Case Report: A child with NFKB1 haploinsufficiency explaining the linkage between immunodeficiency and short stature.

We report the case of a patient with common variable immunodeficiency (CVID) presenting with short stature and treated with recombinant human growth hormone (rhGH). Whole exome sequencing revealed a novel single-nucleotide duplication in the NFKB1 gene (c.904dup, p.Ser302fs), leading to a frameshift and thus causing NFKB1 haploinsufficiency. The variant was considered pathogenic and was later found in the patient's mother, also affected by CVID. This is the first reported case of a patient with CVID due to NFKB1 mutation presenting with short stature. We analyzed the interconnection between NFKB1 and GH - IGF-1 pathways and we hypothesized a common ground for both CVID and short stature in our patient.

Microglial diversity along the hippocampal longitudinal axis impacts synaptic plasticity in adult male mice under homeostatic conditions.

The hippocampus is a plastic brain area that shows functional segregation along its longitudinal axis, reflected by a higher level of long-term potentiation (LTP) in the CA1 region of the dorsal hippocampus (DH) compared to the ventral hippocampus (VH), but the mechanisms underlying this difference remain elusive. Numerous studies have highlighted the importance of microglia-neuronal communication in modulating synaptic transmission and hippocampal plasticity, although its role in physiological contexts is still largely unknown. We characterized in depth the features of microglia in the two hippocampal poles and investigated their contribution to CA1 plasticity under physiological conditions. We unveiled the influence of microglia in differentially modulating the amplitude of LTP in the DH and VH, showing that minocycline or PLX5622 treatment reduced LTP amplitude in the DH, while increasing it in the VH. This was recapitulated in Cx3cr1 knockout mice, indicating that microglia have a key role in setting the conditions for plasticity processes in a region-specific manner, and that the CX3CL1-CX3CR1 pathway is a key element in determining the basal level of CA1 LTP in the two regions. The observed LTP differences at the two poles were associated with transcriptional changes in the expression of genes encoding for Il-1, Tnf-α, Il-6, and Bdnf, essential players of neuronal plasticity. Furthermore, microglia in the CA1 SR region showed an increase in soma and a more extensive arborization, an increased prevalence of immature lysosomes accompanied by an elevation in mRNA expression of phagocytic markers Mertk and Cd68 and a surge in the expression of microglial outward K+ currents in the VH compared to DH, suggesting a distinct basal phenotypic state of microglia across the two hippocampal poles. Overall, we characterized the molecular, morphological, ultrastructural, and functional profile of microglia at the two poles, suggesting that modifications in hippocampal subregions related to different microglial statuses can contribute to dissect the phenotypical aspects of many diseases in which microglia are known to be involved.

Initial Dynamic Susceptibility of Maghemite Nanoparticles Dispersed in Surface-Treated Polymeric Template.

Magnetic nanocomposites based on maghemite nanoparticles supported (ex situ route) on styrene- divinilbenzene (Sty-DVB) copolymer templates were produced and characterized for their structure and morphology. The as-produced nanocomposites were further chemically-treated with different oxidant agents and surface-coated with stearic acid. X-ray diffraction and transmission electron microscopy data show that the incorporated nanoparticles are preserved despite the aggressive chemical treatments employed. From the dynamical susceptibility measurements performed on the nanocomposites, the values of the saturation magnetization (76 emu/g) and the effective magnetic anisotropy (1.7 × 104 J/m³) were obtained, in excellent agreement with the values reported in the literature for maghemite. This finding strongly supports the preservation of the magnetic properties of the supported nanosized maghemite throughout the entire samples' processing.

Deep phenotyping of facioscapulohumeral muscular dystrophy type 2 by magnetic resonance imaging.

BACKGROUND AND PURPOSE: The aim was to define the radiological picture of facioscapulohumeral muscular dystrophy 2 (FSHD2) in comparison with FSHD1 and to explore correlations between imaging and clinical/molecular data. METHODS: Upper girdle and/or lower limb muscle magnetic resonance imaging scans of 34 molecularly confirmed FSHD2 patients from nine European neuromuscular centres were analysed. T1-weighted and short-tau inversion recovery (STIR) sequences were used to evaluate the global pattern and to assess the extent of fatty replacement and muscle oedema. RESULTS: The most frequently affected muscles were obliquus and transversus abdominis, semimembranosus, soleus and gluteus minimus in the lower limbs; trapezius, serratus anterior, latissimus dorsi and pectoralis major in the upper girdle. Iliopsoas, popliteus, obturator internus and tibialis posterior in the lower limbs and subscapularis, spinati, sternocleidomastoid and levator scapulae in the upper girdle were the most spared. Asymmetry and STIR hyperintensities were consistent features. The pattern of muscle involvement was similar to that of FSHD1, and the combined involvement of trapezius, abdominal and hamstring muscles, together with complete sparing of iliopsoas and subscapularis, was detected in 91% of patients. Peculiar differences were identified in a rostro-caudal gradient, a predominant involvement of lower limb muscles compared to the upper girdle, and in the higher percentage of STIR hyperintensities in FSHD2. CONCLUSION: This multicentre study defines the pattern of muscle involvement in FSHD2, providing useful information for diagnostics and clinical trial design. Both similarities and differences between FSHD1 and FSHD2 were detected, which is also relevant to better understand the pathogenic mechanisms underlying the FSHD-related disease spectrum.

