Clinical, genetic, and cardiac magnetic resonance imaging findings in primary desminopathies

We report the clinical, genetic and cardiac magnetic resonance imaging (MRI) findings in 11 German patients with heterozygous E245D, D339Y, R350P and L377P desmin mutations and without cardiac symptoms. Clinical evaluation revealed a marked variability of skeletal muscle, respiratory and cardiac involvement even between patients with identical mutations, ranging from asymptomatic to severely affected. While echocardiography did not show any pathological findings in all 11 patients, cine MRI revealed focal left ventricular hypertrophy in 2 patients and MR delayed enhancement imaging displayed intramyocardial fibrosis in the left ventricle in 4 patients indicating early myocardial involvement. Our data argue against distinct genotype-phenotype correlations and suggest that comprehensive cardiac MRI is superior to conventional echocardiography for the detection of early and clinically asymptomatic stages of cardiomyopathy in desminopathy patients. Therefore, cardiac MRI may serve as a screening tool to identify patients at risk, which might benefit from early pharmacological and/or interventional (e.g. implantable cardioverter-defibrillator devices) therapy.     

The Myc-evoked DNA damage response accounts for treatment resistance in primary lymphomas in vivo

In addition to the ARF/p53 pathway, the DNA damage response (DDR) has been recognized as another oncogene-provoked anticancer barrier in early human tumorigenesis leading to apoptosis or cellular senescence. DDR mutations may promote tumor formation, but their impact on treatment outcome remains unclear. In this study, we generated ataxia telangiectasia mutated (Atm)-proficient and -deficient B-cell lymphomas in Emu-myc transgenic mice to examine the role of DDR defects in lymphomagenesis and treatment sensitivity. Atm inactivation accelerated development of lymphomas, and their DNA damage checkpoint defects were virtually indistinguishable from those observed in Atm+/+-derived lymphomas that spontaneously inactivated the proapoptotic Atm/p53 cascade in response to Myc-evoked reactive oxygen species (ROS). Importantly, acquisition of DDR defects, but not selection against the ARF pathway, could be prevented by lifelong exposure to the ROS scavenger N-acetylcysteine (NAC) in vivo. Following anticancer therapy, DDR-compromised lymphomas displayed apoptotic but, surprisingly, no senescence defects and achieved a much poorer long-term outcome when compared with DDR-competent lymphomas treated in vivo. Hence, Atm eliminates preneoplastic lesions by converting oncogenic signaling into apoptosis, and selection against an Atm-dependent response promotes formation of lymphomas with predetermined treatment insensitivity.     

Different immunogenicity of H-2 Kb-restricted epitopes in natural variants of the hepatitis B surface antigen

The small hepatitis B surface antigen (HBsAg) of hepatitis B virus (HBV) has limited variability, but some serotypes and genotypes have been defined. Although no biological or pathogenetic differences could be traced to HBV serotypes, the clinical picture, response to treatment and long-term prognosis of HBV infection may vary with the HBV genotype, possibly due to differences in specific T cell recognition of HBV antigens from different genotypes. We analyzed murine CD8(+) T cell responses to two K(b)-restricted HBsAg epitopes primed by four different HBsAg variants using protein- and DNA-based vaccination protocols. The K(b)-binding S(208-215) epitope 1 is processed from exogenous but not endogenous HBsAg. Variants of epitope 1 differing at two positions within the epitope (ILSPFLPL in ayw/adr versus IVSPFIPL in adw2) efficiently primed cross-reactive CD8(+) T cell responses. In contrast, the exchange of an N-terminal flanking residue (S to N) completely eliminated the immunogenicity of epitope 1. The K(b)-binding S(190-197) epitope 2 is processed from endogenous but not exogenous HBsAg. A single-residue exchange within the epitope (VWLSVIWM in ayw/adr versus VWLSAIWM in adw2) completely eliminated the immunogenicity of epitope 2. Single, conservative residue exchanges can thus give rise to diverging CD8(+) T cell repertoires, suggesting an impressive complexity and flexibility of the CD8(+) T cell repertoire to antigen variants from viruses with limited diversity.     

