Immunogenicity, efficacy and safety of Nuwiq® (human-cl rhFVIII) in previously untreated patients with severe haemophilia A-Interim results from the NuProtect Study.

INTRODUCTION: Nuwiq® (Human-cl rhFVIII) is a fourth generation recombinant FVIII, produced in a human cell line, without chemical modification or protein fusion. No inhibitors developed in studies with Nuwiq® in 201 previously treated patients with haemophilia A (HA). The immunogenicity, efficacy and safety of Nuwiq® in previously untreated patients (PUPs) with severe HA are being assessed in the ongoing NuProtect study. METHODS: The study, conducted across 38 centres worldwide, is evaluating 110 true PUPs of all ages and ethnicities enrolled for study up to 100 exposure days (EDs) or 5 years maximum. The primary objective is to assess the immunogenicity of Nuwiq® (inhibitor activity ≥0.6 BU) using the Nijmegen-modified Bethesda assay at a central laboratory. RESULTS: Data for 66 PUPs with ≥20 EDs from a preplanned interim analysis were analysed. High-titre (HT) inhibitors developed in 8 of 66 patients after a median of 11.5 EDs (range 6-24). Five patients developed low-titre inhibitors (4 transient). The cumulative incidence (95% confidence interval) was 12.8% (4.5%, 21.2%) for HT inhibitors and 20.8% (10.7%, 31.0%) for all inhibitors. During inhibitor-free periods, median annualized bleeding rates during prophylaxis were 0 for spontaneous bleeds and 2.40 for all bleeds. Efficacy was rated as "excellent" or "good" in treating 91.8% of bleeds. Efficacy of surgical prophylaxis was "excellent" or "good" for 8 (89%) procedures and "moderate" for 1 (11%). No tolerability concerns were evident. CONCLUSION: These interim data show a cumulative incidence of 12.8% for HT inhibitors and convincing efficacy and tolerability in PUPs treated with Nuwiq® .

Complete Heart Block in Hypertrophic Cardiomyopathy: A Rare Association.

Ventricular tachyarrhythmias are common in hypertrophic cardiomyopathy that may lead to syncope and sudden death. Bradyarrhythmia such as atrioventricular conduction disturbance, a relatively rare complication associated with hypertrophic cardiomyopathy, may also cause syncope and sudden death in hypertrophic cardiomyopathy. We report a 28-year old man who was diagnosed as a case of hypertrophic cardiomyopathy presented with syncope and complete heart block. Subsequently, a permanent pacemaker was implanted to the patient.

Correction to: Vilnius Declaration on chronic respiratory diseases: multisectoral care pathways embedding guided self-management, mHealth and air pollution in chronic respiratory diseases.

An amendment to this paper has been published and can be accessed via the original article.

Vilnius Declaration on chronic respiratory diseases: multisectoral care pathways embedding guided self-management, mHealth and air pollution in chronic respiratory diseases.

BACKGROUND: Over 1 billion people suffer from chronic respiratory diseases such as asthma, COPD, rhinitis and rhinosinusitis. They cause an enormous burden and are considered as major non-communicable diseases. Many patients are still uncontrolled and the cost of inaction is unacceptable. A meeting was held in Vilnius, Lithuania (March 23, 2018) under the patronage of the Ministry of Health and several scientific societies to propose multisectoral care pathways embedding guided self-management, mHealth and air pollution in selected chronic respiratory diseases (rhinitis, chronic rhinosinusitis, asthma and COPD). The meeting resulted in the Vilnius Declaration that was developed by the participants of the EU Summit on chronic respiratory diseases under the leadership of Euforea. CONCLUSION: The Vilnius Declaration represents an important step for the fight against air pollution in chronic respiratory diseases globally and has a clear strategic relevance with regard to the EU Health Strategy as it will bring added value to the existing public health knowledge.

Anti-inflammatory action of diltiazem in patients with unstable angina.

