Optimal time for obtaining peak and trough theophylline levels in 12-hour and 24-hour products in children

A direct relationship between bronchodilator efficacy and toxicity by the measurement of serum theophylline concentrations is well established. This study evaluated, in children receiving either 12-hour (Theo-Dur) or an experimental 24-hour (Theo-Beads) preparation, the most common time to reach peak and trough levels in the serum. Twenty-three children with chronic asthma between the ages of 7 and 12 years participated in the study. Twelve received theophylline every 12 hours at a dose ranging from 400 to 800 mg per 24 hours. Eleven children received a 24-hour preparation at a dose ranging between 400 and 1000 mg per 24 hours. The results demonstrated no relationship between dosing interval and the appearance of peak or trough levels with Theo-Dur. Theo-Beads reached its peak in 9 to 11 children between six and eight hours and for 10 to 11 children the trough value was at the end of the dosing interval.     

Fourteen novel OPA1 mutations in autosomal dominant optic atrophy including two de novo mutations in sporadic optic atrophy

The OPA1 gene, encoding a dynamin-related GTPase that plays a role in mitochondrial biogenesis, is implicated in most cases of autosomal dominant optic atrophy (ADOA). Sixty-nine pathogenic OPA1 mutations have been reported so far. Most of these are truncating mutations located in the GTPase domain coding region (exons 8-16) and at the 3'-end (exons 27-28). We screened 44 patients with typical ADOA using PCR-sequencing. We also tested 20 sporadic cases of bilateral optic atrophy compatible with ADOA. Of the 18 OPA1 mutations found, 14 have never been previously reported. The novel mutations include one nonsense mutation, 3 missense mutations, 6 deletions, one insertion and 3 exon-skipping mutations. Two of these are de novo mutations, which were found in 2 patients with sporadic optic atrophy. The recurrent c.2708_2711delTTAG mutation was found in 2 patients with a severe congenital presentation of the disease. These results suggest that screening for OPA1 gene mutations may be useful for patients with optic atrophy who have no affected relatives, or when the presentation of the disease is atypical as in the case of early onset optic atrophy.     

Production of IL-12, IL-23 and IL-27p28 by bone marrow-derived conventional dendritic cells rather than macrophages after LPS/TLR4-dependent induction by Salmonella Enteritidis

Induction of the interleukin-12 (IL-12) cytokine family comprising IL-12, IL-23, IL-27, and IL-12p40 by intracellular pathogens is required for orchestration of cell-mediated immune responses. Macrophages (MΦ) have been shown to be a source of IL-12 following TLR4-dependent activation by Salmonella (S.). In this study another antigen-presenting cell type, the conventional dendritic cell (cDC), was analyzed and its cytokine responses compared with those of MΦ. We generated bone marrow-derived conventional dendritic cells (BMDC) and macrophages (BMMΦ) by incubating murine bone marrow cells with supernatants containing granulocyte/macrophage colony-stimulating factor (GM-CSF) or macrophage colony-stimulating factor (M-CSF), respectively. Stimulation of BMDC and BMMΦ with S. enterica serovar Enteritidis (SE) or LPS resulted in the release of IL-12 and IL-23 by BMDC but not by BMMΦ. Furthermore, BMDC secreted approx. 20-fold more IL-12p40 and IL-27p28 than BMMΦ. However, BMDC and BMMΦ produced similar levels of IL-10. Using BMDC originating from wild-type (wt), TLR2^def and TLR4^def mice, we show that in BMDC the induction of IL-12, IL-23, and IL-27p28 by SE is dependent on TLR4, whereas low-level production of p40 is also mediated by pattern recognition receptors (PRR) other than TLR4. Interestingly, LPS- and SE-provoked responses of BMDC were remarkably similar indicating that LPS is the primary danger molecule of SE. Taken together, our results point to cDC rather than MΦ as the major producers of the IL-12 family members during in vitro infection with SE. The mechanisms of recognition of SE, however, appear to be the same for cDC and MΦ     

Expression of TNFalpha by muscle fibers in biopsies from children with untreated juvenile dermatomyositis: association with the TNFalpha-308A allele

Juvenile dermatomyositis (JDM) is the most common pediatric inflammatory myopathy. In patients with JDM, the A --> G polymorphism in the tumor necrosis factor alpha (TNFalpha)-308 promoter region (TNFalpha-308A) is associated with prolonged disease course and increased production of TNFalpha by peripheral blood mononuclear cells (Arthritis Rheum. 43, 2368-2377, 2000). Magnetic resonance imaging directed biopsies from 21 white children with untreated JDM were evaluated for TNFalpha expression. Using monoclonal antibody to TNFalpha, fresh frozen sections were processed by the standard immunohistochemical technique. We investigated the association among the expression of TNFalpha by muscle fibers, disease activity, duration of untreated disease, and the TNFalpha-308 polymorphism. Untreated children with JDM who had the TNFalpha-308A allele had an increased number of TNFalpha stained muscle fibers than children with the TNFalpha-308G allele (P = 0.001). There was no association with disease activity or duration of untreated disease. We speculate that muscle fiber production of TNFalpha provides a microenvironment in which TNFalpha acts synergistically with other mediators to prolong muscle fiber damage.     

