GEF-H1 controls focal adhesion signaling that regulates mesenchymal stem cell lineage commitment.

Focal adhesions (FAs) undergo maturation that culminates in size and composition changes that modulate adhesion, cytoskeleton remodeling and differentiation. Although it is well recognized that stimuli for osteogenesis of mesenchymal stem cells (MSCs) drive FA maturation, actin organization and stress fiber polarization, the extent to which FA-mediated signals regulated by the FA protein composition specifies MSC commitment remains largely unknown. Here, we demonstrate that, upon dexamethasone (osteogenic induction) treatment, guanine nucleotide exchange factor H1 (GEF-H1, also known as Rho guanine nucleotide exchange factor 2, encoded by ARHGEF2) is significantly enriched in FAs. Perturbation of GEF-H1 inhibits FA formation, anisotropic stress fiber orientation and MSC osteogenesis in an actomyosin-contractility-independent manner. To determine the role of GEF-H1 in MSC osteogenesis, we explore the GEF-H1-modulated FA proteome that reveals non-muscle myosin-II heavy chain-B (NMIIB, also known as myosin-10, encoded by MYH10) as a target of GEF-H1 in FAs. Inhibition of targeting NMIIB into FAs suppresses FA formation, stress fiber polarization, cell stiffness and osteogenic commitments in MSCs. Our data demonstrate a role for FA signaling in specifying MSC commitment.

ß-PIX controls intracellular viscoelasticity to regulate lung cancer cell migration.

Cancer metastasis occurs via a progress involving abnormal cell migration. Cell migration, a dynamic physical process, is controlled by the cytoskeletal system, which includes the dynamics of actin organization and cellular adhesive organelles, focal adhesions (FAs). However, it is not known whether the organization of actin cytoskeletal system has a regulatory role in the physiologically relevant aspects of cancer metastasis. In the present studies, it was found that lung adenocarcinoma cells isolated from the secondary lung cancer of the lymph nodes, H1299 cells, show specific dynamics in terms of the actin cytoskeleton and FAs. This results in a higher level of mobility and this is regulated by an immature FA component, ß-PIX (PAK-interacting exchange factor-ß). In H1299 cells, ß-PIX's activity was found not to be down-regulated by sequestration onto stress fibres, as the cells did not bundle actin filaments into stress fibres. Thus, ß-PIX mainly remained localized at FAs, which allowed maturation of nascent adhesions into focal complexes; this resulted in actin polymerization, increased actin network integrity, changes in the intracellular microrheology at the peripheral of the cell, and cell polarity, which in turn regulated cell migration. Perturbation of ß-PIX caused an inhibition of cell migration, including migration velocity, accumulated distance and directional persistence. Our results demonstrate the importance of ß-PIX to the regulation of high mobility of lung adenocarcinoma cell line H1299 and that this occurs via regulation of FA dynamics, changes in actin cytoskeleton organization and cell polarity.

Collateral projections from vestibular nuclear and inferior olivary neurons to lobules I/II and IX/X of the rat cerebellar vermis: a double retrograde labeling study.

Axon collateral projections to various lobules of the cerebellar cortex are thought to contribute to the coordination of neuronal activities among different parts of the cerebellum. Even though lobules I/II and IX/X of the cerebellar vermis are located at the opposite poles in the anterior-posterior axis, they have been shown to receive dense vestibular mossy fiber projections. For climbing fibers, there is also a mirror-image-like organisation in their axonal collaterals between the anterior and posterior cerebellar cortex. However, the detailed organisation of mossy and climbing fiber collateral afferents to lobules I/II and IX/X is still unclear. Here, we carried out a double-labeling study with two retrograde tracers (FluoroGold and MicroRuby) in lobules I/II and IX/X. We examined labeled cells in the vestibular nuclei and inferior olive. We found a low percentage of double-labeled neurons in the vestibular nuclei (2.1 ± 0.9% of tracer-labeled neurons in this brain region), and a higher percentage of double-labeled neurons in the inferior olive (6.5 ± 1.9%), especially in its four small nuclei (18.5 ± 8.0%; including the ß nucleus, dorsal cap of Kooy, ventrolateral outgrowth, and dorsomedial cell column), which are relevant for vestibular function. These results provide strong anatomical evidence for coordinated information processing in lobules I/II and IX/X for vestibular control.

Neuronal oscillations in Golgi cells and Purkinje cells are accompanied by decreases in Shannon information entropy.

