Mammalian target of rapamycin and its downstream signalling components are activated in psoriatic skin.

BACKGROUND: Mammalian target of rapamycin (mTOR) signalling integrates signals leading to cellular growth, proliferation and differentiation. Disturbance of this tightly regulated interplay leads to malignancies, as reflected by altered mTOR signalling in epidermal tumours. As psoriatic keratinocytes also show features of perturbed cell growth and differentiation, the question arises as to whether mTOR signalling also plays a role in the pathogenesis of psoriasis. OBJECTIVES: To investigate the activation status of mTOR signalling components in psoriasis. METHODS: Biopsies from lesional and nonlesional skin of patients with psoriasis (n = 10), as well as samples from healthy donors (n = 3), were analysed by immunohistochemistry and Western blot, utilizing antibodies detecting phosphorylated mTOR, phospho-S6 kinase and phospho-S6 ribosomal protein. RESULTS: We found mTOR and its downstream signalling molecule, the ribosomal protein S6, to be activated in lesional psoriatic skin. While mTOR is activated throughout the whole epidermis, with particularly strong activation in the basal layer, S6 is active in suprabasal layers of differentiating keratinocytes. CONCLUSIONS: Altogether these results suggest a role for mTOR signalling in the epidermal changes leading to the psoriatic phenotype. mTOR inhibition might be a mode of action to explore in developing innovative antipsoriatic drugs.

Efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in women aged 15-25 years with and without serological evidence of previous exposure to HPV-16/18.

In the Phase III PATRICIA study (NCT00122681), the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (Cervarix(®), GlaxoSmithKline Biologicals) was highly efficacious against HPV-16/18 infections and precancerous lesions in women HPV-16/18 deoxyribose nucleic acid (DNA) negative and seronegative at baseline. We present further data on vaccine efficacy (VE) against HPV-16/18 in the total vaccinated cohort including women who may have been exposed to HPV-16/18 infection before vaccination. In women with no evidence of current or previous HPV-16/18 infection (DNA negative and seronegative), VE was 90.3% (96.1% confidence interval: 87.3-92.6) against 6-month persistent infection (PI), 91.9% (84.6-96.2) against cervical intraepithelial neoplasia (CIN)1+ and 94.6% (86.3-98.4) against CIN2+ [97.7% (91.1-99.8) when using the HPV type assignment algorithm (TAA)]. In women HPV-16/18 DNA negative but with serological evidence of previous HPV-16/18 infection (seropositive), VE was 72.3% (53.0-84.5) against 6-month PI, 67.2% (10.9-89.9) against CIN1+, and 68.8% (-28.3-95.0) against CIN2+ [88.5% (10.8-99.8) when using TAA]. In women with no evidence of current HPV-16/18 infection (DNA negative), regardless of their baseline HPV-16/18 serological status, VE was 88.7% (85.7-91.1) against 6-month PI, 89.1% (81.6-94.0) against CIN1+ and 92.4% (84.0-97.0) against CIN2+ [97.0% (90.6-99.5) when using TAA]. In women who were DNA positive for one vaccine type, the vaccine was efficacious against the other vaccine type. The vaccine did not impact the outcome of HPV-16/18 infections present at the time of vaccination. Vaccination was generally well tolerated regardless of the woman's HPV-16/18 DNA or serological status at entry.

Effective continuous systemic therapy of severe plaque-type psoriasis is accompanied by amelioration of biomarkers of cardiovascular risk: results of a prospective longitudinal observational study.

