Sirolimus monotherapy for Kasabach-Merritt phenomenon in a neonate; Case report.

INTRODUCTION AND IMPORTANCE: The Kasabach-Merritt Phenomenon (KMP), characterized by thrombocytopenia and consumptive coagulopathy due to endothelial cell growth in the infantile vascular tumor kaposiform hemangioendothelioma, presents a therapeutic challenge. This case highlights the novel use of sirolimus in a neonate, an approach less explored in this age group. CASE PRESENTATION: A female neonate presented with a right anterior chest mass, progressing to respiratory distress and congestive heart failure. Diagnosed with KMP, she exhibited low platelet count and coagulation abnormalities. Treatment with sirolimus (0.06 mg/day) led to mass reduction, improved bleeding, and a stable tumor after 12 months, without side effects. This case contrasts with existing literature advocating for combination therapy or higher sirolimus concentrations for effective treatment. Yet, our patient achieved favorable outcomes with low-dose monotherapy, suggesting a potentially safer approach in neonates with immature hepatic and renal metabolism. CLINICAL DISCUSSION: This case demonstrates the efficacy of low-dose sirolimus monotherapy in treating KMP in a neonate, challenging current preferences for combination therapies or higher doses. It emphasizes the need for further research into age-specific treatment protocols in KMP, considering the unique metabolic profiles of neonates and infants. CONCLUSION: Sirolimus has demonstrated potential in treating KMP in pediatric patients. While initial results are promising, determining optimal dosages and trough concentrations, especially in neonates and infants, remains essential.

Effect of sample density in prompt γ-ray analysis.

A high-accuracy analytical method is broadly required to obtain reliable research results. Thus, prompt γ-ray analysis (PGA), one of the most accurate non-destructive analytical methods, has been employed in various fields. However, the measurement accuracy of PGA is also known to degrade in hydrogenous samples. The degradation is caused by variation in the measurement sensitivity (counts per milligram) following the change in neutron energy due to scattering with hydrogen nucleus. Number of scatterings is well known to depend on the hydrogen content in a sample. However, considering multiple scatterings, hydrogen density, which has not been taken into account as yet, may also lead to the accuracy degradation. Here, we show the effect of the hydrogen density in PGA by evaluating the measurement sensitivity of samples with the same hydrogen content and different densities. We find that the measurement sensitivity varies by more than 30% depending on the hydrogen density even at the same hydrogen content. The variation is a particularly serious problem for PGA requiring a few percent accuracy in most cases. Additionally, although the variation is apparently observed in hydrogenous samples, the similar phenomenon can occur in other nuclides with a large scattering cross section; it may affect nuclear cross-section measurements using neutrons in such fields as astrophysics and nuclear energy.

Integrated pathophysiology of schizophrenia, major depression, and bipolar disorder as monoamine axon disorder.

Recent studies provide evidence that similar to early-stage Parkinson's disease, depression is a neurodegenerative disease characterized by the degeneration of monoamine axons. The major difference between the two disorders is that the symptoms of depression become evident without loss of monoamine neurons, while the motor symptoms of Parkinson's disease appear after loss of the cell body. Given that the axonal degeneration of monoamine neurons underlies the pathophysiology of neurological (Parkinson's disease) and neuropsychiatric (depression) diseases, axonal impairment of monoamine neurons is thought to also occur in schizophrenia and bipolar disorder and play a significant role in the pathophysiology of these mental illnesses. The positive symptoms of schizophrenia and manic symptoms of bipolar disorder are known to occur in hyper-monoaminergic states, opposite to depressive symptoms, negative/cognitive symptoms of schizophrenia, and motor disorders of Parkinson's disease, all occurring in hypo-monoaminergic states. Since monoamine axons have the capacity to spontaneously regenerate or sprout in response to damage in the adult brain and sometimes show hyperinnervation due to excessive regeneration/sprouting beyond normal levels, it is possible that schizophrenia and bipolar disorder are disorders that include excessive regeneration/sprouting of monoamine axons leading to hyper-monoaminergic states. Together, based on accumulating data from animal and human studies, the pathophysiology of schizophrenia, major depression, and bipolar disorder is summarized as follows: The degeneration of monoamine axons is associated with the negative and cognitive symptoms of schizophrenia, major and bipolar depression, while hyper-regeneration/sprouting of monoamine axons underlies the positive symptoms of schizophrenia and bipolar mania. The integrated understanding of schizophrenia, major depression, and bipolar disorder as monoamine axon disorder will open the door to the development of new diagnosis and treatment methods for major mental illnesses as well as early-stage Parkinson's disease.

