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PubMed2001

Clinical and genetic evaluation of familial steroid-responsive nephrotic syndrome in childhood.

Steroid-responsive idiopathic nephrotic syndrome (SSINS) is the most common form of nephrotic syndrome in childhood. This article reports a cohort of familial SSINS with disease onset in childhood. The clinical course in terms of age at onset, symptoms during the initial phase, renal morphology, and outcome was evaluated. Furthermore, linkage to NPHS2, the gene for autosomal-recessive steroid-resistant INS on chromosome 1, was examined. Two families with haplotypes consistent with linkage to NPHS2 were evaluated for mutations in the NPHS2 gene. Familial SSINS (32 patients from 15 families, minimal change NS in 12 of 12 biopsies) was found to be a clinically homogeneous entity. Interfamilial and intrafamilial variability with respect to the age at disease onset was low, indicating a strong genetic influence on disease onset. By linkage studies and mutational analysis, familial SSINS was found to be genetically distinct from NPHS2. This is the first report of a large cohort of familial SSINS. Exclusion of linkage to NPHS2 makes likely the existence of a distinct gene locus for SSINS.

Adolescent↗
PubMed1987

Hemolytic uremic syndrome in three adult siblings: a familial study and evolution.

Over a period of 7 years a typical hemolytic uremic syndrome (HUS) developed in 3 brothers, at the age of 27, 31 and 35 years respectively. The patients did not share a common HLA haplotype. Two sisters, now 36 and 39 years old, did not develop HUS despite pregnancy and prolonged oral contraception. We investigated in the 3 patients (outside of the acute phase of the HUS) and in 12 other first degree relatives complement components (C3, C4, C1q, factor B), coagulation factors (i.e., antithrombin III, F VIII, protein C) prostacyclin regulating plasma factor and vitamin E levels: all results were normal. Renal failure was irreversible in the 3 patients, despite fresh plasma infusions in 2 of them. After a 7 to 32-month period on hemodialysis, the 3 patients were transplanted with a cadaver kidney. Twenty-one to 94 months later, they have a functioning graft and no recurrence of the HUS. We conclude that, in this family, HUS is not linked to HLA or female gender. No phenotypic marker of the disease was found. Evolution after dialysis and transplantation is excellent, with no short term recurrence of the HUS.

Adult↗
PubMedDate not supplied

Facilitating T-cell immune reconstitution after haploidentical transplantation in adults.

Delayed reconstitution of cellular immunity following T-cell-depleted, CD34-enriched, allogeneic hematopoietic progenitor cell transplantation (HPCT) is the major cause of morbidity and mortality following haploidentical transplantation in adults. This is illustrated in our recent study of 28 high-risk adult patients (median age 31) who were treated with conditioning regimens containing antithymocyte globulin (ATG) before T-cell-depleted, CD34-enriched allogeneic HPCT. Overall mortality was 93% (26/28 patients) with a median survival of 4 months posttransplant. Poor cellular immune reconstitution contributed to death of 21/28 patients, with eight deaths due to opportunistic infections and seven deaths due to relapse. While recovery of normal numbers of circulating NK cells and B-cells occurred within the first 1-2 months posttransplant, recovery of normal numbers of blood T-cells was suppressed for more than 1 year. The mean half-life of active ATG levels in serum was 6 days; rapid clearance suggested that residual ATG did not contribute to the delay of posttransplant T-cell reconstitution. Rapid T-cell reconstitution was seen only in younger patients, indicating that poor thymic function and the absence of T-cells in the graft are the major causes of delayed recovery of cellular immunity. Improved cellular immunity after T-cell-depleted haploidentical HPCT will thus require novel strategies to adoptively transfer antigen specific donor T-cells without inducing lethal graft-versus-host disease (GvHD). This problem has been addressed in a preclinical murine model of MHC-mismatched bone marrow transplantation. Donor T-cells treated ex vivo with fludarabine or a UVA light-activated psoralen compound (amotosalen) have a markedly reduced ability to induce GvHD, yet the treated T-cells confer protection against murine cytomegalovirus and an infused leukemic cell line. Polyclonal donor T-cells reconstituted the blood and lymphoid compartments posttransplant and expanded in vivo. Derivatives of ex-vivo-treated donor T-cells retained the ability to produce cytokines and proliferate in response to antigen challenge. The mechanism of reduced GvHD potential of ex-vivo-treated T-cells appears to be selection of a subset of memory donor T-cells that do not initially home to secondary lymphoid organs and have reduced capacity for producing inflammation in the immediate posttransplant period. Direct selection of the memory subset by high-speed FACS confirmed the improved therapeutic index in the murine model system. Preclinical data indicate the feasibility of treating human T-cells with fludarabine, psoralen, or direct selection based upon the memory phenotype to efficiently produce a population of polyclonal donor T-cells with reduced GvHD activity. A planned clinical phase 1 trial of adoptive therapy utilizing ex vivo psoralen-treated donor T-cells in recipients of T-cell-depleted haploidentical HPCT is presented.

