Arrowhead Regional Medical Center

BACKGROUND: In phase 2 trials, the nucleotide polymerase inhibitor sofosbuvir was effective in previously untreated patients with chronic hepatitis C virus (HCV) genotype 1, 2, or 3 infection. METHODS: We conducted two phase 3 studies in previously untreated patients with HCV infection. In a single-group, open-label study, we administered a 12-week regimen of sofosbuvir plus peginterferon alfa-2a and ribavirin in 327 patients with HCV genotype 1, 4, 5, or 6 (of whom 98% had genotype 1 or 4). In a noninferiority trial, 499 patients with HCV genotype 2 or 3 infection were randomly assigned to receive sofosbuvir plus ribavirin for 12 weeks or peginterferon alfa-2a plus ribavirin for 24 weeks. In the two studies, the primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: In the single-group study, a sustained virologic response was reported in 90% of patients (95% confidence interval, 87 to 93). In the noninferiority trial, a sustained response was reported in 67% of patients in both the sofosbuvir-ribavirin group and the peginterferon-ribavirin group. Response rates in the sofosbuvir-ribavirin group were lower among patients with genotype 3 infection than among those with genotype 2 infection (56% vs. 97%). Adverse events (including fatigue, headache, nausea, and neutropenia) were less common with sofosbuvir than with peginterferon. CONCLUSIONS: In a single-group study of sofosbuvir combined with peginterferon-ribavirin, patients with predominantly genotype 1 or 4 HCV infection had a rate of sustained virologic response of 90% at 12 weeks. In a noninferiority trial, patients with genotype 2 or 3 infection who received either sofosbuvir or peginterferon with ribavirin had nearly identical rates of response (67%). Adverse events were less frequent with sofosbuvir than with peginterferon. (Funded by Gilead Sciences; FISSION and NEUTRINO ClinicalTrials.gov numbers, NCT01497366 and NCT01641640, respectively.).

BACKGROUND: The benefits and safety of the treatment of mild chronic hypertension (blood pressure, <160/100 mm Hg) during pregnancy are uncertain. Data are needed on whether a strategy of targeting a blood pressure of less than 140/90 mm Hg reduces the incidence of adverse pregnancy outcomes without compromising fetal growth. METHODS: In this open-label, multicenter, randomized trial, we assigned pregnant women with mild chronic hypertension and singleton fetuses at a gestational age of less than 23 weeks to receive antihypertensive medications recommended for use in pregnancy (active-treatment group) or to receive no such treatment unless severe hypertension (systolic pressure, ≥160 mm Hg; or diastolic pressure, ≥105 mm Hg) developed (control group). The primary outcome was a composite of preeclampsia with severe features, medically indicated preterm birth at less than 35 weeks' gestation, placental abruption, or fetal or neonatal death. The safety outcome was small-for-gestational-age birth weight below the 10th percentile for gestational age. Secondary outcomes included composites of serious neonatal or maternal complications, preeclampsia, and preterm birth. RESULTS: A total of 2408 women were enrolled in the trial. The incidence of a primary-outcome event was lower in the active-treatment group than in the control group (30.2% vs. 37.0%), for an adjusted risk ratio of 0.82 (95% confidence interval [CI], 0.74 to 0.92; P<0.001). The percentage of small-for-gestational-age birth weights below the 10th percentile was 11.2% in the active-treatment group and 10.4% in the control group (adjusted risk ratio, 1.04; 95% CI, 0.82 to 1.31; P = 0.76). The incidence of serious maternal complications was 2.1% and 2.8%, respectively (risk ratio, 0.75; 95% CI, 0.45 to 1.26), and the incidence of severe neonatal complications was 2.0% and 2.6% (risk ratio, 0.77; 95% CI, 0.45 to 1.30). The incidence of any preeclampsia in the two groups was 24.4% and 31.1%, respectively (risk ratio, 0.79; 95% CI, 0.69 to 0.89), and the incidence of preterm birth was 27.5% and 31.4% (risk ratio, 0.87; 95% CI, 0.77 to 0.99). CONCLUSIONS: In pregnant women with mild chronic hypertension, a strategy of targeting a blood pressure of less than 140/90 mm Hg was associated with better pregnancy outcomes than a strategy of reserving treatment only for severe hypertension, with no increase in the risk of small-for-gestational-age birth weight. (Funded by the National Heart, Lung, and Blood Institute; CHAP ClinicalTrials.gov number, NCT02299414.).