BACKGROUND AND AIMS: Plasma concentrations of anti-inflammatory cytokine interleukin 10 (IL10) have been shown to be decreased in patients with unstable angina (UA) suggesting that reduced concentrations of IL10 may favour plaque instability and the development of acute coronary syndromes. Diltiazem has been shown to exert beneficial effects in patients with acute coronary syndrome. However, the potential influence of diltiazem on the anti-inflammatory cytokine IL10 in patients with UA has not been investigated. This study was designed to find out the effects of diltiazem on IL10 in UA patients. METHODS AND RESULTS: Thirty patients with UA were divided into two groups: group R and group D (n = 15). Group R was given routine pharmacotherapy for UA, and group D was given routine pharmacotherapy plus diltiazem. Plasma concentrations of IL10 in these groups were measured before the start of the treatment and 28 days after treatment. Plasma concentrations of IL10 in 15 normal subjects (group N) were also measured. Patients with UA had decreased concentrations of IL10 compared with normal group. Four weeks after treatment, plasma concentrations of IL10 significantly increased in group D compared with that before treatment, but the increase in IL10 values in group R was not significant. CONCLUSIONS: These findings showed that concentrations of anti-inflammatory IL10 are considerably decreased in UA patients and diltiazem treatment leads to a significant increase in IL10 concentrations.

Osteomyelitis secondary to trauma or infected contiguous soft tissue.

Nonhematogenous osteomyelitis (NHO) occurred in 24 pediatric patients (ages 8 months to 18 years; median, 14 years; 23 male) admitted from 1980 to 1985. Predisposing factors included compound fracture (12), deep decubiti (4) and foot puncture (3). Infection involved tibia (7), foot bones (6), proximal femur (3) and ulna (2). Patients presented with drainage (64%), pain or tenderness (44%) and fever (32%) lasting for 1 to 180 days (median, 10 days). In 24% both white blood cell count and erythrocyte sedimentation rate were normal. Initial radiographs were nondiagnostic in 42% after compound fractures. Bone cultures were positive in 15 of 18 (83%) patients for: Staphylococcus aureus (9), Staphylococcus epidermidis (2), Pseudomonas aeruginosa (4), Escherichia coli (2), Enterobacter sp. (2), Streptococcus faecalis, Serratia sp., Klebsiella pneumoniae, Achromobacter xylosoxidans, Aeromonas hydrophila and Pseudomonas fluorescens (1 each). Wound cultures failed to predict bone culture results in 12 of 16 patients (75%). NHO recurred in 8 of 19 patients (42%) despite intravenously administered antibiotics for greater than 28 days and debridement in 7 of 8 patients. The indolent nature of NHO complicates diagnosis, especially in patients with recent compound fractures. Only prompt bone culture can confirm the presence of NHO and reliably guide antimicrobial therapy.

Influence of different photoperiods on development of gonad, cloacal gland and circulating thyroid hormones in male Japanese quail Coturnix coturnix japonica.

One day old chicks of Japanese quail were exposed to different photoperiods (LD, 8:16, 13.5:10.5, 16:8 and LL) and observations (testes weight, cloacal gland size, body weight and circulating thyroxine and triiodothyronine) were taken at the age of 3, 5, 7, 9 and 16 weeks. Results indicate that immediate reproductive development occurred in birds exposed to long photoperiods (greater than 12 hr). Growth under LD 8:16, was not apparent till 7th week and by 16 weeks, degree of gonadal development was similar in all the birds, irrespective of photoperiodic treatment. Whereas body weight of the intermediate and long day (LD 13.5:10.5, 16:8 and LL) treated birds increased upto 5th week and remained constant thereafter. But the chicks maintained under short day length (LD 8:16), showed spontaneous increase till the end of the study and birds were much heavier compared to all other groups. Plasma T4 concentration increased with increasing age till 9th week and remained unaltered thereafter. On the other hand T3 level did not change till 7th week followed by a decline. It is suggested that the initiation and degree of gonadal growth in quail depends on the availability of daily photoperiod, until the achievement of full breeding condition. Peak level of T4 observed in 9 week old birds may be involved in the development of photorefractoriness at that age.