Adult↗
PubMed1982

Beta-cell dysfunction in nondiabetic HLA identical siblings of insulin-dependent diabetics.

B-cell function was tested in siblings of insulin-dependent diabetics (IDD). From previous studies, it is now recognized that the risk of developing IDD is highest in those sharing both haplotypes (S2H) and lowest in those sharing neither haplotype (S0H) with the diabetic. Insulin secretion in response to intravenous arginine and glucose was evaluated in S2H, S0H, and matched controls. Intravenous arginine and glucose elicited an exaggerated acute phase of insulin secretion in S2H compared with controls when analyzed as incremental insulin area 0-10', peak level attained, and mean insulin levels postinjection. Insulin responses to arginine and glucose in S0H and matched controls were identical. We hypothesize that the increased beta-cell activity found in S2H predisposes their beta-cells to damage by environmental factors and may be part of the mechanism conferring the increased risk of IDD in S2H.

Adolescent↗
PubMed2006

Intravenous synthetic peptide MBP8298 delayed disease progression in an HLA Class II-defined cohort of patients with progressive multiple sclerosis: results of a 24-month double-blind placebo-controlled clinical trial and 5 years of follow-up treatment.

MBP8298 is a synthetic peptide with a sequence corresponding to amino acid residues 82-98 of human myelin basic protein (DENPVVHFFKNIVTPRT). It represents the immunodominant target for both B cells and T cells in multiple sclerosis (MS) patients with HLA haplotype DR2. Its administration in accordance with the principle of high dose tolerance results in long-term suppression of anti-myelin basic protein (MBP) autoantibody levels in the cerebrospinal fluid (CSF) of a large fraction of progressive MS patients. MBP8298 was evaluated in a 24-month placebo-controlled double-blinded Phase II clinical trial in 32 patients with progressive MS. The objective was to assess the clinical efficacy of 500 mg of MBP8298 administered intravenously every 6 months, as measured by changes in Expanded Disability Status Scale (EDSS) scores. Contingency analysis for all patients at 24 months showed no significant difference between MBP8298 and placebo-treatments (n = 32, P = 0.29). Contingency analysis in an HLA Class II defined subgroup showed a statistically significant benefit of MBP8298 treatment compared with placebo in patients with HLA haplotypes DR2 and/or DR4 (n = 20, P = 0.01). Long-term follow-up treatment and assessment of patients in this responder group showed a median time to progression of 78 months for MBP8298 treated patients compared with 18 months for placebo-treatment (Kaplan-Meier analysis, P = 0.004; relative rate of progression = 0.23). Anti-MBP autoantibody levels in the CSF of most MBP8298 treated patients were suppressed, but antibody suppression was not predictive of clinical benefit. Anti-MBP autoantibodies that reappeared in the CSF of one patient at 36 months, whilst under treatment with MBP8298, were not reactive with the MBP8298 peptide in vitro. The identification of a responder subgroup (62.5% of the patients in this study) enables a more efficient design of a large confirmatory clinical trial of MBP8298. The probability that patients with other less common HLA-DR haplotypes will respond to this treatment should not be ignored.

Adult↗
PubMed2004

Inference on recombination and block structure using unphased data.