Modeling the allosteric modulation on a G-Protein Coupled Receptor: the case of M2 muscarinic Acetylcholine Receptor in complex with LY211960.

Allosteric modulation is involved in a plethora of diverse protein functions, which are fundamental for cells' life. This phenomenon can be thought as communication between two topographically distinct site of a protein structure. How this communication occurs is still matter of debate. Many different descriptions have been presented so far. Here we consider a specific case where any significant conformational change is involved upon allosteric modulator binding and the phenomenon is depicted as a vibrational energy diffusion process between distant protein regions. We applied this model, by employing computational tools, to the human muscarinic receptor M2, a transmembrane protein G-protein coupled receptor known to undergo allosteric modulation whose recently X-ray structure has been recently resolved both with and without the presence of a particular allosteric modulator. Our calculations, performed on these two receptor structures, suggest that for this case the allosteric modulator modifies the energy current between functionally relevant regions of the protein; this allows to identify the main residues responsible for this modulation. These results contribute to shed light on the molecular basis of allosteric modulation and may help design new allosteric ligands.

Value of insoluble PABPN1 accumulation in the diagnosis of oculopharyngeal muscular dystrophy.

BACKGROUND AND PURPOSE: The aim was to assess the value of insoluble PABPN1 muscle fibre nuclei accumulation in the diagnosis of atypical cases of oculopharyngeal muscular dystrophy (OPMD). METHODS: Muscle biopsies from a selected cohort of 423 adult patients from several Italian neuromuscular centres were analysed by immunofluorescence: 30 muscle biopsies of genetically proven OPMD, 30 biopsies from patients not affected by neuromuscular disorders, 220 from genetically undiagnosed patients presenting ptosis or swallowing disturbances, progressive lower proximal weakness and/or isolated rimmed vacuoles at muscle biopsy and 143 muscle biopsies of patients affected by other neuromuscular diseases. RESULTS: The detection of insoluble nuclear PABPN1 accumulation is rapid, sensitive (100%) and specific (96%). The revision of our cohort allowed us to discover 23 new OPMD cases out of 220 patients affected with nonspecific muscle diseases. CONCLUSIONS: Oculopharyngeal muscular dystrophy is often misdiagnosed leading to diagnosis delay, causing waste of time and resources. A great number of these cases present symptoms and histological findings frequently overlapping with other muscle diseases, i.e. inclusion body myositis and progressive external ophthalmoplegia. PABPN1 nuclear accumulation is a reliable method for diagnostic purposes and it is safe and useful in helping pathologists and clinicians to direct genetic analysis in the case of suspected OPMD, even when clinical and histological clues are deceptive.

Evaluation of quality of life and static balance in postmenopausal osteoporosis women after Tai Chi Chuan practice: an observational randomized case control study.

Post-menopausal osteoporosis women are at increased risk for skeletal fractures with higher mortality and lower quality of life. Some studies have reported fall risk reduction in the elderly after Tai chi practice. Tai chi is a weight bearing mind-body exercise that has been reported to positively influence bone mineral density and improve postural control in different pathologies. The aim of this observational randomized case control study is to evaluate the effect of Tai chi on balance and quality of life in postmenopausal women with osteoporosis. A total of 98 postmenopausal osteoporosis women, aged 70.6±8.2 years (mean and standard deviation), (mean T-score of the hip and spine were-2.9± 0.92 and -2.8±1.08), have been recruited in outpatients University Physical Medicine and Rehabilitation Hospital between June 2016 and September 2018. They have been randomized to a Tai group (56 patients, mean age 71.61±7.97 years) practiced 6-month Tai chi program, two times week, plus standard care or to a Control Group (42 patients, mean age 69.71±8.61 years) practiced usual care. Patients with oncological, neurological, cognitive, vestibular and visual diseases were excluded. Patients were evaluated at baseline (T0), prior Tai chi and after 6 month (T1) with 36-Item Short Form Health Survey (SF-36), and a stabilometric-standardized exam performed for the evaluation, respectively, of the quality of life and the static balance. The groups were homogenous at baseline. T1 evaluation showed better results in Tai chi group, in SF36 Physical functioning (p level: 0.021), Physical health pain (p level: 0.020), Physical composite score (p level: 0.003) scores, compared with control group. There were not significant differences between groups in stabilometric analysis. Tai chi group showed significant better stabilometric values at T1 compared with T0 in mean anterior-posterior (p level: 0.001) and medio-lateral (p level: 0.019) velocity, in perimeter (p level 0.001) , and in the area of the ellipse ( p level 0.006) in a within group analysis. Tai chi seemed to be effective in improving physical aspects of quality of life, in postmenopausal women with osteoporosis. Standing balance seems to increase after 6 months Tai chi program, in post-menopausal also if results were not significant. Further studies will be useful to measure effects of a Tai chi longer practice, as literature suggests, and a possible reduction of falling risk and fractures.