Adenine-related compounds modulate UDP-glucuronosyltransferase (UGT) activity in mouse liver microsomes.

Adenine-related compounds are allosteric inhibitors of UDP-glucuronosyltransferase (UGT) in rat liver microsomes (RLM) and human UGT isoforms treated with detergent or pore-forming peptide, alamethicin.To clarify whether the same is true beyond species, the effects of adenine-related compounds on 4-methylumbelliferone (4-MU) glucuronidation were examined using detergent-treated mouse liver microsomes (MLM).Brij-58 treatment of MLM increased the Vmax and the Michaelis constant, Km, of 4-MU. This study was performed using Brij-58-treated MLM as an enzyme source. ATP- and ADP-inhibited 4-MU glucuronidation. In contrast, AMP caused a 1.5-fold increase in glucuronidation. Oxidised forms, NAD+ and NADP+, potently inhibited 4-MU glucuronidation, whereas the reduced forms, NADH and NADPH, did not. Furthermore, the IC50 values of ATP, ADP, NAD+, and NADP+ were approximately 15 µM.In our previous study, ATP was the strongest inhibitor of UGT activity in RLM. However, in this study, the above-mentioned compounds inhibited 4-MU UGT in a comparable and non-competitive manner. Furthermore, AMP antagonised the inhibitory effects of ATP and ADP.These results suggest that ATP, ADP, NAD+, and NADP+ are common endogenous inhibitors of UGT beyond species.

Nondestructive Quantitative Analysis of Difficult-to-Measure Radionuclides 107Pd and 99Tc.

Considering the expanding demand for nuclear waste management of the spent nuclear fuel materials in near future, a nondestructive analytical scheme applicable to one of the most difficult-to-measure nuclides 107Pd, which emits no decay γ-rays and whose half-life is too long to be decayed out during a human lifetime, was designed. The scheme consists of a sophisticated instrument capable of the detection of γ-rays by Ge detectors coupled with time-of-flight measurement of neutrons and a high-intensity pulsed neutron beam and can simultaneously perform time-of-flight-coupled prompt γ-ray analysis (TOF-PGA) as well as PGA and neutron resonance capture analysis (NRCA). The analytical capability for simulated samples of the Tc-platinum group metals (Tc-PGMs) obtained by the group-partitioning process of spent nuclear fuels, which contain not only 107Pd but also 99Tc and other difficult-to-measure fission products, was evaluated. It was confirmed that although PGA and NRCA can accurately analyze both nuclides in individual, single substances, only TOF-PGA can analyze 107Pd as well as 99Tc in the Tc-PGM-simulated sample. The TOF-PGA measurement technique can be widely used for the nondestructive analysis of 107Pd and 99Tc in nuclear wastes.

Fecal metabolite of a gnotobiotic mouse transplanted with gut microbiota from a patient with Alzheimer's disease.

Studies of Alzheimer's disease are based on model mice that have been altered by transgenesis and other techniques to elicit pathogenesis. However, changes in the gut microbiota were recently suggested to diminish cognitive function in patients, as well as in model mice. Accordingly, we have created model mice of the human gut microbiota by transplanting germ-free C57BL/6N mice with fecal samples from a healthy volunteer and from an affected patient. These humanized mice were stably colonized and reproduced the bacterial diversity in donors. Remarkably, performance on Object Location Test and Object Recognition Test was significantly reduced in the latter than in the former at 55 weeks of age, suggesting that gut microbiota transplanted from an affected patient affects mouse behavior. In addition, metabolites related to the nervous system, including γ-aminobutyrate, taurine, and valine, were significantly less abundant in the feces of mice transplanted with microbiota from the affected patient.