In this study compatibility with a tree for unphased genotype data is discussed. If the data are compatible with a tree, the data are consistent with an assumption of no recombination in its evolutionary history. Further, it is said that there is a solution to the perfect phylogeny problem; i.e., for each individual a pair of haplotypes can be defined and the set of all haplotypes can be explained without invoking recombination. A new algorithm to decide whether or not a sample is compatible with a tree is derived. The new algorithm relies on an equivalence relation between sites that mutually determine the phase of each other. (The previous algorithm was based on advanced graph theoretical tools.) The equivalence relation is used to derive the number of solutions to the perfect phylogeny problem. Further, a series of statistics, R ( j ) ( M ), j >or= 2, are defined. These can be used to detect recombination events in the sample's history and to divide the sample into regions that are compatible with a tree. The new statistics are applied to real data from human genes. The results from this application are discussed with reference to recent suggestions that recombination in the human genome is highly heterogeneous.

Biometry↗
PubMed2001

Population structure and genetic diversity of the amphiatlantic haploid peatmoss Sphagnum affine (Sphagnopsida).

Nineteen populations of Sphagnum affine were included in a study of genetic diversity and structure in fragmented and less fragmented landscapes, and differentiation at intercontinental and three regional levels. Isozyme electrophoresis of eight enzyme systems revealed 12 variable loci, which could be used for haplotype identification. A hierachical analysis of variance (AMOVA) revealed no significant intercontinental differentiation, and very limited differentiation among European regions. A trend of decreasing diversity with increasing latitude was apparent. Gametic phase disequilibria was high, suggesting nonrandom mating and regionally high incidences of inbreeding. The partitioning of genetic variation within and among populations in each region varied among regions, the northernmost populations having 86% of the total variation among populations, the southernmost in Scandinavia having 25% of the variation among populations, whereas the American populations displayed 89% of the variation within populations. Fifteen alleles at eight loci occurred in the U.S.A. which were not encountered in Europe, whereas only three European alleles at one locus in three populations were not encountered in U.S.A. The differences in diversity between North America and Europe may result from loss of genetic diversity caused by founder effects during postglacial recolonization of northern Europe. In Europe, the main mountain ranges extend E-W, posing severe barriers to northwards migration of lowland species, compared to the N-S trend of mountain ranges in North America. The decline in genetic diversity and increase in population differentiation and gametic phase disequilibria towards the north in Scandinavia may be caused by a series of founder effects during postglacial migration. These may have corresponded to minor climatic oscillations that influenced the migration front/leading edge in the suboceanic lowlands of Norway. According to this model random genetic drift will be an increasingly important structuring factor with latitude.

Analysis of Variance↗
PubMed1999

A new animal model for relapsing polychondritis, induced by cartilage matrix protein (matrilin-1).

Relapsing polychondritis (RP) differs from rheumatoid arthritis (RA) in that primarily cartilage outside diarthrodial joints is affected. The disease usually involves trachea, nose, and outer ears. To investigate whether the tissue distribution of RP may be explained by a specific immune response, we immunized rats with cartilage matrix protein (matrilin-1), a protein predominantly expressed in tracheal cartilage. After 2-3 weeks, some rats developed a severe inspiratory stridor. They had swollen noses and/or epistaxis, but showed neither joint nor outer ear affection. The inflammatory lesions involved chronic active erosions of cartilage. Female rats were more susceptible than males. The disease susceptibility was controlled by both MHC genes (f, l, d, and a haplotypes are high responders, and u, n, and c are resistant) and non-MHC genes (the LEW strain is susceptible; the DA strain is resistant). However, all strains mounted a pronounced IgG response to cartilage matrix protein. The initiation and effector phase of the laryngotracheal involvement causing the clinical symptoms were shown to depend on alphabeta T cells. Taken together, these results represent a novel model for RP: matrilin-1-induced RP. Our findings also suggest that different cartilage proteins are involved in pathogenic models of RP and RA.

Animals↗
PubMed1985

Natural resistance to salmonellae in mice: control by genes within the major histocompatibility complex.

Determinations of 50% lethal dose (LD50) values in H-2 congenic B10 lines showed that late-emerging resistance (postimmune response phase) to salmonellae of intermediate virulence was less in H-2b and H-2d than in H-2a, H-2k, and H-2f mice. Association of resistance to H-2 was confirmed by backcross analysis, and LD50 determinations on H-2 recombinant haplotype strains showed that resistance maps to the I-E subregion. Bacterial growth curves in liver and spleen showed that susceptible mice carried bacteria for longer in the reticuloendothelial system than did resistant mice and that susceptible mice showed greater splenomegaly. Association of resistance and susceptibility to H-2 was not different when sister transductant salmonellae expressing somatic antigens O4 and O9 were used. Thus a gene(s) within the major histocompatibility complex controls natural resistance to salmonellae in mice by influencing the ability to clear bacteria from the reticuloendothelial system in the later phase of the infection, and the immunodominant O antigen cannot be solely involved.

