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Biomedical subjects

R Baumgarten

Publications and source records attributed to R Baumgarten.

At least 19 recordsLinked to original sources

Risk factors for the development of lithium-induced polyuria.

BACKGROUND: Polyuria is common in patients with bipolar disorder treated with lithium. However, the risk factors for polyuria in these patients have not been established. AIMS: To estimate the prevalence of polyuria associated with the use of lithium and to identify additional risk factors. METHOD: A 4-month prospective follow-up study in an out-patient lithium clinic. The 75 participants were asked to provide 24-h urine samples; polyuria was defined as a urine volume greater than 3 litres per 24 h. Risk factors examined included demographic variables, medications and medical comorbidities. RESULTS: The prevalence of polyuria among lithium users was 37%. Concomitant use of serotonergic antidepressants was strongly associated with polyuria (odds ratio 4.25, 95% CI 1.15-15.68) compared with patients not using these agents. CONCLUSIONS: Our data confirm the high prevalence of lithium-induced polyuria. Physicians should be aware that concurrent use of serotonergic antidepressants and lithium significantly enhances the risk of its occurrence. Although limited polyuria is not harmful, it may be troublesome for the patient. In many cases cessation of lithium therapy is not an option because of difficulty in controlling the manic or depressive symptoms.

Adult↗

Efficacy of a short-term ribavirin plus interferon alpha combination therapy followed by interferon alpha alone in previously untreated patients with chronic hepatitis C: a randomized multicenter trial.

BACKGROUND: Combination therapy with interferon alpha (IFNalpha) plus ribavirin has been shown to improve the sustained response rate in patients with chronic hepatitis C but there is little information regarding the lengths of time for this therapeutic regimen. In this study we therefore tried to evaluate whether the analysis of different virological parameters could provide new clues with respect to the early determination of the efficacy of this form of combination therapy. Furthermore, we also examined whether short-term induction combination therapy followed by IFNalpha alone is more effective than monotherapy in mounting an initial as well as a sustained virological response. METHODS: 185 patients with histologically proven chronic hepatitis C (mean age 42 years (range 19-65 years); 110 males, 75 females) were enrolled in the study. The patients were randomly assigned to receive, over the first 12 weeks, either interferon alpha 2a 6 million units (MU) three times weekly plus ribavirin 14 mg/kg per day (n=93) or the same dose of IFNalpha alone (n=92). Patients with a virological response (serum HCV RNA undetectable) after 12 weeks were subsequently treated with 3 MU IFNalpha alone thrice weekly for a further 40 weeks. Otherwise, treatment was discontinued. After the end of treatment, patients were followed up for 24 weeks. RESULTS: Patient characteristics at baseline were not significantly different in the two treatment groups. An initial virological response at week 12 was seen in 61 (66%) patients receiving IFNalpha plus ribavirin and in 44 (48%) being treated with IFNalpha alone (p=0.015) and this improvement in the response rate was mainly restricted to HCV genotype 1-infected patients (58% vs. 38%). In contrast, end-of-treatment (week 52) and sustained virological response rates were similar in both groups (37% vs. 29% and 26% vs. 17% [p=0.1], respectively). Interestingly, patients with HCV genotype 3, however, clearly benefited from short-term combination therapy. Thus, sustained virological response rates in these patients significantly increased from 25% (IFNalpha monotherapy) to 59% (combination therapy) (p=0.05). CONCLUSIONS: Short-term combined therapy for 12 weeks is more effective than the monotherapy with respect to the induction of an initial virological response but this effect applies only to genotype 1-infected patients. However, there is no significant difference between both therapeutic schedules with regard to the induction of sustained response. Although HCV genotype 3-infected patients seem to benefit from this short-term combined therapy, prolonged combined therapy may be necessary in HCV genotype 1-infected patients.

Adult↗

Dissociation between urine osmolality and urinary excretion of aquaporin-2 in healthy volunteers.

