It has been almost 5 years since the publication of the 2010 hypertension guidelines of the Taiwan Society of Cardiology (TSOC). There is new evidence regarding the management of hypertension, including randomized controlled trials, non-randomized trials, post-hoc analyses, subgroup analyses, retrospective studies, cohort studies, and registries. More recently, the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) published joint hypertension guidelines in 2013. The panel members who were appointed to the Eighth Joint National Committee (JNC) also published the 2014 JNC report. Blood pressure (BP) targets have been changed; in particular, such targets have been loosened in high risk patients. The Executive Board members of TSOC and the Taiwan Hypertension Society (THS) aimed to review updated information about the management of hypertension to publish an updated hypertension guideline in Taiwan. We recognized that hypertension is the most important risk factor for global disease burden. Management of hypertension is especially important in Asia where the prevalence rate grows faster than other parts of the world. In most countries in East Asia, stroke surpassed coronary heart disease (CHD) in causing premature death. A diagnostic algorithm was proposed, emphasizing the importance of home BP monitoring and ambulatory BP monitoring for better detection of night time hypertension, early morning hypertension, white-coat hypertension, and masked hypertension. We disagreed with the ESH/ESH joint hypertension guidelines suggestion to loosen BP targets to <140/90 mmHg for all patients. We strongly disagree with the suggestion by the 2014 JNC report to raise the BP target to <150/90 mmHg for patients between 60-80 years of age. For patients with diabetes, CHD, chronic kidney disease who have proteinuria, and those who are receiving antithrombotic therapy for stroke prevention, we propose BP targets of <130/80 mmHg in our guidelines. BP targets are <140/90 mmHg for all other patient groups, except for patients ≥80 years of age in whom a BP target of <150/90 mmHg would be optimal. For the management of hypertension, we proposed a treatment algorithm, starting with life style modification (LSM) including S-ABCDE (Sodium restriction, Alcohol limitation, Body weight reduction, Cigarette smoke cessation, Diet adaptation, and Exercise adoption). We emphasized a low-salt strategy instead of a no-salt strategy, and that excessively aggressive sodium restriction to <2.0 gram/day may be harmful. When drug therapy is considered, a strategy called "PROCEED" was suggested (Previous experience, Risk factors, Organ damage, Contraindications or unfavorable conditions, Expert's or doctor's judgment, Expenses or cost, and Delivery and compliance issue). To predict drug effects in lowering BP, we proposed the "Rule of 10" and "Rule of 5". With a standard dose of any one of the 5 major classes of anti-hypertensive agents, one can anticipate approximately a 10-mmHg decrease in systolic BP (SBP) (Rule of 10) an...

The human pineal gland and melatonin in aging and Alzheimer's disease Pineal gland and melatoninIn humans, the pineal gland is 5 mm long, 1-4 mm thick and weighs about 100 mg, both in men and in women [1]. The pineal gland contains two major cell types: neuroglial cells and the predominant pinealocytes that produce melatonin.The pineal gland is a central structure in the circadian system that is innervated by a neural multi-synaptic pathway originating in the suprachiasmatic nucleus (SCN) that is located in the anterior hypothalamus. The SCN is the major circadian pacemaker of the mammalian brain and plays a central role in the generation and regulation of biological rhythms [2,3]. The pineal gland produces melatonin in a marked circadian fashion [4], reflecting signals originating in the SCN. The human SCN innervates only a small number of hypothalamic nuclei directly [5,6]. However, it may impose circadian fluctuations indirectly on the organism by means of melatonin released from the pineal gland [7].The biosynthetic pathway of pineal melatonin has been studied thoroughly. l-Tryptophan is taken up from the circulation and converted to serotonin (5-HT) by tryptophan hydroxylase. 5-HT is metabolized by the rate-limiting enzyme arylalkylamine N-acetyltransferase (AA-NAT) to N-acetyl-5-hydroxytryptamine, and in turn by hydroxyindole-o-methyltransferase to melatonin. 5-HT can also be oxidized by monoamine oxidase A (MAOA) to 5-hydroxyindoleacetic acid [4,8]. In all vertebrates, the activity of the rhythm-generating enzyme AA-NAT increases at night by a factor 7-150, depending on the species. The molecular mechanisms regulating AA-NAT are also remarkably different among species. For instance, in the rat, pineal AA-NAT is regulated at both mRNA level and protein level; however, in sheep and rhesus macaque, pineal AA-NAT mRNA levels show relatively little change over a 24-hr period and changes in AA-NAT activity are primarily regulated at the protein level [9,10]. In the human pineal gland, significant daily fluctuations in AA-NAT mRNA levels were not detected either [11], which suggests that pineal AA-NAT activity may be mainly regulated on the post-transcriptional level in human.The main environmental control of the pineal melatonin synthesis is light intensity. Light perceived by the retina reaches the SCN through the retinohypothalamic tract, which has been revealed by an in vitro postmortem tracing procedure, also in the human hypothalamus [12]. The SCN innervates the pineal gland via the dorsomedial hypothalamic nucleus, the upper thoracic intermediolateral cell columns of the spinal cord and the superior cervical ganglia (SCG), resulting in the rhythmic secretion of melatonin [13,14]. The importance of ocular light as a temporal cue has been clearly demonstrated in circadian studies of blind Abstract: The pineal gland is a central structure in the circadian system which produces melatonin under the control of the central clock, the suprachiasmatic nucleus (SCN). The SCN and the output of the pineal gland, i.e....