Correction to: Inert gas narcosis in scuba diving, different gases different reactions.

The original version of this article unfortunately contained a mistake.

Inert gas narcosis in scuba diving, different gases different reactions.

PURPOSE: Underwater divers face several potential neurological hazards when breathing compressed gas mixtures including nitrogen narcosis which can impact diver's safety. Various human studies have clearly demonstrated brain impairment due to nitrogen narcosis in divers at 4 ATA using critical flicker fusion frequency (CFFF) as a cortical performance indicator. However, recently some authors have proposed a probable adaptive phenomenon during repetitive exposure to high nitrogen pressure in rats, where they found a reversal effect on dopamine release. METHODS: Sixty experienced divers breathing Air, Trimix or Heliox, were studied during an open water dive to a depth of 6 ATA with a square profile testing CFFF measurement before (T0), during the dive upon arriving at the bottom (6 ATA) (T1), 20 min of bottom time (T2), and at 5 m (1.5 ATA) (T3). RESULTS: CFFF results showed a slight increase in alertness and arousal during the deep dive regardless of the gas mixture breathed. The percent change in CFFF values at T1 and T2 differed among the three groups being lower in the air group than in the other groups. All CFFF values returned to basal values 5 min before the final ascent at 5 m (T3), but the Trimix measurements were still slightly better than those at T0. CONCLUSIONS: Our results highlight that nitrogen and oxygen alone and in combination can produce neuronal excitability or depression in a dose-related response.

Vibrational Energy in Proteins Correlates with Topology.

The exchange of vibrational energy in proteins is crucial for their function. Here, we establish a connection between quantities related to it with geometry-based properties such as the proteins' residues coordination number. This relation is proven by molecular simulation in a neuro-pharmacologically relevant transmembrane receptor. The connection demonstrated here paves the way to studies of protein allostery and conformational changes based solely on protein structure.

MicroRNA-335-5p modulates spatial memory and hippocampal synaptic plasticity.

MicroRNAs are endogenous, noncoding RNAs crucial for the post-transcriptional regulation of gene expression. In this study, we investigated the role of miR-335-5p in spatial learning and synaptic plasticity. To this end we first showed spatial learning induced down-regulation of miR-335-5p. Next we found impairment in long-term memory and reduction in hippocampal long-term potentiation by exogenous administration of the miRNA. These findings demonstrate that miR-335-5p is a key coordinator of the intracellular pathways that mediate experience-dependent changes in the brain.

Fluoxetine effects on molecular, cellular and behavioral endophenotypes of depression are driven by the living environment.

Selective serotonin reuptake inhibitors (SSRIs) represent the most common treatment for major depression. However, their efficacy is variable and incomplete. In order to elucidate the cause of such incomplete efficacy, we explored the hypothesis positing that SSRIs may not affect mood per se but, by enhancing neural plasticity, render the individual more susceptible to the influence of the environment. Consequently, SSRI administration in a favorable environment promotes a reduction of symptoms, whereas in a stressful environment leads to a worse prognosis. To test such hypothesis, we exposed C57BL/6 mice to chronic stress in order to induce a depression-like phenotype and, subsequently, to fluoxetine treatment (21 days), while being exposed to either an enriched or a stressful condition. We measured the most commonly investigated molecular, cellular and behavioral endophenotypes of depression and SSRI outcome, including depression-like behavior, neurogenesis, brain-derived neurotrophic factor levels, hypothalamic-pituitary-adrenal axis activity and long-term potentiation. Results showed that, in line with our hypothesis, the endophenotypes investigated were affected by the treatment according to the quality of the living environment. In particular, mice treated with fluoxetine in an enriched condition overall improved their depression-like phenotype compared with controls, whereas those treated in a stressful condition showed a distinct worsening. Our findings suggest that the effects of SSRI on the depression- like phenotype is not determined by the drug per se but is induced by the drug and driven by the environment. These findings may be helpful to explain variable effects of SSRI found in clinical practice and to device strategies aimed at enhancing their efficacy by means of controlling environmental conditions.

