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George P. Chrousos, MD; Sevilla D. Detera-Wadleigh, PhD; Michael Karl, MD
Chrousos G., Detera-Wadleigh S., Karl M.; Syndromes of Glucocorticoid Resistance. Ann Intern Med. 1993;119:1113-1124. doi: 10.7326/0003-4819-119-11-199312010-00009
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Published: Ann Intern Med. 1993;119(11):1113-1124.
Glucocorticoid resistance results from the partial, albeit apparently generalized, inability of glucocorticoids to exert their effects on target tissues. The condition is associated with compensatory increases in circulating pituitary corticotropin and cortisol, with the former causing excess secretion of both adrenal androgens and adrenal steroid biosynthesis intermediates with salt-retaining activity. The manifestations of glucocorticoid resistance vary from chronic fatigue (perhaps a result of glucocorticoid deficiency in the central nervous system) to various degrees of hypertension with or without hypokalemic alkalosis or hyperandrogenism, or both, caused by increased cortisol and other salt-retaining steroids and adrenal androgens, respectively. In women, hyperandrogenism can result in acne, hirsutism, menstrual irregularities, oligoanovulation, and infertility; in men, it may lead to infertility and in children, to precocious puberty. Different molecular defects, such as point mutations or a microdeletion of the highly conserved glucocorticoid receptor gene, alter the functional characteristics or concentrations of the intracellular receptor and appear to cause glucocorticoid resistance.
The extreme variability in the clinical manifestations of glucocorticoid resistance and its mimicry of many common diseases can be explained by the overall degree of glucocorticoid resistance, differing sensitivity of target tissues to mineralocorticoids or androgens or both, and perhaps different biochemical defects of the glucocorticoid receptor, with selective resistance of certain glucocorticoid responses in specific tissues. The various different symptoms of classic glucocorticoid resistance and the theoretical potential of this condition to appear surreptitiously emphasize the importance of the glucocorticoid receptor in the pathogenesis of human disease.
Dr. George P. Chrousos (Developmental Endocrinology Branch, National Institute of Child Health and Human Development [NICHD], National Institutes of Health [NIH], Bethesda, Maryland): Glucocorticoids have an important role in human physiology, and almost every tissue in the human body is affected by them [1]. Glucocorticoids are crucial for the integrity of central nervous system function and for the maintenance of cardiovascular and metabolic homeostasis [2]. Increased secretion of glucocorticoids during stress is also pivotal in altering central nervous system function [3], in preventing the inflammatory and immune response systems from over-reacting [4, 5], and in adjusting energy expenditures [6], all changes that improve chances for survival. Given this array of life-sustaining functions, the complete inability of glucocorticoids to exert their effects on target tissues would be incompatible with life; therefore, only syndromes of partial or incomplete glucocorticoid resistance exist. Several patients or members of kindreds with partial forms of this disease have been described [6-18]; they show a wide spectrum of clinical symptoms and an interesting set of pathophysiologic mechanisms (Table 1). Recent advances in our understanding of the mechanism of action of glucocorticoids at the molecular level have allowed a glimpse into the pathophysiology of resistance and have increased our awareness of the potential involvement of this condition in the pathogenesis of human disease.
Table 1.
An elaborate feedback system regulates glucocorticoid homeostasis. Of principal importance is the ability of glucocorticoids to exert negative feedback on secretion by the hypothalamic paraventricular nucleus of corticotropin-releasing hormone and arginine vasopressin, on secretion by the anterior pituitary of corticotropin, and on suprahypothalamic centers that control the activity of the hypothalamic-pituitary-adrenal axis [3, 19-21]. This complex system is activated in states of generalized glucocorticoid resistance and produces compensatory increases in corticotropin and cortisol secretion (Figure 1). Although the increased cortisol concentrations in most affected persons appear to compensate adequately for the inability of target tissues to respond to glucocorticoids, the excess corticotropin secretion results in the increased production of intermediate compounds in adrenal steroidogenesis that have salt-retaining (mineralocorticoid) activity (such as deoxycorticosterone and corticosterone [8]) and in the enhanced secretion of adrenal androgens (such as Delta 4-androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone-sulfate [12]).
The elaborate negative feedback mechanisms responsible for maintaining glucocorticoid homeostasis compensate for the insensitivity of tissues to glucocorticoids by resetting the hypothalamic-pituitary-adrenal axis at a higher level. Thus, corticotropin-releasing hormone (CRH), adrenocorticotropin (ACTH), and cortisol secretion are increased. The compensatory increase in ACTH production causes increased secretion of glucocorticoid precursors with mineralocorticoid activity (DOC, deoxycorticosterone; B, corticosterone) and increased secretion of several adrenal androgens.
The clinical presentation of patients with glucocorticoid resistance is summarized in Table 1 and is related to the pathophysiology described in Figure 1. Generally, clinical manifestations of glucocorticoid deficiency were not present in most of the patients, and most of the patients evaluated in the context of family studies were asymptomatic despite biochemical indices of excessive cortisol production. The chief complaint of members of one particular family and an additional unrelated patient, however, was chronic fatigue, which might indicate inadequate compensation by the increased glucocorticoids in certain resistant target tissues, perhaps parts of the central nervous system or the muscles. In several patients, the increased concentrations of cortisol, deoxycorticosterone, and corticosterone (all steroids known to have inherent mineralocorticoid activity) caused signs of mineralocorticoid excess, such as hypertension and hypokalemic alkalosis. Finally, increased levels of adrenal androgens caused signs of androgen excess, including masculinization in women, with manifestations affecting the skin (acne and hirsutism) and the reproductive system (oligomenorrhea, oligoanovulation, and infertility). Also, early and excessive adrenarche was associated with precocious puberty, and interference of adrenal androgens on the feedback regulation of follicle-stimulating hormone caused abnormal spermatogenesis in men with the syndrome [17]. This abnormal spermatogenesis, however, could also be explained by corticotropin-induced intratesticular growth of adrenal rests, a phenomenon known to occur in classic and late-onset congenital adrenal hyperplasia [22].
Table 2.
These clinical manifestations were not reported in all patients with symptomatic glucocorticoid resistance, and the clinical presentation varied even within families. Two main explanations can be given for this: First, the degree of resistance, as indicated by the compensatory increases of cortisol production, has generally differed among patients, with associated variability in the production of mineralocorticoid and androgen compounds and, therefore, differing effects resulting from excess production. Second, the sensitivity of target tissues to mineralocorticoids and androgens can also vary among persons, resulting in unequal responsiveness to similar increases of circulating steroids. The factors responsible for the different sensitivity of target tissues to these hormones could be individual differences in 1) the activity of key hormone-inactivating or -activating enzymes, such as 11--ketosteroid reductase in the kidney, which inactivates cortisol, deoxycorticosterone, or corticosterone [23], or 5 -reductase and 17-ketosteroid dehydrogenase in the skin, which convert adrenal androgens to more potent metabolites [24]; or 2) the cascades of the mineralocorticoid and androgen-receptor transduction systems, which can vary at different steps [25, 26]. In addition, other genetic or epigenetic factors, such as insulin resistance or upper body (abdominal) obesity or both, may influence the clinical manifestations of the syndrome by altering pituitary and gonadal function and peripheral steroid metabolism.
Of major importance is the definition of appropriate criteria for the correct diagnosis of glucocorticoid resistance and its differentiation from the many diseases it mimics clinically or biochemically. These criteria are summarized in Table 2. First, the patient should not have clinical evidence of the Cushing syndrome, including the phenotypic changes and biochemical consequences of hypercortisolism. Second, indices of increased cortisol production should be present, such as increased 24-hour urinary free cortisol levels or increased 17-hydroxysteroid per gram creatinine excretion, increased plasma total and free cortisol concentrations, or an increased rate of cortisol production. Third, glucocorticoid resistance should be present as determined by dexamethasone testing using either a complete dose-response test, as previously described [8], or by using one or two doses of the compound. The results of this test should be validated against the plasma levels of dexamethasone, because absorption or metabolism of this synthetic glucocorticoid may vary from person to person. Finally, the hypothalamic-pituitary-adrenal axis should retain its normal circadian rhythmicity and its responsiveness to stressors such as hypoglycemia; however, its basal and stimulated activities should be higher than those of normal persons.
Although the single-dose overnight dexamethasone suppression test may be appropriate for screening patients with potential generalized glucocorticoid resistance, its high false-positive rate of 15% to 20% makes measurement of 24-hour urinary free cortisol excretion preferable, if this syndrome is suspected. Levels above 100% (twofold) of the upper normal range are suggestive of glucocorticoid resistance or the Cushing syndrome [27]. Levels between the upper normal range and the 100% limit, however, are compatible with these diagnoses, along with a host of other states characterized by mild hypercortisolism [27, 28].
Assuming proper procedures and techniques, the syndrome of generalized glucocorticoid resistance should be easily distinguished on biochemical grounds from the chronic fatigue syndrome, essential hypertension, hyperaldosteronism, idiopathic hirsutism, polycystic ovarian disease, female infertility, precocious puberty, or male infertility, because none of these conditions is associated with hypercortisolism. It may be difficult to distinguish this syndrome in its mild biochemical form (increases in urinary free cortisol up to 100% of the upper normal range) from other mild forms of hypercortisolism, such as mild or early Cushing syndrome with a lack of or borderline manifestations of hypercortisolism, hypercortisolemic melancholic depression, anorexia nervosa, chronic active alcoholism, and hypercortisolism in persons who exercise heavily [27, 28]. In the case of mild or early Cushing syndrome, the absence of circadian rhythmicity and lack of responsiveness of plasma cortisol during an insulin tolerance test should aid the physician in diagnosing this condition. The patient's clinical course, which is frequently characterized by progressive deterioration and development of the classic Cushing phenotype, should allow eventual differentiation. The history or concurrent symptomatology and the dependence of the hypercortisolism on the actual state of the condition should differentiate glucocorticoid resistance from the other states.