Draft Genome Sequence of Probiotic Lactobacillus acidophilus Strain L-55 Isolated from a Healthy Human Gut.

Probiotic Lactobacillus acidophilus L-55 was isolated from a healthy human gut. Here, we report the draft genome sequence of this organism.

Synergistic effect of combining two nondestructive analytical methods for multielemental analysis.

We developed a new analytical technique that combines prompt gamma-ray analysis (PGA) and time-of-flight elemental analysis (TOF) by using an intense pulsed neutron beam at the Japan Proton Accelerator Research Complex. It allows us to obtain the results from both methods at the same time. Moreover, it can be used to quantify elemental concentrations in the sample, to which neither of these methods can be applied independently, if a new analytical spectrum (TOF-PGA) is used. To assess the effectiveness of the developed method, a mixed sample of Ag, Au, Cd, Co, and Ta, and the Gibeon meteorite were analyzed. The analytical capabilities were compared based on the gamma-ray peak selectivity and signal-to-noise ratios. TOF-PGA method showed high merits, although the capability may differ based on the target and coexisting elements.

Asphyxia induced by umbilical cord occlusion alters glutamatergic and GABAergic synaptic transmission in neurons of the superior colliculus in fetal rats.

Using optical recordings, we studied the effects of asphyxia on intracellular Cl(-) and Ca(2+) concentrations ([Cl(-)]i; [Ca(2+)]i) in the superior colliculus of fetal rats, which were connected via the umbilical cord to the dam. Acute asphyxia was induced by umbilical cord occlusion. The number of fetal superior colliculus neurons showing GABA-mediated increases in [Cl(-)]i (leading to hyperpolarization) following local synaptic electrical stimulation had decreased by 3 h post-asphyxiation, while the number showing GABA-mediated decreases in [Cl(-)]i (leading to depolarization) increased. [Ca(2+)]i rise, which occurred after acute asphyxiation, was antagonized by both non-NMDA and NMDA receptor antagonists. The increase in [Ca(2+)]i following focal superior colliculus stimulation was markedly attenuated at 3 h post-asphyxiation. These findings suggest that asphyxia induced by umbilical occlusion induces changes in glutamatergic and GABAergic synaptic transmission in the fetal brain.

Exposure to 1-bromopropane causes degeneration of noradrenergic axons in the rat brain.

1-Bromopropane (1-BP) has been used as an alternative to ozone-depleting solvents. Previous studies showed that 1-BP is neurotoxic in animals and humans. In humans, exposure to 1-BP caused various neurological and neurobehavioral symptoms or signs including depressive or irritated mood. However, the neurobiological changes underlying the depressive symptoms induced by 1-BP remain to be determined. The depressive symptoms are thought to be associated with degeneration of axons containing noradrenaline and serotonin. Based on this hypothesis, the present study examined the effects of repeated exposure to 1-BP on serotonergic and noradrenergic axons. Exposure to 1-BP induced dose-dependent decreases in the density of noradrenergic axons in the rat prefrontal cortex, but no apparent change in the density of serotonergic axons. The results suggest that depressive symptoms in workers exposed to 1-BP are due, at least in part, to the degeneration of noradrenergic axons in the brain.

Proteomic analysis of proteins expressing in regions of rat brain by a combination of SDS-PAGE with nano-liquid chromatography-quadrupole-time of flight tandem mass spectrometry.

