Refractory congestive heart failure following delayed pericardectomy in a 12-year-old child with Mulibrey nanism due to a novel mutation in TRIM37

Mulibrey nanism (MUL) is a rare autosomal recessive disorder with severe primordial growth retardation and multiorgan involvement, caused by mutations in TRIM37. Early clinical detection is important since more than 50 % of the patients develop congestive heart failure. We report a 12-year-old patient who presented in infancy with severe growth retardation, dysmorphic features, and cleft palate. Clinical diagnosis of MUL was established at the age of 5 years. Postmortem, molecular diagnostic confirmed MUL as a novel 1-bp deletion (c.1233delA) in exon 14 of the TRIM37 coding region. Cardiac examination at the age of 6 years revealed constrictive pericarditis with significant elevation of atrial filling pressures, consecutive hepatomegaly, and protein loosing enteropathy. Since the parents refused pericardectomy, surgery was delayed until the age of 12 years, when congestive heart failure deteriorated. Despite pericardectomy, the boy died from persistent right heart failure. Conclusion: Our report underlines the necessity of early clinical diagnosis of Mulibrey nanism. Careful cardiologic examination is required to detect constrictive pericarditis, which is a major factor of mortality in these patients. Pericardectomy should be performed early, to avoid sequelae of persisting congestive heart failure.     

Repeated bout effect on the cytoskeletal proteins titin,desmin, and dystrophin in rat skeletal muscle

The aim of this study was to evaluate the effect of repeated bouts of exercise on the cytoskeletal proteins titin, desmin, and dystrophin. Rats were made to run downhill for 90 min 1 or 5 times separated by 14 days. Samples were taken from quadriceps femoris muscle 3, 48, 96 h and 50 days after the last exercise session and detected by quantitative PCR, histochemical stainings, and western blot analyses. Histopathological changes in titin, desmin, and dystophin stainings, an increase in β-glucuronidase activity (a quantitative indicator of muscle damage), a significant decrease in the relative content of dystrophin, and intramyocellular Evans blue staining (signs of changes in sarcolemmal permeability) observed after one exercise session were attenuated after 5 exercise sessions. Titin mRNA level was not increased after the initial exercise session but was increased after the fifth session. Desmin and dystrophin mRNA levels were increased after the first and fifth sessions with desmin showing a smaller increase after the fifth session compared to the first session. Prior exercise induces adaptation that protects the sarcolemma as well as subsarcolemmal, intermediate filament, and sarcomeric proteins against disruption. Changes in mRNA levels of titin, desmin, and dystophin after an acute exercise session obviously reflect the need of these proteins in the repair process following damage. After five sessions increase in mRNA of studied proteins suggest a strong involvement in continuing adaptation to the increased exercise.     

Biomarkers in WNT1 and PLS3 Osteoporosis: Altered Concentrations of DKK1 and FGF23

Recent advancements in genetic research have uncovered new forms of monogenic osteoporosis, expanding our understanding of the molecular pathways regulating bone health. Despite active research, knowledge on the pathomechanisms, disease-specific biomarkers, and optimal treatment in these disorders is still limited. Mutations in WNT1, encoding a WNT/β-catenin pathway ligand WNT1, and PLS3, encoding X chromosomally inherited plastin 3 (PLS3), both result in early-onset osteoporosis with prevalent fractures and disrupted bone metabolism. However, despite marked skeletal pathology, conventional bone markers are usually normal in both diseases. Our study aimed to identify novel bone markers in PLS3 and WNT1 osteoporosis that could offer diagnostic potential and shed light on the mechanisms behind these skeletal pathologies. We measured several parameters of bone metabolism, including serum dickkopf-1 (DKK1), sclerostin, and intact and C-terminal fibroblast growth factor 23 (FGF23) concentrations in 17 WNT1 and 14 PLS3 mutation-positive subjects. Findings were compared with 34 healthy mutation-negative subjects from the same families. Results confirmed normal concentrations of conventional metabolic bone markers in both groups. DKK1 concentrations were significantly elevated in PLS3 mutation-positive subjects compared with WNT1 mutation-positive subjects (p < .001) or the mutation-negative subjects (p = .002). Similar differences were not seen in WNT1 subjects. Sclerostin concentrations did not differ between any groups. Both intact and C-terminal FGF23 were significantly elevated in WNT1 mutation-positive subjects (p = .039 and p = .027, respectively) and normal in PLS3 subjects. Our results indicate a link between PLS3 and DKK1 and WNT1 and FGF23 in bone metabolism. The normal sclerostin and DKK1 levels in patients with impaired WNT signaling suggest another parallel regulatory mechanism. These findings provide novel information on the molecular networks in bone. Extended studies are needed to investigate whether these biomarkers offer diagnostic value or potential as treatment targets in osteoporosis. © 2020 American Society for Bone and Mineral Research.     

Communication therapy for people with aphasia and their partners (APPUTE)

Background: Severe aphasia is a chronic condition and can have a big effect on how people with severe aphasia (PWSA) succeed in their communication. The communication partner’s support for the person with aphasia has been shown to be essential in achieving successful communication. However, interventions combining training both the partner and the PWSA to use hierarchical strategies in nonverbal communication are still needed.