Neuronal oscillations have been shown to contribute to the function of the cerebral cortex by coordinating the neuronal activities of distant cortical regions via a temporal synchronization of neuronal discharge patterns. This can occur regardless whether these regions are linked by cortico-cortical pathways or not. Less is known concerning the role of neuronal oscillations in the cerebellum. Golgi cells and Purkinje cells are both principal cell types in the cerebellum. Purkinje cells are the sole output cells of the cerebellar cortex while Golgi cells contribute to information processing at the input stage of the cerebellar cortex. Both cell types have large cell bodies, as well as dendritic structures, that can generate large currents. The discharge patterns of both these cell types also exhibit oscillations. In view of the massive afferent information conveyed by the mossy fiber-granule cell system to different and distant areas of the cerebellar cortex, it is relevant to inquire the role of cerebellar neuronal oscillations in information processing. In this study, we compared the discharge patterns of Golgi cells and Purkinje cells in conscious rats and in rats anesthetized with urethane. We assessed neuronal oscillations by analyzing the regularity in the timing of individual spikes within a spike train by using autocorrelograms and fast-Fourier transform. We measured the differences in neuronal oscillations and the amount of information content in a spike train (defined by Shannon entropy processed per unit time) in rats under anesthesia and in conscious, awake rats. Our findings indicated that anesthesia caused more prominent neuronal oscillations in both Golgi cells and Purkinje cells accompanied by decreases in Shannon information entropy in their spike trains.

GSG2 promotes thyroid cancer via stabilizing AURKB and activating AKT pathway.

Thyroid cancer stands out as the most prevalent endocrine cancer, with its incidence on a global rise. While numerous studies have delved into the roles of GSG2 in the progression of various malignancies, its involvement in thyroid cancer remains relatively unexplored. Therefore, this study was initiated to assess the functional importance of GSG2 in human thyroid cancer development. Our findings revealed a notable upregulation of GSG2 in both thyroid cancer tissues and cell lines, demonstrating a significant correlation with the pathological stage and patients' prognosis. Depletion of GSG2 in thyroid cancer cells resulted in suppressed malignant cell development and inhibited tumor outgrowth. Crucially, our investigation identified AURKB as a downstream gene of GSG2. GSG2 exhibited its regulatory role by stabilizing AURKB, countering SMURF1-mediated ubiquitination of AURKB. Furthermore, overexpressing AURKB restored the functional consequences of GSG2 depletion in thyroid cancer cells. Additionally, we proposed the involvement of the AKT pathway in GSG2-mediated regulation of thyroid cancer. Intriguingly, the reversal of cell phenotype alterations in GSG2-depleted cells following an AKT activator underscored the potential link between GSG2 and the AKT pathway. At the molecular level, GSG2 knockdown downregulated p-AKT, an effect partially restored after AKT activator treatment. In summary, our study concluded that GSG2 played a pivotal role in thyroid carcinogenesis, underscoring its potential as a therapeutic target for thyroid cancer.

Surgery combined with adjuvant radiation and chemotherapy prolonged overall survival in stage IVC anaplastic thyroid cancer: a SEER-based analysis.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a rare but aggressive malignancy, which accounts for only 1-2% of all thyroid cancers. The median overall survival (OS) time for all stages patients is at about 5 months. The benefit of surgery combined with adjuvant radiation and chemotherapy in stage IVC anaplastic thyroid cancer is still controversial. The aim of this study is to investigating surgery combined with adjuvant radiation and chemotherapy and survival outcomes in stage IVC ATC patients. METHOD: Anaplastic thyroid carcinoma patients from the Surveillance, Epidemiology, and End Results database from 2004 to 2016 were used to conduct a cross-sectional study in the analysis. The endpoint of this study was overall survival. RESULTS: The median OS of the overall population was 2.0 months. Multivariate analysis showed that age (<67 vs. ≥67 years old, P = 0.017, HR = 1.355, 95% CI: 1.057-1.738), tumor size (<7 cm vs. ≥7 cm, P = 0.001, HR = 1.579, 95% CI: 1.202-2.073), Surgery (thyroidectomy vs. non-surgery, P < 0.001, HR = 0.554, 95% CI: 0.401-0.766), radiation therapy (P < 0.001, HR = 0.571, 95% CI: 0.445-0.733) and chemotherapy (P = 0.003, HR = 0.684, 95% CI: 0.531-0.881) were independent prognostic factor for worse OS in stage IVC ATC patients. Surgery combined with adjuvant radiation and chemotherapy exhibited the better overall survival time for 4 months. CONCLUSIONS: Surgery combined with adjuvant radiation and chemotherapy can improve overall survival in stage IVC ATC patients. We recommend surgical approach with fully evaluation combined with radiation therapy and chemotherapy for selected stage IVC ATC patients.