Synthetic glucocorticoids with minimal intrinsic mineralocorticoid activity, such as dexamethasone, provide a rational treatment for familial glucocorticoid resistance. These patients should receive oral doses of dexamethasone, usually ranging between 1 and 3 mg/d, that are clearly pharmacologic for normal persons but are equivalent to glucocorticoid replacement for the glucocorticoid-resistance state. Dexamethasone suppresses corticotropin and, therefore, endogenous cortisol, deoxycorticosterone, corticosterone, and adrenal androgen secretion, thus correcting the excess mineralocorticoids and androgens and their effects on these patients [8, 17]. Long-term daily dexamethasone dosage should be individualized and titrated to normalize adrenal mineralocorticoid and androgen secretion and to control the clinical manifestations of the disease.
As early as 1980, it was suggested that glucocorticoid resistance represented a defect in the intracellular cascade of events from the entrance of the glucocorticoid into the cell to its final effect on cellular function. By that time, it was known that most glucocorticoid effects were exerted by interaction with a finite number of intracellular glucocorticoid receptors, proteins with profound modulatory effects on gene transcription once they came into specific contact with their ligand. In addition to their ability to bind the hormone, these receptors recognized specific sites on the chromatin and could bind to nuclei and to naked DNA. Even before the structure of the glucocorticoid receptors was known, studies done in patients with glucocorticoid resistance showed alterations in the functional characteristics of their receptors. Several tissues from the first reported kindred with glucocorticoid resistance had normal concentrations of glucocorticoid receptors but decreased affinity for glucocorticoids [8]. The stability of these receptors, as well as their gross molecular size, was normal [29], the latter suggesting that a point mutation of the glucocorticoid receptor gene was responsible for the defective interaction between the receptor and the steroid. Subsequently, additional kindreds and individual patients whose glucocorticoid receptors were also characterized by decreased binding affinities, low concentration, thermolability, or defective DNA binding were described as well (Table 1).
The cloning of complementary DNA (cDNA) from the human glucocorticoid receptor in 1985 [30] allowed the deduction of its primary structure, definition of its functional domains [31], and cloning of its gene [32], and thus permitted further studies on the molecular mechanisms of glucocorticoid resistance. The glucocorticoid receptor also served as the prototypic member of a large superfamily of ligand-activated receptors homologous to the v-erbA oncogene, including not only the steroid and sterol family of receptors but also the receptors for triiodothyronine and retinoic acid, as well as others whose ligands have not yet been determined [25].
The primary structure of the human glucocorticoid receptor gene and the glucocorticoid receptor protein with its functional domains are shown schematically in Figure 2, panels A and B, respectively, and its homologies to other receptors of the steroid and sterol family are shown in Figure 2, panel C. The 777 amino acid protein (panel B) has three main functional domains: the ligand-binding domain (which lies in the carboxyterminal portion of the protein), the DNA-binding domain (which is in the center), and the aminoterminal domain, which was initially characterized by its property of providing antigenic epitopes for the generation of antireceptor antibodies and hence was called the immunogenic domain. Further characterization of the functional domains of the receptor allowed not only better recognition of the sequences responsible for steroid binding and DNA recognition but also showed a number of domains representing other functions involved in the cascade of events, from ligand binding to modulation of gene transcription [33-41]. Current knowledge about the location of these domains is shown schematically under the primary structure of the glucocorticoid receptor in Figure 2 (panel B). Further discussion of these functions and their potential involvement in the pathogenesis of glucocorticoid resistance will follow.
indicates the position of the pathogenetic mutation in the first kindred from the National Institutes of Health (NIH) ; indicates the 4-basepair deletion and conservative mutation in the second NIH family ; and the black arrowhead indicates the pathogenetic mutation in the family reported by McDermott and colleagues . The gene consists of 10 exons of variable lengths numbered 1 to 8, and 9 and 9 . Exon 2 codes for the amino terminal domain; exons 3 and 4 code for the DNA-binding domain; and exons 5 to 9 code for the ligand-binding domain. The steroid-binding glucocorticoid receptor is glucocorticoid receptor (GR ). Glucocorticoid receptor (GR ) is produced by alternative splicing and does not bind glucocorticoids, and its functional importance is obscure. The three main domains of the human glucocorticoid receptor are represented in a linear model, as originally defined. Subsequent in vitro mutagenesis studies have assigned these and other functions to various regions of the receptor protein, as indicated underneath the schematic representation of the receptor. Numbers correspond to amino acids in the primary sequence of the receptor. HSP = heat-shock protein; NLS = nuclear localization sequences. Homologies of the five other classes of steroid and sterol receptors to the glucocorticoid receptor expressed as percent identity in primary sequence (AR = androgen receptor; ER = estrogen receptor; MR = mineralocorticoid receptor; PR = progesterone receptor; and VDR = 1,25[OH] vitamin D receptor).
A gross similarity exists among the structures of members of the steroid and sterol family of receptors, with most of the homologies occurring primarily in the DNA-binding domains and, secondarily, in the ligand-binding domains (Figure 2, panel C). This similarity explains both the known existing cross-reactivities of ligand binding between the natural steroids and their receptors and explains the sharing of common DNA sequences in the promoter regions or enhancers of steroid-regulated genes with which these receptors interact. Relevant to glucocorticoid resistance is the virtual 100% cross-reactivity of the mineralocorticoid receptor for cortisol [42]. Normally, the kidney mineralocorticoid receptor is partially protected from the mineralocorticoid effects of circulating cortisol by the intracellular enzyme 11-ketosteroid reductase in the cells of the distal convoluted and proximal collecting tubules; this enzyme converts 11--hydroxylated compounds, such as cortisol, into inactive 11-ketosteroids, such as cortisone [23]. The presence of increased amounts of circulating cortisol as well as deoxycorticosterone and corticosterone in patients with glucocorticoid resistance appears to overwhelm the protective enzyme and produces effects of mineralocorticoid excess in some patients. The mineralocorticoid receptor appears to have further relevance to glucocorticoid resistance; recent work suggests that some of the negative feedback effects of glucocorticoids on the hypothalamic-pituitary-adrenal axis are mediated by the mineralocorticoid receptor of the hippocampus, a major restraining influence on the activity of this axis [3].
A wealth of new information on the molecular mechanisms of action of glucocorticoids has led to the refinement of the initial model, which continues to be rapidly modified, and to new explanations for the pathophysiology of glucocorticoid resistance. The cascade of events leading to the modulation of gene transcription is as follows (see also Appendix Table 1 for a glossary of genetic terms): The inactivated ligand-free glucocorticoid receptor is found in the cytoplasm associated with other proteins, such as heat-shock proteins 90 [37] and 70 [43] and immunophilin of the FK506/rapamycin binding type [44], in the form of a hetero-oligomer. It appears that the receptor is anchored to heat-shock protein 90 through sites present in its steroid-binding domain (Figure 2, panel B). This special interaction with heat-shock protein 90 appears to facilitate the binding of the steroid to the receptor and to increase its effectiveness in eliciting a glucocorticoid response [45]. This binding results in the release of the steroid-receptor complex from heat-shock protein 90 and in the unmasking of domains responsible for dimerization, nuclear localization, DNA binding, and transactivation [36] (Figure 2, panel B).
The dimerization domains are found in the steroid-binding domain. In theory, receptor homodimers can be present both in the cytoplasm and in the nucleus. Monomers or dimers from ligand-bound receptors appear to cross into the nucleus through recognition of their nuclear localization domains or nuclear localization sequences by proteins of the nuclear pore [33]. One of these sequences is homologous to that of the SV40 T antigen and other proteins also known to translocate into the nucleus. Heat-shock protein 70 and intracellular fibrils might participate in the alignment of receptors and their translocation through the nuclear pore [46].
Inside the nucleus, the ligand-bound glucocorticoid receptor exerts its genomic effects on transcription in at least three potential ways. First, in the form of a homodimer, it interacts with specific DNA sequences, the glucocorticoid-responsive elements, in the promoter or enhancer regions of glucocorticoid-responsive genes [40, 47]. The DNA-binding domain of the receptor consists of two protein loops held together by a zinc atom, the zinc fingers, which selectively interact with the glucocorticoid-responsive elements [30, 48]. The ligand-bound receptor homodimers appear to stabilize the polymerase II initiation complex of regulated genes, perhaps by binding directly or through another protein to ancillary factor TFIIB, whose interaction with the partial initiation complex may be the rate-limiting step of transcription [49]. The degree of gene transactivation induced by the receptor homodimer may be modulated by separate regulatory elements in the DNA and their specific transcription factors [50]. Examples of these are the CACCC box and the glucocorticoid modulatory element and their binding factors [51, 52]. Although this mechanism has been studied mostly in enhancement systems where the receptor dimer interacts with positive glucocorticoid-responsive elements, glucocorticoids may also repress other genes through the same [53] or different, negative glucocorticoid-responsive elements [54]. Second, negative regulation of transcription can result from the interaction of the glucocorticoid receptor dimer with part of the responsive element of another transcription factor, which can be displaced or hindered from properly exerting its transcription-promoting effect. Such an example is the inhibition by glucocorticoids of glycoprotein hormone -subunit gene transcription induced by cyclic AMP-responsive element-binding protein [55]. Third, another major molecular path through which glucocorticoids seem to exert part of their antigrowth and anti-inflammatory effects appears to be the formation of intranuclear complexes of the glucocorticoid-bound receptor with c-jun, which prevents this transcription factor from exerting the ubiquitous activating and growth-promoting effects produced by its interaction as a c-jun/c-fos heterodimer with its DNA-responsive element, the AP1 site [38-40].
This model of glucocorticoid actions at the cellular level is still evolving and many crucial questions remain. Thus, phosphorylation and dephosphorylation may participate in the activation or inactivation, recycling, and turnover of the receptor [56]. Many earlier rapid effects of glucocorticoids, such as changes in intracellular cyclic GMP and calcium levels and in membrane potential, may take place by as-yet-undefined mechanisms [57, 58]. Finally, the mechanism or mechanisms by which glucocorticoids alter the translatability and stability of specific messenger RNAs (mRNA), an important unequivocal function of these hormones that has been observed with several genes, are still unclear [59, 60].
