Effects of sleep on pain-related somatosensory evoked potentials in humans

We investigated effects of sleep on pain-related somatosensory evoked potentials (SEP) following painful electrical stimulation of the left index finger. The biggest advantage of this method is that signals ascending through both A-beta fibers relating to touch and A-delta fibers relating to pain can be recorded simultaneously. While the subject was awake, non-painful stimulation evoked early- and middle latency components, N20, P30 and N60, at the C4 electrode, and painful stimulation evoked not only early- and middle latency components at the C4 but also later pain-specific components, N130 and P240, at the Cz electrode. During sleep, N20 and P30 did not show a significant change in amplitude, N60 showed a slight but significant amplitude reduction, and N130 and P240 significantly decreased in amplitude or disappeared, as compared with those while awake. Therefore, we speculate on the mechanisms generating each component as follows; (1) N20 and P30 are the primary components generated in SI ascending through A-beta fibers. (2) N60 is the secondary component generated in SI involving cognitive function to some degree. (3) N130-P240 are the pain-specific components ascending through A-delta fibers, and closely related to cognitive function, because they were much affected by consciousness, different from the components ascending through A-beta fibers.     

Recurrent mosaic MTOR c.5930C > T (p.Thr1977Ile) variant causing megalencephaly,asymmetric polymicrogyria,and cutaneous pigmentary mosaicism: Case report and review of the literature

Genetic alterations leading to overactivation of mammalian target of rapamycin (mTOR) signaling result in brain overgrowth syndromes such as focal cortical dysplasia (FCD) and megalencephaly. Megalencephaly with cutis tri‐color of the Blaschko‐linear type pigmentary mosaicism and intellectual disability is a rare neurodevelopmental disorder attributed to the recurrent mosaic c.5930C > T (p.Thr1977Ile) MTOR variant. This variant was previously reported at low to intermediate levels of mosaicism in the peripheral blood of three unrelated individuals with consistent clinical findings. We report a fourth case of a 3‐year‐old female presenting with megalencephaly, obstructive hydrocephalus due to cerebral aqueductal stenosis, asymmetric polymicrogyria, dysgenesis of the corpus callosum, hypotonia, developmental delay, and cutaneous pigmentary mosaicism. Oligonucleotide and SNP chromosomal microarray (CMA), karyotype, and trio whole exome sequencing (WES) in the peripheral blood, as well as a targeted gene variant panel from fibroblasts derived from hyperpigmented and non‐hyperpigmented skin did not detect any abnormalities in MTOR or other genes associated with brain overgrowth syndromes. Unlike the previously reported cases, the de novo c.5930C > T (p.Thr1977Ile) MTOR variant was detected at 32% mosaicism in our patient only after WES was performed on fibroblast‐derived DNA from the hyperpigmented skin. This case demonstrates the tissue variability in mosaic expression of the recurrent p.Thr1977Ile MTOR variant, emphasizes the need for skin biopsies in the genetic evaluation of patients with skin pigmentary mosaicism, and expands the clinical phenotype associated with this pathogenic MTOR variant.     

Effect of systemic calcium deficiency on the expression of transforming growth factor-beta in chick embryonic calvaria.

The developmental process of intramembranous ossification involves bone formation directly from mesenchymal differentiation without a cartilage intermediate. We have previously observed that systemic calcium deficiency in the developing chick embryo, produced by long-term shell-less culture, results in the appearance of chondrocyte-like cells in the calvarium, a parietal bone which normally develops via intramembranous ossification. This investigation aims to analyze the mechanism underlying this calcium deficiency-related, aberrant appearance of cartilage phenotype in the chick embryonic calvarium. In view of the reported involvement of transforming growth factor beta (TGF-beta) in osteogenesis and chondrogenesis, we have examined and compared here the expression of TGF-beta in the chick embryonic calvaria of normal (in ovo development, NL), shell-less (SL), and calcium-supplemented SL (SL+Ca) embryos. TGF-beta expression was analyzed at the mRNA level by blot and in situ cDNA hybridization, and at the protein level by immunohistochemistry and immunoblotting. The results presented here indicate that: 1) TGF-beta is expressed in the chick embryonic calvarium by both periosteal cells and osteocytes, as revealed by in situ hybridization and immunohistochemistry; 2) TGF-beta expression is significantly increased in SL calvarium compared to NL calvarium, at both protein and mRNA levels; 3) the number of TGF-beta expressing cells increases in the SL calvarium, particularly along the central, subcambial core region of the bone; and 4) exogenous calcium repletion to the SL embryo affects the expression of TGF-beta such that the pattern approaches that in the NL embryo. Taken together, these results indicate that altered TGF-beta expression accompanies the aberrant appearance of cartilage phenotype caused by systemic calcium deficiency. We postulate that normal cellular differentiation along the osteogenic pathway during embryonic intramembranous ossification is crucially dependent on regulated TGF-beta expression.     

