Phosphorylation of intracellular signalling molecules in peripheral blood cells from patients with psoriasis on originator or biosimilar infliximab.

BACKGROUND: Psoriasis vulgaris is a chronic, inflammatory skin disease characterized by a dysregulated immune response and it is associated with substantial systemic comorbidities. Biological drugs such as tumour necrosis factor (TNF)-α inhibitors can ameliorate the disease but are expensive. Biosimilar drugs have the same amino-acid sequence as the originator, but differences in manufacturing can affect biological activity, efficacy and tolerability. OBJECTIVES: To explore potential differences in intracellular phosphorylation of signalling molecules in peripheral blood cells from patients with psoriasis treated with the TNF-α inhibitor infliximab compared with healthy controls, and to investigate if the phosphorylation pattern was influenced by switching from the originator infliximab to the biosimilar CT-P13. METHODS: By flow cytometry, we measured phosphorylation of nuclear factor kappa B, extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase and signal transducer and activator of transcription 3, before and after TNF-α stimulation in monocytes and T, B, natural killer and CD3+  CD56+ cells from 25 patients with psoriasis treated with infliximab and 19 healthy controls. RESULTS: At inclusion, phosphorylation levels of peripheral blood mononuclear cells (PBMCs) were increased in patients with psoriasis compared with healthy controls, even though clinical remission had already been achieved. Phosphorylation levels declined in patients on both originator infliximab and biosimilar during continued treatment. No significant differences were detected between the two medications after 12 months. CONCLUSIONS: Patients with psoriasis on infliximab have higher activation levels of PBMCs than do healthy controls, possibly reflecting systemic inflammation. Switching from the originator infliximab to biosimilar CT-P13 did not affect phosphorylation levels or clinical parameters, suggesting that CT-P13 is a noninferior treatment alternative to the originator infliximab.

Conceptualising production, productivity and technology in pharmacy practice: a novel framework for policy, education and research.

CONTEXT AND BACKGROUND: People and health systems worldwide face serious challenges due to shifting disease demographics, rising population demands and weaknesses in healthcare provision, including capacity shortages and lack of impact of healthcare services. These multiple challenges, linked with the global push to achieve universal health coverage, have made apparent the importance of investing in workforce development to improve population health and economic well-being. In relation to medicines, health systems face challenges in terms of access to needed medicines, optimising medicines use and reducing risk. In 2017, the International Pharmaceutical Federation (FIP) published global policy on workforce development ('the Nanjing Statements') that describe an envisioned future for professional education and training. The documents make clear that expanding the pharmacy workforce benefits patients, and continually improving education and training produces better clinical outcomes. AIMS AND PURPOSE: The opportunities for harnessing new technologies in pharmacy practice have been relatively ignored. This paper presents a conceptual framework for analysing production methods, productivity and technology in pharmacy practice that differentiates between dispensing and pharmaceutical care services. We outline a framework that may be employed to study the relationship between pharmacy practice and productivity, shaped by educational and technological inputs. METHOD AND RESULTS: The analysis is performed from the point of view of health systems economics. In relation to pharmaceutical care (patient-oriented practice), pharmacists are service providers; however, their primary purpose is not to deliver consultations, but to maximise the quantum of health gain they secure. Our analysis demonstrates that 'technology shock' is clearly beneficial compared with orthodox notions of productivity or incremental gain implementations. Additionally, the whole process of providing professional services using 'pharmaceutical care technologies' is governed by local institutional frames, suggesting that activities may be structured differently in different places and countries. DISCUSSION AND CONCLUSION: Addressing problems with medication use with the development of a pharmaceutical workforce that is sufficient in quantity and competence is a long-term issue. As a result of this analysis, there emerges a challenge about the profession's relationship with existing and emerging technical innovations. Our novel framework is designed to facilitate policy, education and research by providing an analytical approach to service delivery. By using this approach, the profession could develop examples of good practice in both developed and developing countries worldwide.

Chronic combined hyperandrogenemia and western-style diet in young female rhesus macaques causes greater metabolic impairments compared to either treatment alone.