Dr. Sevilla Detera-Wadleigh (Clinical Neurogenetics Branch, National Institute of Mental Health, NIH, Bethesda, Maryland): Given the many functions served by a single glucocorticoid receptor protein, it is not surprising that the structure of its gene, located on chromosome 5 [61], is quite complex; it consists of 10 different exons [45] (Figure 2, panel A). One exon codes for the immunogenic domain, 2 for the DNA-binding domain (1 for each zinc finger), and 5 for the steroid-binding domain, which carries most of the identified functions (Figure 2, panel B). Alternative splicing appears to result in the synthesis of another receptor form, glucocorticoid receptor , which does not bind glucocorticoid and whose function is unknown; it might form heterodimers with the classic glucocorticoid receptor and might prevent or alter one or more of its many effects. A similar thyroid hormone receptor isoform, thyroid receptor 2, exists; it does not bind triiodothyronine but instead it forms heterodimers with ligand-binding isoforms from thyroid receptor 1 and , and it alters the effects of the latter [62]. Finally, because expression of the glucocorticoid receptor gene might be crucial for understanding states of glucocorticoid resistance resulting from abnormal gene regulation, the 5 regulatory region of this gene should be studied. The human glucocorticoid receptor gene has similarities with several housekeeping genes in that it has no TATA or CAAT boxes but instead has at least 17 SP1 transcription factor sites in a region of approximately 3 kilobases. Several other putative regulatory elements, including half-sites for glucocorticoid-responsive elements, two negative glucocorticoid receptor elements, and an AP1 site have been identified, although it is not yet clear whether these elements are active (63; Encio and Detera-Wadleigh. Unpublished results).
Dr. Michael Karl (Developmental Endocrinology Branch, NICHD, NIH, Bethesda, Maryland): The molecular basis of familial glucocorticoid resistance has been elucidated in three kindreds [64-66]. Two of the three kindreds were investigated at NIH [64, 65]. Point mutations and a gene microdeletion in the glucocorticoid receptor have been identified as causing familial glucocorticoid resistance. The cDNA from affected members of the family reported by Vingerhoeds and colleagues [7] in 1976 (Table 1) was sequenced to find potential mutations altering the affinity of the receptor for the steroid [64]. Affected members had a thymidine for adenine substitution at cDNA position 2054 in the ligand-binding region of the receptor (Figures 2 and 3). This base change resulted in a nonconservative amino acid substitution from aspartate, an acidic amino acid, to the hydrophobic valine at codon 641. The position of this amino acid residue is adjacent to cysteine 638. Its corresponding residue in the rat glucocorticoid receptor, cysteine 656, is intimately involved in hormone binding [67]. Therefore, an alteration in the ligand-binding cavity of the receptor, such as the nonconservative amino acid change described, might explain the low affinity of the receptor observed in this kindred.
Family 1 pedigree showing autosomal codominant transmission of the glucocorticoid resistance (black symbol indicates symptomatic; half-black symbol indicates biochemically affected only). Nucleotide sequence of the glucocorticoid receptor cDNA from the propositus and his asymptomatic but biochemically affected son. The propositus has T in place of A at nucleotide 2054, changing the aspartate codon GAC normally present at position 641 to the valine codon, GTC. Both A and T are present in the son's sequence, suggesting heterozygosity. The cDNA sequence of the asymptomatic but biochemically affected brother was identical to that of the son. From Hurley and colleagues ; reproduced with permission. Family 2 pedigree showing autosomal-dominant segregation of patients with glucocorticoid resistance (black symbols, affected; white symbols, unaffected). Sequences of the glucocorticoid receptor alleles at the 3-donor splice junction of exon 6 in the proposita and her glucocorticoid-resistant brothers. The boxed nucleotides depict the 4-basepair sequence deleted in one allele. The arrow on the right indicates the exon-intron boundary in the normal allele. The autoradiogram shows the sequence of the normal and the affected allele: the 4-basepair deletion in one allele, including the last bases of the exon and the first nucleotides of the intron, results in double bands. Nucleotide sequences of glucocorticoid receptor-exon 2 genomic DNA of the proposita and her affected brothers. On the left side, the proposita and one of her affected brothers were heterozygous for a mutation at codon 363 (cDNA position 1220) with a guanine (G) replacing the wild-type adenine (A) in one allele. On the right side, the second affected brother was homozygous for the wild-type sequence. Analysis of glucocorticoid receptor gene transcripts by direct sequencing of PCR-amplified cDNA obtained by reverse transcription of total RNA. On the left side, analysis of the proposita's cDNA showed only the sequence bearing G at position 1220, whereas transcripts with the wild-type sequence were not detectable. The base substitution results in a conservative amino acid substitution from asparagine to serine. On the right side, in contrast, the second affected brother had only the wild-type sequence. From Karl and colleagues ; reproduced with permission.
The propositus, who presented with severe mineralocorticoid excess, was homozygous for the mutation; his brother and son, who were affected only biochemically, were heterozygous. When the DNA sequences of the glucocorticoid receptor were examined in normal persons, no such alteration was found. The mutated receptor was then tested in an in vitro chloramphenicol transferase assay. The wild-type or the mutant plasmid were separately cotransfected into COS-7 cells with the reporter plasmid pMTVCAT. The latter carries the promoter and enhancer region of the mammary tumor virus, which is responsive to glucocorticoids coupled to the structural chloramphenicol transferase gene. When the chloramphenicol transferase gene expression induced by dexamethasone was assessed by measuring the acetylation of chloramphenicol to acetylchloramphenicol, the nucleotide substitution resulted in a low-affinity, dysfunctional glucocorticoid receptor, thus confirming the pathogenic importance of the mutation detected.
The second family investigated at NIH had been previously reported by Lamberts and colleagues [12, 17] in 1986 and 1992 (Table 1). Circulating leukocytes from the glucocorticoid-resistant members of this kindred had only 50% of the normal concentrations of glucocorticoid receptors [14]. In contrast to the first family, the affinity of the receptor in these patients was normal. It is interesting to note that direct sequencing of the proposita's and of one of her affected brother's glucocorticoid-receptor cDNA (which was amplified using the polymerase chain reaction [PCR]), showed a point mutation at position 1220 [65] (see Figures 2 and 3), where guanine substituted for the wild-type adenine. The cDNA sequence of the second affected brother was normal. This mutation did not segregate with the disorder but rather resulted in a conservative amino acid substitution, from asparagine to serine, at codon 363 of the glucocorticoid receptor. Located in the aminoterminal region of the receptor, the mutation was downstream of the 1 transactivation domain (Figure 2, panel B). Asparagine 363 is conserved at the corresponding positions of the rat and mouse glucocorticoid receptor residues 383 and 371, respectively [68, 69].
The functional importance of the G1220 substitution on gene transcription was tested by introducing the mutation into a glucocorticoid receptor expression vector. No difference was noted in the ability of the wild-type and the Ser363 mutant receptor to activate chloramphenicol transferase expression, thus indicating that the substitution of Asn for Ser363 had no major impact on the ability of the glucocorticoid receptor to activate transcription of its target genes and was, therefore, not responsible for the glucocorticoid insensitivity in this family. This finding was additionally confirmed by the disclosure of guanine at position 1220 in the unaffected sister of the proposita.
The finding of guanine only at cDNA position 1220 provided evidence for the expression of only one of the two glucocorticoid receptor alleles in the affected members of this family, because their parents were not consanguineous. To address this hypothesis, the gene structure of the glucocorticoid receptor had to be investigated for alterations resulting in the expression of only one of the two receptor alleles. Each of the nine exons of the glucocorticoid receptor gene from the proposita and from her two affected brothers was amplified by PCR using primers located in the 5 and 3 flanking intron regions and was directly sequenced [45, 65]. As expected, when exon 2 from the proposita and from one of her brothers was sequenced, a guanine and an adenine base were identified at the second position of codon 363, which corresponds to cDNA position 1220. Thus, as hypothesized above, the proband and one of her affected brothers were heterozygous for this mutation, whereas the second affected brother was homozygous for the wild-type sequence in codon 363. This analysis of the exon-intron boundaries of the glucocorticoid receptor gene disclosed the defect responsible for the end-organ insensitivity to glucocorticoids in this family: a 4-basepair deletion identified at the 3 boundary of exon and intron 6 in all three affected persons studied (see Figures 2 and 3). The deletion removed a donor splice site in one of the two glucocorticoid receptor alleles. When we amplified, using PCR, and examined exon 6 and the exon 6-intron 6 boundary in the two unaffected siblings of the proband, we found the wild-type sequence. This observation was consistent with the conclusion that the 4-basepair deletion segregated with glucocorticoid resistance.
Mutations or deletions involving the first two nucleotides of an intron disrupt normal splicing, the process of removing introns and joining exons in transcribed RNA [70]. Aberrant mRNA variants generated in such cases are probably susceptible to nuclease degradation, which precludes the production of mature, translatable mRNA and therefore excludes the expression of the encoded protein. This hypothesis might explain why the glucocorticoid receptor concentrations in affected members of the second family were 50% of normal.
Thus, in the affected members of this family, translation of the glucocorticoid receptor protein appeared to originate solely from templates of correctly spliced precursor mRNA transcribed from the allele without the 4-base-pair deletion, thereby suggesting that the deletion and the point mutation were located on different alleles. Only the cDNA species, the reverse-transcribed product of the patients' mRNA with guanine at position 1220, was detected in the proposita and in one of her affected brothers. The transcripts of the allele harboring the wild-type adenine in the second position of codon 363 together with the boundary deletion at exon-intron 6 seemed to be rapidly degraded, possibly by endogenous nucleases. No cDNA molecules derived from the allele with the 4-basepair deletion could be detected, thus suggesting that mature mRNA derived from this allele was not present and therefore not translated into glucocorticoid receptor protein.