BACKGROUND: It has been suggested that urinary excretion of the vasopressin-dependent water channel of the kidney collecting duct, aquaporin-2 (AQP2), reflects renal vasopressin action and might be used clinically. It is unclear, however, what relation exists between urine osmolality and urinary excretion of AQP2 (UAQP2) and it is unknown whether UAQP2 is influenced by hyperosmolality of urine or tubular flow rates. METHODS: We measured urine osmolality and UAQP2 in healthy volunteers in various conditions: (i) overnight dehydration continued during the day, (ii) after infusion of 700 ml hypertonic saline (NaCl 2.5%), and (iii) after intranasal administration of 40 microg 1-desamino-8-D-arginine vasopressin (DDAVP). The last two tests were performed after water loading. In addition, a DDAVP test was performed, after administration of frusemide. RESULTS: After overnight dehydration, the urine osmolality increased from 888+/-18 to 1004+/-17 mosmol/kg during additional hours of thirsting, whereas UAQP2 doubled from 140+/-45 to 285+/-63 fmol AQP2/micromol creatinine. Infusion of hypertonic saline increased urine osmolality from 70+/-3 to 451+/-68 mosmol/kg, while UAQP2 remained almost zero. Urine osmolality increased from 101+/-17 to 860+/-30 mosmol/kg after administration of DDAVP, with a parallel increase in UAQP2 from 32+/-14 to 394+/-81 fmol AQP2/micromol creatinine. Pre-treatment with frusemide attenuated the increase in urine osmolality, but had no effect on UAQP2 after DDAVP. CONCLUSIONS: Our data demonstrate that a simple relationship between urine osmolality and UAQP2 does not exist. Therefore, random or once-only measurements of UAQP2 as an index of renal vasopressin action are not useful. In contrast, intranasal application of DDAVP resulted in a parallel rise in urine osmolality and UAQP2. Therefore this test might be useful in studying patients with urine concentration defects. The DDAVP-frusemide test revealed that the release of AQP2 into urine is not caused by hypertonicity of tubular fluid.

Adult↗

Mechanisms of endotoxin tolerance in patients with alcoholic liver cirrhosis: role of interleukin 10, interleukin 1 receptor antagonist, and soluble tumour necrosis factor receptors as well as effector cell desensitisation.

BACKGROUND: In patients with alcoholic liver cirrhosis, endotoxaemia is a frequent finding. Unknown mechanisms, however, prevent typical clinical symptoms of endotoxaemia in many patients. METHODS: We determined plasma levels of pro- and anti-inflammatory mediators, ex vivo cytokine secretion capacity, and expression of tumour necrosis factor (TNF) receptors on phagocytic blood cells in 49 patients with alcoholic cirrhosis and 41 age matched healthy controls. RESULTS: In addition to increased levels of proinflammatory cytokines in cirrhotic patients, we observed consistent upregulation of the anti-inflammatory mediators interleukin 10 (IL-10) (plasma 15.75 (1. 6) v 6.6 (1.3) pg/ml (p<0.001); ex-vivo 108.4 (22.0) v 40.1 (7.4) pg/ml (p<0.05)), interleukin 1 receptor antagonist (plasma 527.1 (83) v 331.4 (56) pg/ml (p<0.05); ex vivo 19.9 (3.4) v 10.2 (2.7) ng/ml (p<0.01)), and soluble TNF receptors (sTNF-R) in plasma (sTNF-RI 3157.2 (506.2) v 607.9 (300.3) pg/ml; sTNF-RII 3331.0 (506. 2) v 1066.4 (225.1) pg/ml (p<0.001 for both)). Desensitisation at the target cell level was indicated by reduced expression of TNF receptor I on granulocytes (64.8 (6.5) v 40.1 (7.3)% positive cells; p<0.05) and unaltered plasma levels of soluble E-selectin. CONCLUSION: In patients with alcoholic liver cirrhosis, upregulation of the pro- and anti-inflammatory cytokine system and simultaneous desensitisation of effector cells could explain the restricted systemic inflammatory response to chronic endotoxaemia. This alteration in immune status may lead to impairment of host defences against infections which are frequent complications of alcoholic cirrhosis.

Adult↗

Pneumocystis carinii pneumonia in the Federal Republic of Germany in the era of changing antiretroviral therapy - IDKF 13 -. German AIDS Study Group (GASG/IdKF).