Animals↗
PubMed1988

Antibody response of three different strains of mice to alpha s1-casein analyzed by using proteolytic and synthetic peptides.

The location of immunodominant regions on bovine alpha s1-casein (alpha s1-CN) was compared among three strains of mice (BALB/c, C3H/He and C57BL/6). Anti-alpha s1-CN antisera were separated 5 weeks after the first immunization. Thirty-seven kinds of peptides were obtained from alpha s1-CN by proteolysis, and the segmental 19- to 20-residue peptides overlapping with their adjacent neighbors by 5 residues were synthesized over the entire polypeptide chain of alpha s1-CN. The ability of the anti-alpha s1-CN antibody to bind peptides was tested by an enzyme-linked immunosorbent assay, in which the peptides were adsorbed to the solid phase. All the strains responded highly to alpha s1-CN. The immunodominant antigenic regions of alpha s1-CN were not common to the three strains of mice, the H-2 haplotypes being different from each other (BALB/c, regions 1, 3, 5, 6 and 7; C3H/He, regions 2, 3, 5, 6, 6', 7 and 7'; and C57BL/6, regions 2, 4, 5, 6 and 7).

Amino Acid Sequence↗
PubMed2006

ABCB1 gene polymorphisms are not associated with treatment outcome in elderly acute myeloid leukemia patients.

OBJECTIVES: The classical multidrug resistance (MDR) gene MDR1 (ABCB1) encodes for the drug efflux pump P-glycoprotein (P-gp). P-gp expression is an adverse prognostic factor for treatment outcome in acute myeloid leukemia (AML) and is more frequently observed in older patients. Single-nucleotide polymorphisms of the ABCB1 gene, C1236T, G2677T, and C3435T, have been associated with altered drug metabolism and treatment outcome. We prospectively determined these single-nucleotide polymorphisms in AML blasts in a cohort of patients aged 60 years or older with AML and evaluated their relevance with regard to P-gp function and expression, ABCB1 messenger ribonucleic acid (mRNA) expression, and clinical outcome. METHODS: We have analyzed purified bone marrow-derived leukemic blasts, obtained at diagnosis, in 150 patients who were treated within a multicenter, randomized, phase 3 trial of elderly patients with AML. The significance of the allelic ABCB1 variants of C1236T, G2677T, and C3435T was evaluated with respect to P-gp expression and function in leukemic blasts and ABCB1 mRNA expression levels, and these values were correlated with treatment outcome. RESULTS: P-gp function and expression in leukemic blasts and ABCB1 mRNA levels in patients with AML did not vary significantly among any of the allelic variants of ABCB1. None of these allelic variations predicted a difference in complete response rate and survival endpoints. CONCLUSIONS: In AML patients aged 60 years or older, allelic ABCB1 variations of C1236T, G2677T, or C3435T are not associated with altered P-gp function or with MDR1 expression at the transcriptional or translational level in leukemic blasts, and they do not significantly affect clinical prognosis.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2006

Sequence diversity at the proximal 14q32.1 SERPIN subcluster: evidence for natural selection favoring the pseudogenization of SERPINA2.

The superfamily of serine protease inhibitors (SERPINs) plays a key role in controlling the activity of proteinases in diverse biological processes. alpha1-antitrypsin (SERPINA1), the most studied member of this family, is encoded by a gene located within the proximal 14q32.1 SERPIN subcluster, together with the highly homologous alpha1-antitrypsin-like sequence (SERPINA2), which was previously proposed to be a pseudogene. Here, we performed a resequencing study encompassing both SERPINA1 and SERPINA2 as well as the adjacent gene coding for corticosteroid-binding globulin (SERPINA6) in samples from Europe and West Africa. In the African sample, we found that a common haplotype carrying a 2-kb deletion in the SERPINA2 gene is associated with remarkable long-range homozygozity as if it was quickly driven to high frequency by natural selection acting on an advantageous variant. An analysis of the HapMap Phase I data for the Yoruba sample confirmed that variation in this subcluster carries a strong signal of positive selection. We also show that the SERPINA2 gene is expressed and probably encodes a functional SERPIN. Finally, comparisons with orthologous sequences in nonhuman primates showed that SERPINA2 is present in some great apes, but in chimpanzees it was lost by a deletion event independent from that observed in humans. In agreement with the "less is more" hypothesis, we propose that loss of SERPINA2 is an ongoing process associated with a selective advantage during recent primate evolution, possibly because of a role in fertility or in host-pathogen interactions.

