Sarcomeric determinants of striated muscle relaxation kinetics

Ca²⁺ is the primary regulator of force generation by cross-bridges in striated muscle activation and relaxation. Relaxation is as necessary as contraction and, while the kinetics of Ca²⁺-induced force development have been investigated extensively, those of force relaxation have been both studied and understood less well. Knowledge of the molecular mechanisms underlying relaxation kinetics is of special importance for understanding diastolic function and dysfunction of the heart. A number of experimental models, from whole muscle organs and intact muscle fibres down to single myofibrils, have been used to explore the cascade of kinetic events leading to mechanical relaxation. By using isolated myofibrils and fast solution switching techniques we can distinguish the sarcomeric mechanisms of relaxation from those of myoplasmic Ca²⁺ removal. There is strong evidence that cross-bridge mechanics and kinetics are major determinants of the time course of striated muscle relaxation whilst thin filament inactivation kinetics and cooperative activation of thin filament by cycling, force-generating cross-bridges do not significantly limit the relaxation rate. Results in myofibrils can be explained well by a simple two-state model of the cross-bridge cycle in which the apparent rate of the force generating transition is modulated by fast, Ca²⁺-dependent equilibration between off- and on-states of actin. Inter-sarcomere dynamics during the final rapid phase of full force relaxation are responsible for deviations from this simple model.     

From surnames to the history of Y chromosomes: the Sardinian population as a paradigm

A total of 202 Sardinian male subjects were examined for 13 biallelic stable markers, the complex 49a,f/TaqI system and three microsatellites of the Y chromosome in order to investigate, through surname analysis, on a possible territorial heterogeneity inside the island. The study of geographical distribution and linguistic derivation of Sardinian surnames allow us to discover their 'probable place of origin' and reconstruct ancient genetic isolates which borders are, today, no more recognizable. The molecular analysis revealed that about 90% of the Sardinian Y chromosomes fell into haplogroups E-M35, G-M201, I-M26, J-12f2 and R-M269. In contrast with the territorial homogeneity of these haplogroups, when the individuals were distributed according to their birthplace, a significant difference between the three historically and culturally distinct geographical areas into which Sardinia can be subdivided was observed when the individuals were distributed according to the ancestral location of surnames. In particular, the major contribution to this heterogeneity is due to the 'Sardinian-specific' haplogroup I-M26 (almost completely associated with the 49a,f-Ht12/12f2-10Kb/YCAIIa-21/YCAIIb-11 compound haplotype), which shows both a significantly higher incidence in the central-eastern (archaic) area and a significantly lower frequency in the northern area. The results of this study agree with the hypothesis that the ancestral homeland of this specific subset of haplogroup I is the mountainous central-eastern area of Sardinia, where the population underwent a long history of isolation since ancient times, and highlight the informative power of the surname analysis.     

Biodegradation of poly(D(–)-3-hydroxybutyrate)/atactic poly(epichlorohydrin) blends by aureobacterium saperdae

The biodegradability of solution-cast films of poly(D (–)-3-hydroxybutyrate) (PHB) blended with the melt-compatible component atactic poly(epichlorohydrin) (aPECH) was investigated. A bacterium which produced extracellular enzymes that degraded PHB even when blended with aPECH was isolated, and tentatively designated as Aureobacterium saperdae. The growth rate of A. saperdae decreased with increasing aPECH content in the blend, up to films containing 60 wt.-% aPECH, at which composition growth was completely inhibited. The decrease in the bacterial growth rate could be due to the dilution of PHB molecules on the blend film surface caused by the presence of aPECH molecules. At the stationary phase of bacterial growth the percentage of weight loss of blend films decreased with increasing aPECH fraction, which was probably due to the lower accessibility of PHB when blended with aPECH. During the bacterial growth only PHB was metabolized, whereas neither degradation nor abiotic release of aPECH was detected for blend films.     

Merlin expression in secretory meningiomas: evidence of an NF2-independent pathogenesis? Immunohistochemical study.

