In vitro efficacy of ARQ 092, an allosteric AKT inhibitor, on primary fibroblast cells derived from patients with PIK3CA-related overgrowth spectrum (PROS).

Postzygotic mutations of the PIK3CA [phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha] gene constitutively activate the PI3K/AKT/mTOR pathway in PIK3CA-related overgrowth spectrum (PROS) patients, causing congenital mosaic tissue overgrowth that even multiple surgeries cannot solve. mTOR inhibitors are empirically tested and given for compassionate use in these patients. PROS patients could be ideal candidates for enrolment in trials with PI3K/AKT pathway inhibitors, considering the "clean" cellular setting in which a unique driver, a PIK3CA mutation, is present. We aimed to assess the effects of blocking the upstream pathway of mTOR on PROS patient-derived cells by using ARQ 092, a potent, selective, allosteric, and experimental orally bioavailable and highly selective AKT-inhibitor with activity and long-term tolerability, currently under clinical development for treatment of cancer and Proteus syndrome. Cell samples (i.e., primary fibroblasts) were derived from cultured tissues obtained from six PROS patients [3 boys, 3 girls; aged 2 to 17 years] whose spectrum of PIK3A-related overgrowth included HHML [hemihyperplasia multiple lipomatosis; n = 1], CLOVES [congenital lipomatosis, overgrowth, vascular malformations, epidermal nevi, spinal/skeletal anomalies, scoliosis; n = 1], and MCAP [megalencephaly capillary malformation syndrome; n = 4]. We performed the following: (a) a deep sequencing assay of PI3K/AKT pathway genes in the six PROS patients' derived cells to identify the causative mutations and (b) a pathway analysis to assess the phosphorylation status of AKT [Ser473 and Thr308] and its downstream targets [pAKTS1 (Thr246), pRPS6 (Ser235/236), and pRPS6Kß1 (Ser371)]. The anti-proliferative effect of ARQ 092 was tested and compared to other PI3K/AKT/mTOR inhibitors [i.e., wortmannin, LY249002, and rapamycin] in the six PROS patient-derived cells. Using ARQ 092 to target AKT, a critical node connecting PI3K and mTOR pathways, we observed the following: (1) strong anti-proliferative activity [ARQ 092 at 0.5, 1, and 2.5 µM blunted phosphorylation of AKT and its downstream targets (in the presence or absence of serum) and inhibited proliferation after 72 h; rapamycin at 100 nM did not decrease AKT phosphorylation] and (2) less cytotoxicity as compared to rapamycin and wortmannin. We demonstrated the following: (a) that PROS cells are dependent on AKT; (b) the advantage of inhibiting the pathway immediately downstream of PI3K to circumventing problems depending on multiple classes a PI3K kinases; and (c) that PROS patients benefit from inhibition of AKT rather than mTOR. Clinical development of ARQ 092 in PROS patients is on going in these patients.

The relationship between cytokine and neutrophil gene network distinguishes SARS-CoV-2-infected patients by sex and age.

The fact that the COVID-19 fatality rate varies by sex and age is poorly understood. Notably, the outcome of SARS-CoV-2 infections mostly depends on the control of cytokine storm and the increasingly recognized pathological role of uncontrolled neutrophil activation. Here, we used an integrative approach with publicly available RNA-Seq data sets of nasopharyngeal swabs and peripheral blood leukocytes from patients with SARS-CoV-2, according to sex and age. Female and young patients infected by SARS-CoV-2 exhibited a larger number of differentially expressed genes (DEGs) compared with male and elderly patients, indicating a stronger immune modulation. Among them, we found an association between upregulated cytokine/chemokine- and downregulated neutrophil-related DEGs. This was correlated with a closer relationship between female and young subjects, while the relationship between male and elderly patients was closer still. The association between these cytokine/chemokines and neutrophil DEGs is marked by a strongly correlated interferome network. Here, female patients exhibited reduced transcriptional levels of key proinflammatory/neutrophil-related genes, such as CXCL8 receptors (CXCR1 and CXCR2), IL-1ß, S100A9, ITGAM, and DBNL, compared with male patients. These genes are well known to be protective against inflammatory damage. Therefore, our work suggests specific immune-regulatory pathways associated with sex and age of patients infected with SARS-CoV-2 and provides a possible association between inverse modulation of cytokine/chemokine and neutrophil transcriptional signatures.

Rehabilitation of children after total correction of tetralogy of Fallot.

