were each detected in 1 (1.2%) of the patients. Among common bacterial pathogens, Haemophilus influenzae (13.8%) and Streptococcus pneumoniae (8.1%) were the most frequently identified. Respiratory viruses and elevated Mycoplasma pneumoniae antibodies were found in 10.3% and 9.1% of patients, respectively.
Conclusion: Chlamydiae are infrequent causes of community-acquired acute lower respiratory tract infections in infants and very young children in Malaysia.     

The Malaysian Telehealth Flagship Application: a national approach to health data protection and utilisation and consumer rights

Telehealth refers to the integration of information, telecommunication, human-machine interface technologies and health technologies to deliver health care, to promote the heath status of the people and to create health. The Malaysian Telehealth Application will, on completion, provide every resident of the country an electronic Lifetime Health Record (LHR) and Lifetime Health Plan (LHP). He or she will also hold a smart card that will contain a subset of the data in the Lifetime Health Record. These will be the means by which Malaysians will receive "seamless continuous quality care" across a range of health facilities and health care providers, and by which Malaysia's health goal of a nation of "healthy individuals, families and communities" is achieved. The challenges to security and privacy in providing access to an electronic Lifetime Health Record at private and government health facilities and to the electronic Lifetime Health Plan at homes of consumers require not only technical mechanisms but also national policies and practices addressing threats while facilitating access to health data during health encounters in different care settings. Organisational policies establish the goals that technical mechanisms serve. They should outline appropriate uses and access to information, create mechanisms for preventing and detecting violations, and set sanctions for violations. Some interesting innovations have been used to address these issues against the background of the launching of the multimedia supercorridor (MSC) in Malaysia.     

WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf-Hirschhorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma [published erratum appears in Hum Mol Genet 1998 Sep;7(9):1527]

Wolf-Hirschhorn syndrome (WHS) is a malformation syndrome associated with a hemizygous deletion of the distal short arm of chromosome 4 (4p16.3). The smallest region of overlap between WHS patients, the WHS critical region, has been confined to 165 kb, of which the complete sequence is known. We have identified and studied a 90 kb gene, designated as WHSC1 , mapping to the 165 kb WHS critical region. This 25 exon gene is expressed ubiquitously in early development and undergoes complex alternative splicing and differential polyadenylation. It encodes a 136 kDa protein containing four domains present in other developmental proteins: a PWWP domain, an HMG box, a SET domain also found in the Drosophila dysmorphy gene ash -encoded protein, and a PHD-type zinc finger. It is expressed preferentially in rapidly growing embryonic tissues, in a pattern corresponding to affected organs in WHS patients. The nature of the protein motifs, the expression pattern and its mapping to the critical region led us to propose WHSC1 as a good candidate gene to be responsible for many of the phenotypic features of WHS. Finally, as a serendipitous finding, of the t(4;14) (p16.3;q32.3) translocations recently described in multiple myelomas, at least three breakpoints merge the IgH and WHSC1 genes, potentially causing fusion proteins replacing WHSC1 exons 1-4 by the IgH 5'-VDJ moiety.      

Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR

Ophthalmological and molecular genetic studies were performed in a consanguineous family with individuals showing either retinitis pigmentosa (RP) or cone-rod dystrophy (CRD). Assuming pseudodominant (recessive) inheritance of allelic defects, linkage analysis positioned the causal gene at 1p21-p13 (lod score 4.22), a genomic segment known to harbor the ABCR gene involved in Stargardt's disease (STGD) and age- related macular degeneration (AMD). We completed the exon-intron structure of the ABCR gene and detected a severe homozygous 5[prime] splice site mutation, IVS30+1G->T, in the four RP patients. The five CRD patients in this family are compound heterozygotes for the IVS30+1G- >T mutation and a 5[prime] splice site mutation in intron 40 (IVS40+5G- >A). Both splice site mutations were found heterozygously in two unrelated STGD patients, but not in 100 control individuals. In these patients the second mutation was either a missense mutation or unknown. Since thus far no STGD patients have been reported to carry two ABCR null alleles and taking into account that the RP phenotype is more severe than the STGD phenotype, we hypothesize that the intron 30 splice site mutation represents a true null allele. Since the intron 30 mutation is found heterozygously in the CRD patients, the IVS40+5G->A mutation probably renders the exon 40 5[prime] splice site partially functional. These results show that mutations in the ABCR gene not only result in STGD and AMD, but can also cause autosomal recessive RP and CRD. Since the heterozygote frequency for ABCR mutations is estimated at 0.02, mutations in ABCR might be an important cause of autosomal recessive and sporadic forms of RP and CRD.      

Anti B cell targeted immunotherapy for treatment of refractory autoimmune haemolytic anaemia in a young infant

We report the case of an 8 week old infant with fulminant autoimmune haemolytic anaemia refractory to conventional immunomodulating treatment. Massive haemolysis resulted in cardiac decompensation and acute renal failure which necessitated mechanical ventilation and peritoneal dialysis. Rituximab, a chimeric anti-CD20 monoclonal antibody, halted progression of the haemolytic process, but the patient died of acute viral pneumonia and disseminated fungal infection. Earlier introduction of rituximab might have prevented the renal complications. Paediatricians should be aware of this useful therapeutic tool for treatment of refractory autoimmune haemolytic anaemia and balance its use against the risk of potential life threatening infection.