Pathogenic variants in GNPTAB and GNPTG encoding distinct subunits of GlcNAc-1-phosphotransferase differentially impact bone resorption in patients with mucolipidosis type II and III.

PURPOSE: Pathogenic variants in GNPTAB and GNPTG, encoding different subunits of GlcNAc-1-phosphotransferase, cause mucolipidosis (ML) II, MLIII alpha/beta, and MLIII gamma. This study aimed to investigate the cellular and molecular bases underlying skeletal abnormalities in patients with MLII and MLIII. METHODS: We analyzed bone biopsies from patients with MLIII alpha/beta or MLIII gamma by undecalcified histology and histomorphometry. The skeletal status of Gnptgko and Gnptab-deficient mice was determined and complemented by biochemical analysis of primary Gnptgko bone cells. The clinical relevance of the mouse data was underscored by systematic urinary collagen crosslinks quantification in patients with MLII, MLIII alpha/beta, and MLIII gamma. RESULTS: The analysis of iliac crest biopsies revealed that bone remodeling is impaired in patients with GNPTAB-associated MLIII alpha/beta but not with GNPTG-associated MLIII gamma. Opposed to Gnptab-deficient mice, skeletal remodeling is not affected in Gnptgko mice. Most importantly, patients with variants in GNPTAB but not in GNPTG exhibited increased bone resorption. CONCLUSION: The gene-specific impact on bone remodeling in human individuals and in mice proposes distinct molecular functions of the GlcNAc-1-phosphotransferase subunits in bone cells. We therefore appeal for the necessity to classify MLIII based on genetic in addition to clinical criteria to ensure appropriate therapy.

Aflatoxin B1-contaminated diet disrupts the blood-brain barrier and affects fish behavior: Involvement of neurotransmitters in brain synaptosomes.

It is known that the cytotoxic effects of aflatoxin B1 (AFB1) in endothelial cells of the blood-brain barrier (BBB) are associated with behavioral dysfunction. However, the effects of a diet contaminated with AFB1 on the behavior of silver catfish remain unknown. Thus, the aim of this study was to evaluate whether an AFB1-contaminated diet (1177 ppb kg feed-1) impaired silver catfish behavior, as well as whether disruption of the BBB and alteration of neurotransmitters in brain synaptosomes are involved. Fish fed a diet contaminated with AFB1 presented a behavioral impairment linked with hyperlocomotion on days 14 and 21 compared with the control group (basal diet). Neurotransmitter levels were also affected on days 14 and 21. The permeability of the BBB to Evans blue dye increased in the intoxicated animals compared with the control group, which suggests that the BBB was disrupted. Moreover, acetylcholinesterase (AChE) activity in brain synaptosomes was increased in fish fed a diet contaminated with AFB1, while activity of the sodium-potassium pump (Na+, K+-ATPase) was decreased. Based on this evidence, the present study shows that silver catfish fed a diet containing AFB1 exhibit behavioral impairments related to hyperlocomotion. This diet caused a disruption of the BBB and brain lesions, which may contribute to the behavioral changes. Also, the alterations in the activities of AChE and Na+, K+-ATPase in brain synaptosomes may directly contribute to this behavior, since they may promote synapse dysfunction. In addition, the hyperlocomotion may be considered an important macroscopic marker indicating possible AFB1 intoxication.

Citrobacter freundii impairs the phosphoryl transfer network in the gills of Rhamdia quelen: Impairment of bioenergetics homeostasis.

