Mutations in PLCE1 are a major cause of isolated diffuse mesangial sclerosis (IDMS)

Background and objectives. Diffuse mesangial sclerosis (DMS)is a histologically distinct variant of nephrotic syndrome (NS)that is characterized by early onset and by progression to end-stagekidney disease (ESKD). Besides syndromic DMS, isolated (non-syndromic)DMS (IDMS) has been described. The etiology and pathogenesisof DMS is not understood. We recently identified by positionalcloning recessive mutations in the gene PLCE1/NPHS3 as a novelcause of IDMS. We demonstrated a role of PLCE1 in glomerulogenesis.Mutations in two other genes WT1 and LAMB2 may also cause IDMS.We therefore determine in this study the relative frequencyof mutations in PLCE1, WT1 or LAMB2 as the cause of IDMS ina worldwide cohort. Methods. We identified 40 children from 35 families with IDMSfrom a worldwide cohort of 1368 children with NS. All the subjectswere analyzed for mutations in all exons of PLCE1 by multiplexcapillary heteroduplex analysis and direct sequencing, by directsequencing of exons 8 and 9 of WT1, and all the exons of LAMB2. Results. The median (range) age at onset of NS was 11 (1–72)months. We detected truncating mutations in PLCE1 in 10/35 (28.6%)families and WT1 mutations in 3/35 (8.5%) families. We foundno mutations in LAMB2. Conclusions. PLCE1 mutation is the most common cause of IDMSin this cohort. We previously reported that one child with truncatingmutation in PLCE1 responded to cyclosporine therapy. If thisobservation is confirmed in a larger study, mutations in PLCE1may serve as a biomarker for selecting patients with IDMS whomay benefit from treatment.     

Enhancing epidemiological surveillance of the emergence of the SARS-CoV-2 Omicron variant using spike gene target failure data,England, 15 November to 31 December 2021

When SARS-CoV-2 Omicron emerged in 2021, S gene target failure enabled differentiation between Omicron and the dominant Delta variant. In England, where S gene target surveillance (SGTS) was already established, this led to rapid identification (within ca 3 days of sample collection) of possible Omicron cases, alongside real-time surveillance and modelling of Omicron growth. SGTS was key to public health action (including case identification and incident management), and we share applied insights on how and when to use SGTS.     

Views and experience of breastfeeding in public: A qualitative systematic review

Breastfeeding rates in many Global North countries are low. Qualitative research highlights that breastfeeding in public is a particular challenge, despite mothers often having the legal right to do so. To identify barriers and facilitators, we systematically searched the qualitative research from Organisation for Economic Co‐operation and Development countries relating to breastfeeding in public spaces from 2007 to 2021. Data were analysed using the Thematic Synthesis technique. The review was registered with PROSPERO (registration number: CRD42017081504). Database searching identified 3570 unique records. In total, 74 papers, theses, or book chapters, relating to 71 studies, were included, accounting for over 17,000 mothers. Overall, data quality was high. Our analysis identified that five core factors influenced mothers'' thought processes and their breastfeeding in public behaviour: legal system; structural (in)equality; knowledge; beliefs and the social environment. Macro‐level factors relating to legislation and inequality urgently require redress if breastfeeding rates are to be increased. Widespread culture change is also required to enhance knowledge, change hostile beliefs and thus the social environment in which mother/infant dyads exist. In particular, the sexualisation of breasts, disgust narratives and lack of exposure among observers to baby‐led infant feeding patterns resulted in beliefs which created a stigmatising environment. In this context, many mothers felt unable to breastfeed in public; those who breastfed outside the home were usually highly self‐aware, attempting to reduce their exposure to conflict. Evidence‐based theoretically informed interventions to remove barriers to breastfeeding in public are urgently required.     

