Investigating the efficacy of baricitinib in new onset type 1 diabetes mellitus (BANDIT)-study protocol for a phase 2, randomized, placebo controlled trial.

BACKGROUND: Type 1 diabetes (T1D) places an extraordinary burden on individuals and their families, as well as on the healthcare system. Despite recent advances in glucose sensors and insulin pump technology, only a minority of patients meet their glucose targets and face the risk of both acute and long-term complications, some of which are life-threatening. The JAK-STAT pathway is critical for the immune-mediated pancreatic beta cell destruction in T1D. Our pre-clinical data show that inhibitors of JAK1/JAK2 prevent diabetes and reverse newly diagnosed diabetes in the T1D non-obese diabetic mouse model. The goal of this study is to determine if the JAK1/JAK2 inhibitor baricitinib impairs type 1 diabetes autoimmunity and preserves beta cell function. METHODS: This will be as a multicentre, two-arm, double-blind, placebo-controlled randomized trial in individuals aged 10-30 years with recent-onset T1D. Eighty-three participants will be randomized in a 2:1 ratio within 100 days of diagnosis to receive either baricitinib 4mg/day or placebo for 48 weeks and then monitored for a further 48 weeks after stopping study drug. The primary outcome is the plasma C-peptide 2h area under the curve following ingestion of a mixed meal. Secondary outcomes include HbA1c, insulin dose, continuous glucose profile and adverse events. Mechanistic assessments will characterize general and diabetes-specific immune responses. DISCUSSION: This study will determine if baricitinib slows the progressive, immune-mediated loss of beta cell function that occurs after clinical presentation of T1D. Preservation of beta cell function would be expected to improve glucose control and prevent diabetes complications, and justify additional trials of baricitinib combined with other therapies and of its use in at-risk populations to prevent T1D. TRIAL REGISTRATION: ANZCTR ACTRN12620000239965 . Registered on 26 February 2020. CLINICALTRIALS: gov NCT04774224. Registered on 01 March 2021.

IGF-2 coated porous collagen microwells for the culture of pancreatic islets.

Islet transplantation, the only curative therapy for type I diabetes, requires isolation of the graft in highly specialized facilities for its later dispatch to remote transplantation centres. During transport and culture, many valuable cells are lost due to several factors such as mechanical stress, islet aggregation and dissociation. Here, we evaluate a porous microwell array sheet made of natural collagen type I extracellular matrix (ECM) protein as a novel islet culture substrate. This culture platform can be coated with IGF-2, a growth factor favorable for islet survival, and allows segregation of the islets within the porous microwell sheet, preventing aggregation. This design shows promising results for improving human pancreatic islets viability and function during culture and could form a novel paradigm for the transport of islets between isolation and transplantation centres.

[Mountaineering for the Prevention of Cardiovascular Diseases?]. / Bergtouren als Präventivmittel von kardiovaskulären Erkrankungen?

INTRODUCTION: People in Western countries are gaining more and more weight, which is mainly due to a lack of physical activity predisposing to cardiovascular illnesses. Mountaineering, in particular multi-pitch climbing, seems to have protective effects on the metabolic and cardiovascular systems because it is a low-intensity activity lasting several hours, which leads to continuous physical stimulation. METHODS: Eight climbers in four two-person rope teams with a good leisure sports level and regular climbing activity completed a multi-pitch climbing route (Pfriendler 2501 metres above sea level Via Fritz/Steingletscher/Sustenpass Canton of Bern/Switzerland) with a total of seven pitches with difficulties between 4b and 5c(+) (French Scale). Climbers were monitored with heart rate gear during the whole climbing activity, which allowed us to analyse heart rates after climbing. RESULTS: During a single climbing pitch, heart rate values increased from 86 ±â€Š18 to 135 ±â€Š4 beats per minute on average. The average heart rate was 126 ±â€Š2 beats per minute, which is 67 % of the maximum heart rate on average. The whole tour lasted 5 h 55 min with an average heart rate of 108 ±â€Š9 beats per minute being measured, yielding an average of 56 ±â€Š5 % of the maximum heart rate. DISCUSSION: The results point out the low intensity of multi-pitch mountaineering and imply a stimulation of fat metabolism, which highlights the potential of mountaineering for preventing metabolic diseases.

[Christ-Siemens-Touraine syndrome]. / Christ-Siemens-Touraine-Syndrom.

The Christ-Siemens-Touraine syndrome (CST syndrome) is the rare an- or hypohidrotic form of the ectodermal dysplasia. During embryonic development, the formation and maturation of the central nervous system and the epithelia of the sense organs, skin, teeth, hair (and less frequently the nails) are disturbed. In addition to the cosmetic impairment, insufficient or absent secretion of sweat and sebum is particularly discomforting as it leads to extreme heat intolerance. The decreased number of apocrine sweat glands and mucous glands in the upper nasopharynx results in diminished resistance to respiratory infections. We describe typical features of the disease in a 60 year old female patient, distinguishing this disease from other forms of ectodermal dysplasia. Diagnostic criteria as well as therapeutic options are discussed.