A mouse model for adolescent alcohol abuse: stunted growth and effects in brain.

BACKGROUND: Adolescent alcohol abuse remains a serious public health concern, with nearly a third of high school seniors reporting heavy drinking in the previous month. METHODS: Using the high ethanol-consuming C57BL/6J mouse strain, we examined the effects of ethanol (3.75 g/kg, IP, daily for 45 days) on body weight and brain region mass (cerebral cortex, cerebellum, corpus callosum) during peri-adolescence (postnatal day [P]25 to 70) or adulthood (P180 to 225) of both males and females. RESULTS: In control peri-adolescent animals, body weight gain was greater in males compared with females. In the peri-adolescent exposure group, ethanol significantly reduced body weight gain to a similar extent in both male and female mice (82 and 84% of controls, respectively). In adult animals, body weight gain was much less than that of the peri-adolescent mice, with ethanol having a small but significant effect in males but not females. Between the control peri-adolescent and adult cohorts (measurements taken at P70 and 225, respectively), there were no significant differences in the mass of the cerebral cortex or the cerebellum from either male or female mice, although the rostro-caudal length of the corpus callosum increased slightly but significantly (6.1%) between these time points. CONCLUSIONS: Ethanol treatment significantly reduced the mass of the cerebral cortex in peri-adolescent (-3.1%), but not adult, treated mice. By contrast, ethanol significantly reduced the length of the corpus callosum in adult (-5.4%), but not peri-adolescent, treated mice. Future studies at the histological level may yield additional details concerning ethanol and the peri-adolescent brain.

Acute ethanol exposure increases firing and induces oscillations in cerebellar Golgi cells of freely moving rats.

BACKGROUND: Alcohol is a widely abused substance and is responsible for significant morbidity and mortality worldwide. The precise mechanisms underlying ethanol (EtOH)'s actions in the central nervous system (CNS) remain elusive. In vitro studies suggest that GABAergic interneurons are important targets of EtOH action in the CNS. Although EtOH generally acts to inhibit CNS neurons, it appears to cause an increase in GABAergic interneuron excitability. However, it has yet to be demonstrated that EtOH produces this effect in the brain of behaving animals. Here, we demonstrate for the first time that acute EtOH exposure excites a subtype of GABAergic interneuron (cerebellar Golgi cell [GoC]) in a freely moving animal. METHODS: Electrophysiological recordings were made from microwire arrays implanted in the anterior cerebellum of freely moving rats. RESULTS: Cerebellar GoCs display a slow, irregular, spontaneous action potential firing pattern under control conditions. EtOH caused dramatic and consistent increases in the rate and regularity of GoC discharges, including a redistribution of the power in the GoC spike train, such that power became concentrated in the 26.7 ± 7.3 Hz region. CONCLUSIONS: Taken together with our previous findings, these data suggest that a major mechanism of EtOH actions on cerebellar function is an EtOH-induced de-afferentation at the input stage of the cerebellar cortex in the form of granule cell inhibition, and that this inhibition is caused by an increase in GoC firing. It is likely that GoCs may play a significant role both in the gating of information transmission to granule cells and in the modulation of the overall excitability of the cerebellum by tonically controlling granule cell activity.

Nursing students' perceptions of online learning and its impact on knowledge level.