There is physiologic coupling of EEG morphology, frequencies, and amplitudes with cerebral blood flow. Intraoperative continuous electroencephalographic monitoring (CEEG) is an established modality that has been used for 30 years to detect cerebral ischemia during carotid surgery. These facts have generated interest in applying EEG/CEEG in the intensive care unit to monitor cerebral ischemia. However, its use in acute ischemic stroke (AIS) has been limited, and its value has been questioned in comparison with modern MRI imaging techniques and the clinical neurologic examination. This review presents evidence that EEG/CEEG adds value to early diagnosis, outcome prediction, patient selection for treatment, clinical management, and seizure detection in AIS. Research studies correlating EEG/CEEG and advanced imaging techniques in AIS are encouraged. Improvements in real-time ischemia detection systems are needed for EEG/CEEG to have wider application in AIS.

OBJECTIVE: Preterm birth is the leading cause of perinatal morbidity and mortality worldwide. Treatment of preterm labor with tocolysis has not been successful in improving infant outcome. The administration of progesterone and related compounds has been proposed as a strategy to prevent preterm birth. The objective of this trial was to determine whether prophylactic administration of vaginal progesterone reduces the risk of preterm birth in women with a history of spontaneous preterm birth. METHODS: This randomized, double-blind, placebo- controlled, multinational trial enrolled and randomized 659 pregnant women with a history of spontaneous preterm birth. Between 18 + 0 and 22 + 6 weeks of gestation, patients were assigned randomly to once-daily treatment with either progesterone vaginal gel or placebo until either delivery, 37 weeks' gestation or development of preterm rupture of membranes. The primary outcome was preterm birth at </= 32 weeks of gestation. The trial was analyzed using an intent-to-treat strategy. RESULTS: Baseline characteristics were similar in the two treatment groups. Progesterone did not decrease the frequency of preterm birth at </= 32 weeks. There was no difference between the groups with respect to the mean gestational age at delivery, infant morbidity or mortality or other maternal or neonatal outcome measures. Adverse events during the course of treatment were similar for the two groups. CONCLUSION: Prophylactic treatment with vaginal progesterone did not reduce the frequency of recurrent preterm birth (</= 32 weeks) in women with a history of spontaneous preterm birth. The effect of progesterone administration in patients at high risk for preterm delivery as determined by methods other than history alone (e.g. sonographic cervical length) requires further investigation.

OBJECTIVE: To investigate the efficacy of vaginal progesterone to prevent early preterm birth in women with sonographic evidence of a short cervical length in the midtrimester. METHODS: This was a planned, but modified, secondary analysis of our multinational, multicenter, randomized, placebo-controlled trial, in which women were randomized between 18 + 0 and 22 + 6 weeks of gestation to receive daily treatment with 90 mg of vaginal progesterone gel or placebo. Cervical length was measured with transvaginal ultrasound at enrollment and at 28 weeks of gestation. Treatment continued until either delivery, 37 weeks of gestation or development of preterm rupture of membranes. Maternal and neonatal outcomes were evaluated for the subset of all randomized women with cervical length < 28 mm at enrollment. The primary outcome was preterm birth at </= 32 weeks. RESULTS: A cervical length < 28 mm was identified in 46 randomized women: 19 of 313 who received progesterone and 27 of 307 who received the placebo. Baseline characteristics of the two groups were similar. In women with a cervical length < 28 mm, the rate of preterm birth at </= 32 weeks was significantly lower for those receiving progesterone than it was for those receiving the placebo (0% vs. 29.6%, P = 0.014). With progesterone, there were fewer admissions into the neonatal intensive care unit (NICU; 15.8% vs. 51.9%, P = 0.016) and shorter NICU stays (1.1 vs. 16.5 days, P = 0.013). There was also a trend toward a decreased rate of neonatal respiratory distress syndrome (5.3% vs. 29.6%, P = 0.060). CONCLUSION: Vaginal progesterone may reduce the rate of early preterm birth and improve neonatal outcome in women with a short sonographic cervical length.