BACKGROUND: Severe psoriasis is associated with significant cardiovascular mortality. OBJECTIVES: We investigated the effects of continuous systemic therapy on the cardiovascular risk of patients with severe plaque-type psoriasis. METHODS: A total of 42 consecutive patients receiving systemic treatment for their severe plaque-type psoriasis were included. The clinical course was monitored over 24 weeks. Initially as well as after 12 and 24 weeks, oral glucose tolerance tests were performed along with comprehensive laboratory monitoring. RESULTS: Responding patients, defined as a Psoriasis Area and Severity Index (PASI)-50 response, showed correlations between the PASI and high-sensitive C-reactive protein (r = 0.45, P = 0.03) as well as with vascular endothelial growth factor (r = 0.76, P = 0.007). The adipokine resistin was positively and the potentially cardio-protective adiponectin was negatively correlated with the PASI (r = 0.50, P = 0.02 and r = -0.56, P = 0.007, respectively). Oral glucose tolerance tests yielded a correlation between the PASI and plasma levels for C-peptide (r = 0.73, P = 0.02) at t = 120 min in patients with a pathological Homeostasis Model Assessment (>2.5), indicating that the state of peripheral insulin resistance is driven at least in part by the severity of the psoriatic inflammation. Correlations between the change of adipokine levels and change in PASI were more pronounced among patients with better clinical improvement (PASI-75 vs. PASI-50). CONCLUSIONS: We document an amelioration of biomarkers of cardiovascular risk in patients with severe plaque-type psoriasis responding to continuous systemic therapy. The impact on the patients'metabolic state was found to be better if the psoriatic inflammation was controlled for longer. Future studies need to compare the cardioprotective effects of different treatment modalities, based on hard clinical endpoints.

Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women.

BACKGROUND: The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine was immunogenic, generally well tolerated, and effective against HPV-16 or HPV-18 infections, and associated precancerous lesions in an event-triggered interim analysis of the phase III randomised, double-blind, controlled PApilloma TRIal against Cancer In young Adults (PATRICIA). We now assess the vaccine efficacy in the final event-driven analysis. METHODS: Women (15-25 years) were vaccinated at months 0, 1, and 6. Analyses were done in the according-to-protocol cohort for efficacy (ATP-E; vaccine, n=8093; control, n=8069), total vaccinated cohort (TVC, included all women receiving at least one vaccine dose, regardless of their baseline HPV status; represents the general population, including those who are sexually active; vaccine, n=9319; control, n=9325), and TVC-naive (no evidence of oncogenic HPV infection at baseline; represents women before sexual debut; vaccine, n=5822; control, n=5819). The primary endpoint was to assess vaccine efficacy against cervical intraepithelial neoplasia 2+ (CIN2+) that was associated with HPV-16 or HPV-18 in women who were seronegative at baseline, and DNA negative at baseline and month 6 for the corresponding type (ATP-E). This trial is registered with ClinicalTrials.gov, number NCT00122681. FINDINGS: Mean follow-up was 34.9 months (SD 6.4) after the third dose. Vaccine efficacy against CIN2+ associated with HPV-16/18 was 92.9% (96.1% CI 79.9-98.3) in the primary analysis and 98.1% (88.4-100) in an analysis in which probable causality to HPV type was assigned in lesions infected with multiple oncogenic types (ATP-E cohort). Vaccine efficacy against CIN2+ irrespective of HPV DNA in lesions was 30.4% (16.4-42.1) in the TVC and 70.2% (54.7-80.9) in the TVC-naive. Corresponding values against CIN3+ were 33.4% (9.1-51.5) in the TVC and 87.0% (54.9-97.7) in the TVC-naive. Vaccine efficacy against CIN2+ associated with 12 non-vaccine oncogenic types was 54.0% (34.0-68.4; ATP-E). Individual cross-protection against CIN2+ associated with HPV-31, HPV-33, and HPV-45 was seen in the TVC. INTERPRETATION: The HPV-16/18 AS04-adjuvanted vaccine showed high efficacy against CIN2+ associated with HPV-16/18 and non-vaccine oncogenic HPV types and substantial overall effect in cohorts that are relevant to universal mass vaccination and catch-up programmes. FUNDING: GlaxoSmithKline Biologicals.

Immunogenicity and Reactogenicity following Primary Immunisation with a Combined DTaP-HBV Vaccine and a Haemophilus influenzae Type B Vaccine Administered by Separate or Mixed Injection.