The precise coupling of spatially separated intracellular adenosine triphosphate (ATP)-producing and ATP-consuming, catalyzed by creatine kinase (CK), adenylate kinase (AK), and pyruvate kinase (PK), is a critical process in the bioenergetics of tissues with high energy demand, such as the branchial tissue. The effects of Citrobacter freundii infection on gills remain poorly understood, limited only to histopathological studies. Thus, the aim of this study was to evaluate whether experimental infection by C. freundii impairs the enzymes of the phosphoryl transfer network in gills of silver catfish (Rhamdia quelen). The CK (cytosolic and mitochondrial) and AK activities decreased in infected compared to uninfected animals, while the PK activity did not differ between groups. The gill histopathology of infected animals revealed extensive degeneration with fusion and necrosis of secondary lamellae, detachment of superficial epithelium, aneurysm, vessel congestion and inflammatory process. Based on these evidences, the inhibition and absence of an efficient communication between CK compartments caused the impairment of the branchial bioenergetics homeostasis, which was not compensated by the augmentation on branchial AK activity in an attempt to restore energy homeostasis. In summary, these alterations contribute to disease pathogenesis linked to branchial tissue in animals infected with C. freundii.

Combined Analysis of Neutrino and Antineutrino Oscillations at T2K.

T2K reports its first results in the search for CP violation in neutrino oscillations using appearance and disappearance channels for neutrino- and antineutrino-mode beams. The data include all runs from January 2010 to May 2016 and comprise 7.482×10^{20} protons on target in neutrino mode, which yielded in the far detector 32 e-like and 135 µ-like events, and 7.471×10^{20} protons on target in antineutrino mode, which yielded 4 e-like and 66 µ-like events. Reactor measurements of sin^{2}2θ_{13} have been used as an additional constraint. The one-dimensional confidence interval at 90% for the phase δ_{CP} spans the range (-3.13, -0.39) for normal mass ordering. The CP conservation hypothesis (δ_{CP}=0, π) is excluded at 90% C.L.

Pseudomonas aeruginosa strain PA01 impairs enzymes of the phosphotransfer network in the gills of Rhamdia quelen.

Integration of mitochondria with cytosolic ATP-consuming/ATP-sensing and substrate supply processes is critical for gills bioenergetics, since this tissue plays an important role in the respiratory energy metabolism. The effects of bacterial infection on gills remain poorly understood, limited only to histopathological analyses. Thus, the aim of this study was to investigate whether experimental infection by Pseudomonas aeruginosa strain PA01 alters the enzymes of the phosphoryltransfer network (adenylate kinase (AK), pyruvate kinase (PK) and cytosolic and mitochondrial creatine kinase (CK)) in gills of silver catfish (Rhamdia quelen). The animals were divided into two groups with six fish each: uninfected (negative control) and infected (positive control). On day 7 post-infection (PI), animals were euthanized and the gills collected. AK, PK, and cytosolic and mitochondrial CK activities in gills decreased in infected compared to uninfected animals. Also, severe gill damage and destruction in the primary and secondary lamellae was observed in the infected animals. Therefore, we have demonstrated, for the first time, that experimental infection by P. aeruginosa inhibits key enzymes linked to the production and utilization of metabolic energy in silver catfish, and consequently, impairs cellular energy homeostasis, which may contribute to disease pathogenesis.

Measurement of Coherent π

We report the first measurement of the flux-averaged cross section for charged current coherent π^{+} production on carbon for neutrino energies less than 1.5 GeV, and with a restriction on the final state phase space volume in the T2K near detector, ND280. Comparisons are made with predictions from the Rein-Sehgal coherent production model and the model by Alvarez-Ruso et al., the latter representing the first implementation of an instance of the new class of microscopic coherent models in a neutrino interaction Monte Carlo event generator. We observe a clear event excess above background, disagreeing with the null results reported by K2K and SciBooNE in a similar neutrino energy region. The measured flux-averaged cross sections are below those predicted by both the Rein-Sehgal and Alvarez-Ruso et al.

Measurement of Muon Antineutrino Oscillations with an Accelerator-Produced Off-Axis Beam.