This article reviews established, emergent, and potential applications of continuous EEG (CEEG) monitoring in the Neuroscience Intensive Care Unit (NICU) and Emergency Department. In each application, its goal as a neurophysiologic monitor is to extend our powers of observation to detect abnormalities at a reversible stage and to guide timely and physiologically sound interventions. Since this subject was reviewed 5 years ago, the use of CEEG monitoring has become more widespread. In a modern NICU, it is no longer novel to have CEEG data contributing to management decisions. A well-trained CEEG monitoring team is important for its optimal implementation. In the diagnosis and management of convulsive and nonconvulsive status epilepticus, its value appears established. It is finding benefit in the early diagnosis and management of precarious cerebral ischemia, including severe acute cerebral infarctions and post-SAH vasospasms. In comatose patients, it can provide diagnostic and prognostic information which is otherwise unobtainable. More recently, it has been found advantageous for targeting management of acute severe head trauma patients. Networking technology has facilitated the implementation and oversight of CEEG monitoring and promises to expand its availability, credibility, and effectiveness. The maturing of CEEG use is reflected in preliminary efforts to assess its cost benefit, cost effectiveness, and impact on patient outcomes.

The pineal hormone melatonin participates in circadian, seasonal, and reproductive physiology. The presence of melatonin binding sites in human brain and peripheral tissues is well documented. However, in the mammalian adrenal gland, low-affinity melatonin binding sites have been detected only in the rat by some but not all authors. Conflicting evidence for a regulatory role of melatonin on adrenal cortisol production, prompted us to investigate this possibility in a New World primate, the capuchin monkey. Expression of melatonin receptors in the adrenal cortex was demonstrated through pharmacological characterization and autoradiographic localization of 2-[125I]iodomelatonin binding sites (dissociation constant = 96.9 +/- 15 pM; maximal binding capacity = 3.8 +/- 0.4 fmol/mg protein). The mt1 identity of these receptors was established by cDNA sequencing. Melatonin treatment of dispersed cells and explants from adrenal gland did not affect basal cortisol production. However, cortisol production stimulated by 100 nM ACTH was significantly inhibited by low melatonin concentrations (0.1-100 nM); this inhibitory effect was reversed by the mt1/MT2 melatonin antagonist luzindole. Melatonin also inhibited dibutyril-cAMP-stimulated cortisol production, suggesting that melatonin acts through a cAMP-independent signaling pathway. The present data demonstrate that the primate adrenal gland cortex expresses functional mt1 melatonin receptors and shows that melatonin inhibits ACTH-stimulated cortisol production.

The number of orphan radio afterglows associated with gamma-ray bursts (GRBs) that should be detected by a flux limited radio survey, is calculated. It is shown that for jetted GRBs this number is smaller for smaller jet opening angle (theta), contrary to naive expectation. For a beaming factor f_b^{-1}=(theta^2/2)^{-1} = 500, roughly the value inferred by Frail et al. (2001) from analysis of afterglow light curves, we predict that between several hundreds to several thousands orphan radio afterglows should be detectable (over all sky) above 1 mJy at GHz frequencies at any given time. This orphan population is dominated by sources lying at distances of a few hundred Mpc, and having an age of ~1 yr. A search for point-like radio transients with flux densities greater than 6 mJy was conducted using the FIRST and NVSS surveys, yielding a list of 25 orphan candidates. We argue that most of the candidates are unlikely to be radio supernovae. However, the possibility that they are radio loud AGNs cannot be ruled out without further observations. Our analysis sets an upper limit for the all sky number of radio orphans, which corresponds to a lower limit f_b^{-1}>10 on the beaming factor. Rejection of all candidates found in our search would imply f_b^{-1}>100. This, and the fact that some candidates may indeed be radio afterglows, strongly motivate further observations of these transients.

Tethered cord syndrome (TCS) is a stretch-induced functional disorder of the spinal cord due to the fact that its caudal portion is anchored by an inelastic structure. The functional lesion of TCS is generally situated in the lumbosacral cord, and many authors have shown that the syndrome is reversible via surgery to untether the cord. To clarify the expressions relevant to TCS, such as "cord tethering" and "tethered cord," the authors have formulated three categories. These categories include cases that show the anatomical appearance of spinal cord stretching. Among them, Category 1 is isolated to represent the "true TCS." The authors focus their discussion of the pathophysiology of TCS on Category 1 to explain the impaired oxidative metabolism and electrophysiological derangements within the tethered spinal cord, which is the primary intrinsic cause of the dysfunction. Furthermore, they extend the discussion to the extrinsic (outside the spinal cord) factors and other complex conditions that mimic TCS.