An additional family studied by Malchoff and colleagues [16] (Table 1) had a guanine-to-adenine point mutation in cDNA position 2317 [66] (Figure 2). This mutation predicted the substitution of a valine residue 729 by an isoleucine within the ligand-binding domain; it also led to decreased affinity and apparently compromised the functional ability of the glucocorticoid receptor.
Dr. George P. Chrousos: Glucocorticoid receptor genes and cDNAs from additional patients with generalized glucocorticoid resistance are currently being studied. Given the large number of sequencing studies that need to be done to determine the defect, even with the assistance of symmetric and asymmetric PCR, we recommend the following procedure to ascertain the diagnosis and to study the mechanisms of glucocorticoid resistance (Table 2). First, clinical and biochemical studies as discussed in the section on Diagnostic Evaluation should be done, both in suspected patients and their families, even though sporadic cases caused by new mutations may exist. Increased urinary free cortisol excretion, resistance of cortisol responsiveness to dexamethasone, and a clear circadian rhythm of plasma cortisol concentrations all need to be present to establish the diagnosis of generalized, classic glucocorticoid resistance. Second, studies to characterize the concentration, affinity, stability, and nuclear or DNA-binding properties of the receptor in circulating leukocytes, cultured skin fibroblasts, or Epstein-Barr virus-transformed B lymphocytes (lymphoblasts) should be done. Even if all these functional features of the receptor are normal, a postreceptor defect related to transactivation is not excluded. Glucocorticoid dose-response bioassays, which measure end points such as inhibition of3 (H)-uridine incorporation, (Carbon-14)-2-deoxyglucose uptake, or lectin-induced transformation by circulating leukocytes [71-73], and induction of aromatase activity [74] or down-regulation of the glucocorticoid receptor mRNA by cultured skin fibroblasts [18] may show postreceptor defects resulting in decreased transactivation function. Third, if a defect in glucocorticoid receptor structure or function is suspected, potential alterations might be screened using newly developed PCR-assisted techniques. These techniques include denaturing gradient gel electrophoresis using a guanine-cytidine clamp [75] and chemical or enzymatic mismatch cleavage [76], which could suggest what fragment of examined DNA carried a mutation and thus what fragment should be sequenced. Finally, once a structural defect has been determined, its deleterious effect on receptor function should be confirmed using in vitro mutagenesis and using standardized assays that examine the ability of the mutant glucocorticoid receptor to activate gene expression and to produce an effect, such as chloramphenicol transferase activity.
Because of the difficulty in diagnosing the syndrome of familial generalized glucocorticoid resistance and because of its variable clinical presentation (including chronic fatigue, mild hypertension, and hyperandrogenism), many patients with these manifestations might have this condition. Accurate prevalence estimates of generalized glucocorticoid resistance do not currently exist, because measurements of urinary free cortisol excretion and dexamethasone tests are not normally done in patients with these conditions. The closest estimate we have is from a recent study [18] in which 7 of 420 consecutive patients presenting to an adrenal disorders clinic had bona fide generalized glucocorticoid resistance with functional abnormalities of their glucocorticoid receptors in cultured skin fibroblasts. These abnormalities included decreased receptor concentration or affinity, or both, thermolability, and defective down-regulation of glucocorticoid receptor mRNA expression by glucocorticoids. One of these patients had chronic fatigue, 1 had obesity and amenorrhea, 1 had hirsutism and chronic fatigue, and 4 had hirsutism alone. The 5 patients with glucocorticoid resistance who had hirsutism represented 14% of the 35 women with this diagnosis seen in the clinic. This is higher than the 5% to 7% incidence of late onset congenital adrenal hyperplasia with 21-hydroxylase deficiency in women with hirsutism [22]. Thus, screening women with hyperandrogenism by obtaining measurements of urinary free cortisol excretion per 24 hours may be cost effective at this time.
Acquired forms of generalized incomplete glucocorticoid resistance may also exist. In a recent study [77], patients with the acquired immunodeficiency syndrome (AIDS) were described as having symptoms similar to patients with Addison disease (weakness, weight loss, hypotension, hyponatremia, and intense mucocutaneous melanosis) and as having increased plasma corticotropin and cortisol levels, as well as peripheral mononuclear leukocyte glucocorticoid receptors with reduced affinity for dexamethasone. Further studies should be done in patients suspected of having acquired glucocorticoid resistance, and the mechanism(s) of such a state should be examined.
Finally, research on the mechanism of action of glucocorticoids at a cellular or molecular level or both and on the profound effects of glucocorticoids on central nervous system function and on the immune response could have a substantial impact on society. Given the complexity of glucocorticoid receptor regulation and the varying effect of potential mutations, glucocorticoid resistance states may exist that are not generalized but that influence a limited number of tissues or functions. Thus, a mutation might not affect regulation of the hypothalamic-pituitary-adrenal axis (in which case the patients would not be classified as having glucocorticoid resistance by the classic biochemical criteria) but might affect the action of the hormone in some other system, such as the dopaminergic mesocortical or mesolimbic system (responsible for pleasure and reward phenomena) or the norepinephrine-locus ceruleus system (responsible for sustaining proper arousal [28, 78-80]). In both instances, emotional disorders characterized, respectively, by stimulus or drug-seeking behaviors and chronic fatigue could result despite normal cortisol production.
If only part of the immunosuppressive effects of glucocorticoids were exerted because of immune system-specific resistance, we would expect phenomena resulting from an unrestrained immune system, such as autoimmune, allergic, or inflammatory diseases. Potential examples are rheumatoid arthritis and glucocorticoid-resistant asthma, a severe form that starts early in life and does not respond to glucocorticoid therapy. Rheumatoid arthritis is associated with normal or decreased plasma cortisol concentration and a decrease in the concentrations of glucocorticoid receptors in circulating peripheral leukocytes to approximately 50% of control levels [81-83]. In this disease, the response to glucocorticoid treatment can be predicted by an in vitro cell-mediated immune assay [84]. Glucocorticoid-resistant asthma is associated with normal hypothalamic-pituitary-adrenal axis function and normal glucocorticoid receptor concentration and affinity in peripheral leukocytes but with abnormal suppression of several cellular immune functions by glucocorticoids in vitro or in vivo [85-87].
The mirror image of these phenomena would be expected in a nongeneralized glucocorticoid hypersensitivity syndrome. The generalized form of this condition has recently been described [88], and super receptors have been artificially created in vitro [89]. Extricating pathologic mutations of the glucocorticoid receptor associated with normal hypothalamic-pituitary-adrenal axis activity and proving their pathogenic potential in diseases characterized by nongeneralized glucocorticoid resistance or hypersensitivity will be an interesting and provocative challenge.
Appendix Table 1.
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text: What to keep on hand for when a fire gets close to your house Print Email Keep a flashlight in your fire kit because the power often fails during large wildfires. Photo by Jeffery Cross Pinterest PagesPrevious 4 of 7 Next View All Flashlight Because the power often fails during large wildfires. Mag-Lite LED 2-Cell D flashlight. From $29 Around The Web Related Links Living with the new wave of wildfire 5 great firefighting plants The beautiful & fire-smart yard

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LBB Chartered Surveyors, Langley Byers Bennett are a client focused firm of Chartered Surveyors dealing with a number of specialist areas of property business.
Established in 1994, LBB are situated in Fleet Street, serving both the City and West End in Central London; and working throughout other parts of the UK.
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We hope you will find the information and resources on our website helpful. We look forward to working with you.


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2003 Dodge Dakota Quad Cab 4dr Quad Cab Sport Rwd SB (3.9L 6cyl 5M)
This truck has been a steady performer. It is functional enough for light construction duty and family recreation. Our family of 3 + 1 large dog has found there is plenty of int. room and adequate cargo capacity for our road trips and camping outings. The ride is truck like, but without much road noise. There have been no major problems, but the broken emergency brake release lever and the poor seal around the gas intake pipe are annoying. The V6 provides pep and the transmission shifts smoothly. The gear shift on the steering column is a little tempermental and requires perfect placement before finding the right gear. Traction on wet pavement and snow is weak when the bed is empty.
The cargo light for the bed is a handy feature when unloading the bed at the campground after sunset.
A bigger glove box and a pouch behind the driver's seat would be nice.
I bought the truck from a private owner with 63,000 miles on it. Starts and rides like a new vehicle. Only problem I found was a warped front brake disk. Since grinding it no more clicks. Use it every day and sometimes overloaded, full or empty runs all the same. Fuel efficency is lousy (14 mpg) and A/C only cools to 48 F, which is within specs but in summery Florida we need all the cooling you can get. Overall highly satisfied
Power. Roomy interior. Good finish
Improve fuel consumption. Colder A/C. It feels as if the transmission could upshift at lower speeds (perhaps this would improve mileage a little)
Bought after Toyota dealership got
stupid dealing for a Tacoma. Love the
rugged look of the quad. While the
interior isn't 100% as nice as others,
it's still a comfortable place to do
business. Like the wide-open rear
doors! CD player didn't work upon
arrival, but was taken care of under
Large access rear doors. Overall look
of the vehicle.
Base engine could use some work. SXT
trim is really stripped.
quad cab, 4.7 ,5 speed auto ,limited
slip diff ,towing package ,16 tires
and 11 inch rotors front and back,
anti lock breaks,lower gear ratio,e
upgrade stero w 6CD player,
love the way it handles and drives
lots of room in back for 3 kids
27 miles to a canadian gallon on hyway
21 miles to canadian gallon in city ,
not bad it gets better gas milage than
my 3 liter Voyager
I was so close to getting a Tacoma and
now I wish I had. Gas guzzling and
noisy truck with bad fit.
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Factors to Consider When Deciding to Remove a Tree
Trees have always held an important place in the development of human civilization, from the cavemen from thousands of years ago to modern man with all his modern conveniences. With the senseless destruction of thousands of acres of rain forest every year, it is important that we the save the trees we can. What that means is proactively searching for a solution to save a tree and only resorting to cutting it down once all other avenues are exhausted.