Nine children who had undergone total correction of tetralogy of Fallot were studied with the purpose of observing the physical changes that might be produced by a period of rehabilitation in hospital and comparing these results with those of a control group having the same pathology but which had not followed a protocol for physical activity. Precise criteria were used in the selection of the patients. Careful clinical examinations and exercise tests were conducted before and after the programme, in particular maximal stress testing on the bicycle ergometer and submaximal exercise on the treadmill. The sessions were held three times weekly in a gymnasium over three months, gradually increasing the duration of each session to a maximum of one hour. During the session, heart rate was monitored with a Sport-tester 3000 so as not to exceed 60%, then 70%, of the maximal heart rate recorded during the stress test. Testing at the end of the programme demonstrated an improvement in tolerance under maximal stress in 7 of the 9 patients. As for submaximal performance, 8 out of 9 children covered a greater distance using the same parameters as for initial testing. At the end of the programme, the children all showed increased independence and initiative and more self-confidence in establishing social relations. The programme has proven to be a comprehensive method for safely improving physical fitness in these patients and represents an important starting point for a better future.

Evaluation of hepatitis C virus serotypes and IgM anti-HCV antibodies in two groups of anti-HCV positive subjects in south-east Italy.

We investigated the relation between the presence of IgM antibodies to hepatitis C virus (HCV) and serotypes of HCV, in particular when a high level of IgM antibodies are present in patients infected with HCV serotype I and may be associated with the source, duration and evolution of infection. The study involved two anti-HCV positive groups with chronic liver disease from the same area, one of which was a group of haemodialysis patients attending the same haemodialysis centre.

What's his ECG telling you? A guide for nurses (continuing education credit)

Knowing how to interpret an ECG will help every nurse--no matter what unit she works on--improve assessment skills and patient care. Here's how to organize your approach to mastering the basics.

The department of psychology within a pediatric cardiac transplant unit.

In 1979, the department of Psychology started its activity to provide psychological support to patients and their families during the course of treatment and during the follow-up period. Since 1986, a transplantation program was initiated in the cardiology and pediatric cardiac surgery departments, performing 179 cardiac, 3 heart-kidney, 18 heart-lung 14 both lung, 1 heart-lung-liver, and 1 single lung transplantation. From 1993, to September 2010 the kidney transplant program has performed. 218 cases. Since 2008, we performed (32 liver and 1 intestinal transplantations). We examined the quality of life and coping with transplantation attitudes because there is recent evidence of high levels of family anxiety and depression related to a child's poor response to the disease and compliance. Our work associated post-traumatic stress disorder (PTSD) with anxiety and with these clinical variables: gender pathology, rejection, number of drugs frequency of hospital visits, number of hospitalizations, as well as age at and time from transplantation. We examined 56 parents (25 fathers and 31 mothers) of cardiac transplant recipients. Our most relevant data demonstrated the presence of PTSD among 52% of mothers and 40% of fathers. Significant correlations were observed within the trait of anxiety. No correlations were noted between PTSD and other variables. Testing anxiety levels of parents is considered to be basic to provide psychological support to parents, encourage personal skills, and avoid PTSD symptoms.

Hepatitis C virus-RNA, immunoglobulin M anti-HCV and risk factors in haemodialysis patients.

In order to evaluate hepatitis C virus-RNA (HCV-RNA), immunoglobulin M (IgM) anti-HCV and risk factors in haemodialysis patients, 180 subjects (45 HCV negative and 135 HCV positive) were studied. Sex, age, duration of dialysis, number of transfusions and ALT were also considered. HCV-RNA was determined by the Amplicor HCV test, and IgM anti-HCV by the Abbott HCV IgM EIA. These markers were present in 40% and 30.4% of anti-HCV positive subjects. The agreement between the two tests employed was 77%. The results showed a close association between HCV-RNA and IgM anti-HCV with abnormal ALT levels and between HCV-RNA and the number of transfusions. Both of these markers were different when correlated with age and time on dialysis, respectively. Therefore, IgM anti-HCV may also serve as a serological marker of HCV infection and a complementary marker of virus replication.

Hepatitis C virus serotypes in haemodialysis patients in South-East Italy.

Hepatitis C virus (HCV) infection is highly prevalent in haemodialysis patients. To date, only a few studies involving a small number of subjects have characterized HCV-infected dialysis patients by serotyping. The spread of HCV serotypes in 114 HCV-positive dialysis patients from the same geographical area was evaluated by Murex HCV serotyping assay. Serotypes were detected in 102 subjects (89.5%), with type 1 being the most frequent (37.7%), followed by types 2 (19.3%), 4 (8.8%) and 3 (7.9%). Types 5 and 6 were the least prevalent (3.5%). Ten samples (8.8%) revealed mixed infections: type 1 was detectable in all and the co-infecting HCV types were types 2, 3 and 4 in 3, 4 and 3 cases, respectively. These results suggest that the serotyping assay as an alternative method of distinguishing the major types of HCV, also for particular risk groups and especially in laboratories that lack the specific expertise to perform genotyping methods. Age-related differences in patients with type 5 compared with those with types 3 and 6 may provide evidence of a more recent spread of these latter types.