INTRODUCTION: Necrotizing fasciitis (NF) is an uncommon but rapidly progressive infection that results in gross morbidity and mortality if not treated in its early stages. The Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score is used to distinguish NF from other soft tissue infections such as cellulitis or abscess. This study analyzed the ability of the LRINEC score to accurately rule out NF in patients who were confirmed to have cellulitis, as well as the capability to differentiate cellulitis from NF. METHODS: This was a 10-year retrospective chart-review study that included emergency department (ED) patients ≥18 years old with a diagnosis of cellulitis or NF. We calculated a LRINEC score ranging from 0-13 for each patient with all pertinent laboratory values. Three categories were developed per the original LRINEC score guidelines denoting NF risk stratification: high risk (LRINEC score ≥8), moderate risk (LRINEC score 6-7), and low risk (LRINEC score ≤5). All cases missing laboratory values were due to the absence of a C-reactive protein (CRP) value. Since the score for a negative or positive CRP value for the LRINEC score was 0 or 4 respectively, a LRINEC score of 0 or 1 without a CRP value would have placed the patient in the "low risk" group and a LRINEC score of 8 or greater without CRP value would have placed the patient in the "high risk" group. These patients missing CRP values were added to these respective groups. RESULTS: Among the 948 ED patients with cellulitis, more than one-tenth (10.7%, n=102 of 948) were moderate or high risk for NF based on LRINEC score. Of the 135 ED patients with a diagnosis of NF, 22 patients had valid CRP laboratory values and LRINEC scores were calculated. Among the other 113 patients without CRP values, six patients had a LRINEC score ≥ 8, and 19 patients had a LRINEC score ≤ 1. Thus, a total of 47 patients were further classified based on LRINEC score without a CRP value. More than half of the NF group (63.8%, n=30 of 47) had a low risk based on LRINEC ≤5. Moreover, LRINEC appeared to perform better in the diabetes population than in the non-diabetes population. CONCLUSION: The LRINEC score may not be an accurate tool for NF risk stratification and differentiation between cellulitis and NF in the ED setting. This decision instrument demonstrated a high false positive rate when determining NF risk stratification in confirmed cases of cellulitis and a high false negative rate in cases of confirmed NF.

We have discovered seven type Ia cluster supernovae (SNe) in the course of the Wise Observatory Optical Transients Search in the fields of galaxy clusters with redshifts between z=0.06 and z=0.2. Two of these events, SN 1998fc in Abell 403 (z=0.10) and SN 2001al in Abell 2122/4 (z = 0.066), have no obvious hosts. Both events appear projected on the halos of the central cD galaxies, but have velocity offsets of 750-2000 km/s relative to those galaxies, suggesting they are not bound to them. We use deep Keck imaging of the locations of the two SNe to put upper limits on the luminosities of possible dwarf hosts, M_R &gt; -14 mag for SN 1998fc and M_R &gt; -11.8 mag for SN 2001al. The fractions of the cluster luminosities in dwarf galaxies fainter than our limits are less than 3 x 10^-3 and 3 x 10^-4, respectively. Thus, 2/7 of the SNe would be associated with less than 3 x 10^-3 of the luminosity attributed to galaxies. We argue, instead, that the progenitors of both events were probably members of a diffuse population of intergalactic stars, recently detected in local clusters via planetary nebulae and red giants. Considering the higher detectability of hostless SNe compared to normal SNe, we estimate that 20^{+12}_{-15} percent of the SN Ia parent stellar population in clusters is intergalactic. This fraction is consistent with other measurements of the intergalactic stellar population, and implies that the process that produces intergalactic stars (e.g., tidal disruption of cluster dwarfs) does not disrupt or enhance significantly the SN Ia formation mechanism. Hostless SNe are potentially powerful tracers of the formation of the intergalactic stellar population out to high redshift.