BACKGROUND: Online learning in nursing education has been demonstrated to exert positive effects on knowledge, skills, learning attitudes, and confidence in performance. However, a noteworthy caveat has been that such benefits could vary depending on the content of pedagogical materials. AIM: To examine the impact of online-tutorials in place of face-to-face tutorials on knowledge level and understand the perspectives of learners who experience online-tutorials. METHODS: This study adopted a mixed method experiential design in which the perspectives of learners who experience online-tutorials are embedded within the trial. Two cohort of nursing students enrolled for the module on Psychology for Nurses were recruited to evaluate the impact of online-tutorials compared to face-to-face tutorials in terms of knowledge level. Apart from the dissimilar mode of delivery, both cohorts experienced the same teaching structure, content, and assessments. Examination results from these two cohorts were compared upon completion of the course. For the online group, additional one-to-one interviews were conducted to further understand the impacts exerted by online learning on the level of knowledge among them. RESULTS: There was a significant difference between the knowledge level of the two cohorts. Responses elicited during the interviews revealed five themes: lack of motivation; limited teamwork; missed learning opportunities; decreased interactions; and differences between online and face-to-face learning. CONCLUSION: Online-tutorials may be a feasible pedagogical approach but the motivation to learn, teamwork and quality of discussion may be compromised due to the lack of socialization and interactions between students and tutors.

Clinical features and diagnosis of new malignancy in patients with acute pulmonary embolism and without a history of cancer.

BACKGROUND: Pulmonary embolism (PE) is frequently associated with cancer. This study aimed to assess patients with acute PE and identify diagnostic predictors of new cancer after 1 year of follow-up. METHODS: One hundred and twenty-one patients with PE were enrolled consecutively from the emergency department of a single medical center in Taiwan. Data from computed tomography angiography, echocardiogram, electrocardiogram and for baseline comorbidities, clinical presentation, and laboratory parameters were recorded. The surviving discharged patients without a cancer diagnosis were followed-up for 1 year, and new malignancies were recorded. RESULTS: Of 121 patients with acute PE, 44 (36%) had an underlying cancer history (cancer group), and 77 (64%) did not (noncancer group). Baseline demographic characteristics, comorbidities, clinical symptoms, biochemical parameters, echocardiogram data, and electrocardiogram data of the two groups were similar except for a higher hospital mortality rate (56.8% vs 9.1%; p < 0.001), lower body mass index (22.6 ± 4.1 vs 25.5 ± 4.9; p =0.02), higher systolic blood pressure (139.7 ± 33.7 vs 125.4 ± 24.1; p = 0.02), lower low-density lipoprotein level (67.4 ± 38.3 vs 90.4 ± 33.8; p = 0.04), lower creatinine kinase (CK; 43.0 ± 43.0 vs 83.5 ± 83.1; p = 0.01), higher myocardial band (MB) form of CK ratio (0.2 ± 0.2 vs 0.1 ± 0.1; p < 0.01), higher partial pressure of arterial oxygen (122.81 ± 81.2 vs 90.2 ± 59.4; p = 0.03), and less presentation of chest pain (15.9% vs 40.3%; p = 0.01) in the cancer group. Kaplan-Meier curve analysis revealed that the 30-day survival rate was higher in the noncancer group than in the cancer group (log-rank p = 0.04). After 1 year of follow-up, 6 of 59 (10.17%) initial non-cancer-related PE survivors were diagnosed with malignancies. After multivariate analysis, only the initial CK-MB level was associated with a diagnosis of new cancer (hazard ratio [HR]: 1.37, 95% confidence interval [CI]: 1.029-1.811; p = 0.03). CONCLUSION: This study suggests that the CK-MB level is associated with future malignancy in patients with PE. Patients with cancer-related PE had a worse 30-day survival rate.

Centrosome guides spatial activation of Rac to control cell polarization and directed cell migration.

Directed cell migration requires centrosome-mediated cell polarization and dynamical control of focal adhesions (FAs). To examine how FAs cooperate with centrosomes for directed cell migration, we used centrosome-deficient cells and found that loss of centrosomes enhanced the formation of acentrosomal microtubules, which failed to form polarized structures in wound-edge cells. In acentrosomal cells, we detected higher levels of Rac1-guanine nucleotide exchange factor TRIO (Triple Functional Domain Protein) on microtubules and FAs. Acentrosomal microtubules deliver TRIO to FAs for Rac1 regulation. Indeed, centrosome disruption induced excessive Rac1 activation around the cell periphery via TRIO, causing rapid FA turnover, a disorganized actin meshwork, randomly protruding lamellipodia, and loss of cell polarity. This study reveals the importance of centrosomes to balance the assembly of centrosomal and acentrosomal microtubules and to deliver microtubule-associated TRIO proteins to FAs at the cell front for proper spatial activation of Rac1, FA turnover, lamillipodial protrusion, and cell polarization, thereby allowing directed cell migration.

Implications on cerebellar function from information coding.