BACKGROUND: Pneumocystis carinii pneumonia (PCP) is one of the most common AIDS defining diagnoses. METHODS: In a prospective observational trial all cases of Pneumocystis carinii pneumonia (PCP) were evaluated. Patients with and without PCP-prophylaxis were compared for symptoms, efficacy, side effects and mortality at week 4 and 26. RESULTS: 293 patients developed a PCP episode. Patients with no prophylaxis had a significant lower CD4 cell count and a more severe clinical status at time of diagnosis. This was pronounced in the group with first positive HIV test at time of diagnosis. There was no difference in the rate of successful treatment between both groups. At week four a tendency to a better survival in the group with prophylaxis was observed, however this changed to a trend to a better survival at week 26 for the group without prophylaxis. CONCLUSION: Even in the era of highly active antiretroviral treatment many patients present with PCP. Nearly 60% of patients presented without antiretroviral treatment or PCP-prophylaxis. Nearly 25% of all patients had their first HIV-test at time of PCP diagnosis.

AIDS-Related Opportunistic Infections↗

Safety and immunogenicity of hepatitis A vaccine in patients with chronic liver disease.

Acute hepatitis A superimposed on chronic liver disease (CLD) has been associated with severe or fulminant hepatitis. An open, multicenter study was performed to compare the safety and immunogenicity of an inactivated hepatitis A vaccine in patients with CLD with that in healthy subjects. A secondary objective was to compare the safety of the hepatitis A vaccine with that of a commercial hepatitis B vaccine in subjects with chronic hepatitis C. A total of 475 subjects over the age of 18 years were enrolled into 1 of 5 groups according to history, serological data, and previous diagnosis. Patients in groups 1 (healthy adults), 2 (chronic hepatitis B), 3 (chronic hepatitis C), and 5 (other CLD not caused by viral hepatitis) were vaccinated with two doses of inactivated hepatitis A vaccine, 6 months apart. Patients in group 4 (chronic hepatitis C) received 3 doses of a recombinant hepatitis B vaccine, according to a 0-, 1-, and 6-month schedule. Local injection-site symptoms were the most common reactions reported following vaccination in all groups (35.5% of all doses), with the hepatitis B vaccine eliciting fewer injection-site symptoms than the hepatitis A vaccine (19.8% compared with 37.5%). Although a higher percentage of healthy subjects (93%) seroconverted after a single dose of the hepatitis A vaccine than did subjects with chronic hepatitis C (73.7%) or CLD of nonviral etiologies (83.1%), more than 94% of all vaccinees were seropositive for anti-HAV after the complete vaccination course. At each time point, a lower geometric mean concentration of anti-HAV was observed for each group of CLD patients compared with the healthy control subjects. In conclusion, hepatitis A vaccine was well tolerated and induced a satisfactory immune response in patients with chronic hepatitis B, chronic hepatitis C, and miscellaneous CLD.

Adolescent↗

Glycosylation is not essential for vasopressin-dependent routing of aquaporin-2 in transfected Madin-Darby canine kidney cells.

Glycosylation has been shown to be important for proper routing and membrane insertion of a number of proteins. In the collecting duct, aquaporin-2 (AQP2) is inserted into the apical membrane after stimulation of vasopressin type-2 receptors and retrieved into an endosomal compartment after withdrawal of vasopressin. The extent of glycosylation of AQP2 in human kidney and urine and the effects of deglycoylation on routing of AQP2 in an AQP2-transfected Madin-Darby canine kidney cell line (clone WT10) were investigated. Semiquantitative immunoblotting of human kidney membranes and urine showed an AQP2 glycosylation of 35 to 45% for medulla, papilla, and urine, with low variation among individuals. The 1-desamino-8-D-arginine vasopressin-induced transcellular osmotic water permeability (Pf) of WT10 cells by a factor of 2.6 +/- 0.2 was reduced to 1.5 +/- 0.1 after pretreatment with the glycosylation inhibitor tunicamycin. However, when WT10 cells were incubated with 8-br-cAMP, the Pf increased by a factor 2.8 +/- 0.2 and by 2.9 +/- 0.2 after prior incubation with tunicamycin. Immunoblot analyses revealed that in WT10 cells, 34% of AQP2 is glycosylated, which was reduced to 2% after tunicamycin treatment. Surface biotinylation and subsequent semiquantitative immunoblotting revealed that stimulation by cAMP increased the level of AQP2 in the apical membrane of WT10 cells 1.5-fold. independent of the presence of tunicamycin. However, in tunicamycin-treated WT10 cells, all AQP2 in the apical membrane was unglycosylated, whereas in untreated cells 30% of AQP2 in the apical membrane was glycosylated. These results prove that glycosylation has no function in the routing of AQP2 in Madin-Darby canine kidney cells.