Aims: The aim of the present paper is to describe a new intervention (APPUTE) where both the person with aphasia and the partner receive therapy equally and practise finding functional communication strategies to convey everyday messages or more complicated ones. The data collection during the APPUTE intervention is also presented.

Methods & Procedures: The data were collected during a development project including an evaluation period, two rehabilitation periods and follow-up measurement. Thirty-four PWSA and their partners participated. The linguistic functions and communication efficiency of PWSA were evaluated three times during the rehabilitation. The communication skills of the partner were also assessed, along with the success of the mutual communication.

Outcomes & Results: The communication skills and communication efficiency of the PWSA and their partners improved significantly during the rehabilitation period, and the acquired skills were retained for 6 months after the intervention. The linguistic skills of the PWSA also improved. The advanced age of the partner explained both the variance of the partner’s communication skills and the success in the mutual communication. The amount of earlier outpatient speech therapy explained the variance of the communication efficiency of PWSA as evaluated by the partners. Regarding success in mutual communication, all of the couples were able to communicate at least simple issues at the end of the rehabilitation period. The more demanding the tasks, the more difficult it became for them to succeed, especially for older PWSA with severe motor paralysis. Both the people with aphasia and their partners mainly experienced benefits from the APPUTE intervention and for the most part, the benefits were retained during follow-up.

Conclusions: The APPUTE method appears to improve the communication skills of PWSA and their partners, as well as the linguistic skills of PWSA.     

Nordic MCL2 trial update: six-year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC + autologous stem-cell support: still very long survival but late relapses do occur

Mantle cell lymphoma (MCL) is a heterogenic non-Hodgkin lymphoma entity, with a median survival of about 5 years. In 2008 we reported the early - based on the median observation time of 4 years - results of the Nordic Lymphoma Group MCL2 study of frontline intensive induction immunochemotherapy and autologous stem cell transplantation (ASCT), with more than 60% event-free survival at 5 years, and no subsequent relapses reported. Here we present an update after a median observation time of 6·5 years. The overall results are still excellent, with median overall survival and response duration longer than 10 years, and a median event-free survival of 7·4 years. However, six patients have now progressed later than 5 years after end of treatment. The international MCL Prognostic Index (MIPI) and Ki-67-expression were the only independent prognostic factors. Subdivided by the MIPI-Biological Index (MIPI + Ki-67, MIPI-B), more than 70% of patients with low-intermediate MIPI-B were alive at 10 years, but only 23% of the patients with high MIPI-B. These results, although highly encouraging regarding the majority of the patients, underline the need of a risk-adapted treatment strategy for MCL. The study was registered at www.isrctn.org as ISRCTN 87866680.     

Promoting positive motherhood among nulliparous pregnant women with an intense fear of childbirth: RCT intervention

This RCT intervention among nulliparous pregnant women with an intense fear of childbirth sought to promote preparedness for childbirth and to enhance positive parenting. Pregnant women (n = 8,611) filled in a 'fear of childbirth' questionnaire. Nulliparous women with severe fear of childbirth (n = 355) were randomized into intervention (n = 131; 41 refused) and control (n = 224) groups. They rated themselves on a preparedness scale in middle and late pregnancy, and on a motherhood scale three months after childbirth. The intervention included six psycho-education group sessions during pregnancy and one after childbirth. This intervention increased the mothers' preparedness for childbirth, which predicted an increase in positive motherhood.     

Symptoms of attention deficit hyperactivity disorder in children are associated with cortisol responses to psychosocial stress but not with daily cortisol levels

We tested associations of diurnal hypothalamic-pituitary adrenal axis (HPAA) activity and its response to stress with behavioral symptoms of Attention Deficit Hyperactivity Disorder (ADHD) among 272 eight-year-old children. We measured their diurnal salivary cortisol and salivary cortisol responses to the Trier Social Stress Test for Children (TSST-C). Mothers rated their child’s behavior with the ADHD-IV Rating Scale and the Child Behavior Checklist (CBCL). There were no significant associations between ADHD symptoms and diurnal cortisol concentrations. The boys with predominantly inattentive symptoms of ADHD (ADHD-I; scores at or above the 90th percentile) had 26% lower mean salivary cortisol levels during the TSST-C than the boys with scores below this cutoff. In the girls with symptoms of ADHD-I, initial salivary cortisol levels prior to the TSST-C were higher and fell more rapidly during and after the TSST-C, which was not seen in the remaining girls (P = 0.007 for interaction ‘ADHD-I × sampling time’). Controlling for Oppositional Defiant Disorder/Conduct Disorder and Anxiety Disorder or excluding children with these comorbid problems did not substantially affect these findings. We conclude that the boys and the girls with behavioral symptoms of ADHD-I had reduced HPAA responsiveness to stress, which is also seen in people after traumatic events or with chronic stress. Their diurnal cortisol rhythm was not affected. Thus, ADHD-I may be associated with dysregulation of the HPAA or reduced engagement with stressful stimuli.