Arborists and tree service workers make their living removing trees. Ironically, these tree care specialists will be the first to tell you the only time cutting down a tree will bring them joy is when they are removing a hazardous/dangerous tree that poses a threat to a home or a business.
These are some of the factors that need to be considered when removing a tree. The age of the tree could be the reason because if it is weak or dying than it should be removed. Before the tree care professional considers removing the tree they will examine it first, and determine if there are alternative options.
"Felling a tree is always our last option. If the owner of the tree is on board, we can try several different strategies that would allow us to stabilize the tree, the most common being tree cabling," said the owner of a tree removal service near Jacksonville Florida. Tree cabling is an alternative solution that involves anchoring steel cable throughout the tree to strengthen certain areas. This route will extend the life of a living tree considerably.
The biggest priority a tree company has is safety. Safety for the property owner's and safety for the crews. Any tree care service worth its weight should always consider the surroundings where the tree is positioned. There could be people and properties that are present where the tree is located. Safety must be present at all times when tree is being removed. Sometimes a tree is being removed because of its age and the danger that it can cause to the properties or people surrounding it. It is recommended that only professionals complete tree removal so the recommended equipment and tools are being used.
Tree removal cost is typically the biggest priority for the customer. And as they normally find out, it can vary significantly from company to company. The costs vary as well because of the size, width and height of the tree. Tree removal companies have many different ways in charging their customers. This could be according to the expertise, equipment, location of the tree, and the risk that is associated when removing the tree. An example of a risk is electrical lines near the tree. This creates a high risk situation for the workers.
Remember! In some local ordinances you are required to have a permit to cut down a tree. Failure to do so can result in a hefty fine. Ask your local tree service if they can assist you with process, as they will be familiar with the local laws.


text:
Much has been written about Boeing's murky future. Will its customers cancel orders? Will the 787 ever be delivered? What new production snafu will happen next? However, little has been mentioned about its crumbling balance sheet.
In two previous articles, I wrote about Boeing's weakening financials (Boeing Can't Afford Another Strike and Boeing Headed The Way Of GM?) and predicted a miserable Q4. Boeing did not disappoint. Its balance sheet saw tremendous asset destruction this quarter. Below are a series of graphs depicting the blow-up.
Short term investments went from $2.3 billion to practically zero. (See graph Short Term Investments).
Pension plan assets tumbled from $5.9 billion to nothing. (See graph Pension Plan Assets).
In the meantime, inventory climbed from $9.6 to $15.6 billion on the halt in commercial plane production. (See graph Inventory).
...while goodwill and other intangibles rose from $5.2 to $6.3 billion (not much to hold onto). (See graph Goodwill and Other Intangibles).
The liability side grew. Pension plan liabilities soared from $1.2 to $8.4 billion. Ouch! (See graph Pension Plan Liabilities).
All in all, tangible equity dropped from $2.7 to a minus $6.8 billion, a sad $9.5 billion loss. (See graph Tangible Equity).
Boeing goes into 2009 with a weak balance sheet. It needed its cash, investments, and pension plan assets, all victims of strikes, production misteps, and a falling stock market. Those cushions are now gone. It faces a large $7 billion debt.
Moreover, it now faces a whole new problem in the form of an $8.4 billion pension liability that dwarfs its debt. So far this year, Boeing has lost $9.5 billion in tangible equity. That's not how you want to enter one of the most trying times in our nation's economic history.
Disclosure: Short BA


text:
Irwin Mitchell chooses DeviceLock for network security
Law firm Irwin Mitchell has deployed Smartline's DeviceLock across the organisation to ensure data security and confidentiality.
This Article Covers
Risk management
Law firm Irwin Mitchell has deployed Smartline's DeviceLock across the organisation to ensure data security and confidentiality.
DeviceLock controls access to all ports and devices on the corporate network, including USB ports and memory sticks, preventing information from being removed or copied without authorisation.
Your exclusive guide to CIO trends
A collection of our most popular articles for IT leaders from the first few months of 2016, including: - Corporate giants recruit digitally-minded outsiders to drive transformation - Analytics platforms to drive strategy in 2016 - Next generation: The changing role of IT leaders.
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"We recognise that one of the most common ways to lose [data] is through otherwise innocuous portable storage devices that users connect to our network," said Craig Thomas, IT network manager at Irwin Mitchell.
He said DeviceLock enables the firm to protect the endpoints of its network and still have the flexibility that enables staff to use laptops without compromising security. Individual ports and devices can be blocked or limited to particular users.
DeviceLock also protects Irwin Michell against hardware keyloggers. "Keyloggers are a major concern for companies of all sizes. It takes almost no time for for someone with malicious intent to install one on a PC and start siphoning off data," said Thomas.
Sacha Chahrvin, Smartline managing director UK, says Irwin Mitchell is proactively ensuring it is not vulnerable to security breaches and stays on the right side of data protection law by putting all the necessary protection in place before a problem has occurred.
Law firm gains British standard for IT quality >>
Firms risk breaching Data Protection Act with live data application tests >>
Comment on this article: firstname.lastname@example.com
Enjoy the benefits of CW+ membership, learn more and join.
Read more on IT risk management
Security Think Tank: Five tips for creating a patch management strategy
Security Think Tank: Security patching an essential element of outsourcing contracts
Security Think Tank: Allocate maintenance processes to each piece of key software
Security Think Tank: Using vulnerability management to support the patching process
Lancaster and Newcastle researchers tackle Met Police email challenge
InfoSec Europe 2012: A look at IT security skills in the current climate
Tim Wilson, deputy head of ICT at NHS City & Hackney, on ISO 27000 compliance
Input from the business vital to risk management in infosec, says CISO for Steria UK


text:
realmagick.com The shrine of knowledge.
Art Of Fighting Characters
A selection of articles related to art of fighting characters.
Original articles from our library related to the Art Of Fighting Characters. See Table of Contents for further available material (downloadable resources) on Art Of Fighting Characters.
- Art during the Age of Faith
- The Age of Faith is the one thousand medieval years from 400 A.D. to 1400 A.D. It must be noted though that faith was not a uniquely medieval phenomenon as medieval pursuits were not purely geared towards faith only.
Saga of Times Past >> History & Anthropology
- 14 - Art
- The word Art refers to the alchemist art of transforming matter through purification from an imperfect state into a perfect one. This was done by first analysing and transforming the different elements and then mingling opposites in the right proportions. But...
Tarot Cards >> The Major Arcana
- Our Mother Who Art In Heaven
- (First some Excerpts from an article by Richard Owen in The Times, London September 10, 1999 ) THE Pope, who this year said that God was not "an old man with a white beard", went a step further yesterday and referred to "God the Mother"....
Religions >> Christianity & Paganism
- Autonomous Spirituality and the Art of Being Your Own God
- As we continue to develop in our religious thinking, we have begun to move away from the old mythological, doctrinal and heteronomous, externally controlling religions, and towards autonomous religion, totally relevant to the individual who develops himself...
Religion & Philosophy >> Religions
- Ritual - Expression of Will, Art and Creativity
- Most of our lives involve traditions, regular observances. These might relate to annual or seasonal holiday, it might just be meeting a friend every year at a particular time to go shopping, or have a beer and catch up. The main thing these informal...
Paganism & Wicca >> Ritual
- Candle Magick: A Basic Guide to the Art
- Research your spell– colours, herbs, gems, moon and astrological phases. Create a visualisation for your intent, a symbol, maybe a rune? Light incense and cast your sacred circle. Invoke the deities needed for your work. Relax, ground and centre. Now you need...
Spells >> Charms
Art Of Fighting Characters is described in multiple online sources, as addition to our editors' articles, see section below for printable documents, Art Of Fighting Characters books and related discussion.
Suggested News Resources
- Games Inbox: Are RPGs a dying breed or bigger than ever?
- What I can't understand is why they can't patch it in nearly immediately as a survival option – the characters are all there (M. Bison can be boss) and there is a difficulty rating already for CPU characters.
- Behind the music on "Vinyl": The New York Dolls & Lou Reed take the stage, and
- Episode 5 of "Vinyl," Martin Scorsese's new HBO drama, opens with Clark Morelle (Jack Quaid) still fighting for his A&R job, bringing the American Century team to see a band called Wizard Fist sing about dragons. ...
- 'Vice Principals' Review: A Worthy 'Eastbound' Successor
- Hamby's fighting style is blunt and brash, while Russell is basically playing at the Art of War. The bickering banter ...
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text:
Skip to comments.Pelosi says no to C-SPAN request on floor proceedings
Posted on 12/22/2006 9:52:21 PM PST by txradioguy
Article Launched: 12/22/2006 04:38:28 PM MST
WASHINGTON -- Speaker-to-be Nancy Pelosi cited the need to preserve the ''dignity and decorum'' of the House as she rejected a request Friday that C-SPAN operate its own cameras in covering the chamber.
The public service network has provided gavel-to-gavel television coverage of House proceedings since 1979. But the House leader has kept control of the cameras, with coverage generally limited to tight shots of the speaker or the podium.
The situation is similar in the Senate, which C-SPAN has televised since 1986.
C-SPAN's chairman and chief executive told Pelosi, D-Calif., that under this arrangement, cameras are prevented ''from taking individual reaction shots or from panning the chamber, leaving viewers with an incomplete picture of what's happening in the House of Representatives.''
HAR! Mrs. Control Freak versus full public view of the proceedings?
FYI Ping
Since when have Democrats been concerned about dignity and decorum?
I guess she doesn't want us to see her breaking arms.
I am not surprised, are you?
I was wondering the same thing
Except for the laughable "digntiy and decorum" part, she has a point.
I could see the CSPAN types panning around trying to find a member snoozing, or making a face as Pelosi - or Hastert - speaks.
It would become a circus.
More of a circus, that is.