One function of the cerebellar cortex is to process information. There are at least two types of information. Temporal information is encoded in the timing pattern of action and synaptic potentials, whereas structural information is encoded in the spatial pattern of the cerebellar synaptic circuitry. Intuitively, analysis of highly complex information in the time domain would require a cerebellar cortex with structural complexity to match. Information theory offers a way to estimate quantitatively both types of information and thereby helps to test hypotheses or advance theories of cerebellar neurobiology. These estimates suggest: (i) That the mossy-fiber-granule-cell system carries far more (temporal) information than the climbing fiber system, (ii) that Purkinje cells extract only a fraction of the (temporal) information from their afferents, and (iii) that the cerebellar cortex has a large (spatial) information coding capacity. Concerning information, one can argue that the cerebellar cortex analyzes temporal information in its afferents as a search engine, in search of coincidental mossy fiber events based on timing cues provided by climbing fiber events. Results of successive searches are continuously being converted into structural information encoded in the spatial distribution pattern of granule-cell-Purkinje-cell synapses along granule cell axons, thereby providing an adaptive and indeed self-correcting dimension to the structural information code. The search engine operation involves cellular mechanisms acting on temporal events and is part of an associative learning process. The conversion and generation of structural information involves neuroplasticity mechanisms acting at the synaptic level, with electrophysiological as well as structural consequences, and may be part of the short- and long-term memory process. These and other attributes qualify the cerebellar cortex as a dynamic information processing center, contributing to memory and learning while linking motor output with sensory events.

A wavelet approach for the identification of axonal synaptic varicosities from microscope images.

Direct visualization of synapses is a prerequisite to the analysis of the spatial distribution patterns of synaptic systems. Such an analysis is essential to the understanding of synaptic circuitry. In order to facilitate the visualization of individual synapses at the subcellular level from microscope images, we have introduced a wavelet-based approach for the semiautomated recognition of axonal synaptic varicosities. The proposed approach to image analysis employs a family of redundant wavelet representations. They are specifically designed for the recognition of signal peaks, which correspond to the presence of axonal synaptic varicosities. In this paper, the two-dimensional image of an axon together with its synaptic varicosities is first transformed into a one-dimensional (1-D) profile in which the axonal varicosities are represented by peaks in the signal. Next, by decomposing the 1-D profile in the differential wavelet domain, we employ the multi-scale point-wise product to distinguish between peaks and noises. The ability to separate the true signals (due to synaptic varicosities) from noise makes possible a reliable and accurate recognition of axonal synaptic varicosities. The proposed algorithms are also designed with a variable threshold that effectively allows variable sensitivities in varicosity detection. The algorithm has been systematically validated using images containing varicosities (< or =30) that have been consistently identified by seven human observers. The proposed algorithm can give high sensitivity and specificity with appropriate threshold. The results have indicated that the semiautomatic approach is satisfactory for processing a variety of microscopic images of axons under different conditions.

Fibronectin in cell adhesion and migration via N-glycosylation.

Directed cell migration is an important step in effective wound healing and requires the dynamic control of the formation of cell-extracellular matrix interactions. Plasma fibronectin is an extracellular matrix glycoprotein present in blood plasma that plays crucial roles in modulating cellular adhesion and migration and thereby helping to mediate all steps of wound healing. In order to seek safe sources of plasma fibronectin for its practical use in wound dressing, we isolated fibronectin from human (homo) and porcine plasma and demonstrated that both have a similar ability as a suitable substrate for the stimulation of cell adhesion and for directing cell migration. In addition, we also defined the N-glycosylation sites and N-glycans present on homo and porcine plasma fibronectin. These N-glycosylation modifications of the plasma fibronectin synergistically support the integrin-mediated signals to bring about mediating cellular adhesion and directed cell migration. This study not only determines the important function of N-glycans in both homo and porcine plasma fibronectin-mediated cell adhesion and directed cell migration, but also reveals the potential applications of porcine plasma fibronectin if it was applied as a material for clinical wound healing and tissue repair.

Information coding capacity of cerebellar parallel fibers.