Feline sporotrichosis: a report of five cases with transmission to humans

Sporotrichosis was diagnosed in five cats. Seven humans exposed to these cats subsequently developed the disease. All feline cases developed draining ulcers, and in four of five cases there was disseminated cutaneous involvement. Histologically, numerous Sporothrix organisms were noted in cutaneous lesions and overlying exudate. The seven humans who became infected were involved in cleaning and medicating cats with the disease; all human patients developed a localized lymphocutaneous form of sporotrichosis. In four of the human cases there was no history of an associated penetrating wound. The large number of Sporothrix organisms is a distinct feature of feline sporotrichosis and indicates that the cat may be the only domestic animal species that can readily transmit this disease to humans. In addition, any contact with the draining lesions of affected cats offers the potential for human infection.     

Effects of omalizumab, a humanized monoclonal anti-IgE antibody, on nasal reactivity to allergen and local IgE synthesis.

BACKGROUND: Treatment with omalizumab has been shown to reduce serum free IgE concentrations and to have beneficial effects on allergic airway disease. However, its effect on IgE synthesis is unknown. OBJECTIVE: To determine whether omalizumab therapy affects nasal reactivity to allergen and local IgE production. METHODS: Nineteen patients with perennial allergic rhinitis were treated with intravenous omalizumab every 2 weeks for 26 weeks in an open-label study. Serum free and total IgE concentrations were measured at baseline and every 2 weeks throughout the study. Nasal challenge to dust mite allergen was performed at baseline and after 12 and 24 weeks of treatment. Nasal lavage fluid obtained before and after each nasal challenge was evaluated for mite-specific antibodies, plaque-forming cells, and productive epsilon messenger RNA (mRNA). RESULTS: During treatment, serum free IgE concentrations were decreased by 97% to 99%, and the nasal response to allergen challenge was significantly reduced on days 80 and 164. The postchallenge increase in nasal lavage mite specific IgE was significantly reduced by treatment with omalizumab on day 168. IgE plaque-forming cells and productive epsilon mRNA were not significantly affected by omalizumab treatment. CONCLUSIONS: Omalizumab treatment markedly reduced serum free IgE and the clinical response to nasal allergen challenge. However, the absence of an effect on IgE-secreting B cells and epsilon mRNA in nasal lavage fluid suggests that omalizumab treatment for 6 months does not significantly modulate synthesis of nasal IgE.     

Arterial stiffness profiles: investigating various sections of the arterial tree of African and Caucasian people

In Africans, arterial stiffness progression seems more pronounced compared to Caucasians. We compared the arterial stiffness profiles of different age groups and focused on muscular arteries and two more central arterial segments in African and Caucasian people from South Africa. In African (N = 374) and Caucasian (N = 376) participants (20-70 years), we measured carotid-radial (C-R) and carotid-dorsalis pedis (C-DP) pulse wave velocity (PWV) and aortic characteristic impedance (Zao). Major findings were that normotensive and high-normal/hypertensive (HT) Caucasians indicated increased trends of C-R PWV with aging (P = .029 and P = .067), not seen in the African groups (P = .122 and P = .526). Both ethnic groups showed significant increases of C-DP PWV and Zao with aging. High-normal/hypertensive Africans had significantly stiffer arteries than hypertensive Caucasians for almost all age groups, and for all stiffness measures. African C-R PWV correlated significantly with blood pressure (BP), but not with age. Opposite results were observed for Caucasians. In conclusion, the stiffness of muscular arteries is already elevated in young Africans, in both those with normal or elevated BP. This is possibly due to an earlier deterioration during childhood, or perhaps already present from birth. Also, in Caucasians stiffness seems more age-related, while in Africans it seems to be more pressure-related.     