Since they decided they don't want the viewing public to wittness their full moonbattery on siaplay before the '08 Election.
I mean seriously...if all their open floor debates about MIHOP/LIHOP...The Downing Street Memo...Impeachnment and how they will consipire to confiscate more of our money isn't helpful to their chances two years from now.
What is she trying to hide?
You'd think the press would wise up and realize that they're only useful idiots. democrats NEVER want to conduct their "bidness" in full public view.
As I read it, nothing changes. Pelosi keeps the same control as Hastert did, and for the same reason...no-one wants to see their House member sleeping during the proceedings.
They don't really have to pan the crowd to make it a circus...
For some reason, there are groups of Congresscritters that will boo and hiss if they don't like what is being said...you can hear it...even if you don't know who is doing it..
I watch the House quite often...and I haven't ever felt that I haven't seen anything that important.
I WOULD like them to show the votes though..who voted how, on the screen so that we will know at the vote is going on.
In the Senate, we are told who is voting which way...but in the House we have to wait until it is posted on the internet sometimes hours later...
Really? I do.
Pelosi is doing what the Pubbies did, I think. I don't think this represents a change. But I could be wrong.
Many in the press are WILLING useful idiots
I can't think of even one who's not.
no-one wants to see their House member sleeping during the proceedings
Really? I do.
Think about it...Barney Frank snoring? Nadler popping Milk Duds? Kusinich picking his nose?
No thanks.
I want to see the dems. non-culture of corruption, or just maybe their screaming hissies in the corners.
Absolutely. I wish every voter could see them "working."
This sounds like what a dictator does, control of the press. It was just a short while ago that putin shut down the BBC station in russia during the polonium 210 poisoning incident. Pelosi is doing the same thing here, as they poison US with their whacko-agenda. I know, I know, the drive-by media is wall-to-wall unrepentent liberals, but shutting off C-SPAN is one more door closing on our freedoms. It will take a united effort to bounce this clown before she becomes dangerous, are we up to it?
A change ... No
Hypocrisy ... Yes
The outgoing congressional Republicans need to be recalled quickly to pass a bill giving C-SPAN statutory authority to broadcast from the House chamber. The dems would then need to wait until they could get a president's signature before passing another bill to undo it.
"This sounds like what a dictator does, control of the press."
You've got it.
Having observed House Chamber proceedings a few months ago, I can assure you there was no one sleeping in there. They just weren't there at all. Not more than four or five Congress critters at any one time in the chamber. We noted at the time this must be why C-SPAN cameras are only trained on the podium.
Mine was tongue-in-cheek, yours is the truth, though.
Yup, pelosi isn't ready for prime time, the incident with murtha proved that. Oh, the liberals will say : she's a "work in progress". Yeah, sure, like clinton was a "work in progress". Just an idle speculation : the dems ran a few conservative candidates, then promptly ignored them. What if enough of them got togeather with the republicans and voted in Steny Hoyer as speaker? How does voting for speaker actually work?
There ya go! Thanks for another reason!!
CSPAN longs for "GOTCHAS" to spice it up and increase viewership.
A dictator indeed. How is it Pelosi can take away a right that was without question granted to CSPAN 12 years ago when the GOP took over Congress?
Dennis Hastert should take the Floor when CSPAN is broadcasting and explain to American People that the Democrats are taking the First Amendment Rights Away from CSPAN and the American People.
How completely useless they will be.
I'm with you!
HELP!!!! I need some advice in case I meet her Royal Highness Nance Pelosi, do women curtsy and men bow to her?
Same as Hastert, and Gingrich before him, and Foley, Wright and O'Neill before them.
The main issue is "special orders." Basically, it's a periiod in which any member can give a one-minute speech on whatever strikes his fancy, with the license to "revise and extend" those remarks. In practice, it's an opportunity for any member to put anything he wants into the Congressional Record. Even bothering to give a spoken address at all is a bit of cermony and protocol. No one watches and no one really cares until it shows up in a press release and folks quote it on talk shows.
In the early days of C-SPAN, under House speaker Tip O'Neill, the camera panned the chamber during special orders, showing a completely empty house chamber. One speaker in the well, a presiding member in the Speaker's chair, a stenographer and a couple of pages, and an otherwise empty room.
It made the whole exercise look silly, which it pretty much is. After that flap, the C-SPAN camera angles have been pretty conservative, conventional, and actually incredibly predictable. There are really only about half a dozen shots.
The "news" in this story is that there is no news, that nothing has changed. The House and Senate maintain control over day-to-day operations. A media pool operates for special occasions like the State of the Union Address or joint sessions of Congress.
I see your point, but shouldn't coverage be that as if one were actually there, sitting in the public gallery? I say pan away and let the elected reps worry about being on their best behavior.
The part that I find maddening is that we pay for this bunch of posturing, preening, power-hungry predators. They have wonderful salaries, health care, pensions, etc., and it's all at our expense, literally. We must be fools.
Maybe Mzzzzz. Pelosi does not want the C-Span cameras to catch DemocRATS taking lobbyist cash on the chamber floor.
Yup, the reps who stayed home last 11/7 to "send a message", or voted libertarian, are getting their reward now : the REAL dem agenda. Most of us knew full well that their campaign promises of holier-than-thou/anti-war was just another lie, and kicking CSPAN out is proof positive.
Disclaimer: Opinions posted on Free Republic are those of the individual posters and do not necessarily represent the opinion of Free Republic or its management. All materials posted herein are protected by copyright law and the exemption for fair use of copyrighted works.


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Begin Your Search
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WineAccess Travel Log
Read stories from the world's greatest wine trails.
More About This Wine
About Dehlinger Winery
Founded in 1973 by Tom Dehlinger, a UC Davis graduate, Dehlinger Winery has a rep for quality not quantity. Production here has topped out at about 7,000 cases per vintage, a figure that has risen steadily since the initial 14 acres were planted in 1975.
2007 Dehlinger Winery Chardonnay Estate Russian River Valley
Producer: Dehlinger Winery
Style: White Wine
Grape Type: Chardonnay
Origin: California
Region: Sonoma
92 Points | Stephen Tanzer's IWC - May/June 2010
($37) Pale gold. Smoky, mineral-driven nose hints at apple butter, iodine, jasmine and buttered toast. Juicy and tight, with bracing acidity and a distinctly saline, iodiney character to its fresh orchard fruit flavors. A refreshingly bitter lemon pith quality adds lift and cut to a long, smoky, penetrating finish.


text:
When you stay at Rivavi Fashion Hotel in Legian, you'll be connected to a shopping center and minutes from Honorary Consulate of Brazil and Honorary Consulate of Malaysia. This hotel is close to Kuta Beach and Carrefour Plaza Kuta.
Make yourself at home in one of the 95 air-conditioned rooms featuring refrigerators and LCD televisions. Complimentary wireless Internet access keeps you connected, and cable programming is available for your entertainment. Conveniences include phones, as well as safes and desks.
Enjoy recreational amenities such as an outdoor pool and an indoor pool. Additional amenities at this hotel include complimentary wireless Internet access, concierge services, and complimentary babysitting/childcare.
Grab a bite to eat at the hotel's restaurant, where you can take in a pool view, or stay in and take advantage of room service (during limited hours). Quench your thirst with your favorite drink at a bar/lounge. Buffet breakfasts are available daily for a fee.
Business, Other Amenities
Featured amenities include express check-in, express check-out, and dry cleaning/laundry services. A roundtrip airport shuttle is provided for a surcharge (available 24 hours), and free valet parking is available onsite.


text:
Real Madrid 4-0 Auxerre Highlights
Watch UEFA Champions League Group G football match, Real Madrid Vs Auxerre highlights here. Final Score: Real Madrid 4-0 Auxerre
Real Madrid 2-0 Valencia Highlights
Cristiano Ronaldo struck both goals as Real Madrid recovered from their Camp Nou mauling with a hard-fought victory over ten-man Valencia at the Bernabeu. Watch Spanish league football match, Real Madrid...
Barcelona 5-0 Real Madrid Highlights
Barcelona produce a sensational performance as they demolish Real Madrid 5-0 in El Clasico in La Liga, with David Villa scoring twice as they go top of the table. Watch Barcelona...
Ajax 0-4 Real Madrid Highlights
Watch UEFA Champions League Group G football match, Ajax Vs Real Madrid highlights here.
AC Milan 2-2 Real Madrid Highlights
Substitute Pedro Leon's injury-time goal rescues a draw for Real Madrid at AC Milan as Jose Mourinho's Spanish giants qualify for the last 16 of the Champions League. Watch UEFA Champions League...
Real Madrid Vs AC Milan Highlights (2-0)
Watch UEFA Champions League Group G football match, Real Madrid Vs AC Milan highlights here.
Auxerre 0-1 Real Madrid Highlights
Watch UEFA Champions League Group G football match, Auxerre Vs Real Madrid highlights here.
Real Madrid 2-0 Ajax Highlights
Watch UEFA Champions League Group G football match, Real Madrid Vs Ajax Highlights here.
Malaga 1-1 Real Madrid Highlights
Madrid drew 1-1 away with Malaga, a result that is likely to fuel speculation that Real's coach Manuel Pellegrini will be sacked after just a season in charge at the Bernabeu....
Real Madrid 2-0 Valencia Highlights
Leading scorers Gonzalo Higuain and Cristiano Ronaldo were again on the mark as Real Madrid reduced Barcelona's lead at the summit to one point with a deserved win over third-placed Valencia....
Real Madrid 0-2 Barcelona Highlights
Barcelona took a huge step towards successfully defending their Spanish title with a key win over Real Madrid. Watch Spanish League (La Liga) – El Clasico – football match, Real Madrid...
Racing Santander 0-2 Real Madrid Highlights
In-form strike duo Cristiano Ronaldo and Gonzalo Higuain earned Real Madrid their 12th successive Primera Division win. Watch Spanish League (La Liga) football match, Racing Santander Vs Real Madrid highlights here.