MYH7-related myopathies: clinical, histopathological and imaging findings in a cohort of Italian patients.

BACKGROUND: Myosin heavy chain 7 (MYH7)-related myopathies are emerging as an important group of muscle diseases of childhood and adulthood, with variable clinical and histopathological expression depending on the type and location of the mutation. Mutations in the head and neck domains are a well-established cause of hypertrophic cardiomyopathy whereas mutation in the distal regions have been associated with a range of skeletal myopathies with or without cardiac involvement, including Laing distal myopathy and Myosin storage myopathy. Recently the spectrum of clinical phenotypes associated with mutations in MYH7 has increased, blurring this scheme and adding further phenotypes to the list. A broader disease spectrum could lead to misdiagnosis of different congenital myopathies, neurogenic atrophy and other neuromuscular conditions. RESULTS: As a result of a multicenter Italian study we collected clinical, histopathological and imaging data from a population of 21 cases from 15 families, carrying reported or novel mutations in MYH7. Patients displayed a variable phenotype including atypical pictures, as dropped head and bent spine, which cannot be classified in previously described groups. Half of the patients showed congenital or early infantile weakness with predominant distal weakness. Conversely, patients with later onset present prevalent proximal weakness. Seven patients were also affected by cardiomyopathy mostly in the form of non-compacted left ventricle. Muscle biopsy was consistent with minicores myopathy in numerous cases. Muscle MRI was meaningful in delineating a shared pattern of selective involvement of tibialis anterior muscles, with relative sparing of quadriceps. CONCLUSION: This work adds to the genotype-phenotype correlation of MYH7-relatedmyopathies confirming the complexity of the disorder.

Response to pneumococcal polysaccharide vaccine in children with asthma, and children with recurrent respiratory infections, and healthy children.

BACKGROUND: To analyse specific immune response to the 23-valent pneumococcal polysaccharide vaccine by measuring pneumococcal antibodies in children with asthma and with respiratory recurrent infection (RRI) as compared to healthy children. METHODS: The study included 60 children, divided into three groups: 20 with asthma, 20 with RRI, and 20 healthy controls. Post-vaccination specific IgG antibodies against 10 pneumococcal serotypes (S1, S3, S4, S5, S6B, S9V, S14, S18C, S19F, and S23F) contained in the 23-valent pneumococcal polysaccharide vaccine (PPV) were measured. A specific IgG concentration ≥1.3µg/mL was considered a protective response to the vaccine. For statistical analysis, levels of specific IgG antibodies against each of the 10 pneumococcal serotypes were compared across the three groups of children using the x(2) test. RESULTS: All of the children showed antipneumococcal antibody levels >1.3µg/mL for over 70% of the serotypes, considered within the normal range of response. Average IgG antibody levels and percentages of children protected were statistically comparable among the three groups studied. CONCLUSION: The asthmatic children without RRI had pneumococcal antibody levels and percentages of serotype-specific protection to PPV comparable to those of healthy children. Asthmatic children with recurrent infections should be evaluated for specific antibody deficiency (SAD). Because asthma patients are at high risk for invasive pneumococcal infections, it would be worthwhile to explore systematic administration of PPV in children over the age of two years who have not received a pneumococcal conjugate vaccine, considering the positive response to PPV reported here.

Consumer interest in specialty beers in three European markets.

This study explores the quality perception of specialty beers (SBs) in Italy, Spain and Poland. Five-hundred and fifty mainstream beer consumers were enrolled in this study (two-hundred and thirty Italians, one hundred and sixty Poles and Spaniards respectively). The authors adopted a conjoint rating experiment in which the respondents were given forty SB profiles to evaluate. Each profile was described on six attributes (malt type, adjuncts, alternative source of sugars, characterizing ingredients, sensory characteristics, and retail price) varied at different levels and were asked to state his/her preference for each profile on a 9-point scale of interest. The results of this study showed that the ideal SB: (1) for the aggregate Polish panel is brewed from malted wheat, raw wheat, honey, and tropical fruits, is alcoholic and is priced below 2.00 Euros; (2) for the aggregate Italian panel consists of a beer brewed from malted wheat, maize, honey, and vanilla, is blonde and costs a maximum of 2.00 Euros; (3) for the aggregate Spanish panel is brewed from malted wheat, rye or maize, vanilla, is fruity and is priced below 2.00 Euros. The heterogeneity of interest in specialty beers observed in the three countries under test requires for the adaptation of a SB specifically to each culture in which it is sold. In this process of customization, brewers must take into account that gender modulates the effect of culture on consumer interest in SB sensory characteristics and ingredient formulation.