STUDY QUESTION: Does developmental exposure to the combination of hyperandrogenemia and western-style diet (WSD) worsen adult metabolic function compared to either treatment alone? SUMMARY ANSWER: Young female rhesus macaques treated for 3 years, beginning at menarche, with combined testosterone (T) and WSD have increased weight gain and insulin resistance compared to controls and animals treated with either T or WSD alone. WHAT IS KNOWN ALREADY: Hyperandrogenemia is a well-established component of polycystic ovary syndrome (PCOS) and can be observed in peripubertal girls, indicating a potential pubertal onset of the disease. Obesity is often associated with hyperandrogenemia in peripubertal girls, and overweight girls appear to be at higher risk for the development of PCOS later in life. STUDY DESIGN, SIZE, DURATION: Juvenile (2.5- year old) female rhesus macaques were divided into four groups (n = 10/group): control animals receiving cholesterol implants and a control diet with 15% of calories derived from fat (C), animals receiving T implants (mean serum levels: 1.35 ± 0.01 ng/ml) and a control diet (T), animals receiving a cholesterol implant and a WSD with 36% of calories derived from fat (WSD) and animals receiving a T implant and a WSD (T + WSD). Animals were maintained on the treatments for 36 months and were 5.5 years old at study completion. PARTICIPANTS/MATERIALS, SETTING, METHODS: Metabolic testing consisted of body measurements including weight, dual-energy X-ray absorptiometry scans, activity monitoring, and glucose tolerance testing at zero months and at least once every 12 months for the remainder of the study. Indirect calorimetry and serum hormone assays were performed following 36 months of treatment. MAIN RESULTS AND THE ROLE OF CHANCE: Body weight and fat mass gain were significantly increased in T + WSD at 24 and 36 months of treatment compared to the other three groups. Log transformed fasting insulin and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) were significantly increased in T + WSD animals at 3 years of treatment compared to all other groups. T-treatment caused a greater rate of decline in activity after 18 months, while food intake and metabolic rate were largely unaffected by treatments. LIMITATIONS REASONS FOR CAUTION: Variability was present in the metabolic parameters measured; however, this is similar to the heterogeneity observed in human populations. WIDER IMPLICATIONS OF THE FINDINGS: Chronic hyperandrogenemia beginning at puberty may exacerbate metabolic dysfunction in women consuming a WSD and account for the increased rates of obesity and insulin resistance observed in PCOS patients. Counseling of female patient populations with elevated androgens about the potential benefit of consuming a lower fat diet could improve long-term metabolic health outcomes. STUDY FUNDING/COMPETING INTEREST(S): Eunice Kennedy Shriver National Institute of Child Health & Human Development P50HD071836 and Oregon National Primate Center Grant P51 OD011092. The authors have no competing conflict of interests to disclose.

Assays for Infliximab Drug Levels and Antibodies: A Matter of Scales and Categories.

Immunogenicity is a frequent cause of secondary non-response to tumour necrosis factor (TNF) inhibitors. Drug level measurement and detection of antidrug antibodies have been shown to be cost effective and clinically relevant, and a large number of assays are available for these purposes. It is, however, difficult to compare assays and translate results into clinical meaningful information due to different methodological approaches and a lack of assay standardization. We have analysed infliximab drug levels and antidrug antibodies in 107 patient samples using enzyme-linked immunoassays (ELISA), immunofluorometric assays (IFMA) and reporter-gene assays (RGA). The RGA gave the lowest results for drug levels, whereas the IFMA detected the highest number of antidrug antibody positive sera. Applying individualized therapeutic ranges to each assay resulted in agreement among all three assays in 74% of samples for drug levels and 98% of samples for antidrug antibodies. We found that TNF inhibitor monitoring assays measure on different scales and that the agreement between quantitative results is limited. However, interassay differences can partially be overcome by assay-individualized translations of quantities into categories, which also is necessary for a meaningful clinical application. Our data demonstrate that assays should not be used interchangeably and that direct comparison of quantitative drug levels obtained with different assays should be avoided.

Vasoconstrictor eicosanoids and impaired microvascular function in inactive and insulin-resistant primates.

The inability to augment capillary blood volume (CBV) in response to insulin or glucose is thought to contribute to insulin resistance (IR) by limiting glucose uptake in key storage sites. Understanding the mechanisms that contribute to impaired CBV augmentation early in the onset of IR may lead to new future therapies. We hypothesized that inactivity alters the balance of vasoactive eicosanoids and contributes to microvascular IR. In ten activity-restricted (AR) and six normal activity adult male rhesus macaques, contrast-enhanced ultrasound of skeletal muscle blood flow and CBV was performed at baseline and during intravenous glucose tolerance test (IVGTT). Plasma was analyzed for vasoconstrictor hydroxyeicosatetraenoic acids (HETEs) and the ratio of vasodilatory epoxyeicosatrienoic acids (EETs) to their less biologically active dihydroxyeicosatrienoic acids (DHETs) as an indirect measure of soluble epoxide hydrolase activity. AR primates were IR during IVGTT and had a 45% lower glucose-stimulated CBV response. Vasoconstrictor 18-HETE and 19-HETE and the DHET/EET ratio were markedly elevated in the AR group and correlated inversely with the CBV response. In addition, levels of 18-HETE and 19-HETE correlated directly with microvascular IR. We conclude that a shift toward increased eicosanoid vasoconstrictor tone correlates with abnormal skeletal muscle vascular recruitment and may contribute to IR.

Stenotrophomonas maltophilia induced post-cataract-surgery endophthalmitis: Outbreak investigation and clinical courses of 26 patients.