Getafe 2-4 Real Madrid Highlights
Cristiano Ronaldo and Gonzalo Higuain both struck braces as Real Madrid moved back to the top of the Primera Division table with victory over local rivals Getafe. Watch Spanish League (La...
Real Zaragoza 2-4 Barcelona Highlights
Lionel Messi continued his remarkable goalscoring form with a hat-trick as Barcelona moved level once more with Real Madrid at the Primera Liga summit with victory at Real Zaragoza. Watch Spanish...
Real Madrid 3-1 Sporting Gijon Highlights
Real Madrid continued their perfect home record and provisionally moved three points clear at the top of Primera Division tonight, but they were given a scare by Sporting Gijon. Watch Spanish...
Valladolid 1-4 Real Madrid Highlights
Gonzalo Higuain hit a hat-trick as Real Madrid provided the ideal response to crashing out of the Champions League with a 4-1 victory. Watch Spanish League (La Liga) football match, Valladolid...
Real Madrid 1-1 Lyon Highlights (agg 1-2)
European giants Real Madrid crashed out of the Champions League at the first knockout round for the sixth year in succession after being held by Lyon. Watch Champions League last 16 second...
Real Madrid 3-2 Sevilla Highlights
Real Madrid came from two goals behind to beat Sevilla in a thrilling game as Manuel Pellegrini's side moved ahead of champions Barcelona on goal difference. Watch Spanish League (La Liga)...
Tenerife 1-5 Real Madrid Highlights
Gonzalo Higuain was the star of the show as Real Madrid recorded a 5-1 victory over Tenerife as they claimed a tougher sixth successive Primera Division win than the scoreline suggests....
Real Madrid 6-2 Villarreal Highlights
A Cristiano Ronaldo-inspired Real Madrid answered their critics following their midweek Champions League defeat at Lyon and eased some of the pressure on coach Manuel Pellegrini with a thumping victory...


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Today's "Cool Science" saw Martin Fisher use a device called a "Tornado Gun"
It's a device that fires a pencil down a tube at a block of wood or drywall at tornado-force winds. Tornado damage and injury is caused by debris flying around at high wind speeds. The Tornado Gun simulates twigs or straws that can impale the side of a building or telephone pole.
Click on the video to see this week's "Cool Science" Monday.
What are your thoughts CLICK HERE to leave us a "QUESTION OF THE DAY" comment.
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Dr. Baker is a Penn Medicine employed physician.
A facility of the Hospital of the University of Pennsylvania
Medical School: University of Pennsylvania School of Medicine
Residency: Hospital of the University of Pennsylvania
Fellowship: Hospital of the University of Pennsylvania
Rheumatoid ArthritisBody CompositionBone Health
Baker JF, Pullman-Mooar S, Ibrahim S: Objective management of rheumatoid arthritis in the era of patient preference Rheumatology (Oxford) 53 (10): 1721-1722,2014.
Baker JF, Von Feldt JM, Mostoufi-Moab S, Noaiseh G, Taratuta E, Kim W, Leonard MB: Deficits in Muscle Mass, Muscle Density, and Modified Association with Fat in Rheumatoid Arthritis Arthritis Care & Research 66 (11): 1612-1618,2014.
Baker JF, Conaghan PG, Smolen JS, Aletaha D, Shults J, Emery P, Baker DG, Ostergaard M: Development and validation of modified disease activity scores in rheumatoid arthritis: Superior correlation with MRI synovitis and X-ray progressoin Arthritis and Rheumatism 66 (4): 794-802,2013.
Baker JF, Ostergaard M, Emery P, Hsia EC, Lu JD, Baker DG, Conaghan PG: Early MRI Measures Independently Predict 1- and 2-year Radiographic Progression in Rheumatoid Arthritis: Secondary Analysis from a Large Clinical Trial Annals of Rheumatic Disease 73 (11): 1968-1974,2013.
Baker JF, Mehta N, Baker DG, Toedter G, Shults J, Von Feldt JM, Leonard MB: Vitamin D, Metabolic Dyslipidemia, and Metabolic Syndrome in Rheumatoid Arthritis American Journal of Medicine 125 (10): 1036.e9-1036.e15,2012.
Baker JF, George M, Baker DG, Toedter G, Von Feldt JM, Leonard MB.: Associations Between Body Mass, Radiographic Joint Damage, Adipokines, and Risk Factors for Bone Loss in Rheumatoid Arthritis. Rheumatology (Oxford) 50 (11): 2100-7,2011.
Baker JF, Davis M, Alexander R, Zemel BS, Mostoufi-Moab S, Shults J, Sulik M, Schiferl DJ, Leonard MB: Associations between body composition and bone density and structure in men and women across the adult age spectrum Bone 53 (1): 34-41,2012.
Baker JF, Katz P: Sex Differences in Lean Mass Deficits in Rheumatoid Arthritis Arthritis and Rheumatism Supplement : 2013.
Baker JF, Qatanani M, Morales M, Cucchiara A, Nackos E, Lazar MA, Teff K, Von Feldt JM.: Resistin Levels in Lupus and Associations with Disease-Specific Measures, Insulin Resistance, and Coronary Calcification. J Rheumatol. 38 (11): 2369-75,2011.
Joshua F. Baker, Edna Schwab: Rheumatoid Arthritis Encyclopedia of Elder Care, 3rd Edition. : 176-180,2013.
Congratulations to the 184 Penn physicians listed below who were included in Philadelphia Magazine's Top Doctors 2016.
Penn Medicine is one of the world's leading academic medical centers.
A clinical trial is a research study involving patient volunteers that are conducted to find safe and effective treatments for a variety of health conditions.


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realmagick.com The shrine of knowledge.
Scheduling Np Hard
A selection of articles related to scheduling np hard.
Original articles from our library related to the Scheduling Np Hard. See Table of Contents for further available material (downloadable resources) on Scheduling Np Hard.
- Harding, Deborah
- Deborah Harding began gardening alongside her parents when she was just able to walk. She lives in Ohio with her husband and two daughters. She writes articles on herbal concerns for magazines and web-zines, and gives lectures and workshops on growing herbs...
Real Interviews >> Authors
- What day are you born on?
- The day of the month on which the you were born - regardless of which month or year it is - is a key numerological indicator, providing an excellent "thumbnail sketch" of standout traits. It strongly influences your Life Path and is helpful in...
Symbology >> Numerology
- A Treatise on Astral Projection, Part 2: Training
- To trigger the projection of the Astral body, while fully conscious, there are four major requirements: Relaxing your body 100% while staying awake. Concentrating 100% on what you are doing. Having enough energy available. Pressuring the astral body to...
Parapsychology >> Astral Projection
- Calcium carbonicum (Oyster Shell)
- This remedy is made of the shell of the oyster. Let's have a look at an oyster: Inside a thick hard calcium-made shell lies a soft and quite formless animal. When the oyster feels at ease it opens its shell and passively lets through the sea water and...
Remedies >> Remedies C
- What is the History of Reiki?
- Usui Shiki Ryoho: The Usui System of Natural Healing Ancient Origins The Development of Usui Reiki Dr. Mikao Usui Dr. Chujiro Hayashi Hawayo Takata Mrs. Takata Talks about Reiki (transcript) Usui Shiki Ryoho: The Usui System of Natural Healing Reiki In Japan...
Body Mysteries >> Reiki
- Morrison, Dorothy
- Dorothy is a Wiccan High Priestess of the Georgian tradition and an avid practitioner of the ancient arts for over 20 years. She teaches the Craft to students throughout the US and in Australia. Her interests include archery and bowhunting, magical herbalism,...
Real Interviews >> Authors
- Shamanic Death
- What is a Shaman's death, and who's likely to have one? The death itself is a suspension between worlds. States of consciousness. The individual today, who is likely to have a "Shamanic Death" is chasing extinction itself. Through that process the...
Religions >> Native American, Shamanism
Scheduling Np Hard is described in multiple online sources, as addition to our editors' articles, see section below for printable documents, Scheduling Np Hard books and related discussion.
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- Superior mayor won't back down
- She and her Muslim partner have destroyed the fabric of democracy that was so very hard fought for.
- Dayton proposes 6 weeks parental leave for state workers; Minnesota lawmakers
- "For far too long, we have forced tens of thousands of hard-working parents to make an impossible choice: to spend time with their newborn or recently adopted child, or earn the money they need to care for their families," Dayton said.
- 'Padded room' protest targets Superior elementary school
- "It's a hard skill to learn when they're just little, but we're really trying to help these kids who are struggling." News Tribune reporter Jana Hollingsworth contributed to this story. Recommended for you.
- Customers gather to find bargains — and lament — as Aurora's only grocery
- "In a small community, it's hard to survive as a grocery store," Zupancich said. He said the local customers and employees have been wonderful to work with, and the Zupancich family agonized over the decision to close the store.
- Superior mayor would support recall election
- She and her Muslim partner have destroyed the fabric of democracy that was so very hard fought for.
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This documentary follows a group of Beyoncé fans who camp out for two months for her 2013 concert in Sao Paulo, Brazil. This lively film captures the community that forms out of the queue as they become friends, best mates and lovers. It showcases their loveable moments recounting the inspiration Beyoncé has had on their life, festivities in recreating their best Beyoncé dance routines and intimate conversations about their sexuality and identity. What begins to unfold is the power of music and celebrity in strengthening these already fierce individuals to make them capable of tackling everyday struggles such as homophobia, poverty and racial slurs within their gay community.
The film is reminiscent of the pop cultural sensation documentary, Paris is Burning, as it shines a candid light on a subculture of starstruck lovers. Their diva-like antics, fashion runway walks and a Beyoncé sing-a-long will ensure the lighthearted ambiance continues to the very end of the film. A heartwarming crowd-pleaser that shows a disparate community of fans coming together and quoting fan-favourite one liners like "all the single ladies" or crying heartbroken tears when they have to disband after the concert.
