A cohort study of guselkumab in the treatment of psoriasis refractory to previous biologic therapies: effectiveness,safety and adherence

International Journal of Clinical Pharmacy - Background Guselkumab is indicated for moderate-to-severe plaque psoriasis. Data from real-life clinical practice regarding its use are scarce,...     

Coagulation factors determine tumor transduction in vivo

A critical obstacle for efficient gene therapy and virotherapy of cancer with adenoviral vectors and oncolytic adenoviruses is to target tumor cells in vivo. Recent reports indicate that, contrary to the natural airborne infection of epithelial cells with adenovirus type 5 mediated by coxsackievirus B and adenovirus receptor (CAR) and integrins, blood-borne adenovirus infects hepatocytes mainly through an indirect pathway that involves blood coagulation factors. In this report we have studied whether adenovirus also infects tumor cells in vivo by this pathway. In vitro and in vivo analyses show that vitamin K-dependent coagulation zymogens mediate tumor transduction and that the elimination of these factors abrogates tumor transduction. This finding imposes new challenges to retarget adenoviruses in vivo.     

Muscle wasting associated with cancer cachexia is linked to an important activation of the atp-dependent ubiquitin-mediated proteolysis

Rats bearing the Yoshida AH-130 ascites hepatoma for 7 days showed an important decrease in muscle mass—over 30% in gastrocnemius and extensor digitorum longus (EDL)—in relation to non-tumour-bearing controls, which is associated with an increased proteolytic rate-in in vitro incubation. In order to identify the precise biochemical process which was involved, we measured different proteolytic systems in incubated EDL muscles. The capacity for intralysosomal proteolysis, as measured by sensitivity to methylamine, was not increased in tumour-bearing rats, suggesting that the mechanism involved in the increased proteolytic rate was extralysosomal. Incubations using the Ca²⁺ ionophore A23187 revealed no change in the activity of calcium-dependent proteases as a consequence of tumour growth. Finally, muscle incubation in an ATP-depleted medium allowed us to conclude that energy-dependent proteases were involved in the activation of muscle proteolysis in tumour-bearing rats. In particular, the ubiquitin-dependent proteolytic system is involved, since there is an important increase in ubiquitin conjugates in the skeletal muscle of tumour-bearing rats. It may thus be suggested that extralysosomal ATP-and ubiquitin-dependent proteases underlie the biochemical mechanism of muscle wastage associated with cancer cachexia. © 1995 Wiley-Liss, Inc.     

Reduced ovulation rate in adolescent girls born small for gestational age

FSH and insulin are key hormones involved in spontaneous ovulation. Adolescent girls born small for gestational age (SGA) are at risk for FSH and insulin resistance. We have assessed whether ovulation rate is reduced in SGA girls. Ovulatory function was assessed by weekly filter paper progesterone measurements, obtained by finger-stick auto-sampling for 3 consecutive months in matched populations of asymptomatic, nonobese girls (mean age, 15.5 yr; > or =3 yr postmenarche) who were either born with an appropriate weight for gestational age (AGA; n = 24; mean birthweight, 3.3 kg) or born small for gestational age (SGA; n = 25; mean birthweight, 2.3 kg). The prevalence of anovulation was higher among SGA than AGA girls (40% vs. 4%; P = 0.002). Moreover, in the relatively small fraction of ovulating SGA girls, the ovulation rate was lower than in AGA adolescents (average number of ovulations during the study, 1.4 vs. 1.9; P < 0.01). In conclusion, the endocrine correlates of prenatal growth restraint are herewith extended to include oligo-ovulation and anovulation in adolescence. It remains to be verified whether this SGA-related phenomenon persists into the reproductive age range. If it does, then fetal growth restraint may prove to be one of the enigmatic components underpinning hitherto unexplained female subfertility.     