OBJECTIVES: The aim of this open, randomised, multicentre trial was to evaluate the immunogenicity and reactogenicity of the tetravalent diphtheria-tetanus-acellular pertussis-hepatitis B (DTaP-HBV) vaccine when given either as a mixed or as a separate concomitant injection with the Haemophilus influenzae type b (Hib) vaccine at 3, 5 and 11 months of age. METHODS: Antibody against diphtheria, tetanus, pertussis (ELISA), hepatitis B (radioimmunoassay) and Hib polyribosylribitol phosphate (PRP) [radiolabeled antigen binding assay] was determined. Solicited local and systemic adverse events were evaluated on the day of each vaccination and for three subsequent days. Follow-up of unsolicited and serious adverse events was conducted for 30 days following each vaccination. RESULTS: A total of 360 subjects were enrolled in the study. After completion of the three-dose vaccination course, seroprotective antibody concentrations against diphtheria, tetanus and hepatitis B, together with a pertussis vaccine response, were seen in almost all subjects with immunogenicity results (n = 336). All subjects had post-vaccination Hib anti-PRP antibody concentrations of at least 0.15 mug/mL, and 97.0% and 99.4%, respectively, of the subjects receiving a single or separate injections had Hib anti-PRP antibody concentrations >/=1.0 mug/mL. Addition of the Hib vaccine to the tetravalent DTaP-HBV vaccine did not increase the incidence of local or systemic reactions. CONCLUSIONS: Combination of DTaP-HBV and Hib vaccines in a single injection is safe, immunogenic and well tolerated, and thus has the potential to simplify the childhood immunisation schedule in Italy.

Early responses to nonconjugated polyribosylribitol phosphate challenge as evidence of immune memory after combined diphtheria-tetanus-pertussis-polio-Haemophilus influenzae type b primary vaccination.

OBJECTIVES: A high risk of invasive Haemophilus influenzae type b (Hib) disease exists in the first few years of life. A reduction in anti-polyribosylribitol phosphate (PRP) antibody concentrations follows the administration of certain diphtheria-tetanus-acellular pertussis (DTPa)-based Hib conjugate combined vaccines. However, these combined vaccines prime the immune memory, which is an important factor in protection. As yet there is no direct evidence of the time scale involved in the development of the immune memory post-primary vaccination. In this report we investigated the presence of immune memory at 10 and 12 months of age, 4 and 6 months after primary vaccination of young infants with a pentavalent combination of DTPa, inactivated poliovirus vaccine (IPV) and Hib (DTPa-IPV/Hib) vaccine. METHODS: In two trials (A and B) infants received DTPa-IPV combined with Hib-tetanus conjugate (PRP-T) vaccine at 2, 4 and 6 months of age. The presence of immune memory was assessed by measuring anti-PRP concentrations 7 to 10 days after a nonconjugated PRP challenge given at 10 months in Trial A and at 12 months in Trial B. RESULTS: Administration of a nonconjugated PRP challenge 4 and 6 months after primary vaccination in Trials A and B, respectively, elicited an increase in anti-PRP geometric mean concentrations (4.5 and 5.8 microg/ml, respectively) within 7 to 10 days. These concentrations exceed those reported in the literature involving unprimed children who had received a single dose of nonconjugated PRP at the same age. CONCLUSION: The results demonstrate the development of anti-PRP immune memory at an early age, 4 and 6 months after completion of a three dose primary vaccination course of combined DTPa-IPV/Hib vaccine. The ability of primed infants to mount a rapid response is an important observation given the high risk of Hib infection at this critical age.

Positive I-123-MIBG-scintigraphy in osteosarcoma.

I-123-MIBG scintigraphy has become a standard imaging technique in the detection of neuroendocrine or neurocrest derived tumors, especially neuroblastoma and pheochromocytoma. We report on a positive I-123-MIBG uptake in a pediatric osteosarcoma patient and demonstrate, that unusual results still occur with this established imaging method.

Screening for anxiety, depressive and somatoform disorders in rehabilitation--validity of HADS and GHQ-12 in patients with musculoskeletal disease.