Animals↗

[Viral hepatitis: preventable illnesses].

The availability of vaccines had made on Hepatitis A as well as Hepatitis B an avoidable illnesses. However, there is a lack of knowledge referring to the epidemiological situation. This might be due to the physician's as well as the patient's underestimation of the risk of a new infection but also insufficient knowledge about indication, management of vaccination, adverse events and cost effectiveness might. Vaccination against Hepatitis A and B produce a longlasting immunisation which is indicated in every age. A combined vaccination for both infectious diseases are effective and support the compliance. The role of the family physician is decisive in the management of a sufficient vaccination strategy.

Adult↗

Distribution of hepatitis C virus genotypes in German patients with chronic hepatitis C: correlation with clinical and virological parameters.

BACKGROUND/AIMS: The hepatitis C virus genotypes have been shown to be differently distributed between distinct geographical areas and to be associated with different clinical presentations. In the present study we investigated the distribution of HCV genotypes in 379 German patients with chronic hepatitis C in relation to age, sex, route of infection, liver histology and viremia. METHODS: Typing of HCV was done using restriction fragment length polymorphism analysis as well as a DNA enzyme immunoassay. HCV RNA concentrations were determined by quantitative polymerase chain reaction. Liver biopsies were performed in 187 patients and the histological activity was graded by the Knodell score. RESULTS: Seventy percent were infected with genotype 1 (20% subtype 1a, 80% subtype 1b), 4% with genotype 2 and 26% with genotype 3 (all subtype 3a). Genotype 3a and 1a infection was significantly associated with intravenous drug abuse. In contrast, genotype 1 predominated in patients with post-transfusion hepatitis and infection of unknown origin. A changing relative prevalence of HCV genotypes in relation to age was also observed. Patients with genotype 3 infection showed significantly lower HCV RNA levels and a lower mean histological activity score as compared to patients with genotype 1 and genotype 2. However, using multivariate analysis, only age and mode of transmission but not histological activitiy score were shown to be independent variables. CONCLUSIONS: Our study confirms previous reports from other countries that HCV variants can be classified into a relatively small number of discrete genotypes, and that the subtype 1b clearly predominates. However, we found evidence that there is a changing relative prevalence of HCV genotypes in relation to age, and that the mode of transmission is reflected in the predominance of certain genotypes.

Adolescent↗

Patterns of mycobacterium avium culture and PCR positivity in immunodeficient HIV-infected patients: progression from localized to systematic disease, German Aids Study Group (GASG/IDKF).

Our aim was to establish the frequency and the longitudinal pattern of MAC culture positivity in late stage HIV-infected patients. Two other aims were to analyse risk factors for progression from localized to systemic disease and the value of PCR diagnosis using blood specimens. A total of 107 patients were recruited to be followed for 32 weeks. Prior MAC treatment and CD4 > 100/microliters were exclusion criteria. A total of 56 patients showed M. avium in at least 1 culture. 10/37 patients with MAC detected by culture first in 'non-sterile' specimens (stool, sputum) and urine progressed to systemic disease as determined by positive blood culture. Risk factors associated with this progression were a high symptom score at baseline, lymphadenopathy, anaemia, and low platelets. PCR was less sensitive than culture in detection of M. avium in blood specimens: Only 7/29 patients with positive blood cultures had a positive PCR at the same time. We conclude that symptomatic patients with advanced HIV-infection have a high frequency of MAC detection. Progression from localized to systemic culture positivity is associated with risk factors. Early 'pre-emptive' therapy is discussed.

Acquired Immunodeficiency Syndrome↗

[HIV infection and long-term health: therapeutically attainable?].

New knowledges about the pathogenesis of HIV-induced immune deficiency syndrome suggest that a change of the natural history of HIV disease by support with antiviral medicaments will be possible. Most important insights are the non-existence of a viral latency phase and the existence of a strong correlation between active viral replication and loss of immunological capacity. Monitoring of HIV replication for detection of efficacy of antiviral therapies is necessary. Potent combinations of antiviral drugs seem to decrease the tendency for development of drug resistant viruses. It seems to be possible to remain healthy for a long time by effective drugs.

Anti-HIV Agents↗

[Sexually transmitted liver diseases: infection risk and prevention possibilities].