CD34+-enriched-CD19+-depleted autologous peripheral blood stem cell transplantation for chronic lymphoproliferative disorders: high purging efficiency but increased risk of severe infections

OBJECTIVE: The main objective of this work was to decrease the incidence of relapse after autologous stem cell transplantation with a "double purging" procedure. METHODS: We used a "positive" (CD34) and "negative" (CD19) double selection method to improve the efficacy of "single purging" of hematopoietic harvests in poor-prognosis lymphoproliferative disorders. All patients included in the study had a positive molecular marker of their disease. Minimal residual disease (MRD) was studied by flow cytometry and PCR techniques during the purging procedure and after transplantation. RESULTS: Twenty-six patients fulfilled entry criteria. Median age of patients was 50 years (range: 33-66); 17 were male and 9 female. Thirteen (50%) of the patients mobilized an adequate number of CD34+ cells (>or=3 x 10(6)/kg) to proceed with the double-selection protocol. Twelve of the 13 harvests became PCR negative after purging. Ten patients were grafted with the selected products and all but one engrafted without delay. After a median follow-up of 30 months, 2 of 10 patients suffered a molecular relapse at 7 and 19 months respectively. The earlier relapse was observed in the patient who received a MRD+ product. Only one patient experienced a clinical relapse. Three patients died due to obliterans bronchiolitis, pneumococcal sepsis, and septic shock of unknown origin, respectively, and three others presented life-threatening infections. CONCLUSION: Therefore, CD34+/CD19+ positive/negative selection is an effective purging approach in patients with chronic lymphoproliferative disorders. This favorable effect is, however, counterbalanced by the high frequency of life-threatening infections.     

The p21(Cip1) protein, a cyclin inhibitor, regulates the levels and the intracellular localization of CDC25A in mice regenerating livers

Liver cells from p21(Cip1-/-) mice subjected to partial hepatectomy (PH) progress into DNA synthesis faster than those from wild-type mice. These cells also show a premature induction of cyclin E/cyclin-dependent kinase (CDK) 2 activity. We studied the mechanisms whereby cells lacking p21(Cip1) showed a premature induction of this activity. Whereas the levels of CDK2, cyclin E, and p27(Kip1) were similar in both wild-type and p21(Cip1-/-) mice, those of the activator CDC25A were much higher in p21(Cip1-/-) quiescent and regenerating livers than in wild-type animals. Moreover, p21(Cip1-/-) cells also showed a premature translocation of CDC25A from cytoplasm into the nucleus. The ectopic expression of p21(Cip1) into mice embryo fibroblasts from p21(Cip1-/-) mice decreased the levels of CDC25A and delayed its nuclear translocation. The levels of CDC25A messenger RNA in p21(Cip1-/-) cells were higher than in wild-type cells, suggesting that this increase might be responsible, at least in part, for the high levels of CDC25A protein in these cells. Thus, the results reported here indicate that p21(Cip1) regulates the levels and the intracellular localization of CDC25A. We also found a good correlation between CDC25A nuclear translocation and cyclin E/CDK2 activation. In conclusion, premature translocation of CDC25A to the nucleus might be involved in the advanced induction of cyclin E/CDK2 activity and DNA replication in cells from animals lacking p21(Cip1).     

The value of detecting surface and cytoplasmic antigens in acute myeloid leukaemia