T2K reports its first measurements of the parameters governing the disappearance of ν[over ¯]_{µ} in an off-axis beam due to flavor change induced by neutrino oscillations. The quasimonochromatic ν[over ¯]_{µ} beam, produced with a peak energy of 0.6 GeV at J-PARC, is observed at the far detector Super-Kamiokande, 295 km away, where the ν[over ¯]_{µ} survival probability is expected to be minimal. Using a data set corresponding to 4.01×10^{20} protons on target, 34 fully contained µ-like events were observed. The best-fit oscillation parameters are sin^{2}(θ[over ¯]_{23})=0.45 and |Δm[over ¯]_{32}^{2}|=2.51×10^{-3} eV^{2} with 68% confidence intervals of 0.38-0.64 and 2.26-2.80×10^{-3} eV^{2}, respectively. These results are in agreement with existing antineutrino parameter measurements and also with the ν_{µ} disappearance parameters measured by T2K.

High concentration capsaicin for treatment of peripheral neuropathic pain: effect on somatosensory symptoms and identification of treatment responders.

BACKGROUND: Pain is usually assessed by spontaneous pain ratings. Time-dependent (brief attacks) or evoked (allodynia) phenomena, common in neuropathic pain, are not captured. To evaluate the overall effectiveness of a treatment, improvement of all sensory symptoms should be measured. Since the pattern of sensory abnormalities might hint at the underlying mechanisms of pain, this baseline information may aid in predicting the treatment effect. Data on sensory neuropathic abnormalities (painDETECT questionnaire) were analyzed aiming to (1) evaluate the frequency of neuropathic symptoms in different peripheral neuropathic pain syndromes, (2) assess the effect of capsaicin 8% patch on neuropathic symptoms and (3) identify treatment responders based on baseline values. METHODS: Data analysis of a prospective 12 week non-interventional trial in peripheral neuropathic pain treated with capsaicin 8% cutaneous patch. Average pain intensity during the past 24 hours, pain descriptors and qualities of neuropathic pain were assessed to characterize the patients' sensory symptoms at baseline and to document changes. RESULTS: (1) Characteristic symptoms of neuropathic pain were present in all peripheral neuropathic pain syndromes, but frequencies varied in the individual syndromes. (2) Topical capsaicin 8% treatment significantly reduced the overall pain intensity and resulted in a reduction of sensory abnormalities. (3) Short disease duration predicted a better treatment effect. High painDETECT scores, the presence of burning and pressure-evoked pain were weakly associated with treatment response. CONCLUSIONS: Topical capsaicin 8% treatment effectively reduced sensory abnormalities in peripheral neuropathic pain. The association of sensory symptoms and treatment response aids in understanding the mechanism of action of high concentration capsaicin. It is, however, not possible to use sensory symptom patterns to predict treatment response to capsaicin on an individual level. LIMITATIONS: Completion of painDETECT was optional and therefore data was not available for all patients. Further studies for confirmation of these results are needed.

Effect of side-stream smoking on random-pattern skin flap survival in rats.

The secondhand exposure to cigarette smoke is being considered evil, and damage caused by this passive exposure has been proven by several studies. To investigate the effects of sidestream smoke exposure on random-pattern skin flap survival, 20 female rats were separated into 2 groups: group A (n = 10) was exposed 6 weeks to the smoke from the burning cigarette (passive smoking) and group B (n = 10) was the control group. After 6 weeks of exposition, a dorsal McFarlane flap of 4 × 10 cm was performed in all rats. Two weeks after this procedure, the ratio of necrotic and total areas was calculated using computer programs. The median area of necrosis in group A was 29.5%, significantly higher than that in group B with 17.5% (P < 0.024). In conclusion, this study suggests increased risk of random-pattern skin flap necrosis after sidestream exposure to cigarette smoke.

Six-month evaluation of the benefits of the low-dose combined oral contraceptive chlormadinone acetate 2 mg/ethinylestradiol 0.03 mg in young women: results of the prospective, observational, non-interventional, multicentre TeeNIS study.