One of the most common chromosomal regions implicated in the meningiomas tumorigenesis is 22q12 where the neurofibromatosis 2 (NF2) gene resides. The NF2 tumor-suppressor gene encodes for the merlin/schwannomin protein, which is responsible for the inherited disease neurofibromatosis 2. NF2 gene mutations predominantly occur in transitional and fibroblastic meningiomas, whereas the meningothelial variant is less affected. Secretory meningioma is an infrequent meningioma subtype. Its most typical morphologic feature is the presence of intracytoplasmic or extracytoplasmic round hyaline, eosinophilic, and periodic acid Shiff-positive bodies in a lesion frequently otherwise classifiable as meningothelial meningioma. This study reviews the immunohistochemical merlin expression in 14 consecutive secretory meningiomas. Our purpose was to investigate if secretory meningiomas, analogous to meningothelial meningiomas, follow a molecular route of pathogenesis independent of the neurorofibromatosis 2 gene-associated pathway. All meningiomas showed positive immunocoloration involving the majority of the hyaline inclusions and secretory cells; in 12 (86%) meningiomas, a positive immunoreaction was also documented in nonsecretory tumoral cells. Our results may indicate a molecular, besides morphologic, similarity between secretory and meningothelial meningiomas: the almost constant merlin immunohistochemical expression in our series gives evidence for a possible NF2 gene-independent pathogenesis in secretory meningiomas.     

Distinct immunological signatures discriminate severe COVID-19 from non-SARS-CoV-2-driven critical pneumonia

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Reduced Left Ventricular Compliance and Mechanical Efficiency after Prolonged Inhibition of NO Synthesis in Conscious Dogs

Acute inhibition of NO synthesis decreases left ventricular (LV) work and external efficiency, but it is unknown whether compensatory mechanisms can limit the alterations in LV mechanoenergetics after prolonged NO deficiency. Eight chronically instrumented male mongrel dogs received 35 mg kg⁻¹ day⁻¹ of N ^ω-nitro-L-arginine methyl ester orally for 10 days to inhibit NO synthesis. At spontaneous beating frequency, heart rate, coronary blood flow, peak LV pressure, end-diastolic LV pressure and the maximum derivative of LV pressure (d P /d t _max) were not significantly different vs. baseline, whereas LV end-diastolic diameter (32.5 ± 1.0 vs. 37.6 ± 1.4 mm) and LV stroke work (515 ± 38 vs. 650 ± 44 mmHg mm), were reduced (all P < 0.05). The slope of the LV end-systolic pressure-diameter relationship was increased at 10 days vs. baseline (13.9 ± 1.0 vs. 9.6 ± 0.9 mmHg mm⁻¹, P < 0.05), while the end-diastolic LV diameter was smaller at matched LV end-diastolic pressures. At fixed heart rate (130 beats min⁻¹), cardiac oxygen consumption was increased (12.2 ± 1.5 vs. 9.9 ± 1.0 ml min⁻¹), and the ratio between stroke work and oxygen consumption was decreased by 33 ±7 % (all P < 0.05) after NO inhibition. We conclude that sustained inhibition of NO synthesis in dogs causes a decrease in LV work despite an increased contractility, which is most probably due to reduced diastolic compliance and a decrease in external efficiency. Thus, prolonged NO deficiency is not compensated for on the level of LV mechanoenergetics in vivo .     

Listening to patients' needs to improve their subjective quality of life

BACKGROUND: Subjective quality of life has gained a crucial role as a global measure of outcome in mental health care. This study aimed to investigate the impact of meeting needs for care, as assessed by both patients and mental health professionals, to improve the subjective quality of life in a sample of patients receiving community-based psychiatric care. METHOD: The study was conducted using a 4-year prospective longitudinal design. A cohort of patients from the South-Verona Community-based Mental Health Service (CMHS) was assessed at baseline and follow-up using, among other social and clinical measures, the Camberwell Assessment of Need (both staff and patient versions) and the Lancashire Quality of Life Profile. Predictors of changes of subjective quality of life were explored using block-stratified multiple regression procedures. RESULTS: Improvement in patients' clinical conditions as well as the reduction in patient-rated unmet needs in the social domain predicted an increase in subjective quality of life over 4 years; changes in staff-rated needs did not show any association with changes in subjective quality of life. CONCLUSIONS: Meeting self-perceived social needs, beyond symptoms reduction, seems to be of particular importance for ensuring a better quality of life for people with mental disorders. If the main goal of mental health care is to improve the quality of life of users, a policy of actively addressing patient-rated needs should be implemented.     