In the adult mammal the circadian system, which allows predictive adaptation to daily environmental changes, comprises peripheral oscillators in most tissues, commanded by the suprachiasmatic nucleus (SCN) of the hypothalamus. The external environment of the fetus is provided by its mother. In primates, maternal melatonin is a candidate to entrain fetal circadian rhythms, including the SCN rhythms of metabolic activity. We found in the 90% of gestation capuchin monkey fetus expression of the clock genes Bmal-1, Per-2, Cry-2, and Clock in the SCN, adrenal, pituitary, brown fat, and pineal. Bmal-1, Per-2, and the melatonin 1 receptor (MT1) showed a robust oscillatory expression in SCN and adrenal gland, whereas a circadian rhythm of dehydroepiandrosterone sulphate was found in plasma. Maternal melatonin suppression changed the expression of Bmal-1, Per-2, and MT1 in the fetal SCN. These effects were reversed by maternal melatonin replacement. In contrast, neither maternal melatonin suppression nor its replacement had effects on the expression of Per-2 and Bmal-1 or MT1 in the fetal adrenal gland or the circadian rhythm of fetal plasma dehydroepiandrosterone sulphate. Our data suggest that maternal melatonin is a Zeitgeber for the fetal SCN but probably not for the adrenal gland.

Surprisingly, in our modern 24/7 society, there is scant information on the impact of developmental chronodisruption like the one experienced by shift worker pregnant women on fetal and postnatal physiology. There are important differences between the maternal and fetal circadian systems; for instance, the suprachiasmatic nucleus is the master clock in the mother but not in the fetus. Despite this, several tissues/organs display circadian oscillations in the fetus. Our hypothesis is that the maternal plasma melatonin rhythm drives the fetal circadian system, which in turn relies this information to other fetal tissues through corticosterone rhythmic signaling. The present data show that suppression of the maternal plasma melatonin circadian rhythm, secondary to exposure of pregnant rats to constant light along the second half of gestation, had several effects on fetal development. First, it induced intrauterine growth retardation. Second, in the fetal adrenal in vivo it markedly affected the mRNA expression level of clock genes and clock-controlled genes as well as it lowered the content and precluded the rhythm of corticosterone. Third, an altered in vitro fetal adrenal response to ACTH of both, corticosterone production and relative expression of clock genes and steroidogenic genes was observed. All these changes were reversed when the mother received a daily dose of melatonin during the subjective night; supporting a role of melatonin on overall fetal development and pointing to it as a 'time giver' for the fetal adrenal gland. Thus, the present results collectively support that the maternal circadian rhythm of melatonin is a key signal for the generation and/or synchronization of the circadian rhythms in the fetal adrenal gland. In turn, low levels and lack of a circadian rhythm of fetal corticosterone may be responsible of fetal growth restriction; potentially inducing long term effects in the offspring, possibility that warrants further research.

Abstract Circadian rhythmicity is a fundamental characteristic of organisms, which helps ensure that vital functions occur in an appropriate and precise temporal sequence and in accordance with cyclic environmental changes. Living beings are endowed with a system of biological clocks that measure time on a 24‐hr basis, termed the circadian timing system. In mammals, the system is organized as a master clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus, commanding peripheral clocks located in almost every tissue of the body. At the cell level, interlocking transcription/translation feedback loops of the genes Bmal‐1, Clock, Per1–2, and Cry1–2, named clock genes, and their protein products results in circadian oscillation of clock genes and of genes involved in almost every cellular function. During gestation, the conceptus follows a complex and dynamic program by which it is simultaneously fit to develop and live in a circadian environment provided by its mother and to prepare for the very different environment that it will experience after birth. It has been known for a number of years that the mother tells the fetus the time of day and season of the year, and that the fetus uses this information to set the phase of fetal and neonatal circadian rhythms. There is evidence that the maternal rhythm of melatonin is one of the time signals to the fetus. In the last few years, the study of the development of the circadian system has turned to the investigation of the oscillatory expression of clock genes and their possible role in development, and to answering questions on the organization of the fetal circadian system. Emerging evidence shows that clock genes are expressed in the oocyte and during early and late development in embryo/fetal organs in the rat and in a fetal primate. The data available raise the intriguing possibility that the fetal SCN and fetal tissues may be peripheral clocks commanded by separate maternal signals. The rapid methodological and conceptual advances on chronobiology may help to unravel how the developing embryo and fetus faces time in this plastic period of life. Birth Defects Research (Part C) 81:204–214, 2007. © 2007 Wiley‐Liss, Inc.