Western blot analysis of antibody to varicella-zoster virus.

We used western blot (WB) to compare the IgG response to varicella-zoster virus (VZV) after chickenpox (CP), zoster, and administration of a live attenuated varicella vaccine (LAVV). After CP, 13 of 14 normal children had antibody to glycoprotein (gp) I (99 and 92 kilodaltons [kDa]), 11 had antibody to gpII (133 kDa), and 10 had antibody to gpIII (119 kDa). Bands at 150 and 35 kDa were also seen in 13 and 11 sera, respectively. Bands to gpI, gpII, and p35 were more intense after zoster than CP. After one dose of LAVV, eight of eight normal children had gpI antibody. In leukemic children, gpI antibody appeared in 18 (56%) after one dose and in 25 (89%) after two doses. Upon household exposure, leukemic vaccinees who developed CP were less likely than those protected to have prior gpIII and p35 antibodies. As seen after zoster, WBs after breakthrough CP showed intense responses to VZV antigens. Thus, WB helps distinguish secondary from primary antibody responses to VZV.

Risk factors in subacute sclerosing panencephalitis: a case-control study.

Fifty-two persons with subacute sclerosing panencephalitis (SSPE) were compared with playmate and hospital controls matched for age, sex, and race. Persons with SSPE were more likely to have had measles than their age-matched controls. The age at measles infection for children with SSPE was significantly younger than that for controls who had had measles. Persons with SSPE were less likely to have received measles vaccine than were playmate or hospital controls. There were no differences with regard to the average age at vaccination, having received more than one measles vaccination, or having received measles vaccine after natural measles. Although measles vaccine may rarely predispose a child to develop SSPE, the overall impact of vaccination has been to prevent SSPE by preventing natural measles. No significant differences were observed between cases and controls for infections other than measles, or for vaccines other than measles vaccine. Previous epidemiologic studies have noted significant geographic clustering of SSPE and higher rates in children living in rural areas. These findings suggest that environmental factors other than measles are important in the pathogenesis of SSPE. In this study, children with SSPE were more likely to have suffered a serious head injury and to have come from larger families and more crowded homes than control children. Persons with SSPE were significantly more likely to have close exposure to birds (p less than 0.001) and to swine (p less than 0.05) than were control persons. No differences between cases and controls were found for exposure to other animals. These data suggest that some infectious agent(s), transmitted from birds to man, may have contributed to the development of SSPE in predisposed individuals. A variety of other factors were investigated and found not to correlate with SSPE. These included birth weight, breastfeeding, maternal age at birth, nutritional status, source of drinking water, development, and allergic or atopic disorders.

Varicella-zoster virus glycoprotein oligosaccharides are phosphorylated during posttranslational maturation.

Varicella-zoster virus (VZV)-infected human embryonic lung fibroblasts (HELF) do not release infectious virions into their growth medium. Extracellular virions are pleomorphic, suggesting that they are partially degraded before their release from cells. To examine the intracellular pathway of viral maturation, [2-3H]mannose-labeled virus-encoded glycoproteins were isolated from VZV-infected HELF. Oligosaccharides attached to the glycoproteins were processed to complex-type units, some of which were phosphorylated. The major intracellular site of accumulation of VZV gpI was found to be perinuclear and to correspond to that of the cation-independent mannose 6-phosphate (Man 6-P) receptor. Subsets of VZV-containing cytoplasmic vacuoles were coated, Golgi-associated, or accessible to endocytic tracers. Phosphorylated monosaccharides protected HELF from the cytopathic effect of VZV in proportion to their ability to block Man 6-P receptor-mediated endocytosis. These data suggest that the unusual phosphorylated oligosaccharides mediate an interaction between VZV and Man 6-P receptors of the host cell; this interaction may be responsible for withdrawal of newly synthesized virions from the secretory pathway and for their diversion to prelysosomal structures.