Metabolic fate of zetidoline,a new neuroleptic agent,in man

Summary Healthy volunteers administered orally a single dose (20 mg) of [2-¹⁴C]zetidoline, a new dopamine antagonist, exhibited rapid absorption of radioactivity with peak plasma levels of 250–300 ng/ml achieved in 1 h. The compound underwent intensive metabolic first-pass so that plasma radioactivity was represented mostly by two products, metabolite B endowed with neuroleptic activity, and metabolite D inactive, while unchanged zetidoline was not detected. Disappearance of radioactivity from plasma was rapid with a half-life of 1.78±0.20 h.The simultaneous assay of plasma prolactin showed increased levels of the hormone (+464% at the peak time) up to the 6th h after dosing, with plasma concentration profile which mimic those of metabolite B.The radioactive test-dose was eliminated mainly via the kidneys with an average urinary recovery of 84.7±1.7% in 4 days (73.4±1.1% within 8 h). The main urinary metabolite (metabolite G) and two minor ones (metabolites B and D) were purified and their structures assigned by IR, MS and NMR spectroscopy, they are: 1-(3-chloro-4-hydroxyphenyl)-3[2-(3,3-dimethyl-1-azetidinyl)ethyl]imidazolidin-2-one, metabolite B; 1-[2-(3,3-dimethyl-1-azetidinyl)ethyl]imidazolidin-2-one, metabolite D and the 4-O-sulphate ester of metabolite B, metabolite G.The metabolic fate of zetidoline in man follows the same phase I reactions demonstrated in rats and dogs, while the phase II reaction is sulphoconjugation instead of the glucuronidation observed in animals.     

氨基胍对胶原酶诱导脑出血大鼠模型的影响

目的研究氨基胍对脑出血的影响。方法以Ⅶ胶原酶诱导脑出血大鼠模型,观察动物行为学和脑内血肿的变化,用Western blot检测诱导型一氧化氮合酶蛋白表达的变化。结果氨基胍能明显加快脑出血大鼠行为缺陷的恢复,但对于血肿吸收没有明显影响;Western blot显示:氨基胍能明显抑制脑出血大鼠患侧皮质和基底节诱导型一氧化氮合酶蛋白表达。结论通过广泛抑制脑内诱导型一氧化氮合酶的表达,氨基胍能促进脑出血大鼠的运动功能恢复。     

p14ARF protein expression is a predictor of both relapse and survival in squamous cell carcinoma of the anterior tongue.

PURPOSE: The INK4A-ARF locus at chromosome 9p21 is frequently altered in head and neck squamous cell carcinoma (SCC) and encodes two distinct tumor suppressors, p16(INK4A) and p14(ARF). This study addressed the role of p14(ARF) as a potential prognostic marker in this disease. EXPERIMENTAL DESIGN: p14(ARF) protein expression was assessed by immunohistochemistry in a cohort of 140 patients with SCC of the anterior tongue. Using univariate and multivariate Cox's proportional hazards models, the outcomes examined were time to disease recurrence or death, with or without clinicopathologic covariates, including nodal status, disease stage, treatment status, Ki-67 staining, and molecular markers with known functional or genetic relationships with p14(ARF) (p16(INK4A), p53, pRb, p21(WAF1/CIP1), E2F-1). RESULTS: On multivariate analysis, p14(ARF) positivity (nucleolar p14(ARF) staining and/or nuclear p14(ARF) staining in >/=30% of tumor cells) was an independent predictor of improved disease-free survival (DFS; P = 0.002) and overall survival (OS; P = 0.002). This was further enhanced when p14(ARF) positivity was cosegregated with positive (>/=1%) p16(INK4A) staining (DFS, P < 0.001; OS, P < 0.001). Patients whose cancers were p14(ARF) negative and p53 positive (>50%) had the poorest outcome (DFS, P < 0.001; OS, P < 0.001) of any patient subgroup analyzed. CONCLUSIONS: These data show that in patients with SCC of the tongue, combined nuclear and nucleolar expression of p14(ARF) protein predicts for improved DFS and OS independent of established prognostic markers.     

What Do We Need beyond Hemoglobin A1c to Get the Complete Picture of

Hemoglobin A1c (HbA1c) is currently the most commonly used marker for the determination of the glycemic status in people with diabetes and it is frequently used to guide therapy and especially medical treatment of people with diabetes. The measurement of HbA1c has reached a high level of analytical quality and, therefore, this biomarker is currently also suggested to be used for the diagnosis of diabetes. Nevertheless, it is crucial for people with diabetes and their treating physicians to be aware of possible interferences during its measurement as well as physiological or pathological factors that contribute to the HbA1c concentration without being related to glycemia, which are discussed in this review. We performed a comprehensive review of the literature based on PubMed searches on HbA1c in the treatment and diagnosis of diabetes including its most relevant limitations, glycemic variability and self-monitoring of blood glucose (SMBG). Although the high analytical quality of the HbA1c test is widely acknowledged, the clinical relevance of this marker regarding risk reduction of cardiovascular morbidity and mortality is still under debate. In this respect, we argue that glycemic variability as a further risk factor should deserve more attention in the treatment of diabetes.