Central integrative role of oestrogen in the regulation of placental steroidogenic maturation and the development of the fetal pituitary-adrenocortical axis in the baboon

The purpose of this review is to summarize the experimentaldata establishing the baboon as a non-human primate model forthe study of the endocrinology of human pregnancy, and to outlinethe results of in-vivo experiments in the baboon which showthat oestrogen plays a central integrative role in the regulationof placental steroidogenic maturation as well as the functionand maturation of the fetal adrenal gland. Thus, oestrogen regulatesthe receptor-mediated uptake of low-density lipoprotein-cholesteroland the P450 cholesterol side chain cleavage system within sycytiotrophoblaststo promote the production of progesterone. Oestrogen concomitantlyacts on the fetal adrenal gland to modulate the production ofandrogen precursors which ensures maintenance of physiologiclevels of oestrogen during the course of gestation. In addition,oestrogen regulates the 11ß-hydroxysteroid dehydrogenaseenzymes controlling placental cortisol-cortisone metabolismand their secretion into the fetal circulation and thus indirectlyregulates the fetal hypothalamic-pituitary-adrenocortical axis.Collectively, these oestrogen-regulated processes ensure themaintenance of pregnancy and the maturation of the fetus includingthe development in utero of adrenocortical self-sufficiencyessential for neonatal survival.     

Marrow transplantation for chronic myelocytic leukemia: a controlled trial of cyclosporine versus methotrexate for prophylaxis of graft- versus-host disease

Forty-eight patients with chronic myelocytic leukemia, aged 11 to 47, were treated with high-dose cyclophosphamide and fractionated total body irradiation, followed by infusion of marrow from HLA-identical siblings. They were randomized to receive either methotrexate (MTX) (n = 23) or cyclosporine (CSP) (n = 25) as postgrafting prophylaxis for graft-v-host disease (GVHD). All patients had evidence of sustained hematopoietic engraftment. Seventeen of the 25 patients receiving CSP and 17 of the 23 patients receiving MTX are alive between one and almost four (median, 1.7) years, with an actuarial survival rate at three years of 62% and 66%, respectively (P = .60). Also, with respect to most other parameters studied, the two drugs were identical. The probability of acute GVHD was .42 and .46, respectively (P = .70), that of chronic GVHD, .50 and .63 (P = .44), and that of death from transplant-related causes, .30 and .24 (P = .51). There were no differences in the speed of granulocyte and platelet engraftment (P = .82 and .94, respectively), and the duration of hospitalization was comparable (P = .58). Patients receiving MTX required red cell transfusions for a shorter period of time (P = .02), but had a slightly increased morbidity from early oral mucositis. The leukemia recurrence rates were comparable (P = .60). With the regimens used in this study, we conclude that CSP failed to reduce the incidence of GVHD and improve the survival of patients with chronic myelocytic leukemia when compared to results with standard MTX.     

In vitro regulation of immunoglobulin synthesis after marrow transplantation. I. T-cell and B-cell deficiencies in patients with and without chronic graft-versus-host disease

Twenty-four patients with aplastic anemia or acute leukemia were treated by marrow grafts from HLA-identical donors after conditioning with high doses of cyclophosphamide and/or today body irradiation. They were studied between 4 and 63 mo (median 14.2) after transplantation. Seventeen patients had chronic graft-versus-host disease (C-GVHD) and 7 were healthy. They were studied for defects in their T- and B-cell function using and indirect hemolytic plaque assay for Ig production after 6 days of culture in the presence of pokeweek mitogen. T or B cells from the patients with or without C-GVHD were cocultured with T or B cells from their HLA-identical marrow donors or unrelated normal controls. Intrinsic B-cell defects, lack of helper T-cell activity, and suppressor T-cell activity were more frequently found in patients with C-GVHD than in healthy patients. Fifteen of the 17 patients with C-GVHD showed on or more defects in their T-and B-cell function compared to only 3 of the 7 patients without C-GVHD. None of the healthy controls, including the marrow donors, showed defects in their T- and B-cell functions. These in vitro findings may be helpful in assessing the process of immune reconstitution and the immunologic aberration found after human marrow transplantation.     

Long-term stable hematopoietic chimerism following marrow transplantation for acute lymphoblastic leukemia: a case report with in vitro marrow culture studies

This article describes the course of a patient who received an allogeneic marrow graft from his HLA-identical sister for acute lymphoblastic leukemia in second remission. In the second month after grafting, marrow aspirates showed the presence of 7%-10% lymphoblasts. In addition, cytogenetic examination indicated the persistence of host cells. Thereafter, the patient had morphologically normal marrow examinations, with no evidence for recurrent leukemia. In addition, stable hematopoietic chimerism in both the lymphoid and myeloid cell lines has persisted for over 5 yr. Between 20% and 50% of phytohemagglutinin-stimulated peripheral blood mononuclear cells were host-derived on repeated studies. A marrow sample 4 yr after transplantation was established in long-term culture and produced 2% host granulocyte-macrophage colonies at its inception, but 24% host colonies by week 4. Despite this persistent chimerism, no in vitro or in vivo abnormalities of hematopoiesis have been detected.     