Nucleolar vacuoles observed in rat oocytes

Recently Merveille and al (1984) using light microscope have observed intranucleolar cavities in rat ovocytes from large antral follicles. They have showed that the frequency of these vacuoles increases when follicular growth is stimulated by gonadotropins. In this paper, the ultrastructure of the nucleolar cavities has been studied. Two types of cavities are visible in these nucleoli: 1. nucleolar "interstices" present at the periphery of the nucleoli in remnants of the granular component and of the dense fibrillar components; 2. nucleolar "vacuoles" which are located in the homogeneous substance forming the greatest part of the nucleolus. The nucleolar vacuoli generally are clear-cut and spherical. The density of their content is similar to the nucleoplasm but they don't communicate to the nucleoplasm. By means of cytochemical to detect Ag-NOR proteins (Ploton and al [1983]) and basic proteins (Sheridan and Barnett [1984]), dense fibrillar component of the nucleolus but no basic proteins may be seen in the wall of the cavity. Moreover no evidence of relation between the presence of the vacuoles and the process of follicular atresia has been found.     

Views of Dutch general practitioners about premenstrual symptoms: A qualitative interview study

BackgroundGeneral practitioners (GPs) encounter women suffering from premenstrual symptoms. Often women with premenstrual problems experience little understanding from GPs. Views of GPs will influence their approach to these women and their care. Insight into these views is lacking but could help in designing educational programmes for GPs.ObjectivesTo explore the views of Dutch GPs towards aetiology, diagnostic process, and preferred treatment of premenstrual symptoms.MethodsIn 2017, we conducted a qualitative, semi-structured, interview survey among 27 GPs, varying in age, gender, and practice setting.ResultsImportant themes emerged from the interviews: ‘no need for a symptom diary,’ ‘PMS defined as illness’ exclusively in case of disruption of normal functioning, and ‘symptomatic treatment’ as preferred approach. Most GPs considered PMS to be a physiological phenomenon, with taking history as an adequate diagnostic tool. Almost all GPs regarded a normal cyclical hormonal cycle as causal; many also mentioned the combination with personal sensitivity. Some pointed to a dividing line between physiological condition and illness if women could not function normally in daily life. Lastly, the approach GPs preferred was focussing on relieving symptoms of individual patients. In addition to explaining the hormonal cycle and lifestyle advice, all GPs advocated oral contraceptives, and if necessary psychological support. GPs expressed negative feelings about prescribing antidepressants.ConclusionGPs considered physiological changes and personal sensitivity as aetiological factors. We recommend more training to improve GPs knowledge and more insight into the burden of women with PMS. A symptom diary is an essential diagnostic tool for GPs.     

Survivorship and Patient-Reported Outcomes of an Uncemented Vitamin E–Infused Monoblock Acetabular Cup: A Multicenter Prospective Cohort Study

BackgroundAddition of vitamin E to polyethylene is theorized to reduce the potential for oxidative wear in acetabular components. This paper presents a multicenter prospective cohort study that reports on outcomes from use of a Vitamin E–infused highly cross-linked polyethylene acetabular cup.MethodsPatients were recruited across nine medical institutions. Clinical outcome measures recorded were the Harris Hip Score, visual analogue score for pain and satisfaction. Evidence of implant loosening or osteolysis was collected radiologically. Cup survival and reasons for revision in relevant cases were also recorded. Data collection was undertaken preoperatively, at 6-12 weeks, 6 months, 1 year, 2 years, and 5 years. A total of 675 patients were recruited, with 450 cases available at final review. Data regarding cup survival was available to 8 years and 9 months postoperatively.ResultsImprovements in both the Harris Hip Score and visual analogue score for pain and satisfaction were recorded at all time points, with these being maintained through the length of follow-up. In total, 89% of cups were implanted within the Lewinnek safe zone. A lucent line was identified in one case, with no evidence of acetabular osteolysis observed throughout the follow-up period. Cup survival was 98.9% at 8 years and 9 months. No revisions for aseptic loosening were observed.ConclusionsThe use of a vitamin E–infused polyethylene acetabular cup demonstrates reassuring patient-reported outcomes, radiological measures, and cup survival at medium to long-term follow-up.     

What happens after graft loss? A large,long-term,single-center observation

The number of patients returning to dialysis after graft failure increases. Surprisingly, little is known about the clinical and immunological outcomes of this cohort. We retrospectively analyzed 254 patients after kidney allograft loss between 1997 and 2017 and report clinical outcomes such as mortality, relisting, retransplantations, transplant nephrectomies, and immunization status. Of the 254 patients, 49% had died 5 years after graft loss, while 27% were relisted, 14% were on dialysis and not relisted, and only 11% were retransplanted 5 years after graft loss. In the complete observational period, 111/254 (43.7%) patients were relisted. Of these, 72.1% of patients were under 55 years of age at time of graft loss and only 13.5% of patients were ≥65 years. Age at graft loss was associated with relisting in a logistic regression analysis. In the complete observational period, 42 patients (16.5%) were retransplanted. Only 4 of those (9.5%) were ≥65 years at time of graft loss. Nephrectomy had no impact on survival, relisting, or development of dnDSA. Patients after allograft loss have a high overall mortality. Immunization contributes to long waiting times. Only a very limited number of patients are retransplanted especially when ≥65 years at time of graft loss.