Sexual exposures every time were associated with increased risks for transmission of infectious agents. In the different kinds of infectious hepatitis actual hepatitis B is sexual transmitted mainly. The most effective prevention is possible by immunization early in the lifetime. Hepatitis C very rarely is sexual transmitted. There is no strong correlation between viral load and risk of transmission by sexual contacts. Like in other infectious diseases including the HIV-infection only the use of condoms and avoiding of unprotected sexual intercourse is the most effective preventive measure.

Female↗

Active syphilis in HIV infection: a multicentre retrospective survey. The German AIDS Study Group (GASG).

OBJECTIVE: To study syphilis in HIV infection focusing on immunocompromised patients with an atypical or aggressive clinical course of syphilis, inappropriate serological reactions or an unreliable response to therapy. STUDY DESIGN: A multicentre retrospective chart review using a standardised questionnaire for all patients with active syphilis. SETTINGS: Thirteen dermatological and medical centres throughout Germany, all members of the German AIDS Study Group (GASG). PATIENTS: Clinical data of 11,368 HIV infected patients have been analysed for cases of active syphilis requiring treatment. Asymptotic patients with reactive serological parameters indicating latent syphilis without a need for treatment were excluded. RESULTS: Active syphilis was reported in 151 of 11,368 HIV infected patients (1.33%, range per centre 0.3%-5.1%). Most of the 151 syphilis patients were male (93%) and belonged to the homosexual or bisexual exposure category for HIV infection (79%); another 6% were iv drug users. Among the 151 syphilis patients primary syphilis was diagnosed in 17.2%, maculopapular secondary syphilis in 29.1%, ulcerating secondary syphilis in 7.3%, neurosyphilis in 16.6% and latent seropositive syphilis without clinical symptoms but serological abnormalities indicating active syphilis in 25.2%. A history of prior treatments for syphilis was reported in 50%. At the time of syphilis diagnosis 26.5% of the patients were in CDC stage II, 33.8% in stage III and 24.5% in stage IV of HIV disease (CDC classification 1987). CD4 cell count was lowest in those with ulcerating secondary syphilis (mean 307, SD 140/microliters) and neurosyphilis (351, SD 235/ microliters). The highest CD4 count was found in patients with early primary and early secondary syphilis (444, SD 163/microliters and 470, SD 355/microliters). Inappropriate serological response to syphilis infection was found in 81 of 151 patients (54%). Remarkable findings were false negative VDRL titres (11 patients with non primary syphilis), false negative TPHA (1) or 19S-IgM-FTA-ABS-tests (16), and strongly reactive VDRL (> or = 512, 8) or TPHA titres (> or = 10 240, 47). Treatment failures were reported in at least 6 of 151 cases (4%). CONCLUSIONS: Atypical clinical and serological courses of syphilis were observed in HIV infected patients. Ulcerating secondary syphilis with general symptoms ("malignant syphilis") was 60 times more frequent than in historic syphilis series. Neurosyphilis was found in one sixth of those with active syphilis. Therefore lumbar puncture should be considered a routine in coinfections with HIV and syphilis. Treatment efficacy should be monitored carefully.

Adult↗

Accelerated Schedule for Hepatitis B Immunization.

Background: A considerable number of people remain unprotected against hepatitis B. These people may require immunization at short notice before being exposed to situations or locations where a risk of infection is present. Currently, full active immunization against hepatitis B, when administered according to recommended schedules, takes 2-6 months. This open, randomized multicentric study evaluated the reactogenicity and immunogenicity of a recombinant hepatitis B vaccine in adults when it was administered according to three different rapid vaccination schedules. Methods: Five hundred and twenty four healthy adults (aged 18-59 years) were randomly divided into three groups. Hepatitis B vaccine was given intramuscularly in the deltoid muscle at months 0, 1, and 2 (group A); weeks 0, 14, and 28 (group B); and weeks 0, 7, and 21 (group C). Symptoms were recorded by the subjects on individual diary cards. AntiHBs were measured using radioimmunoassay (Ausab-Abbott); a seroprotective titer was defined as 10 IU/L. Results: At day 28, no significant difference in seroprotection rates (SPRs) i.e., seroconversion >= 10 IU/L,was observed, between groups B (55.6%) and C (65.2%), but both these groups had significantly greater SPRs than group A (15.0%). Although not significant (p=.07), groups B and C also had higher SPRs than group A (78.5% and 76.4% versus 65%) at day 56. One month after completing the three dose schedules, the SPRs were as follows: 89.0% (group A); 78.5% (group B); and 76.4% (group C), increasing to > 94% at month 7 to 8 in all three groups. The SPRs at month 13 were 95.8%, 98.9%, and 98.6%, respectively. Among the three groups, no significant differences were observed from month 2 onwards in either SPRs or geometric mean titers. In groups A, B, and C, 3.7%, 5.0%, and 7.1% of the vaccine injections were associated with local symptoms. Also 8.3%, 6.2%, and 6.3% of subjects exhibited general symptoms following each vaccine dose; all symptoms were transient and resolved spontaneously. Conclusions: This recombinant hepatitis B vaccine administered at weeks 0, 7, 21, or at weeks 0, 14, 28, rapidly elicits high rates of seroprotection, which persist at least until month 12.