A randomized controlled prospective outcome study of a psychological and pharmacological intervention protocol for procedural distress in pediatric leukemia.

Evaluated distress during invasive procedures in childhood leukemia. Child and parent distress, assessed by questionnaires and ratings, were compared in two arms of a randomized, controlled prospective study, one a pharmacologic only (PO) (n = 45) and the other a combined pharmacologic and psychological intervention (Cl) (n = 47), at 1, 2, and 6 months after diagnosis. The cross-sectional control group (CC) consisted of parents of 70 patients in first remission prior to the prospective study. Mothers' and nurses' ratings of child distress indicated less child distress in the Cl group than the PO. When contrasted with the CC group, the Cl group showed lower levels of child distress. Data showed decreases over time in distress and concurrent improvements in quality of life and parenting stress and supported an inverse association between distress and child age.

The Perception of Procedures Questionnaire: psychometric properties of a brief parent report measure of procedural distress.

Reported the reliability and validity of the Perception of Procedures Questionnaire (PPQ), a 19-item parent-report measure developed to assess child and parent distress related to lumbar punctures and bone marrow aspirates in the diagnosis and treatment of childhood cancer. PPQ data from 140 mothers and 96 fathers of children and adolescents with leukemia in a first remission were analyzed separately. Factor analyses yielded five factors for mothers and fathers: Parent Satisfaction; Child Distress: During; Child Distress: Before; Parent Distress; and Parent Involvement. Internal consistency (Cronbach's alpha) was high for the total score and the five factor scores as were interrater reliabilities between mothers and fathers. Validity was determined using the Parenting Stress Index-Short Form, the Pediatric Oncology Quality of Life Scale, and parent and nurse ratings during procedures. Factors 2 and 3, assessing child distress, show strong associations with the validation measures and support the distinction between distress before and during procedures. This developing scale is recommended for use in the assessment and evaluation of child and parent procedure-related distress in pediatric oncology.

Tumors of the pilosebaceous unit.

Appendage tumors of the pilosebaceous apparatus are relatively rare, and their clinical aspect is usually nonspecific. In most cases pilosebaceous tumors are benign; however, malignant neoplasias (e.g. trichilemmal carcinoma, malignant pilomatricoma) have been described. In the present review we propose the classification of pilosebaceous tumors by degree and by direction of differentiation and by histological configuration. Three different histological patterns have to be distinguished: tumors with central dilated hair follicle, tumors consisting of epithelial islands and keratotic cysts in the corium and neoplasias with predominantly mesenchymal components surrounding epithelial formations. Careful histopathological examination of pilar appendage tumors will help to classify the wide range of clinically and histologically different tumors and to establish the exact diagnosis.

[Granulocyte colony stimulating factor (G-CSF) in treatment of patients with HIV-associated mucocutaneous Kaposi sarcoma. Successful use in virus and drug-induced leukopenia]. / Granulozyten-Koloniestimulierender Faktor (G-CSF) in der Behandlung von Patienten mit HIV-assoziiertem mukokutanem Kaposi-Sarkom. Erfolgreicher Einsatz bei virus- bzw. medikamenteninduzierter Leukopenie.

Three patients with HIV-associated Kaposi sarcoma were treated with human recombinant granulocyte colony stimulating factor (G-CSF). They had all developed leucopenia during treatment with recombinant interferon-alpha-2a, in two cases combined with vincristine. In all three patients, there was an obvious rapid stimulation after s.c. injection of 300 or 150 micrograms G-CSF per day; the white blood count reached normal values within only a few days and partial transformation to leucocytosis took place. After discontinuation of G-CSF, leucocyte counts regressed rapidly to pretreatment levels. A dose of 150 micrograms of G-CSF twice to three times per week proved to be sufficient to keep the white blood cell count in the normal range allowing the treatment necessary for Kaposi sarcoma. G-CSF therapy had no serious side effects. One of the patients developed a tumour-like infiltration in his left upper jaw, which histologically simulated Burkitt's lymphoma and which regressed spontaneously after discontinuation of the G-CSF therapy. G-CSF plays an important role in the treatment of patients with HIV-associated Kaposi sarcoma and enables combined treatment with zidovudine, interferon, and cytostatic drugs.

[Combination of interferon-alpha with cytostatic drugs: a potentially successful therapeutic approach in metastatic melanoma]. / Kombination von Interferon-alpha mit Zytostatika: erfolgversprechender Therapieansatz beim metastasierten Melanom.