"Waiting for B is a compelling portrait of an entire (fan) culture, where pop is political and a twerk is a protesting stinky finger pointed at society's narrow standards." - CPH:DOX
Festival Bar (6pm to late): A Beyonce night to celebrate the screening of Waiting for B. After the film join us for a special Beyonce surprise performance brought to you by Heaps Gay.
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Chicago Dem Mayor Rahm Emanuel Proposes Videotaping Every Legal Gun Purchase Made In The City
You know, it's the people jumping through all the legal hoops that are always the dangerous ones:
Mayor Rahm Emanuel is proposing a far-reaching ordinance that would keep gun stores out of most parts of the city and require them to videotape every sale to deter customers from buying firearms for crooks.
The ordinance is a response to a federal judge's ruling in January that Chicago's longtime ban on gun stores was unconstitutional.
Emanuel chose not to fight the decision, and the court gave the city six months to approve store restrictions short of a ban. The deadline is July 14.
Under the proposed ordinance, special-use zoning would keep gun stores out of 99.5 percent of Chicago, limiting them to pockets of the North, West and South sides, city officials said. The stores could not be within 500 feet of a school or park.
Store owners would have to conduct quarterly audits of their gun sales and allow police to inspect their records. They also would have to get the police to approve a security plan before they could open their doors.
"There is no question it will be the smartest, toughest regulation on gun stores in the country," said Janey Rountree, the mayor's deputy chief of staff for public safety. "It's designed to prevent gun trafficking and illegal sales in these stores."
I'm going to ask the hard questions no one else is going to ask, starting with: : who still uses videotape?
Seriously, that stuff is 1980s tech. : Does it have to be Betamax too?
Is this another way to stop gun sales?
Just kidding, it's all tyranny and not at all funny.
This is not a free country. : At least not Chicago.
Hat Tip: : Weasel Zippers
See also: : Michelle Obama's Daughters Get Meatball Subs And Ice Cream For School Lunch While Public School Kids Get Stuck With Her Bland "Healthy" Lunches
Also see...
Even though my father, brother, uncles and grandfather were in the military, I seldom handled guns growing up. That's because unlike many of the other people in my family, I've...Read More
Duane Lester
Duane Lester is co-founder of All American Blogger, and the primary writer. Following graduation, Duane entered the United States Navy as a journalist. He spent five years touring the world, reporting on local news and sports. Following his enlistment, Duane spent almost 10 years working with adjudicated youth in residential treatment environments. Duane discovered politics after September 11. He credits Erich "Mancow" Muller for opening his eyes to his conservative beliefs. Since then, Duane has devoured books and literature on politics, reading everything he can from Adam Smith to Larry Elder to Thomas Sowell. He refers to his style of politics as "conserva-tarian", a mixture of conservative and libertarian beliefs.
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Mister Rogers' Neighborhood TV Show Watchlist
Season 1, Episode 52 Mister Rogers' Neighborhood
Putting a puzzle together.
Cast & Details See all »
- Rating: TV-Y
- Premise: The genial, soft-spoken man made every day `special' and every kid welcome in this long-running series. Once described as `a singing psychiatrist for children,' Rogers used puppetry, songs and storytelling to teach youngsters about family values and how to… (more)
Trending TonightSee all »
The Vampire Diaries8:00 pm | CWI'll Watch384 Watching
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Watch This
American Horror Story: Roanoke's Big Twist Explained
Here's how everything changed in "Chapter 6"
Revisiting Mister Rogers' Neighborhood: Essays on Lessons About Self and Community
By McFarlandBuy New: $35.00
Mister Rogers' Neighborhood: Work (#1530) Mister Rogers Talks About His Work
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US private equity fundraising surged in the fourth quarter of 2013 as buyout houses closed on $40bn of new capital, new research has shown.
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How Simon Calder blew the budget on a trip to 'North Korea on Sea'
This year Simon Calder took his family on a cruise in northern Canada. Their most expensive holiday ever didn't go well
This year Simon Calder took his family on a cruise in northern Canada. Their most expensive holiday ever didn't go well
The ship making the biggest splash in 2016 is Harmony of the Seas, for 5,497 passengers, making its maiden voyage in May
A passenger said: 'It was a real life scene of 'The Shining''
A world cruise is a tempting way to escape the British winter. But if you don't have deep pockets, or simply don't have the time to take three or more months off, you can still experience a grand ocean voyage by joining it for part of the voyage.
Fashion houses claim to theme their cruises around the creative -a Tokyo venue for a Manga-inspired Dior show oe California for Vuitton's take on Americana
From three-nighters to 4D cinemas and the route of the Vikings
The rats have yet to master our language but may be plotting a government coup
Never cruised before? Or, thinking of trying a different ship? Cruise lines step up their game in the new year, tempting us with new vessels and satisfaction guarantees.
Attorneys for Cruise and Bauer Publishing Company made the mutual decision to drop the case
Homeland's newest recruit has already undergone a secret mission of her own, having reportedly been vetted by Tom Cruise to become his Scientologist wife.
Bodies 'absolutely consistent' with descriptions of two missing people but are yet to be officially identified
The fraught international operation to right the capsized 'Costa Concordia' begins tomorrow, and tensions are high
Antarctica's monumental icebergs, history of heroic exploration and fearless wildlife give it an allure that is enhanced by its remoteness. The only realistic way for tourists to visit the vast White Continent is by ship. For most, it's a once-in-a-lifetime trip, so it is important to choose carefully.
The row over the presence of giant cruise ships in Venice's lagoon was reignited this weekend after claims that a huge vessel belonging to the same company as the wrecked Costa Concordia sailed dangerously close to St Mark's Square.
Captain Francesco Schettino only person still on trial
Schettino says he saved many lives on Concordia as he faces 20 years in jail at manslaughter trial


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After several years of work, local underground metal band Nightmare plans to finally release their first solo album before April, members of the group said last week.
The band's guitar player, Aung Myo Linn, told The Myanmar Times that the group has been preparing the 12-song album titled Nga Dto Thamine (Our History) since 2010, but every time they recorded a song they were dissatisfied with the result.
"So we played the songs again and again, which is why we've spent so much time on the album," he said, adding that all the songs were original tunes written by band members.
Nightmare vocalist Novem Htoo said most of the songs were "extremely explosive" but there were also some softer, slower moments on the album.
"Metal is a branch of rock music, but with metal the style is extremely explosive and the singers scream very loudly to express their feelings," he said.
Aung Myo Linn said most people in Myanmar were unfamiliar with metal music, so the band did not expect to make a profit from album sales.
"After listening to our album, people who already know our music can enjoy our new songs, and those who don't know our songs will become familiar with our music style. That's our only expectation from the album," he said.
He added that the band members produced the album themselves, since most music producers were not interested in their music style and they did not have a sponsor.
"We produced the album ourselves to document our music," he said.
Aung Myo Linn said all the music for the album has already been recorded and the band is now mixing the songs, after which they will have to be submitted to the censors.
"If the censors give us permission, we can finally release our album," he said. "We hope this will be an easy step because the rules are changing in our country and the censorship board is also changing."
Nightmare was formed in 2007 with Aung Myo Linn, Novem Htoo, bassist Nyi Phyu and drummer Squeeze.
"We've spent a lot of time and money on our music," said Aung Myo Linn.
"To produce a good song, guitarists must spend a lot of time learning to play, vocalists must train their voices, and everything else. We're very tired but we like to play music and some people want to listen to our songs. We've put a lot of effort into creating metal music for a very small audience."
He added that there was no plan to release a VCD with music videos, but one video will be included on the CD as a bonus track.
Myanmar Times Restaurants Reviewed
Looking for someplace out of your usual routine? Let The Myanmar Times help! Find restaurants, cafes, and bars our Pulse team has reviewed.
Don't see your favourite spot here? Let us know! Send tips to email@example.com


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Kings guard Tyreke Evans continues to produce at a level that has kept him at the top of the rookie leaderboard. The 6-foot-6, 220-pound point guard is averaging a team-leading 20.3 points and 5.4 assists, along with 4.8 rebounds a game. He has displayed a surprising ability to run the offense - some critics complain that he dribbles too much - and his perimeter shooting is solid. The only negative is his three-point shooting (26 percent).
The Blazers will get a chance to see the two top candidates for the rookie of the year award in the next three days. Tonight, the player who is the current leader for the award will play tonight when Portland hosts Sacramento.
Evans may be able to run out the clock on the award, but Golden State's Stephen Curry is closing fast. Curry has quickly learned how to play the point guard position while maintaining his sweet shooting stroke and is averaging 16 points, 5.4 assists and 4.2 rebounds a game this season. The Blazers play at Golden State Thursday and will see Curry for the first time since he enjoyed a great month in February, averaging 21.5 points, 7.3 assists and 5.3 rebounds a game. Curry is playing so well that the Warriors considered trading Monta Ellis before the trade deadline and will almost certainly explore moving Ellis this summer.
Another fast riser is New Orleans' Darren Collison. The point guard handed out 20 assists in the Hornets' 135-131 win against Golden State Monday night. Collison's assist total tied Phoenix's Steve Nash for the most in a NBA game this season and was one short of his teammate Chris Paul's franchise record. Collison has played more than 40 minutes in 15 consecutive games, averaging 22.1 points, 9.1 assists and 2.1 steals during that stretch of games. His play must have management, at the very least, thinking about Paul's future with the team. The Blazers will play at New Orleans March 27.
The early leader for the award, Brandon Jennings has fallen behind Evans, Curry and Collison as his shooting percentage dropped. However, while Jennings' numbers have fallen, his team is rising. The Milwaukee Bucks have posted a record of 13-4 since the beginning of February and are now fifth in the Eastern Conference standings.
Here's what others are saying about the Blazers:
Adam Morrison says Nate McMillan wanted him instead of Brandon Roy.
Rudy Fernandez wants to play in world championships.
Here's what others are saying about the Kings, the Blazers opponent tonight:
Frustrated Kings lose to Thunder.