BACKGROUND: Most biological functions controlled by the brain and their related disorders are closely associated with activation in specific regions of the brain. Neuroproteomics has been applied to the analysis of whole brain, and the general pattern of protein expression in all regions has been elucidated. However, the comprehensive proteome of each brain region remains unclear. RESULTS: In this study, we carried out comparative proteomics of six regions of the adult rat brain: thalamus, hippocampus, frontal cortex, parietal cortex, occipital cortex, and amygdala using semi-quantitative analysis by Mascot Score of the identified proteins. In order to identify efficiently the proteins that are present in the brain, the proteins were separated by a combination of SDS-PAGE on a C18 column-equipped nano-liquid chromatograph, and analyzed by quadrupole-time of flight-tandem-mass spectrometry. The proteomic data show 2,909 peptides in the rat brain, with more than 200 identified as region-abundant proteins by semi-quantitative analysis. The regions containing the identified proteins are membrane (20.0%), cytoplasm (19.5%), mitochondrion (17.1%), cytoskeleton (8.2%), nucleus (4.7%), extracellular region (3.3%), and other (18.0%). Of the identified proteins, the expressions of glial fibrillary acidic protein, GABA transporter 3, Septin 5, heat shock protein 90, synaptotagmin, heat shock protein 70, and pyruvate kinase were confirmed by immunoblotting. We examined the distributions in rat brain of GABA transporter 3, glial fibrillary acidic protein, and heat shock protein 70 by immunohistochemistry, and found that the proteins are localized around the regions observed by proteomic analysis and immunoblotting. IPA analysis indicates that pathways closely related to the biological functions of each region may be activated in rat brain. CONCLUSIONS: These observations indicate that proteomics in each region of adult rat brain may provide a novel way to elucidate biological actions associated with the activation of regions of the brain.

Gene expression profiling in progressively MPTP-lesioned macaques reveals molecular pathways associated with sporadic Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disease characterized by progressive loss of midbrain dopaminergic neurons. To gain an insight into the mechanisms underlying the progression of PD, gene expression analysis was performed using two different brain regions, the substantia nigra pars compacta (SN) and the striatum (STR), of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkey model of PD. 230 genes were differentially expressed in the MPTP-treated SN compared to control, whereas 452 genes showed altered expression in the MPTP-treated STR, implying that MPTP elicits more damages in the striatal gene expression than in the SN. Comparative data analysis of the transcription profiles on the PD patients and MPTP monkey models, and pathway analysis indicated several signaling pathways as possible routes to MPTP-induced neurodegeneration. Interestingly, the networks which associated with cytoskeletal stability, ubiquitin-proteasome system (UPS) and Wnt signaling gained prominence in our study. Further transcriptional regulatory network analysis suggested the association of the neuronal repressor REST (RE1-silencing transcription factor; NRSF) and androgen receptor with the dysregulation of the striatal genes. Our study suggests the possibility that the dysfunction of multi-network signaling may induce abnormalities in a diverse range of biological processes, such as synaptic function, cytoskeletal stability, survival and differentiation.

Stimulation of fetal hypothalamus induces uterine contractions in pregnant rats at term.

The fetal brain is thought to have a role in the onset and progression of labor. Evidence also exists for fetal oxytocin release just before and during parturition. The present study examined whether activation of the fetal brain could induce uterine myometrial contractions through oxytocin receptors in the dam. Under urethane anesthesia, electrical stimulation of the hypothalamus of fetal rats that were still connected with the dams by an intact umbilical cord induced uterine contractions in term pregnant rats. Intraperitoneal injections of synthetic oxytocin in fetuses induced uterine contractions in the dams similar to those induced by electrical stimulation of the fetal hypothalamus. Maternal intravenous injections of an oxytocin antagonist immediately attenuated uterine contractions induced by fetal oxytocin injections and electrical stimulation of the fetal hypothalamus. These findings suggest the possibility that oxytocin released from the fetal hypothalamus is involved in parturition.

Effects of retinoic acids on the dendritic morphology of cultured hippocampal neurons.

Vitamin A-derived retinoic acids (RAs) are known to exert a variety of biological actions, including modulatory effects on cell differentiation and apoptosis. A recent study has demonstrated that 13-cis-RA and all-trans-RA suppressed neurogenesis in the dentate gyrus of the hippocampus in adult mice. The present experiments were performed to see whether 13-cis-RA and all-trans-RA could alter the dendritic morphology of cultured hippocampal neurons via RA receptors: retinoic acid receptor (RAR) and retinoid X receptor (RXR). High doses of 13-cis-RA and all-trans-RA exerted a negative effect on the cultured hippocampal neurons, while a low dose of 13-cis-RA but not all-trans-RA caused a positive effect. The negative changes induced by 13-cis-RA and all-trans-RA were antagonized by RXR antagonists and RAR antagonists, respectively. The positive changes induced by a low dose of 13-cis-RA were blocked by both RXR antagonists and RAR antagonists. These results suggest that RAs at high concentrations cause a negative effect on the dendritic morphology of cultured hippocampal neurons through RA receptors, while RAs at low concentrations exert a positive influence on cultured hippocampal neurons.