Tethered cord syndrome (TCS) is a stretch-induced functional disorder of the spinal cord. The mechanical cause of TCS is an inelastic structure anchoring the caudal end of the spinal cord that prevents cephalad movement of the lumbosacral cord. Stretching of the spinal cord occurs in patients either when the spinal column grows faster than the spinal cord or when the spinal cord undergoes forcible flexion and extension. Research in patients and experimental animals suggests that there is a link between the clinical dysfunctions that characterize TCS and putative pathophysiological changes that accompany this syndrome. Among these changes are depression of electrophysiological activity and shifts in the reduction/oxidation ratio of cytochrome oxidase. The latter suggests that there is impairment of oxidative metabolism. These putative pathophysiological changes in TCS occur mainly within the lumbosacral cord under excessive tension. The authors discuss the pathophysiology of TCS and examine related symptoms.

The adrenal gland in the adult is a peripheral circadian clock involved in the coordination of energy intake and expenditure, required for adaptation to the external environment. During fetal life, a peripheral circadian clock is present in the nonhuman primate adrenal gland. Whether this extends to the fetal adrenal gland like the rat is unknown. Here we explored in vivo and in vitro whether the rat fetal adrenal is a peripheral circadian clock entrained by melatonin. We measured the 24-h changes in adrenal content of corticosterone and in the expression of clock genes Per-2 and Bmal-1 and of steroidogenic acute regulatory protein (StAR), Mt1 melatonin receptor, and early growth response protein 1 (Egr-1) expression. In culture, we explored whether oscillatory expression of these genes persisted during 48 h and the effect of a 4-h melatonin pulse on their expression. In vivo, the rat fetal adrenal gland showed circadian expression of Bmal-1 and Per-2 in antiphase (acrophases at 2200 and 1300 h, respectively) as well as of Mt1 and Egr-1. This was accompanied by circadian rhythms of corticosterone content and of StAR expression both peaking at 0600 h. The 24-h oscillatory expression of Bmal-1, Per-2, StAR, Mt1, and Egr-1 persisted during 48 h in culture; however, the antiphase between Per-2 and Bmal-1 was lost. The pulse of melatonin shifted the acrophases of all the genes studied and restored the antiphase between Per-2 and Bmal-1. Thus, in the rat, the fetal adrenal is a strong peripheral clock potentially amenable to regulation by maternal melatonin.

Whether or not nonconvulsive status epilepticus produces permanent brain damage is a source of controversy. Contributing to the controversy is the lack of clarity for classifying the clinical and electrographic phenomena that constitute nonconvulsive status epilepticus. Nonconvulsive status epilepticus commonly occurs in the context of an acute brain injury. For example, it commonly persists in generalized convulsive status epilepticus after convulsive activity has stopped, and it is not uncommonly associated with acute cerebral ischemia. Its clinical characteristics are ambiguous, subtle, and nonspecific making the diagnosis difficult. In the absence of EEG testing, it is likely to be missed or delayed. When acute brain injury and nonconvulsive status epilepticus occur concurrently, the severity of acute brain injury has traditionally been accepted as determining patient outcome. However, increasing evidence suggests that the two conditions are synergistically detrimental and increase brain injury. Guidelines remain to be established for the intensity and duration of anticonvulsant therapy in these patients. Evidence suggests that, in the absence of extreme and irreversible acute brain injury, early intensive intervention is necessary to improve the otherwise poor outcome of these patients.

To help physicians with the appropriate use of antibiotics in children and adults with upper respiratory tract infection, a multidisciplinary team evaluated existing guidelines and summarized key practice points. Acute otitis media in children should be diagnosed only if there is abrupt onset, signs of middle ear effusion, and symptoms of inflammation. A period of observation without immediate use of antibiotics is an option for certain children. In patients with sinus infection, acute bacterial rhinosinusitis should be diagnosed and treated with antibiotics only if symptoms have not improved after 10 days or have worsened after five to seven days. In patients with sore throat, a diagnosis of group A beta-hemolytic streptococcus pharyngitis generally requires confirmation with rapid antigen testing, although other guidelines allow for empiric therapy if a validated clinical rule suggests a high likelihood of infection. Acute bronchitis in otherwise healthy adults should not be treated with antibiotics; delayed prescriptions may help ease patient fears and simultaneously reduce inappropriate use of antibiotics.