Africa↗
PubMed2001

Segregation of hematuria in thin basement membrane disease with haplotypes at the loci for Alport syndrome.

BACKGROUND: Inherited hematuria is common and is usually attributed to thin basement membrane disease (TBMD). The aim of this study was to determine how often hematuria in families with TBMD segregated with haplotypes at the chromosomal loci for autosomal recessive and X-linked Alport syndrome (COL4A3/COL4A4 and COL4A5, respectively). METHODS: The families of 22 individuals with TBMD on renal biopsy and with urinary glomerular red blood cell (RBC) counts of more than 50,000/mL were studied using phase-contrast microscopy of the urine and DNA microsatellite markers. Eighteen families had at least two members with hematuria. RESULTS: Hematuria segregated with or was consistent with segregation at the COL4A3/COL4A4 locus in eight (36%) families (P < 0.05 in 5 of these) and at the COL4A5 locus in four (18%) families (P < 0.05 in 2). The lack of segregation in the other 10 (45%) families may have occurred because of incomplete penetrance of the hematuria, de novo mutations, coincidental hematuria in other family members, or the presence of a novel gene locus. In four different families, three of which had hematuria that segregated with the COL4A3/COL4A4 locus, four family members with the hematuria haplotype had spouses with coincidental hematuria (4 of 29, 14%). However, none of their four offspring who had also inherited the hematuria haplotype had the clinical features of autosomal recessive Alport syndrome. CONCLUSIONS: Hematuria in families with TBMD commonly segregates with the COL4A3/COL4A4 locus and thus results from mutations in the same genes as autosomal recessive Alport syndrome. Sometimes TBMD may be confused with the carrier state for X-linked Alport syndrome. However, nearly half of the families in this study had hematuria that did not segregate with the loci for either autosomal recessive or X-linked Alport syndrome.

Adolescent↗
PubMed1992

Japanese study of kidney transplantation: 1. Results of early phase II study.

For a 4-month period from July to October 1990, 37 primary renal transplant patients were enrolled in the early phase II study of FK 506. An i.v. dose of FK 506 0.075 mg/kg twice a day was administered initially, and then in oral dose of 0.15 mg/kg twice a day followed. Prednisolone was started at 1 mg/kg daily as an additioned drug. Some 32 live related donors with one-mismatched haplotype of HLA and 5 cadaveric donors underwent transplantation. All patients are alive, and all kidney allografts are functioning. A correlation between the trough level of FK 506 in whole blood and acute rejection or adverse events was retrospectively investigated. There was a significant correlation between the trough level in whole blood and acute rejection or renal impairment. In conclusion, the therapeutic dose of FK 506 should be adjusted by monitoring the trough level in whole blood, the range of which might be recommended to be 15-20 ng/ml during the early phase after transplantation.

Adolescent↗
PubMed2004

HLA- and dose-dependent immunogenicity of a peptide-based HIV-1 immunotherapy candidate (Vacc-4x).

OBJECTIVE: The Vacc-4x immunotherapy candidate is composed of four modified peptides corresponding to conserved domains of the HIV-1 protein p24 that preferentially include HLA-A2 restricted elements. Dose-dependent safety and immunogenicity of Vacc-4x and the significance of a HLA-A2 haplotype were examined. DESIGN: Non-AIDS, HIV-1 infected healthy patients (n = 40) stable on HAART with CD4 counts > 300 x 10 cells/l were randomized to receive either low-dose or high-dose Vacc-4x over 26 weeks in an open, prospective phase II clinical trial. METHODS: Patients received a total of 10 intradermal injections, using recombinant granulocyte-macrophage colony stimulating factor as a local adjuvant. Vacc-4x-specific cellular responses were monitored in vivo by delayed-type hypersensitivity (DTH) skin test infiltrates and in vitro by both T-cell proliferation, and induction /secretion of cytokines. RESULTS: Most patients developed Vacc-4x-specific DTHs (90%) and proliferative T-cell responses (80%) that were inter-related in magnitude. High-dose Vacc-4x generally induced stronger specific immune responses than low dose in terms of DTH areas and CD4 and CD8 T-cell proliferation. Only HLA-A2 negative patients had a definite dose advantage, and this subgroup had in fact the best overall DTH and proliferative responses. In contrast, no significant dose difference was observed for HLA-A2 positive patients. No serious adverse events were reported. CONCLUSIONS: HIV-associated specific responses were safely induced in most patients by Vacc-4x in a dose-dependent manner and were also influenced by the HLA haplotype.