The immunophenotype of leukaemia cells from 60 patients with acute myeloid leukaemia (AML) was analysed with the APAAP technique using a panel of anti-myeloid and lymphoid associated monoclonal antibodies (McAb). Cells from all cases, including three with negative cytochemical features, were labelled by at least one of the anti-myeloid McAb CD13, anti-myeloperoxidase (anti-Mpo), and/or CD14. The most sensitive marker was CD13, since it was positive in 90% of cases. In two out of three AML cases defined as M0-AML, CD13 was expressed in the cytoplasm but not on the membrane; in these three cases peroxidase (Mpo) was not detected by conventional cytochemistry, but could be demonstrated in all of them using the McAb anti-Mpo. The simultaneous expression of CD14 and CD68 McAb was often confined to the M4 and M5 FAB AML subtypes (92% cases) as compared to the others: M1, M2, M3 (18% cases). Lymphoid antigens were rarely positive (TdT+: 13%, CD7+: 15%, CD19+: 5%) and none of the AML cases were CD3+ or CD10+. By contrast, CD4 was expressed in blasts from 44% of cases and this was not restricted to AML with a monocytic component (M4, M5) but also found in other subtypes. There were no significant differences in the clinical or prognostic features according to the positivity or negativity with TdT and CD4. By contrast, expression of CD7 was associated with refractoriness to the treatment or short complete remission duration, although the number of patients is too small to draw firm conclusions. Our findings support the clinical and diagnostic relevance of immunophenotypic studies in AML.     

HIV screening and linkage to care in a health department in Valencia,Spain: Lessons learned from a healthcare quality improvement project

Spain’s rate of new human immunodeficiency virus (HIV) diagnoses exceeds that of the European Economic Area average (8.6 vs 5.6:100,000 in 2018). The country has failed to meet the first of United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 targets for HIV control by 2020, with 87.0% of people living with HIV knowing their status, and late presentation rates of 47.6% and 51.5% country-wide and in the Valencian autonomous community, respectively. Advancing screening and linkage to care (SLTC) practices is necessary to effectively control the epidemic. The Valencia Viral Screening (CRIVALVIR) project adopted the TEST model for opportunistic and systematic HIV SLTC in individuals aged 18 to 80 who required blood work for any purpose, as of February 2019. SLTC was integrated into routine clinical workflow across primary care centers serving a population of 360,000 people in Valencia, Spain. Our project successfully upscaled total HIV testing by 194% to over 32,000 patients tested in 14 months. We found an overall prevalence of 0.13% (0.08–0.21) among those screened per protocol (n = 13,061), with foreign-born citizens presenting a 12.5 times significantly higher likelihood of acquiring HIV (95% confidence interval 4.63–33.96, P < .0001). We improved late presentation by 18.2 percentage points and prevented an estimated 58 to 70 new secondary infections. HIV screening of the general population in primary care is an effective strategy for achieving timely diagnosis and preventing new infections. Opportunistic, systematic, opt-out approaches are essential to control the HIV epidemic.     

Psychological Pathways to Paranoia and Psychotic-Like Experiences in Daily-Life: The Mediating Role of Distinct Affective Disturbances

Background and HypothesisInfluential models of psychosis indicate that the impact of putative causal factors on positive symptoms might be explained partly through affective disturbances. We aimed to investigate whether pathways from stress and self-esteem to positive symptoms, as well as reversal pathways from symptoms to stress and self-esteem, were mediated through specific affective disturbances across the extended psychosis phenotype.Study DesignUsing experience sampling methodology, 178 participants (65 high-schizotypy, 74 at-risk mental state, and 39 first-episode psychosis) were assessed on levels of momentary stress, self-esteem, anxiety, sadness, psychotic-like experiences (PLE), and paranoia. Multilevel mediation models were fit to examine indirect effects of each of these pathways. Considering evidence of mediation, each indirect pathway will be combined in a single model to explore their relative contributions.Study ResultsAnxiety, sadness, and self-esteem mediated the pathways from stress to PLE and paranoia in daily-life. In the pathway to paranoia, sadness, and self-esteem showed larger contributions than anxiety. Pathways from self-esteem to PLE and paranoia were mediated by anxiety and sadness, the later showing a larger contribution. Pathways from symptoms to stress, but not from symptoms to self-esteem, were differently explained by emotional states; sadness lost its mediating effect and anxiety was the most important mediator. Few differences across groups were found.ConclusionsThis study lends support to psychological models of psychosis that highlight the relevance of affective disturbances in the risk and expression of psychosis. Furthermore, specific influences of different negative emotional states were identified, which could enhance psychological treatments.