PURPOSE: The detection of patients with comorbid mental illness is of high clinical importance in orthopaedic rehabilitation. To simplify detection of cases, screening instruments are recommended. The study investigated the discriminant validity of the Hospital Anxiety and Depression Scale (HADS) and the General Health Questionnaire (GHQ-12) to identify patients with comorbid mental disorders, specifically anxiety, depressive and somatoform disorders. METHOD: Two hundred and six patients with musculoskeletal disease from four orthopaedic rehabilitation clinics participated in a two-stage survey: (1) patients were assessed with the GHQ-12 and HADS; and (2) they were examined for DSM-IV mental disorders by clinical standardized interview (CIDI). Validity of the two instruments regarding the detection of mental disorders was compared using ROC-analysis and CIDI-diagnoses as criteria. RESULTS: The HADS sumscale performed better in all analyses compared to the GHQ-12, specifically in detecting depressive and anxiety disorders. Best results are achieved for depressive disorders with an area under the curve (AUC) of 0.79, a sensitivity of 78% and a specificity of 71% (cut off point= 16). The positive predictive value (PPV) is best for the detection of any mental disorder with a cut-off point of 16 (46%). CONCLUSION: The HADS can be used as a screening instrument for the detection of comorbid depressive and anxiety disorders in patients with musculoskeletal disorders. Limitations in performance of screening instruments are due to: (1) different methodological approaches of tests (dimensional approach) and criterion (categorical approach); and (2) difficulties in diagnosing mental disorders in patients with prominent physical illness.

[Primary wound healing of the sacral cavity following rectum amputation, also a comment on the discussion contribution by G. Jatzko and D. Schlapper, Chirurg (1988) 59: 855]. / Die primäre Wundheilung der Sacralhöhle nach Rectumamputation, zugleich Anmerkung zum Diskussionsbeitrag von G. Jatzko und D. Schlapper. Chirurg (1988) 59:855.

A retrospective study has shown that 46 consecutive abdominoperineal resections (including 3 proctocolectomies due to Crohn's disease or non-classifiable colitis) performed by 6 surgeons showed no signs of wound-healing impairment at the site of the perineal wound or in the sacral cavity. The main points which describe the solution are: orthograde intestinal lavage, prophylactic perioperative antibiotics, closure of the pelvic peritoneum, combined treatment of the sacral cavity with iodoform tamponade and closed drainage.

A short report on highlights of worldwide development of RIX4414: a Singaporean experience.

In Singapore, we conducted a phase II randomized, double-blind, placebo-controlled dose ranging study using an attenuated human rotavirus vaccine, RIX4414. Altogether, 2464 healthy infants were recruited. Two oral doses of vaccine at 104.7, 105.2 or 106.1 ffu or placebo were administered with routine immunizations at 3 and 4 months of age. Seroconversion and 'vaccine take' in the vaccine groups 1-month post dose 2 varied from 76 to 91% and 98 to 100% respectively. Vaccine was well tolerated and did not interfere with response of concomitantly administered vaccines.

A short report on highlights of world-wide development of RIX4414: a Latin American experience.

An oral, human-derived monovalent (G1P1A) rotavirus vaccine, strain RIX4414, has been developed by GlaxoSmithKline, Rixensart, Belgium. The safety, immunogenicity and efficacy of this vaccine were evaluated in a randomized, double-blind, placebo-controlled, phase IIb trial conducted in Brazil, Mexico and Venezuela. Healthy infants were given two doses of vaccine (104.7, 105.2 or 105.8 ffu) or placebo at age 2 and 4 months, with routine DTPw-HBV and Hib vaccines. OPV was given separately, at least 2 weeks before or after administration of the study vaccine. A total of 2155 infants were enrolled, of whom 1618 received one of the three vaccine viral concentrations and 537 were given placebo. Analysis of efficacy included diarrheal episodes occurring from 2 weeks after second dose until one year of age. Efficacy rates against any rotavirus gastroenteritis, severe rotavirus gastroenteritis and hospitalizations for rotavirus disease were as high as 70% (46-84%; 95%CI), 86% (63-96%; 95%CI), and 93% (54-100%; 95%CI), respectively. For non-G1 (mainly G9) serotypes, RIX4414 vaccine conferred protection as high as 83% (40-97%; 95%CI) against severe gastroenteritis. A decrease was noted in the incidence of severe rotavirus-related gastroenteritis after first dose. It is demonstrated that two doses of RIX4414 are highly efficacious against severe rotavirus gastroenteritis and hospitalization, including disease caused by non-G1 strains, namely G9 serotypes.