Understanding synaptic connectivity is a prerequisite to gaining insight on how the central nervous system processes information. Cerebellar parallel fibers make an impressive number of synapses with the Purkinje cells. These synapses are the major structural elements of a large information processing system. The objective of the present report is to describe a method to estimate the coding capacity of this information processing system. We propose to derive the coding capacity from the linear distribution pattern of synaptic varicosities along parallel fibers in a manner consistent with Shannon's information theory formalism. The coding capacity of an average parallel fiber synapse is S=-kappaSigmaP(l(i))lnP(l(i)), where kappa=1/ln2, P(l(i)) is the probability of observing a particular inter-varicosital distance l(i), and ln is the natural logarithm to the base e. In the cerebellar parallel fibers of the mouse, and in a number of other unmyelinated axonal systems, the distribution pattern of P(l(i)) as a function of l(i) is exponential-like. According to information theory, the exponential-like distribution pattern suggests that information transmission in these axonal synaptic systems is operating at near-optimal coding capacity. This optimization in information coding may be the result of a stochastic-like process regulating the formation or elimination of parallel fiber synapses during development and maturation. In the adult nervous system, neuroplasticity-mediated synaptic remodeling may also regulate the coding capacity of axonal synapses via a similar stochastic-like process. The conceptual framework herein may be applicable to other axonal systems in the nervous system.

Plasticity of cerebellar Purkinje cells in behavioral training of body balance control.

Neural responses to sensory inputs caused by self-generated movements (reafference) and external passive stimulation (exafference) differ in various brain regions. The ability to differentiate such sensory information can lead to movement execution with better accuracy. However, how sensory responses are adjusted in regard to this distinguishability during motor learning is still poorly understood. The cerebellum has been hypothesized to analyze the functional significance of sensory information during motor learning, and is thought to be a key region of reafference computation in the vestibular system. In this study, we investigated Purkinje cell (PC) spike trains as cerebellar cortical output when rats learned to balance on a suspended dowel. Rats progressively reduced the amplitude of body swing and made fewer foot slips during a 5-min balancing task. Both PC simple (SSs; 17 of 26) and complex spikes (CSs; 7 of 12) were found to code initially on the angle of the heads with respect to a fixed reference. Using periods with comparable degrees of movement, we found that such SS coding of information in most PCs (10 of 17) decreased rapidly during balance learning. In response to unexpected perturbations and under anesthesia, SS coding capability of these PCs recovered. By plotting SS and CS firing frequencies over 15-s time windows in double-logarithmic plots, a negative correlation between SS and CS was found in awake, but not anesthetized, rats. PCs with prominent SS coding attenuation during motor learning showed weaker SS-CS correlation. Hence, we demonstrate that neural plasticity for filtering out sensory reafference from active motion occurs in the cerebellar cortex in rats during balance learning. SS-CS interaction may contribute to this rapid plasticity as a form of receptive field plasticity in the cerebellar cortex between two receptive maps of sensory inputs from the external world and of efference copies from the will center for volitional movements.

An experimental method for measuring the mean length of cerebellar parallel fibers: validation and derivation of a correction factor by computational simulation and probability analysis.

The length of cerebellar parallel fibers is important for information integration by the Purkinje cells. Based on the Copernican principle for analyzing the length of stochastic events, we have recently devised a stochastic method to estimate the mean length of parallel fibers within a given cerebellar region. The purpose of the present report is to provide validation of this methodology via computational simulations. We create virtual parallel fibers with known lengths and program each step of our stochastic method for computational simulation. We then compare the observed mean length obtained from our computational simulation with the known mean length of the virtual parallel fibers. In particular, we investigate the effect of cutting parallel fibers into segments during histological sectioning. Our computational results reveal an over-estimation factor ranging from 1.0 (no correction is necessary) to 2.0 as the parallel fiber segmentation becomes increasingly severe. Based on probability theory considerations, we have confirmed the existence of this over-estimation. We have further determined the cause of this over-estimation to be an artificial consequence of one of the sampling steps in our stochastic method. These results provide validation of our methodology, as well as a correction factor, which can be derived directly from the experimentally measured parameters and used to obtain the true mean length of parallel fibers. Potential applications of the stochastic method include a comparative analysis of the length of parallel fibers as an approach to gain clues about cerebellar circuit principles and function. In addition, the stochastic method may also find promising applications in other functionally important axonal systems in the brain.

Sitagliptin and the risk of hospitalization for heart failure: a population-based study.