Characteristics associated with the transition to partial breastfeeding prior to 6 months of age: Data from seven sites in a birth cohort study

The WHO recommends exclusive breastfeeding for the first 6 months of life. However, the transition of the infants'' diet to partial breastfeeding with the addition of animal milks and/or solids typically occurs earlier than this. Here, we explored factors associated with the timing of an early transition to partial breastfeeding across seven sites of a birth cohort study in which twice weekly information on infant feeding practices was collected. Infant (size, sex, illness and temperament), maternal (age, education, parity and depressive symptoms), breastfeeding initiation practices (time of initiation, colostrum and pre‐lacteal feeding) and household factors (food security, crowding, assets, income and resources) were considered. Three consecutive caregiver reports of feeding animal milks and/or solids (over a 10‐day period) were characterized as a transition to partial breastfeeding, and Cox proportional hazard models with time (in days) to partial breastfeeding were used to evaluate associations with both fixed and time‐varying characteristics. Overall, 1470 infants were included in this analysis. Median age of transition to partial breastfeeding ranged from 59 days (South Africa and Tanzania) to 178 days (Bangladesh). Overall, higher weight‐for‐length z‐scores were associated with later transitions to partial breastfeeding, as were food insecurity, and infant cough in the past 30 days. Maternal depressive symptoms (evaluated amongst 1227 infants from six sites) were associated with an earlier transition to partial breastfeeding. Relative thinness or heaviness within each site was related to breastfeeding transitions, as opposed to absolute z‐scores. Further research is needed to understand relationships between local perceptions of infant body size and decisions about breastfeeding.     

High incidence of symptomatic incisional hernia after midline extraction in laparoscopic colon resection

Background

The incidence of incisional hernia has not decreased despite the use of laparoscopy for colon resections. The objective of this study is to evaluate the impact of the incision used for specimen extraction on the incidence of incisional hernia after laparoscopic colectomy.

Methods

Patients who underwent laparoscopic colectomy without stoma at a single university tertiary-care centre from 2003 to 2009 were identified from an operating room database. Patients were contacted by telephone for participation, and underwent physical examination ± ultrasonography for incisional hernia at the specimen extraction site and completed the Body Image Questionnaire. Specimen extraction incisions were classified into midline, transverse and Pfannenstiel groups.

Results

Out of a total of 251 patients, 99 patients agreed to participate (68 midline, 7 transverse, 24 Pfannenstiel), while 73 patients refused consent and 79 patients could not be contacted. Patients who refused consent were older (69.8 vs 62.4?years, p?=?0.001) but otherwise were similar to participants with respect to gender, malignant disease, postoperative complications and extraction site. Mean length of follow-up was 37.0?months. The overall incidence of incisional hernia was 21% (21/99), being 29?% (20/68) after midline incision compared with 14?% (1/7) after transverse and 0?% (0/24) after Pfannenstiel incisions (p?=?0.002). Of patients with incisional hernia, 47?% (10/21) were symptomatic. Patients with incisional hernia had lower cosmetic score (14.4 vs 17.7, p?=?0.02) compared with those without, but there was no difference in body image score. There were no differences in body image or cosmesis between the three incisions.

Conclusions

There is a high incidence of symptomatic incisional hernia after midline specimen extraction in laparoscopic colectomy, which negatively impacts cosmesis. The risk of hernia may be lower with the use of a transverse or Pfannenstiel incision for specimen extraction.     

The clinical utility of whole‐exome sequencing in the context of rare diseases – the changing tides of medical practice

Whole‐exome sequencing (WES) carries the potential to facilitate the identification of disease causing genes. This is particularly relevant concerning rare diseases, which proves particularly difficult for physicians to diagnose. However, the complexity of this technology renders its applicability onto the clinical setting uncertain. Our study thus aims to understand physicians' perspectives regarding the clinical utility of WES, particularly for providing a diagnosis for patients with rare diseases. Ten semi‐structured interviews were conducted with physicians with experience and familiarity with WES, and the major themes that emerged from our interviews were (i) the relevance of WES in diagnosing patients with rare diseases (appropriateness); (ii) the cost‐effectiveness of WES (accessibility), (iii) the practical issues related to the clinical implementation of WES (practicability); and (iv) ethical, legal and social issues (acceptability). Our study highlights how the clinical implementation of WES presents additional challenges where rare diseases are taken into consideration.     

Chronic intracranial recordings after resection for epilepsy reveal a "running down" of epileptiform activity

We describe an electrical "running down" phenomenon and also a consistent spectral change (in the aperiodic component of the power spectrum) derived from chronic interictal electrocorticography (ECoG) after surgery in a patient with drug-resistant epilepsy. These data were recorded using a closed-loop neurostimulation system that was implanted after resection. The patient has been seizure-free for 2.5 years since resection without requiring the neurostimulator to be turned on to stimulate. Concurrently, there was an exponential decrease in the number of epileptiform electrographic detections recorded by the device, particularly over the first 26 weeks, indicative of an electrical running down phenomenon as the brain adapted to an extended period of seizure freedom. We also find that the aperiodic exponent of the power spectrum gradually decreases over time. The aperiodic component of intracranial ECoG may represent a novel marker of epileptogenicity, independent of seizures.     

COVID-19-associated coagulopathy in children: A multicenter observational cohort study

SARS-CoV-2 infection (coronavirus disease 2019 [COVID-19]) induces a stark procoagulant state, with many hospitalized adults developing thrombosis despite prophylactic anticoagulation. This study aimed to characterize hemostatic parameters and associated clinical outcomes of COVID-19, such as thrombosis and bleeding, in children and to assess thromboprophylaxis use. This multicenter observational cohort study included 79 patients aged up to 18 years admitted to all pediatric hospitals in Québec, Canada, with SARS-CoV-2 infection during a 5-month period. D-dimers were elevated in 18/19 patients (94.7%) and fibrinogen in 15/26 patients (60%). Eleven patients (13.9%) received anticoagulant thromboprophylaxis. One thrombotic event and one major bleed were observed.