BACKGROUND: In clinical trials and non-interventional studies encompassing > 50,000 women, the monophasic, low-dose combined oral contraceptive (OC) chlormadinone acetate 2 mg/ethinylestradiol 0.03 mg (CMA/EE) has been shown to have various non-contraceptive benefits, as well as contraceptive efficacy and good tolerability. However, there is a paucity of data on use of this OC in young women. OBJECTIVE: To investigate the relevance of, and changes in, cycle disorders, dysmenorrhoea and skin problems in addition to the efficacy and tolerability of CMA/EE in young women. METHODS: In this prospective, observational, non-interventional, multicentre study (TeeNIS [Teenager in Non-Interventional Study 2 mg CMA/0.03 mg EE]), young women (< or =20 years of age) were administered CMA/EE (Belara) once daily for 21 days (one blister strip), followed by either a 7-day pill-free interval (conventional cycle regimen; 89.3%) or a pill-free interval after two blister strips or more (extended cycle regimen; 3.7%), over a 6-month treatment period. Data on the mode of administration were missing for 7.1% of patients. The study included a safety population of 7462 patients (the efficacy population consisted of 6885 patients) from 886 gynaecological centres throughout Germany. RESULTS: Compared with baseline, CMA/EE intake resulted in significant reductions in the numbers of patients with cycle disorders, i.e. spotting (-46%), breakthrough bleeding (-64%), heavy bleeding (-95%) and absence of any bleeding (secondary amenorrhoea; -76%) [all p < or = 0.001], and with dysmenorrhoea (-56%) [p < or = 0.001]. Similarly, there was a significant decrease in the number of patients who used analgesics (-75%), had dysmenorrhoea-associated symptoms (back pain [-69%], headache [-70%], nausea/vomiting [-85%], diarrhoea [-80%], mood swings [-75%] or absence from school/job due to dysmenorrhoea [-92%]), or were restricted in their leisure/sporting activities because of dysmenorrhoea (-83%) [all p < or = 0.001]. Another major benefit of CMA/EE was a significant reduction in the number of patients with skin problems (acne and acne-prone skin) [-55%; p < or = 0.001]. In parallel, the number of patients who needed dermatological treatment (-67%; p < or = 0.001) and concealer cosmetics (-55%; p < or = 0.001) was significantly reduced, and significantly fewer patients felt that their self-esteem was restricted due to skin problems (-67%; p < or = 0.001). There were no relevant weight changes during the observation period; mean bodyweight remained virtually constant (mean weight change <1 kg). At final assessment, physicians' expectations were either 'completely fulfilled' or 'exceeded' with regard to cycle stability, regular bleeding, dysmenorrhoea, effects on weight, and skin problems in 78-95% of patients. CMA/EE provided high contraceptive efficacy with an unadjusted Pearl index of 0.25, calculated from 41 601 cycles of exposure; seven out of eight pregnancies were attributable to user failure, thus resulting in an adjusted Pearl index of 0.03. The tolerability of CMA/EE was excellent, with no unexpected adverse effects. CONCLUSIONS: This observational, non-interventional study in young women showed that CMA/EE had a significantly beneficial effect on cycle disorders, dysmenorrhoea and skin disorders, and confirmed the good efficacy and tolerability of this combined OC.

Efficacy of the low-dose combined oral contraceptive chlormadinone acetate/ethinylestradiol: physical and emotional benefits.

BACKGROUND: This study investigated the effects of the low-dose combined oral contraceptive (COC) 2.0 mg chlormadinone acetate (CMA)/0.03 mg ethinylestradiol (EE) (Belara, Balanca) on cycle-related physical and emotional disorders in women >or=25 years of age. STUDY DESIGN: A prospective, non-interventional, observational study of 3772 women over six cycles was conducted in 303 office-based gynecological centers throughout Germany. RESULTS: CMA/EE provided high contraceptive efficacy with a Pearl index of 0 (95% confidence interval=0.00-0.22) and was generally well tolerated, with no statistically significant weight changes during the observation period (p=.147). CMA/EE intake resulted in a statistically significant improvement in cycle-related physical and emotional symptoms, with a 67% overall reduction in sum score for number and intensity of cycle-related symptoms per patient. CONCLUSIONS: The results of this study in women >or=25 years of age support previous findings that 2.0 mg CMA/0.03 mg EE is an effective low-dose COC, with an excellent tolerability profile, with the additional benefits of significantly reducing both cycle-related physical and emotional symptoms (p

Effect of an oral contraceptive with chlormadinone acetate on depressive mood : analysis of data from four observational studies.