AIDS Vaccines↗
PubMed2003

Transmission/disequilibrium test based on haplotype sharing for tightly linked markers.

Studies using haplotypes of multiple tightly linked markers are more informative than those using a single marker. However, studies based on multimarker haplotypes have some difficulties. First, if we consider each haplotype as an allele and use the conventional single-marker transmission/disequilibrium test (TDT), then the rapid increase in the degrees of freedom with an increasing number of markers means that the statistical power of the conventional tests will be low. Second, the parental haplotypes cannot always be unambiguously reconstructed. In the present article, we propose a haplotype-sharing TDT (HS-TDT) for linkage or association between a disease-susceptibility locus and a chromosome region in which several tightly linked markers have been typed. This method is applicable to both quantitative traits and qualitative traits. It is applicable to any size of nuclear family, with or without ambiguous phase information, and it is applicable to any number of alleles at each of the markers. The degrees of freedom (in a broad sense) of the test increase linearly as the number of markers considered increases but do not increase as the number of alleles at the markers increases. Our simulation results show that the HS-TDT has the correct type I error rate in structured populations and that, in most cases, the power of HS-TDT is higher than the power of the existing single-marker TDTs and haplotype-based TDTs.

Computer Simulation↗
PubMed2001

Chronopharmacology of oral prednisolone in rats.

The chronopharmacology of oral prednisolone (PSL) was studied in rat models. Differences in the dosing-time-dependent toxicity were evaluated at four time points (3, 9, 15 and 21 HALO) in adult male Wistar rats and confirmed in an inbred strain of Lewis rats (MHC haplotype; RTIl) at two time points (9 and 21 HALO). The total body weight and that of the immunologic-related organs were maximally reduced when PSL was repeatedly administered during the late active phase (21 HALO). This chronotoxicity was independent of plasma concentrations of PSL, adrenocorticotropic hormone, and corticosterone. Repeated administration of PSL prolonged cardiac allograft survival in a DA (RTIa) -to-Lewis combination, and there was a tendency to be more effective in the 21 HALO trial. These results suggested that single dose therapy of PSL at the selected point of the day may be less harmful, protecting against allograft rejection.

Administration, Oral↗
PubMed1984

The effect of cytomegalovirus infection on the host response to foreign and hapten-modified self histocompatibility antigens.

The effect of murine cytomegalovirus (MCMV) infection on the host's ability to respond to allogeneic or hapten-modified syngeneic histocompatibility antigens was characterized by an early suppressive phase followed by a phase of enhancement. Suppression of the potential to respond to allogeneic H-2 antigens, as measured by an in vitro cell-mediated lympholysis assay, was seen on days 2-4 postinfection with MCMV, and was greatest at larger doses of virus and in mice with H-2 haplotypes associated with genetic susceptibility to MCMV. In mice of the C57BL genetic background, such responses had returned to normal levels by day 6 and thereafter (days 7-13) the potential of the infected host to respond to allogeneic histocompatibility determinants was markedly enhanced compared with uninfected control mice. This enhancement of alloreactivity was maximal at lower doses of virus and was coincident with the emergence of reactivity to self antigens, as measured by autoantibody production. A similar pattern of time-dependent suppression and enhancement of the hapten modified self cytotoxic response was observed. Enhancement of alloreactivity during MCMV infection was dependent on the genetic constitution of the host with the response of BALB/c mice remaining in a suppressive phase for up to 17 days postinfection. The possibility that this in vitro finding of enhanced alloreactivity during MCMV infection underlies the clinical observations of association between episodes of kidney allograft rejection and cytomegalovirus infection is discussed.

Animals↗