Determining the Influence of Habitual Dietary Protein Intake on Physiological Muscle Parameters in Youth and Older Age

Protein ingestion is a potent stimulator of skeletal muscle protein synthesis (MPS). However, older adults demonstrate resistance to anabolic stimuli. Some evidence has demonstrated that a larger acute protein dose is required in older compared to younger adults to elicit the same synthetic response, suggesting that older adults should be consuming higher habitual dietary protein to optimise muscle mass. However, limited research has explored dietary habits in different age groups or the relationship between habitual dietary intake and mechanistic physiological parameters associated with muscle mass and function. This work investigated the effect of habitual dietary intake in young (n = 10, 25.9 (3.2y)) and older (n = 16, 70.2 (3.2y)) community-dwelling adults (16:10 male: female) on physiological muscle parameters. Dietary intake was assessed using four-day diet diaries. Post-absorptive MPS and MPS responses to feeding (4.25x basal metabolic rate; 16% protein) were determined in muscle biopsies of the m. vastus lateralis via stable isotope tracer ([1, 2⁻¹³C₂]-leucine) infusions with mass-spectrometric analyses. Body composition was measured by dual-energy x-ray absorptiometry. Whole body strength was assessed via 1-repetition maximum assessments. No significant differences in habitual dietary intake (protein, fat, carbohydrate and leucine as g.kgWBLM⁻¹.day⁻¹) were observed between age groups. Whole-body lean mass (61.8 ± 9.9 vs. 49.8 ± 11.9 kg, p = 0.01) and knee-extensor strength (87.7 ± 28.3 vs. 56.8 ± 16.4 kg, p = 0.002) were significantly higher in young adults. Habitual protein intake (g.kg⁻¹.day⁻¹) was not associated with whole-body lean mass, upper-leg lean mass, whole-body strength, knee-extensor strength, basal MPS or fed-state MPS across both age groups. These findings suggest that differences in muscle mass and strength parameters between youth and older age are not explained by differences in habitual dietary protein intake. Further research with a larger sample size is needed to fully explore these relationships and inform on interventions to mitigate sarcopenia development.     

A Shot in the Dark: Failing to Recognize the Link Between Physical and Mental Illness

A 74-year-old widowed white man with chronic rheumatoid arthritis presented with nausea and weight loss. He was diagnosed with failure to thrive and admitted for hydration. Misoprostol was determined to be the etiology of his symptoms and he was discharged home. Three days later, he killed himself with a gunshot to the head. Clinicians often fail to recognize those at high risk for suicide. Suicidal risk is increased in both psychiatric and physical illness, and particularly when both are present. Psychiatric illness, particularly depression, often underlies chronic medical illness. The purpose of this case report is to remind health care providers of the strong association between depression and chronic medical illness, and to consider this in all patients, including those who present solely with physical symptoms. Recognizing this association and screening for it, as recommended by the U.S. Preventive Services Task Force, may prevent the unnecessary tragedy of suicide.     

Maternal CASPR2 antibodies and neurodevelopmental disorders in the offspring: epidemiological findings and an animal model

Background

CNS disorders can be caused by IgG antibodies to neuronal surface proteins, and these antibodies have the potential to cross the placenta. Since some of them target proteins involved in neurodevelopment, such as contactin-associated protein-2 (CASPR2), we hypothesised that they could alter developing neuronal circuits in utero and lead to neurodevelopmental disorders in the children.

Neither myonuclear accretion nor a myonuclear domain size ceiling is a feature of the attenuated hypertrophic potential of aged human skeletal muscle