BACKGROUND AND OBJECTIVE: Many women of reproductive age experience depressive mood symptoms such as sudden mood swings, irritability, nervousness, excitability and anxiety. Although not defined as a disease, these disturbing mental symptoms are associated with a considerable decrease in quality of life. Molecular pharmacology research over the last 20 years has shown that endogenous steroid hormones may interact with the CNS. Some of these hormones, i.e. the sex hormone progesterone and its 3alpha-reduced metabolites allopregnanolone (3alpha,5alpha-tetrahydroprogesterone) and epipregnanolone (3alpha,5beta-tetrahydroprogesterone, eltanolone), influence mood-balancing and anxiolytic effects via the gamma-aminobutyric acid receptor A (GABA(A)), a major inhibiting receptor of the CNS. Activation of GABA(A) receptor results in mood balancing, anxiolytic, antiepileptic and sedative actions. When oral contraception is considered, it should be taken into account that the various synthetic progestogens used may differ in their influence on mental state. For instance, there is strong clinical evidence of mood-balancing effects for the progesterone derivative chlormadinone acetate (CMA). The aim of these studies was to describe the clinical effects of CMA in combination with ethinylestradiol on depressive mood symptoms. METHODS: Data from four prospective, non-interventional observational studies involving nearly 50 000 women were analysed. The studies documented use of four, six and 12 treatment cycles of the 28-day conventional regimen, as well as providing data on extended cycle regimens. The women in these studies were prescribed CMA 2 mg and ethinylestradiol (EE) 0.03 mg according to gynaecologists' usual practice. RESULTS: Clinical data from the studies confirmed that intake of CMA 2 mg and EE 0.03 mg promotes emotional well-being and reduces mood swings. Improvement in depressive mood was documented after four, six and 12 treatment cycles of the conventional intake regimen as well as with an extended-cycle regimen of CMA/EE. CONCLUSION: CMA 2 mg combined with EE 0.3 mg improves symptoms of depressive mood. The high structural congruence between the endogenous GABA(A) modulator epipregnanolone and the CMA metabolite M-V suggests a direct GABAergic, mood stabilizing function of CMA. We propose a theoretical concept - the CMA-GABA(A) model - that could explain the positive psychotropic effect of CMA.

Neuropsychological-neurophysiological alterations and brain atrophy in cirrhotic patients.

Psychometric performance has been reported to be related to brain atrophy in cirrhotics, but the relationship between brain atrophy and EEG findings is still unknown. The aim of this study was to ascertain the relationship among brain atrophy, EEG, and cognitive performance in cirrhotics. Sixty-eight cirrhotics (age = 55 +/- 10 years; males-66%) underwent psychometric evaluation (Symbol Digit Test, Trail Making Test-Part A, Scan test), EEG recording and spectral analysis (S-EEG), and brain CT scan. Central brain atrophy was ascertained by the following indexes of brain atrophy: the Evans' index, the bicaudate index, the cella media index, the bifrontal index, and the ventricular index; cortical brain atrophy by the sulci index. The severity of liver failure was assessed by the Child-Pugh score: 18% of patients were Child-Pugh Class A, 50% Class B, and 32% Class C. Central and cortical atrophies were found to be correlated with age, but not with the Child-Pugh score. Psychometric performance and the EEG mean dominant frequency (MDF) were found to be correlated with brain atrophy. Multivariate analysis showed that a poor psychometric performance was independently predicted by EEG slowing (MDF: p < 0.01) and by central brain atrophy (cella media index: p < 0.01). In conclusion, brain atrophy was associated with a poor psychometric performance and EEG alterations in cirrhosis. Both brain atrophy and EEG alterations independently predicted cognitive dysfunction in cirrhotic patients.