A disturbed sleep-wake rhythm is common in Alzheimer disease (AD) patients and correlated with decreased melatonin levels and a disrupted circadian melatonin rhythm. Melatonin levels in the cerebrospinal fluid are decreased during the progression of AD neuropathology (as determined by the Braak stages), already in cognitively intact subjects with the earliest AD neuropathology (Braak stages I-II) (preclinical AD). To investigate the molecular mechanisms behind the decreased melatonin levels, we measured monoamines and mRNA levels of enzymes of the melatonin synthesis and its noradrenergic regulation in pineal glands from 18 controls, 33 preclinical AD subjects, and 25 definite AD patients. Pineal melatonin levels were highly correlated with cerebrospinal fluid melatonin levels. The circadian melatonin rhythm disappeared because of decreased nocturnal melatonin levels in both the preclinical AD and AD patients. Also the circadian rhythm of beta(1)-adrenergic receptor mRNA disappeared in both patient groups. The precursor of melatonin, serotonin was stepwise depleted during the course of AD, as indicated by the up-regulated monoamine oxidase A mRNA and activity (5-hydroxyindoleacetic acid:serotonin ratio). We conclude that a dysfunction of noradrenergic regulation and the depletion of serotonin by increased monoamine oxidase A result in the loss of melatonin rhythm already in preclinical AD.

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The suprachiasmatic nucleus (SCN) is the "master clock" of the mammalian brain. It coordinates the peripheral clocks in the body, including the pineal clock that receives SCN input via a multisynaptic noradrenergic pathway. Rhythmic pineal melatonin production is disrupted in Alzheimer's disease (AD). Here we show that the clock genes hBmal1, hCry1, and hPer1 were rhythmically expressed in the pineal of controls (Braak 0). Moreover, hPer1 and hbeta1-adrenergic receptor (hbeta1-ADR) mRNA were positively correlated and showed a similar daily pattern. In contrast, in both preclinical (Braak I-II) and clinical AD patients (Braak V-VI), the rhythmic expression of clock genes was lost as well as the correlation between hPer1 and hbeta1-ADR mRNA. Intriguingly, hCry1 mRNA was increased in clinical AD. These changes are probably due to a disruption of the SCN control, as they were mirrored in the rat pineal deprived of SCN control. Indeed, a functional disruption of the SCN was observed from the earliest AD stages onward, as shown by decreased vasopressin mRNA, a clock-controlled major output of the SCN. Thus, a functional disconnection between the SCN and the pineal from the earliest AD stage onward could account for the pineal clock gene changes and underlie the circadian rhythm disturbances in AD.

Melatonin is implicated in numerous physiological processes, including circadian rhythms, stress, and reproduction, many of which are mediated by the hypothalamus and pituitary. The physiological actions of melatonin are mainly mediated by melatonin receptors. We here describe the distribution of the melatonin receptor MT1 in the human hypothalamus and pituitary by immunocytochemistry. MT1 immunoreactivity showed a widespread pattern in the hypothalamus. In addition to the area of the suprachiasmatic nucleus (SCN), a number of novel sites, including the paraventricular nucleus (PVN), periventricular nucleus, supraoptic nucleus (SON), sexually dimorphic nucleus, the diagonal band of Broca, the nucleus basalis of Meynert, infundibular nucleus, ventromedial and dorsomedial nucleus, tuberomamillary nucleus, mamillary body, and paraventricular thalamic nucleus were observed to have neuronal MT1 receptor expression. No staining was observed in the nucleus tuberalis lateralis and bed nucleus of the stria terminalis. The MT1 receptor was colocalized with some vasopressin (AVP) neurons in the SCN, colocalized with some parvocellular and magnocellular AVP and oxytocine (OXT) neurons in the PVN and SON, and colocalized with some parvocellular corticotropin-releasing hormone (CRH) neurons in the PVN. In the pituitary, strong MT1 expression was observed in the pars tuberalis, while a weak staining was found in the posterior and anterior pituitary. These findings provide a neurobiological basis for the participation of melatonin in the regulation of various hypothalamic and pituitary functions. The colocalization of MT1 and CRH suggests that melatonin might directly modulate the hypothalamus-pituitary-adrenal axis in the PVN, which may have implications for stress conditions such as depression.

Vascular endothelial growth factor (VEGF) and bone morphogenetic protein-2 (BMP-2) have been widely used in the fields of tissue engineering and regenerative medicine to stimulate angiogenesis and bone formation. The goal of this study was to determine whether VEGF and BMP-2 are involved in the homing of bone marrow stem cells (BMSCs) for bone regeneration and to provide insights into their mechanism of action. The chemoattraction of BMSCs to VEGF and BMP-2 was analysed in vitro using a checkerboard assay. VEGF and BMP-2 stimulated the chemotaxis of BMSCs but not chemokinesis. In vivo, both VEGF and BMP-2 also have been confirmed to induce the homing of tail vein injected BMSCs to the site of silk scaffold subcutaneous implantation in nude mice. When the scaffolds were implanted in the rabbit skull defects, more SSEA4+ mesenchymal stem cells were mobilised and homed to silk scaffolds containing VEGF and/or BMP-2. More importantly, autogenic BMSCs were reinjected via the ear vein after labelling with lenti-GFP, and the cells were detected to home to the defects and differentiate into endothelial cells and osteogenic cells induced by VEGF and BMP-2. Finally, perfusion with Microfil showed that initial angiogenesis was enhanced in tissue-engineered complexes containing VEGF. Observations based on µCT assay and histological study revealed that bone formation was accelerated on BMP-2-containing scaffolds. These findings support our hypothesis that the localised release of VEGF and BMP-2 promote bone regeneration, in part by facilitating the mobilisation of endogenous stem cells and directing the differentiation of these cells into endothelial and osteogenic lineages.

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