Pharmacological treatment of disseminated melanoma is characterized by rather low objective response rates with mono- and combined chemotherapy and by significant toxicity. For these reasons, many centres do not now offer any systemic treatment to melanoma patients with distant metastases. Systemic treatment with interferons has not fulfilled all that was expected of it, but type-I interferons (-alpha, -beta) have proved to be effective in about 10-15% of patients treated. The antitumour activity of these substances seems to be related mainly to their antiproliferative effect, whereas no immunomodulatory effects have been substantiated in clinical trials. Combined therapy with interferons and cytostatic drugs was introduced into clinical trials only a few years ago, and the initial results are promising. Large studies with a total of over 200 patients have already been performed to evaluate the combination of interferon-alpha and dacarbazine. This treatment was effective in around 50% of the patients, complete or partial remission being achieved in 30% and stabilization of the disease, in 20%. Toxicity is significant, but still manageable; the new generation of antiemetic drugs (serotonin receptor blockers), in particular appears promising. Up to now, no improvement of efficacy has been found following addition of interferon-alpha to cisplatin in four clinical trials. In a study in our own department, however, the combined action of interferon alpha and vindesine was found to be superior to that of either used as a single agent, and the combination was well tolerated on an outpatient basis.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of gastrin, gastrin receptor blockers, epidermal growth factor, and difluoromethylornithine on the growth and the activity of ornithine decarboxylase of colonic carcinoma cells.

Polyamines are essential factors of cell growth and differentiation. Modulation of the cellular polyamine content by 2-difluoromethylornithine (DFMO) inhibiting ornithine decarboxylase (ODC), or by hormones inducing ODC, influences cell growth. Gastrin acts trophically on some colonic carcinomas and their growth is inhibited by gastrin receptor blockers. The mechanism of the trophic action of gastrin on colonic carcinomas is not known. In this study the effect of gastrin, gastrin receptor blockers, epidermal growth factor (EGF) and DFMO on growth and ODC activity of four human colon carcinoma cell lines (SW 403, SW 1116, LS 174 T and Lovo) was investigated. Growth and ODC activity of all cell lines were inhibited by DFMO. Growth of the SW 403 cell line was increased by gastrin and inhibited by the gastrin receptor blocker benzotrypte. The other cell lines did not respond to gastrin and the gastrin receptor blocker. In SW 403 cells ODC activity was increased by gastrin, and was also elevated after treatment with the gastrin receptor blocker. These in vitro results were confirmed by studies on tumours that developed from SW 403 cells in nude mice. Combination of benzotrypte and DFMO did not enhance the antiproliferative effect. EGF increased growth of SW 403 cells, but no induction of ODC activity was measured. LS 174 T cells were not stimulated by EGF. Medium replacement was the strongest stimulus of ODC activity in SW 403 cells already inducing ODC after 3 h. During cell culture ODC activity was high after seeding and decreased continuously with increasing cell density. These data suggest that gastrin induces ODC in gastrin-sensitive colonic carcinoma cells. DFMO appears to be a valuable antiproliferative agent in colonic carcinoma cells.

[Merkel cell tumor (neuroendocrine carcinoma of the skin) in an unusual location. Immunohistochemical and lectin histochemical findings]. / Ungewöhnlich lokalisierter Merkelzelltumor (Neuroendokrines Karzinom der Haut). Immunohistochemische und lektinhistochemische Befunde.

Neuroendocrine carcinoma of the skin usually occurs in elderly individuals. Head and neck are the most common primary sites followed by the extremities and trunk. As this tumor represents a remarkable rarity in younger people, we report the case of a 33-year-old woman with a neuroendocrine carcinoma in an unusual localization. Diagnosis was based on the results of the examination of a metastasis in the inguinal lymph nodes. The lesion at the Labium minus pudendi which is to be considered the primary tumor was detected several months later. Diagnosis of Merkel cell tumor until recently had depended on ultrastructural demonstration of dense-core membrane-bound granules. Today, diagnosis can be secured also by optical light microscopy, on the basis of a certain constellation of immunohistochemical and lectin histochemical findings.

[Air and water contamination by road abrasion (author's transl)]. / Luft- und Gewässerverunreinigung durch 3.4-Benzpyren-haltigen Strassenabrieb

Owing to the abrasion of tar-containing or bituminous road surfaces particles are liberated which contain carcinophilic poly-aromatic hydrocarbons e.g. 3.4-benzpyrenes (BP). The effects of abrasion were determined by comparative measurements alongside a highway section of tar asphalt and one of concrete, both subjected to an identical traffic load. Airborne dust, sedimented dust near the ground and the degree of sewage pollution were measured. The wearing layer of the tar-asphalt surface consisted of TA16: max. grain size 16 mm; bonding agent TB 2000(containing 13 per cent tar pitch and 87 per cent bitumen). With a mean traffic load of 9000 vehicles per day abrasion liberated 15 mg 3.4-benzpyrene per month in winter and in summer 10 mg 3.4-benzpyrene per month and per 1 meter length of a two-laned highway. It was found that in the coarser dust particles the abrasion material containing 3.4-benzpyrene prevails. As a result, the tar asphalt abrasion in precipitated dust contained more than 50 per cent of total benzpyrene, while its share amounted even to 70 per cent of the total load in the floating fraction of waste water.