13-cis-retinoic acid alters the cellular morphology of slice-cultured serotonergic neurons in the rat.

Retinoids influence cellular processes such as differentiation, proliferation and apoptosis via retinoic acid receptor (RAR) and retinoid X receptor (RXR), and have therapeutic applications in several cancers and dermatologic diseases. Recent reports indicate that depression occasionally occurs in patients using the acne drug Accutane, the active component of which is 13-cis-retinoic acid (13-cis-RA). Although impairment of serotonin (5-HT)-expressing neurons, including morphologic changes, is thought to be associated with depressive symptoms, the effects of 13-cis-RA on 5-HT neurons have not been examined. The present study demonstrated that 13-cis-RA alters the morphology of 5-HT neurons in cultured rat midbrain slices. The 13-cis-RA-induced changes were partially blocked by RXR and RAR antagonists. Furthermore, cotreatment with RAR and RXR agonists altered the morphology of 5-HT neurons to a greater extent than the individual application of each agonist. The morphologic changes were completely blocked by RXR antagonist, whereas RAR antagonist partially blocked the effects. These results suggest that 13-cis-RA exerts its action on slice-cultured 5-HT neurons, at least in part, through specific retinoid receptors. Moreover, RXR has a greater influence on the morphology of 5-HT neurons than RAR. The receptor-mediated actions of 13-cis-RA presented here may provide a clue for further research on depression associated with the use of 13-cis-RA.

Interferon-alpha reduces the density of monoaminergic axons in the rat brain.

Interferon-alpha commonly induces depressive symptoms in clinical populations; however, the mechanism by which this occurs is unclear. Recent studies suggest that the degeneration of axons containing serotonin and noradrenaline is involved in the pathophysiology of depression. The present immunohistochemical study shows that the density of serotonergic axons decreased in the ventral medial prefrontal cortex and amygdala in the interferon-alpha-treated animals. Additionally, interferon-alpha induced decreases in the density of noradrenergic axons in the dorsal medial prefrontal cortex, ventral medial prefrontal cortex, and dentate gyrus. These results support the hypothesis that long-term administration of interferon-alpha causes the degeneration of monoaminergic axons in specific brain regions, which might be associated with depressive symptoms occurring in interferon-alpha-treated patients.

Postural stabilizing effect of alfacalcidol and active absorbable algal calcium (AAA Ca) compared with calcium carbonate assessed by computerized posturography.

Sway and postural instability have drawn attention as a risk factor for osteoporotic fracture, in addition to low bone mineral density (BMD) and poor bone quality. In view of the fracture-reducing effect of alfacalcidol and active absorbable algal calcium (AAA Ca) not readily explained by rather mild increases of BMD, attempts were made to evaluate postural stabilizing effect of alfacalcidol, AAA Ca, and calcium carbonate (CaCO(3)) by computerized posturography. Track of the gravity center was analyzed to calculate parameters related to tract length, track range, and track density to express the degree of sway before and after supplementation in 126 subjects ranging in age between 20 and 81 years randomly divided into four groups. Supplementation with AAA Ca containing 900 mg elemental Ca (group A), no calcium (group B), CaCO(3) also containing 900 mg elemental Ca (group C), or alfacalcidol (group D) continued daily for 12 months. For each parameter, the ratio closed eye value/open eye value (Romberg ratio) was calculated to detect aggravation of sway by eye closure. Age, parameters of Ca and P, and proportions of subjects with fracture and those with low BMD showed no marked deviation among the groups. With eyes open, significant decreases of a track range parameter (REC) from group B was noted in groups A (P = 0.0397) and D (P = 0.0296), but not in group C according to multiple comparison by Scheffe, indicating superior postural stabilizing effect of A and D over C. In the first 2 months, a significant fall was already evident in REC from group B in group D (P = 0.0120) with eyes open. Paired comparison of sway parameters before and after supplementation revealed a significant increase of track density parameter (LNGA), indicating sway control efficiency and a significant decrease of REC in groups A and D compared to group B with eyes open. With eyes closed, only group A showed a significant improvement from group B (P = 0.0456; Fig. 1), with a significant shortening on paired After/Before comparison (P = 0.0142; Fig. 2). Computerized posturography appears to be useful in analyzing sway phenomena especially as to the effects of vitamin D and various Ca preparations.