Humoral immunity against diphtheria, tetanus and poliomyelitis after antineoplastic therapy in children and adolescents--a retrospective analysis.

Serum antibodies against diphtheria- and tetanus-toxin were measured in 71 children and against poliomyelitis viruses 1-3 in 65 children and adolescents 0-18 months after cessation of antineoplastic therapy. Non or marginally protective serum titers were found in 62% of patients against diphtheria, in 18% of patients against tetanus and in 72% of patients against one or more poliomyelitis virus serotypes. Of these patients, 55%, 46% and 75% were immunized adequately according to age against diphtheria, tetanus and poliomyelitis, respectively. In 50% or more of patients a lack of protective immunity against diphtheria, tetanus and poliomyelitis was found which could not be explained by an inadequate immunization status. This suggests that other factors (e.g. influence of underlying illness, antineoplastic therapy or both on lymphocytes) might be responsible for these findings and this deserves further investigation. Measurement of serum antibodies against vaccine-preventable illnesses and consecutive booster immunizations are an essential part of long-term follow up in pediatric patients after antineoplastic therapy.

Persistent improvement of gas exchange and lung mechanics by aerosolized perfluorocarbon.

The effect of aerosolized perfluorocarbon (PFC) (FC77) on pulmonary gas exchange and lung mechanics was studied in a surfactant depleted piglet model. Sixty minutes after induction of lung injury by bronchoalveolar lavage, 20 piglets were randomized to receive aerosolized PFC (Aerosol-PFC, 10 ml/kg/h, n = 5), partial liquid ventilation (PLV) at FRC capacity volume (FRC-PLV, 30 ml/kg, n = 5) or low volume (LV-PLV, 10 ml/kg/h, n = 5), or intermittent mandatory ventilation (IMV) (Control, n = 5). After 2 h, perfluorocarbon application was stopped and IMV was continued for 6 h. Sixty minutes after the onset of therapy, PaO2 was significantly higher and PaCO2 was significantly lower in the Aerosol-PFC and the FRC-PLV groups than in the LV-PLV and the Control groups; p < 0.001. Six hours after treatment, maximum PaO2 was found in the Aerosol-PFC group: 406.4 +/- 26.9 mm Hg, FRC-PLV: 217.3 +/- 50.5 mm Hg, LV-PLV: 96.3 +/- 18.9 mm Hg, Control: 67.6 +/- 8.4 mm Hg; p < 0.001. PaCO2 was lowest in the Aerosol-PFC group: 24.2 +/- 1.7 mm Hg, FRC-PLV: 35.9 +/- 2.8 mm Hg, LV-PLV: 56.7 +/- 12.4 mm Hg, Control: 60.6 +/- 5.1 mm Hg; p < 0.01. Dynamic compliance (C20/c) was highest in the Aerosol-PFC group; p < 0.01. Aerosolized perfluorocarbon improved pulmonary gas exchange and lung mechanics as effectively as PLV did in surfactant-depleted piglets, and the improvement was sustained longer.

Brief adrenomedullin inhalation leads to sustained reduction of pulmonary artery pressure.