Clinical,immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study

A questionnaire-based retrospective clinical and immunological survey was conducted in 73 males with a definite diagnosis of X-linked agammaglobulinemia based on BTK sequence analysis. Forty-four were sporadic and 29 familial cases. At December 2000, the patients' ages ranged from 2 to 33 years; mean age at diagnosis and mean duration of follow-up were 3.5 and 10 years respectively. After the mid-1980s all but 2 were on intravenous immunoglobulin (IVIG) substitution therapy, with residual IgG >500 mg/dl in 94% of the patients at the time of enrollment. Respiratory infections were the most frequent manifestation both prior to diagnosis and over follow-up. Chronic lung disease (CLD) was present in 24 patients, in 15 already at diagnosis and in 9 more by 2000. The cumulative risk to present at diagnosis with CLD increased from 0.17 to 0.40 and 0.78 when the diagnosis was made at the ages of 5, 10, and 15 years respectively. For the 9 patients who developed CLD during follow-up, the duration of follow-up, rather than age at diagnosis; previous administration of intramuscular immunoglobulin; and residual IgG levels had a significant effect on the development of CLD. Chronic sinusitis was present in 35 patients (48%), in 15 already at diagnosis and in 20 by 2000. Sistemic infections such as sepsis and meningitis/meningoencephalitis decreased over follow-up, probably due to optimal protection provided by high circulating IgG levels reached with IVIG.     

Deletion of the mental retardation gene Gdi1 impairs associative memory and alters social behavior in mice

Non-specific mental retardation (NSMR) is a common human disorder characterized by mental handicap as the only clinical symptom. Among the recently identified MR genes is GDI1, which encodes alpha Gdi, one of the proteins controlling the activity of the small GTPases of the Rab family in vesicle fusion and intracellular trafficking. We report the cognitive and behavioral characterization of mice carrying a deletion of Gdi1. The Gdi1-deficient mice are fertile and anatomically normal. They appear normal also in many tasks to assess spatial and episodic memory and emotional behavior. Gdi1-deficient mice are impaired in tasks requiring formation of short-term temporal associations, suggesting a defect in short-term memory. In addition, they show lowered aggression and altered social behavior. In mice, as in humans, lack of Gdi1 spares most central nervous system functions and preferentially impairs only a few forebrain functions required to form temporal associations. The general similarity to human mental retardation is striking, and suggests that the Gdi1 mutants may provide insights into the human defect and into the molecular mechanisms important for development of cognitive functions.     

Asymmetrical hemispheric EEG activation evoked by stimulus position during the Simon task

The Simon effect has been previously shown to be asymmetric at both the behavioral and electrophysiological levels. The present investigation was aimed to clarify whether, during a Simon task, hemispheric asymmetry is also observed in the early phases of stimulus processing. In a group of healthy subjects performing the Simon task, we analyzed scalp potentials evoked by the first lateralized cue (left or right), instead of the classical readiness potential preceding the motor response. ERP results showed a significant left cortical activation to stimuli presented in the right visual field at the 140–160 ms time window. Instead, left stimuli elicited a significant activation of the right versus left hemisphere starting at the next 160–180 ms time interval. We linked this asymmetry to that observed in behavioral data: the Simon effect recorded with left stimuli is smaller than the Simon effect recorded with right stimuli. Results confirm the hypothesis that in right handed subjects, left hemisphere is specialized for motor response selection and is able to process right stimuli faster than the right hemisphere does for left stimuli.