Journal Article↗

[Hepatitis A--new aspects of an old disease].

Since decades, hepatitis A has been a very rare disease in most industrialized countries. According to this, immune reactivity in the adult population is low and susceptibility for the infection is high. Thus, endemic cumlations of hepatitis A diseases are possible. The rate of complications in patients aged over 40 years has increased. Chronic courses in hepatitis A do not exist. There is no specific treatment against the virus. Management of hepatitis A is mainly supportive and symptomatic. There is no indication for steroids. Years ago, a liver diet was the basis of every treatment in every acute hepatitis. This should be refused because there is no reason for this measure.

Adult↗

Hepatitis C virus (HCV) genotype distribution in German isolates: studies on the sequence variability in the E2 and NS5 region.

We report on molecular characterization of hepatitis C virus (HCV) isolates in intravenous drug abusers, as compared to non-drug using patients with posttransfusion hepatitis or sporadic hepatitis of unknown origin. Virus typing was performed by RFLP analysis of PCR products in the 5' NCR. Subtyping was done by hybridization with subtype specific probes or by sequencing in the NS4 and NS5 region, respectively. HCV subtype 1b was found most commonly among all the isolates. However, the subtype 3a had a high prevalence (about 46%) in the group of drug addicts. In these subtype 3a isolates the N-terminal part of the E2 protein was highly variable. This confirms the presence of a hypervariable region (HVR1) in this envelope protein found in all hepatitis C viruses. Each subtype 3a isolate examined had a characteristic unique hypervariable region in the E2 protein. It is noteworthy that there are four amino acids in this region which were highly conserved between all HCV sequences published. It can be assumed that such conserved amino acids are significant for structure and function of this viral protein. In our HCV subtype 3a isolates the NS5 sequences were highly conserved.

Amino Acid Sequence↗

Human red cell Aquaporin CHIP. II. Expression during normal fetal development and in a novel form of congenital dyserythropoietic anemia.

Channel-forming integral protein (CHIP) is the archetypal member of the Aquaporin family of water channels. Delayed CHIP expression was shown recently in perinatal rat (Smith, B. L., R. Baumgarten, S. Nielsen, D. Raben, M. L. Zeidel, and P. Agre. 1993. J. Clin. Invest. 92:2035-2041); here we delineate the human patterns. Compared with adult, second and third trimester human fetal red cells had lower CHIP/spectrin ratios (0.72 +/- 0.12, 0.94 +/- 0.22 vs 1.18 +/- 0.11) and reduced osmotic water permeability (0.029, 0.026 vs 0.037 cm/s); CHIP was already present in human renal tubules by the second trimester. A patient with a novel form of congenital dyserythropoietic anemia (CDA) with persistent embryonic and fetal globins and absent red cell CD44 protein was studied because of reduced CHIP-associated Colton antigens. Novel CDA red cells contained < 10% of the normal level of CHIP and had remarkably low osmotic water permeability (< 0.01 cm/s), but no mutation was identified in Aquaporin-1, the gene encoding CHIP. These studies demonstrate: (a) unlike rat, human CHIP expression occurs early in fetal development; (b) red cell water channels are greatly reduced in a rare phenotype; and (c) disrupted expression of red cell CHIP and CD44 suggests an approach to the molecular defect in a novel form of CDA.

Adult↗