BACKGROUND: Stenotrophomonas maltophilia, a microorganism which colonizes plastic material, is a rare causative agent of iatrogenic endophthalmitis. PATIENTS AND METHODS: A cluster of 26 cases of acute post-cataract-surgery endophthalmitis (PE) was identified. An outbreak investigation was performed. Information was abstracted from patients' charts and questionnaires sent to patients and their general practitioners. Vision was examined before, during, as well as one and six months after acute PE. Bacterial isolates were subjected to molecular typing. RESULTS: All patients initially received empiric systemic antibiotic treatment. The source of the infections was identified to be the rinsing solution used during cataract surgery, which was contaminated with two strains of S. maltophilia. Antibiotic therapy was subsequently changed to trimethoprim/sulfamethoxazol and ciprofloxacin for 30 days, complemented with iv fluocortolone and topical treatment with prednisolone, ciprofloxacin, and chloramphenicol. Twenty-one patients (81%) received pars plana vitrectomy and were additionally treated with intravitreal injections of vancomycin, amikacin and dexamethasone, or imipenem and dexamethasone, respectively. In addition, oxacillin, mezlocillin, and prednisolone were applied subconjunctivally after vitrectomy. Six months after acute infection, a final visual acuity of > or = 0.2 was achieved by 21/26 patients (80%), a visual acuity of > or = 0.5 by 14/26 patients (54%). Twenty of 26 patients (77%, 17 of whom had undergone vitrectomy) achieved a higher visual acuity than before surgery. Patients from the vitrectomy group had a median final visual acuity of 0.5 compared to 0.4 in the 5 patients without vitrectomy. There was 1 retinal ablation, 2 intra-retinal bleedings, and relapse of infection in 2/26 patients (8%), with isolation of S. maltophilia in one of the relapsing infection cases. CONCLUSIONS: Empiric antibiotic treatment of PE may not adequately treat rare pathogens such as S. maltophilia. Administration of an effective systemic or intravitreal antibiotic treatment after identification of S. maltophilia may have contributed to the favorable clinical course and relatively low relapse frequency in our patients. Despite the known problem of persistence of S. maltophilia, visual acuity outcome after treatment is comparable to PE induced by other Gram-positive or Gram-negative bacteria.

[Bacterial infections following injections and infusion caused by errors of hygiene--how to avoid them]. / Infektionen nach Injektion und Infusion: So vermeiden Sie Hygienefehler.

Even minor medical interventions, such as injections, are associated with the risk of life-threatening infections--both in the doctor's office and hospital settings. Medical personnel in particular must always assume that they may be contaminated by facultative pathogenic, but potentially highly virulent, germs, although they themselves remain asymptomatic. Against this background, hygienic hand disinfection and proper skin disinfection are important hygiene measures for the prevention of infections, in particular in the case of invasive interventions. Strict attention must be paid to asepsis when preparing for injections and infusions. Sterile items must be protected against contamination. With regard to compliance with and application of hygiene standards, every physician must be an exemplary role model. Furthermore, all medical professional groups must receive appropriate training in hygiene management.

Presence of the major outer-membrane protein of Chlamydia trachomatis in patients with chronic salpingitis and salpingitis isthmica nodosa with tubal occlusion.

OBJECTIVE: To determine the presence of the major outer-membrane protein of Chlamydia trachomatis in fallopian tube tissue specimens of infertile women with chronic salpingitis and/or salpingitis isthmica nodosa with tubal occlusion. DESIGN: Prospective controlled study. SETTING: Department of Obstetrics and Gynecology, University of Bochum, Herne, Germany. PATIENT(S): Fifty-six consecutive infertile women with histologically documented chronic salpingitis and/or salpingitis isthmica nodosa and bilateral tubal occlusions were evaluated. They were compared with 28 fertile women. INTERVENTION(S): Fallopian tube tissue specimens were taken during reconstructive infertility surgery, including cesarean section and tubal ligation. MAIN OUTCOME MEASURE(S): Detection of the major outer-membrane protein of C. trachomatis in fallopian tube tissue specimens by a direct fluorescent antibody test. RESULT(S): The major outer-membrane protein of C. trachomatis was found in fallopian tube tissue specimens in 11 of 56 infertile patients (20%) with chronic salpingitis and/or salpingitis isthmica nodosa. The median titer of IgG serum antibodies to Chlamydia was significantly higher in women with the major outer-membrane protein of C. trachomatis than in patients without this antigen. In comparison, the major outer-membrane protein of C. trachomatis was not found in any of the fallopian tube tissue specimens of the control group. CONCLUSION(S): The presence of the major outer-membrane protein of C. trachomatis is associated with chronic salpingitis and/or salpingitis isthmica nodosa with tubal occlusion.

Some relations of grammar and lexicon in aphasia.