Ageing limits growth capacity of skeletal muscle (e.g. in response to resistance exercise), but the role of satellite cell (SC) function in driving this phenomenon is poorly defined. Younger (Y) (~?23 years) and older (O) men (~?69 years) (normal-weight BMI) underwent 6 weeks of unilateral resistance exercise training (RET). Muscle biopsies were taken at baseline and after 3-/6-week training. We determined muscle size by fibre CSA (and type), SC number, myonuclei counts and DNA synthesis (via D₂O ingestion). At baseline, there were no significant differences in fibre areas between Y and O. RET increased type I fibre area in Y from baseline at both 3 weeks and 6 weeks (baseline: 4509?±?534 µm², 3 weeks; 5497?±?510 µm² P?<?0.05, 6 weeks; 5402?±?352 µm² P?<?0.05), whilst O increased from baseline at 6 weeks only (baseline 5120?±?403 µm², 3 weeks; 5606?±?620 µm², 6 weeks; 6017?±?482 µm² P?<?0.05). However, type II fibre area increased from baseline in Y at both 3 weeks and 6 weeks (baseline: 4949?±?459 µm², 3 weeks; 6145?±?484 µm² (P?<?0.01), 6 weeks; 5992?±?491 µm² (P?<?0.01), whilst O showed no change (baseline 5210?±?410 µm², 3 weeks; 5356?±?535 µm² (P?=?0.9), 6 weeks; 5857?±?478 µm² (P?=?0.1). At baseline, there were no differences in fibre myonuclei number between Y and O. RET increased type I fibre myonuclei number from baseline in both Y and O at 3 weeks and 6 weeks with RET (younger: baseline 2.47?±?0.16, 3 weeks; 3.19?±?0.16 (P?<?0.001), 6 weeks; 3.70?±?0.29 (P?<?0.0001); older: baseline 2.29?±?0.09, 3 weeks; 3.01?±?0.09 (P?<?0.001), 6 weeks; 3.65?±?0.18 (P?<?0.0001)). Similarly, type II fibre myonuclei number increased from baseline in both Y and O at 3 weeks and 6 weeks (younger: baseline 2.49?±?0.14, 3 weeks; 3.31?±?0.21 (P?<?0.001), 6 weeks; 3.86?±?0.29 (P?<?0.0001); older: baseline 2.43?±?0.12, 3 weeks; 3.37?±?0.12 (P?<?0.001), 6 weeks; 3.81?±?0.15 (P?<?0.0001)). DNA synthesis rates %.d^?1 exhibited a main effect of training but no age discrimination. Declines in myonuclei addition do not underlie impaired muscle growth capacity in older humans, supporting ribosomal and proteostasis impairments as we have previously reported.

     

Diagnosis and management of maternal thrombocytopenia in pregnancy

Thrombocytopenia is a common finding in pregnancy, occurring in approximately 7-10% of pregnancies. It may be a diagnostic and management problem, and has many causes, some of which are specific to pregnancy. Although most cases of thrombocytopenia in pregnancy are mild, and have no adverse outcome for either mother or baby, occasionally a low platelet count may be part of a more complex disorder with significant morbidity and may be life-threatening. Overall, about 75% of cases are due to gestational thrombocytopenia, 15-20% secondary to hypertensive disorders; 3-4% due to an immune process, and the remaining 1-2% made up of rare constitutional thrombocytopenias, infections and malignancies. In this review, a diagnostic approach to investigating thrombocytopenia in pregnancy is presented, together with antenatal, anaesthetic and peri-natal management issues for mother and baby, followed by a detailed discussion on the specific causes of thrombocytopenia and the management options in each case.     

Characteristic phenotypes associated with congenital dyserythropoietic anemia (type II) manifest at different stages of erythropoiesis

Congenital dyserythropoietic anemia type II is an autosomally recessive form of hereditary anemia caused by SEC23B gene mutations. Patients exhibit characteristic phenotypes including multinucleate erythroblasts, erythrocytes with hypoglycosylated membrane proteins and an apparent double plasma membrane. Despite ubiquitous expression of SEC23B, the effects of mutations in this gene are confined to the erythroid lineage and the basis of this erythroid specificity remains to be defined. In addition, little is known regarding the stage at which the disparate phenotypes of this disease manifest during erythropoiesis. We employ an in vitro culture system to monitor the appearance of the defining phenotypes associated with congenital dyserythropoietic anemia type II during terminal differentiation of erythroblasts derived from small volumes of patient peripheral blood. Membrane protein hypoglycosylation was detected by the basophilic stage, preceding the onset of multinuclearity in orthochromatic erythroblasts that occurs coincident with the loss of secretory pathway proteins including SEC23A during erythropoiesis. Endoplasmic reticulum remnants were observed in nascent reticulocytes of both diseased and healthy donor cultures but were lost upon further maturation of normal reticulocytes, implicating a defect of ER clearance during reticulocyte maturation in congenital dyserythropoietic anemia type II. We also demonstrate distinct isoform and species-specific expression profiles of SEC23 during terminal erythroid differentiation and identify a prolonged expression of SEC23A in murine erythropoiesis compared to humans. We propose that SEC23A is able to compensate for the absence of SEC23B in mouse erythroblasts, providing a basis for the absence of phenotype within the erythroid lineage of a recently described SEC23B knockout mouse.