Distribution of hepatitis C virus serotypes and duration of infection in HCV infected subjects from a geographical area in Southeast Italy.

Hepatitis C virus serotypes and the duration of infection HCV positive subjects from a restricted geographical area in Italy, were evaluated. HCV serotypes were determined by Murex serotyping assay. Serotypes were detected in 592 (88.0%) of 669 samples. Type 1 proved to be the most frequent (48.9%), followed by types 2 (29%), 3(4.5%) and 4 (2.1%). The transmission of HCV 3 and 4 were observed only in the past 20 years whilst those of other types were recorded during 40 or more years. The results support the view that the prevalence of different HCV types of infection in one restricted geographical area may be associated with the source and duration of infection.

Hepatitis C virus serotypes and sources of infection in patients with HCV-related chronic liver disease from one geographical area in southeast Italy.

Hepatitis C virus serotypes and sources of infection in HCV-positive patients from a restricted geographical area were evaluated. HCV serotypes were determined by Murex serotyping assay. Of 192 samples, serotypes were detected in 189 (98.5%): type 1 proved to be the most common (53.1%), followed by types 2 (15.2%), 3 (6.2%), 6 (5.3%), 4 (3.6%) and 5 (1.6%). Intravenous drug users were significantly younger than the rest of the patients and infected mainly with HCV type 3. Transmission of HCV 3 has only been observed over the past 20 years; other types have been transmitted for up to 40 years. These results support the view that the prevalence of the infection by different HCV types in one restricted geographical area may be associated with the source and duration of infection.

Avaliação de prescrições médicas no Hopital Geral de Bonsucesso a fim de garantir a qualidade da dispensação

Introdução: Na distribuição dos medicamentos, a qualidade deve ser assegurada em todas as etapas do processo, que iniciando na leitura e interpretação das prescrições médicas e finalizando na dispensação do medicamento para o paciente. Neste contexto, a má qualidade das prescrições, algumas vezes feitas com bases irracionais, sem considerar as Boas Práticas da Prescrição e a legislação vigente, tem função determinante na ocorrência de problemas relacionados a medicamentos. Atualmente sabe-se que tais eventos podem decorrer de prescrições ambíguas, ilegíveis ou incompletas, má qualidade da grafia médica, transcrição de prescrição médica, utilização de abreviaturas não padronizadas e de nomes comerciais em desacordo com a Denominação Comum Brasileira (DCB), especificação incorreta da forma farmacêutica, posologia, concentração e via de administração. Esses problemas podem comprometer a qualidade de vida do paciente, provocar a hospitalização, prolongar seu tempo de internação ou até mesmo levar ao óbito. Portanto se faz necessário um incremento da assistência farmacêutica em todo o processo, objetivando o uso racional do medicamento. Objetivo: Estudar a qualidade das prescrições médicas do Hospital Geral de Bonsucesso empregando indicadores de qualidade. Método: Avaliação das prescrições farmacológicas de pacientes internados em clínicas pré-selecionadas, através de um formulário previamente elaborado, onde foram analisados itens como: prescrição padrão da instituição, legibilidade, identificação completa do paciente, adequação à DCB, identificação de forma farmacêutica, posologia, concentração e via de administração do medicamento e identificação do profissional prescritor . Resultados: Do total de 643 prescrições analisadas, 86,63% se apresentaram legíveis; 88,52% estavam em desacordo com a DCB; 89,42% não apresentaram a forma farmacêutica do medicamento prescrito, porém 85,07% citaram a via de administração; 95,65% determinaram a posologia, enquanto 50,70% não apresentaram a concentração do medicamento. Discussão e Conclusão: O presente estudo mostrou que os problemas mais preponderantes encontrados foram a não utilização da DCB com utilização de siglas e a omissão da dose do medicamento. Conseqüentemente surgem dúvidas no momento da sua administração pela enfermagem, causando possíveis Problemas Relacionados a Medicamentos principalmente de efetividade e segurança. Nos casos em que se observou a presença da via de administração do medicamento, não foi citada a forma farmacêutica, sugerindo que para os profissionais prescritores há uma correlação direta entre esses fatores. As prescrições do HGB apresentam falhas comuns a todas as clínicas, devendo-se portanto conscientizar os médicos sobre as Boas Práticas da Prescrição visando a melhoria da sua qualidade