We tested the hypothesis that in primates, maternal melatonin restrains fetal and newborn adrenal cortisol production. A functional G-protein-coupled MT1 membrane-bound melatonin receptor was detected in 90% gestation capuchin monkey fetal adrenals by (a) 2-[(125)I] iodomelatonin binding (K(d), 75.7 +/- 6.9 pm; B(max), 2.6 +/- 0.4 fmol (mg protein)(-1)), (b) cDNA identification, and (c) melatonin inhibition of adrenocorticotrophic hormone (ACTH)- and corticotrophin-releasing hormone (CRH)-stimulated cortisol but not of dehydroepiandrosterone sulphate (DHAS) production in vitro. Melatonin also inhibited ACTH-induced 3beta-hydroxysteroid dehydrogenase mRNA expression. To assess the physiological relevance of these findings, we next studied the effect of chronic maternal melatonin suppression (induced by exposure to constant light during the last third of gestation) on maternal plasma oestradiol during gestation and on plasma cortisol concentration in the 4- to 6-day-old newborn. Constant light suppressed maternal melatonin without affecting maternal plasma oestradiol concentration, consistent with no effect on fetal DHAS, the precursor of maternal oestradiol. However, newborns from mothers under constant light condition had twice as much plasma cortisol as newborns from mothers maintained under a normal light-dark schedule. Newborns from mothers exposed to chronic constant light and daily melatonin replacement had normal plasma cortisol concentration. Our results support a role of maternal melatonin in fetal and neonatal primate cortisol regulation.

This article is a clinical review of Moyamoya disease (MMD) and Moyamoya syndrome (MMS). We review the incidence, epidemiology, pathology, historical context, clinical and radiographic findings, diagnostic imaging modalities, radiographic grading systems, the effectiveness of medical, interventional, and surgical treatment, and some of the nuances of surgical treatment options. This article will help pediatricians, neurologists, neurosurgeons, and other clinical practitioners who are involved in caring for patients with this rare clinical entity. MMD is an intrinsic primary disease process that causes bilateral progressive stenosis of the anterior intracranial circulation with the involvement of the proximal portions of the intracranial internal carotid artery (ICA) extending to involve the proximal portions of the anterior cerebral artery (ACA) and middle cerebral artery (MCA); posterior circulation involvement is very rare. This causes a compensatory response where large numbers of smaller vessels such as the lenticulostriate arteries begin to enlarge and proliferate, which gives the angiographic appearance of a "Puff of Smoke", which is translated into Japanese as "Moyamoya". MMS is a secondary process that occurs in response to another underlying pathological process that causes stenosis of intracranial blood vessels, such as radiation. For example, an external source of radiation causes stenosis of the ICA with a compensatory response of smaller blood vessels, which then enlarge and proliferate in response and has the same "Puff of Smoke" appearance on the diagnostic cerebral angiogram (DCA). Histological findings include an irregular internal elastic lamina with luminal narrowing, hyperplasia of the tunica media, and intimal thickening with vacuolar degeneration in smooth muscle cells in the tunica media. Compensation for diminishing blood supply occurs through angiogenesis, which causes the proliferation and enlargement of smaller collateral blood vessels to increase blood supply to under-perfused areas of the brain. MMD is rare in the United States, with just 0.086 newly diagnosed cases per 100,000 individuals per year, which is approximately one per million new cases annually. Risk factors for MMD include Eastern Asian ancestry and predisposing conditions such as neurofibromatosis and Down's syndrome. Clinically, patients often present with stroke signs and symptoms from cerebral ischemia. The proliferation of collateral blood vessels within the basal ganglia can produce movement disorders. Catheter-based DCA is the current gold standard for obtaining a diagnosis. CT perfusion allows preoperative identification of ischemic vascular territories, which may be amenable to surgical intervention. MRI enables rapid detection of acute ischemic stroke using diffusion-weighted Imaging (DWI) and apparent diffusion coefficient (ADC) sequences to assess for any diffusion restriction. Non-contrast CT of the head is used to rule out acute hemorrhage in the presentation of a progressive neurological deficit. The treatment option for Moyamoya is generally surgical; medical treatment has failed to halt disease progression and neuro-interventional techniques such as attempted stenting of stenosed vessels have failed. Surgical options include direct and indirect cerebrovascular bypass.