BACKGROUND: Saxagliptin was associated with an increased risk of hospitalization for heart failure (HHF) in diabetic patients with high cardiovascular risk. This study assessed the risk of HHF during an exposure to sitagliptin in general diabetic patients. METHODS: In Taiwan National Health Insurance research database, a study of the beneficiaries aged ≥ 45 years with diabetes treated with or without sitagliptin between March 2009 and July 2011 was conducted. Patients treated with sitagliptin were matched to patients never exposed to a dipeptidyl peptidase-4 (DPP-4) inhibitor by the propensity score methodology. The outcome measures were the first and the total number of HHF, and mortality for heart failure or all causes. RESULTS: A total of 8288 matched pairs of patients were analyzed. During a median of 1.5 years, the first event of HHF occurred in 339 patients with sitagliptin and 275 patients never exposed to a DPP-4 inhibitor (hazard ratio: 1.21, 95% confidence interval: 1.04-1.42, P = 0.017); all-cause mortality was similar (hazard ratio: 0.87, 95% confidence interval: 0.74-1.03, P = 0.109). The risk for HHF was proportional to exposure (hazard ratio: 1.09, 95% confidence interval: 1.06-1.11, P < 0.001 for every 10% increase in adherence to sitagliptin). Overall, there were 935 events of HHF, in which the association between the number of HHF and the adherence to sitagliptin was linear. The greatest total number of HHF occurred in the patients with the highest adherence. CONCLUSIONS: The use of sitagliptin was associated with a higher risk of HHF but no excessive risk for mortality was observed.

Risk of new-onset diabetes mellitus versus reduction in cardiovascular events with statin therapy.

The Food and Drug Administration recently updated the safety warning concerning the association between statin therapy and new-onset diabetes mellitus (NODM). For prediabetes, little information is available for statins on cardiovascular outcome reduction and diabetogenic consequences. This study aimed to examine the risk of NODM and the reduction of cardiovascular events and death (MACE) after statin therapy in the prediabetic subjects. The medical and pharmacy claims of the prediabetic beneficiaries were retrieved from Taiwan National Health Insurance research database. The occurrence of NODM, MACE, and morbidity indexed by hospitalizations and emergency visits was ascertained by ambulatory and inpatient database. A propensity score-matched model was constructed for statin users and nonusers. During follow-up (4.1 ± 2.5 years), NODM and MACE occurred in 23.5% and 16.7%, respectively, of nonusers and 28.5% and 12.0%, respectively, of users. Statin therapy was associated with a greater risk of NODM (hazard ratio 1.20, 95% confidence interval 1.08 to 1.32) and less risk of MACE (hazard ratio 0.70, 95% confidence interval 0.61 to 0.80), both in dose-dependent fashions. The earlier and more persistent use correlated with the greater increase in risk of NODM offset by the proportionally larger reduction in MACE. Furthermore, the early persistent users had the lowest rate of hospitalizations and emergency visits. In conclusion, our findings suggested that the relation between NODM and therapeutic advantages of statins was parallel in the prediabetic population. Treatment benefits outweighed diabetic consequences in subjects receiving the earlier and more persistent treatment.

Long-term use of angiotensin II receptor blockers and risk of cancer: a population-based cohort analysis.

BACKGROUND: The risk of incident cancer after angiotensin II receptor blockers (ARBs) exposure was controversially reported by analyses of clinical trials and database. We assessed the occurrence of overall and site-specific cancers among ARB users and nonusers in the cohort with indications for ARB treatment. METHODS: Data were obtained from the Taiwan National Health Insurance research database. Subjects exposed to ARBs ≥ 180 days with no cancer prior to the first year of ARB initiation were identified; age-, sex-, comorbidity- and time-matched nonusers without cancer before the index date plus 1 year were selected. Incidences of overall and the most common cancers between users and nonusers were compared. RESULTS: There were 42,921 subjects enrolled in each group. During the mean follow-up of 4.8 ± 2.4 years, the cumulative incidence of cancer was 4% (ARB users) and 6% (ARB nonusers) (hazard ratio: 0.58, 95% confidence intervals 0.55-0.62; P<0.001). All ARBs significantly correlated with lower rates of cancer. Malignancies from the 7 most common sites were fewer in ARB users with the relative risk reduction of 28 to 49%. ARBs were associated with a decrease in incident cancer across subgroups including prior and concomitant exposure to angiotensin-converting enzyme inhibitors. CONCLUSIONS: In the cohort with indications for ARB treatment, exposure to ARBs was associated with lower risk of overall and site-specific cancers compared to nonusers. These findings reassure the safety of ARBs and support further investigations on ARBs and cancer prevention at the molecular level.