A new form of a Sentence Order Test was applied to a group of Broca's, Wernicke's and total aphasics. Sentences cut into three movable cards should be put together. Some of the sentences could be arranged in two different ways. Broca's aphasics prefered to order the parts according to a logical string of lexical items neglecting the grammatical errors. Wernicke's aphasics arranged the material according to the grammatical structure being unaware of the odd lexical meaning. Most of the results of total aphasics were similar to those of Wernicke's aphasics others however performed like Broca's aphasics.

Multiple biogenic amine-secreting 'carcinoid' tumour of the stomach: a case report.

An unusual case of a gastric carcinoid tumour producing multiple biogenic amines is described in a patient with pernicious anaemia. Electron microscopy demonstrated two distinct types of secretory granules.

Ion-chromatography of metals with post-column ion displacement.

A post-column reagent mixture of Eriochrome Black T and magnesium-EDTA complex is added to the eluent from an ion-chromatograph. Eluted metal cations displace the magnesium, which then forms a complex with the Eriochrome Black T. The absorbance of this complex is measured at 520 nm. Detection limits for several cations are in the mug/ml range.

[Synthesis of somatostatin in Escherichia coli cells: isolation and characteristics]. / Sintez somatostatina v kletkakh Escherichia coli. Vydelenie i kharakteristika.

A synthetic gene coding for somatostatin-14 (SST) was cloned in plasmid expression vectors in frame with the chloramphenicol acetyl transferase (CAT) gene, both genes being divided by a Met residue. The hybrid gene was expressed under the control of the CAT gene promoter (Pcat) or the tryptophan operon promoter (Ptrp). Them fused genes gave insoluble polypeptide products amounting from 5% of the total cellular protein under constitutive biosynthesis conditions (Pcat) to 30% upon induction (Ptrp). SST was liberated from the fused polypeptide by treatment with cyanogen bromide, purified to homogeneity by gel-filtration and reverse phase HPLC, and finally refolded by dilution and air oxidation. The renaturated recombinant SST showed the specific biological and immunological activities of the native peptide.

Effect on discourse on processing of left- and right-embedded syntactic structures.

This study attempted to obtain information on the processing of syntactic structures under conditions of related and unrelated discourse. Eye movements were recorded while 30 competent adult readers silently read right-embedded or left-embedded sentences in conditions of unrelated sentences and in conditions of cohesive paragraphs. Analysis of eye movements for number and duration of forward fixations and regressions showed that left-embedded sentences were significantly more difficult to process than right-embedded sentences. However, context also significantly affected the visual processing of syntactic structures.

[Genetic engineering in the bacterial synthesis of somatostatin]. / Genno-inzhenernye podkhody k bakterialnomu syntezu somatostatina.

Series of recombinant plasmids for expression of the synthetic gene somatostatin-14 (SST) as a fusion protein were obtained. The somatostatin gene was fused to chloramphenicol acetyltransferase (cat) or its deleted variant genes. Both parts of the resultant fusion protein were joined through a Met residue. The hybrid gene was expressed under the control of the cat gene promoter (Pcat), the tryptophan operon promoter (Ptrp) or the promoter of bacteriophage T5 (PT5). These fusions gave insoluble polypeptide products amounting from 5-10% of the total cellular protein under constitutive biosynthetic conditions (Pcat) to 5-30% upon induction (Ptrp, PT5). A correlation between the efficiency of expression and the length of cat, the power of the promoter used and the absence or presence of transcription terminators, was studied. The scheme for SST isolation from bacterial cells was developed. SST was liberated from the fused polypeptide by treatment with cyanogen bromide and purified to homogenity by a combination of chromatographic steps: gel filtration, ion-exchange and rpHPLC. The renaturated recombinant SST showed specific biological and immunological activities and had 98% purity. The yield was 1 mg of the purified cyclic SST/1 culture of E.coli.

[Five years of the Robert Koch Institute guidelines for reprocessing of flexible endoscopes. A look back and a look forward]. / Fünf Jahre Empfehlungen der Kommission für Krankenhaushygiene zur Aufbereitung flexibler Endoskope. Blick zurück und Blick nach vorn.

In a short review the national and international reception of the German guidelines for reprocessing flexible endoscopes is presented. The recommendations of the guidelines are discussed in view of recent knowledge on old problems such as prion inactivation and new infectious diseases and new microorganisms such as SARS, avian influenza and C. difficile. New disinfectants and new methods for endoscope disinfection are mentioned, the importance of careful cleaning is underlined. The German guidelines of the Robert Koch Institute and the US Multi-Society guidelines, published in 2003, are compared. The discrepancies concerning recommendations for water quality for final rinsing and need of microbiological controls of endoscope reprocessing are stressed. Aspects not mentioned in the German guidelines, e.g. duration of storage after reprocessing and risk of infection transmission by the endo-washer, are discussed.