Selective rapid eye movement sleep deprivation impairs the maintenance of long-term potentiation in the rat hippocampus.

Rapid eye movement (REM) sleep deprivation (RSD) is known to impair learning and memory. Previous studies have demonstrated that RSD induces an impairment of hippocampal long-term potentiation (LTP). In most of these studies, RSD was set up prior to LTP induction. In this work, we focused on RSD after LTP induction. We investigated the effect of RSD for 24-48 h after induction of LTP in the dentate gyrus on LTP maintenance and whether a REM rebound after 48 h RSD affected LTP. RSD rats were deprived of REM sleep by stroking their backs using a brush, whereas control rats were allowed to sleep freely. Another control group of rats was awoken during non-REM sleep (NRS) under the same conditions (NRS group). REM-deprived rats displayed a faster decay of population spike amplitudes compared with the control and NRS groups over a 24-h recording time. After 48 h RSD, there was no difference in the population spike amplitudes before or after 4 h of release from RSD. These results suggest that REM sleep after LTP induction in the dentate gyrus plays an essential role in LTP maintenance, whereas a REM rebound does not restore the RSD-induced impairment of LTP.

Ventral hippocampal neurons project axons simultaneously to the medial prefrontal cortex and amygdala in the rat.

The ventral hippocampus (VH) may have an important role in spatial memory processes and emotional behaviors through connections with the medial prefrontal cortex (mPFC) and amygdala. Although the mPFC and amygdala receive afferent projections from the VH, it has not been determined whether the individual VH neurons project to both the mPFC and the amygdala. In this study, antidromic responses to the mPFC and amygdala stimulation were evoked in single VH neurons. In addition, VH neurons were retrogradely double-labeled with fluorescent tracers injected in the mPFC and amygdala. VH neurons projecting to both the mPFC and amygdala were predominantly located in the subiculum and CA1 and bifurcated near or at the soma. Our anatomical and electrophysiological evidence for the presence of VH neurons projecting to both the mPFC and amygdala provides a previously unrecognized pathway from the hippocampus that simultaneously activates the mPFC and amygdala.

Evaluation of the centroid method of occlusion for studying mandibular and maxillary growth.

The aim of this study was to evaluate the centroid method of occlusion for studying mandibular growth and development. This novel technique comparatively expresses the direction of growth of the maxilla and mandible as a single unit. The centroid 'G' was geometrically calculated from the triangle Deltaabc, which comprised the palatal, articulare-gnathion (Ar-Gn), and A-B planes. The plane angles and positional relationship of the centroid with the upper first molar was investigated, focusing on differences between genders and malocclusions. Lateral cephalograms were obtained of 26 males and 51 females with a 'normal' Class I occlusion, 216 females with a Class III incisor relationship, and 230 females, all aged >18 years, with a Class II incisor relationship. Bolton standards and Sakamoto's data were used to determine changes in the angle of the palatal plane to the Ar-Gn plane. Non-significant levels of variation were observed in the angle of the palatal plane to the Ar-Gn plane during the developmental period from childhood to adulthood. Among Class I adult subjects, Deltaabc was similar between genders and the centroid G was located near the occlusal surface of the upper first molar. There was no difference in the area of Deltaabc between malocclusion types. The positional relationship of the centroid G with the upper first molar revealed a shift of the centroid mesially and cervically during the transition from Class III to Class I to Class II. These findings indicate that the centroid method can contribute to orthopaedic diagnosis and the planning of treatment strategies.