The effect of aerosolised adrenomedullin (ADM), a potent vasodilator peptide, on pulmonary artery pressure was studied for 24 h in a surfactant-depleted piglet model. Animals received either aerosolised ADM (50 ng.kg(-1).min(-1), ADM, n=6), or aerosolised normal saline solution (control, n=6). Aerosol therapy was performed for a 2 h treatment period followed by a 22 h observation period. Ventilator settings were adapted to keep arterial oxygen tension and carbon dioxide arterial tension between 13.3-14.6 kPa and 4.9-5.7 kPa, respectively. Aerosolised ADM reduced mean pulmonary artery pressure (MPAP) compared with the control group (end-point median 24 h after therapy start: DeltaMPAP -14.0 versus -8.0 mmHg; 23.5 h after therapy start). After therapy start, mean systemic arterial pressure (MAP) was not significantly different between the groups (end-point median: MAP ADM 70 (61/74) versus control 72 (54/81) mmHg). Endothelin-1, a potent pulmonary vasoconstrictor, is regulated by ADM via cAMP. Twenty two hours after inhalation of aerosolised ADM, endothelin-1 mRNA in lung tissue and endothelin-1 protein expression in pulmonary arteries was reduced compared with controls (median semi-quantitative immunhistochemical score: ADM 0.21, control 0.76). Aerosolised adrenomedullin significantly reduced mean pulmonary artery pressure independently of arterial oxygen tension.

[After-care of children and young adults surviving cancer. Initial recommendations by the late sequelae study group]. / Die Nachsorge der von einer Krebserkrankung geheilten Kinder und jungen Erwachsenen. Erste Empfehlungen der Arbeitsgemeinschaft Spätfolgen.

An increasing number of children suffering from cancer has been treated successfully during the last 25 years using therapy protocols of the Gesellschaft für Pädiatrische Onkologie und Hämatologie. The patients had to undergo an interdisciplinary treatment modality and a mostly intensive chemotherapy. Late effects could result from this approach for the now 20,000 survivors in the Federal Republik of Germany. The executive committee of the GPOH founded a working group for the detection of late effects stretching over all therapy studies. The first report of this group describes a spectrum of relevant late effects and proposes investigations for their detection.

The penicillin sensory transducer, BlaR, involved in the inducibility of beta-lactamase synthesis in Bacillus licheniformis is embedded in the plasma membrane via a four-alpha-helix bundle.

Prediction studies, conformational analyses and membrane-topology mapping lead to the conclusion that the penicillin sensory transducer, BlaR, involved in the inducibility of beta-lactamase synthesis in Bacillus licheniformis, is embedded in the plasma membrane bilayer via four transmembrane segments TM1-TM4 that form a four-alpha-helix bundle. The extracellular 262-amino-acid-residue polypeptide, S340-R601, that is fused at the carboxy end of TM4, possesses the amino acid sequence signature of a penicilloyl serine transferase. It probably functions as penicillin sensor. As an independent entity, this polypeptide behaves as a high-affinity penicillin-binding protein. As a component of the full-size BlaR, it adopts a different conformation presumably because of interactions with the extracellular 63-amino-acid-residue P53-S115 loop that connects TM2 and TM3. Reception of the penicillin-induced signal requires a precise conformation of the sensor but it does not involve penicilloylation of the serine residue S402 of motif STYK. Signal transmission through the plasma membrane by the four-alpha-helix bundle may proceed in a way comparable to that of the aspartate receptor, Tar. Signal emission in the cytosol by the intracellular 189-amino-acid-residue Y134-K322 loop that connects TM3 and TM4, may proceed via the activation of a putative metallopeptidase.

Defective sexual development in an infant with 46, XY, der(9)t(8;9)(q23.1;p23)mat.

UNLABELLED: We report on a male infant with ambiguous genitalia (scrotal hypospadias, sinus urogenitalis) trisomic for 8q23-ter and monosomic for 9p23-ter, who shared craniofacial and other abnormalities with either phenotype. Gonadal histology was nearly normal for age. Normal endocrinological findings and exclusion of mutations in SRY, androgen receptor and alpha-reductase genes point to supplementary gene(s) located in 9p2305-ter, haplo-insufficiency (by deletion) of which is expected to cause defective male morphogenesis. CONCLUSION: This observation lends further support to the hypothesis that genetic factors are located at 9p23-ter which are involved in normal sex determination.