CP7_E2alf: a safe and efficient marker vaccine strain for oral immunisation of wild boar against Classical swine fever virus (CSFV)

Wild boar are an important reservoir of Classical swine fever virus (CSFV) in several European countries, where most of the primary outbreaks in domestic pigs are directly related to the endemic disease situation in the wild boar population. Oral immunisation has been introduced as an additional control measure to accelerate CSF eradication in wild boar in Germany since 1993. Immunisation with an oral bait vaccine based on the conventionally attenuated live vaccine strain "C" proved to be safe and effective, but does not allow differentiation between infected and vaccinated animals. Therefore, we examined the vaccine efficacy of the recently constructed chimeric pestivirus CP7_E2alf, whose coding sequences for the major envelope protein E2 of BVDV strain CP7 are replaced by E2 of the CSFV strain Alfort187 [Reimann I, Depner K, Trapp S, Beer M. An avirulent chimeric pestivirus with altered cell tropism protects pigs against lethal infection with classical swine fever virus. Virology 2004;322(1):143-57]. Following oral immunisation of wild boar, CP7_E2alf proved to be completely avirulent. Furthermore, all vaccinees were fully protected from clinical disease after a highly virulent CSFV challenge infection. The immunised animals seroconverted within 3 weeks after vaccination for CSFV E2-specific and CSFV neutralising antibodies, whereas prior to challenge infection no antibodies against CSFV E(rns) were detected with an appropriate CSFV-specific marker ELISA test. Thus, the BVDV backbone of CP7_E2alf enables serological and genetic differentiation from wild type CSFV infection. In conclusion, CP7_E2alf represents the first efficient and safe marker vaccine candidate for oral immunisation of wild boar against CSFV.     

Antiretroviral activity of the anti-CD4 monoclonal antibody TNX-355 in patients infected with HIV type 1

BACKGROUND: We wished to determine the safety and anti-human immunodeficiency virus (HIV) type 1 activity of single doses of TNX-355, a humanized IgG4 anti-CD4 monoclonal antibody with potent activity against HIV-1 in vitro, in HIV-infected subjects. METHODS: Sequential cohorts of 6 HIV-1-infected subjects each received infusions of TNX-355. Data included plasma HIV-1 RNA level, CD4+ T cell count, TNX-355 coating of CD4+ T cells, and serum TNX-355 levels. RESULTS: Dose-related reductions in plasma HIV-1 RNA loads correlated with complete CD4+ T cell coating by TNX-355. Peak median decreases in plasma HIV-1 RNA loads were 0.56, 1.33, and 1.11 log10 copies/mL and occurred on days 4-7, 14, and 21 for the 3.0, 10, and 25 mg/kg doses, respectively. Dose-dependent increases in CD4+ T cell count occurred within 24 h of dosing. CONCLUSIONS: Single doses of TNX-355 reduced plasma HIV-1 RNA loads and increased CD4+ T cell counts in HIV-infected subjects. The further assessment of therapeutic potential awaits data from longer-duration trials.     

Adverse drug reaction monitoring in Jena: Relevance of polymorphic drug metabolizing enzymes for inducing adverse drug reactions

Inter-subject variability in therapeutic drug response and drug toxicity is a major problem in clinical practice. In this field genetic polymorphisms of drug metabolizing enzymes play an important role. In a multicenter study supported by the German Federal Institute for Drugs and Medical Devices (BfArM, Z 12.01-68502-201) adverse drug reactions (ADRs) leading to hospital admission to departments of internal medicine have been registered and evaluated. The aim of the presented part of the study was to look for evident differences in genotypes for polymorphic drug metabolizing enzymes between adverse drug reaction cases and controls. All cases found in the local area – Jena and Weimar – were genotyped for N-acetyl-transferase 2 (NAT2), cytochrom P450 (CYP) 2D6 and 2C19 in comparison to a control population of the same region. The investigation on genotype was carried out for about 2 years (2000–2002). 254 blood samples from patients of the ADR study were analyzed. The genotype of drug metabolizing enzymes was determined by means of polymerase chain reaction using allel specific primers or restriction enzyme analysis. Within all ADRs cases genotyped, no exceptional frequencies for slow acetylators or poor metabolizers (PM) of CYP2D6 or CYP2C19 were found. About 65% of the individuals with ADR genotypically displayed a slow acetylator state. 6.3% PM for CYP2D6, including CYP2D6*3, *4 and *6 alleles, and 2.0% PM frequency for CYP2C19 (*2) have been found in ADR cases. A direct connection between PM genotype and the ADR observed may be assumed only in few of them. Further investigations on genotype and ADR-associated drugs require a much larger sample of patients to obtain more data allowing to focus an association on specific drugs, ADR and polymorphisms genotype of drug metabolizing enzymes might be useful.