Neutralizing mutations of carboxylates that bind metal 2 in T5 flap endonuclease result in an enzyme that still requires two metal ions.

Flap endonucleases (FENs) are divalent metal ion-dependent phosphodiesterases. Metallonucleases are often assigned a "two-metal ion mechanism" where both metals contact the scissile phosphate diester. The spacing of the two metal ions observed in T5FEN structures appears to preclude this mechanism.

Transdermal opioids for cancer pain.

Purpose Of Review: Cancer patients with moderate-to-severe pain require opioids for analgesia. Whereas early guidelines recommend oral morphine as the 'drug of choice', newer synthetic opioids can be given by a reliable and effective nonoral transdermal route. We examine the mode of action of transdermal patches and we review the evidence on two drugs, which are currently available in this formulation - buprenorphine and fentanyl - covering physicochemical characteristics and pharmacokinetics of the patches, clinical efficacy data and adverse effects.

Regulation of neutrophil senescence by microRNAs.

Neutrophils are rapidly recruited to sites of tissue injury or infection, where they protect against invading pathogens. Neutrophil functions are limited by a process of neutrophil senescence, which renders the cells unable to respond to chemoattractants, carry out respiratory burst, or degranulate. In parallel, aged neutrophils also undergo spontaneous apoptosis, which can be delayed by factors such as GMCSF.

Nasopharyngeal colonization by Neisseria lactamica and induction of protective immunity against Neisseria meningitidis.

Background: Natural immunity to Neisseria meningitidis may result from nasopharyngeal carriage of closely related commensals, such as Neisseria lactamica.

Methods: We enrolled 61 students with no current carriage of Neisseria species and inoculated them intranasally with 10,000 colony-forming units of Neisseria lactamica or sham control. Colonization was monitored in oropharyngeal samples over 6 months.

Nuclear hormone receptors in parasitic helminths.

Nuclear receptors (NRs) belong to a large protein superfamily that are important transcriptional modulators in metazoans. Parasitic helminths include parasitic worms from the Lophotrochozoa (Platyhelminths) and Ecdysozoa (Nematoda). NRs in parasitic helminths diverged into two different evolutionary lineages.

Genetic variation in pro-inflammatory cytokines and meningococcal sepsis.

Purpose Of Review: Pro-inflammatory cytokines are an essential component of host defence in patients who are susceptible to meningococcal disease. This review summarizes what is currently known about genetic variations in genes encoding these defensive proteins and focuses on recent work investigating the potential role polymorphisms may play insusceptibility and severity of the disease.

Recent Findings: A recently developed porcine model revealed significant cytokine derangement early in severe meningococcal sepsis raising the suggestion of a causative role for maladaptive cytokine release in the disease course.

Methotrexate and psoriasis: 2009 National Psoriasis Foundation Consensus Conference.

Background: Methotrexate remains a valuable option for the treatment of psoriasis. This report will summarize studies regarding the use of methotrexate since the last guidelines were published in 1998.

Objective: A task force of the National Psoriasis Foundation Medical Board was convened to evaluate treatment options.

Nuclear factor I-C is essential for odontogenic cell proliferation and odontoblast differentiation during tooth root development.

Our previous studies have demonstrated that nuclear factor I-C (NFI-C) null mice developed short molar roots that contain aberrant odontoblasts and abnormal dentin formation. Based on these findings, we performed studies to elucidate the function of NFI-C in odontoblasts. Initial studies demonstrated that aberrant odontoblasts become dissociated and trapped in an osteodentin-like mineralized tissue.

Geranylgeranyl transferase type II inhibition prevents myeloma bone disease.

Geranylgeranyl transferase II (GGTase II) is an enzyme that plays a key role in the isoprenylation of proteins. 3-PEHPC, a novel GGTase II inhibitor, blocks bone resorption and induces myeloma cell apoptosis in vitro. Its effect on bone resorption and tumor growth in vivo is unknown.

Effects of COX-2 inhibition on expression of vascular endothelial growth factor and interleukin-8 in lung cancer cells.

Background: Cyclooxygenase (COX)-2 has been implicated in tumour progression, angiogenesis and metastasis in non-small cell lung cancer (NSCLC). We speculated that inhibition of COX-2 activity might reduce expression of the pro-angiogenic factors vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) in lung cancer cells.

Methods: The levels of IL-8, VEGF and prostaglandin E2 (PGE2) were measured by ELISA.

Contemporary approach to the diagnosis and management of non-ST-segment elevation acute coronary syndromes.

The management of patients with acute coronary syndromes (ACS) has evolved dramatically over the past decade and, in many respects, represents a rapidly moving target for the cardiologist and internist who seek to integrate these recent advances into contemporary clinical practice. Unstable angina and non-ST-segment elevation myocardial infarction (MI) comprise a growing percentage of patients with ACS and is emerging as a major public health problem worldwide, especially in Western countries, despite significant improvements and refinements in management over the past 20 years. Against this backdrop of a multitude of randomized, controlled clinical trials that have established the scientific foundation upon which evidence-based treatment strategies have emerged and become increasingly refined, the clinician is frequently confronted with panoply of choices that can create uncertainty or confusion regarding "optimal management".

Influence of genetics on disease susceptibility and progression.

For many chronic diseases, the influence of genetics is complex and phenotypes do not conform to simple Mendelian patterns of inheritance. Discussed here are two types of genetic influences on healthy aging. The first involves variation in the gene sequence itself and how this may influence disease susceptibility, progression, and severity, interacting with other recognized risk factors.

Nelson's Syndrome.

Nelson's syndrome is a potentially severe complication of bilateral adrenalectomy performed in the treatment of Cushing's disease, and its management remains difficult. Of all of the features of Nelson's syndrome, the one that causes most concern is the development of a locally aggressive pituitary tumour, which, unusually for pituitary disease, may occasionally cause death from the tumour itself. This feature is especially pertinent given the increasing use in Cushing's disease of laparoscopic bilateral adrenal surgery as a highly effective treatment modality to control cortisol-excess.

Differential diagnosis of Cushing's syndrome.

The differential diagnosis of Cushing's syndrome requires careful multidisciplinary interaction with a number of specialities, co-ordinated through endocrine centres with good experience of this condition. It is essential that the diagnosis of Cushing's syndrome be fully established before differential diagnosis is attempted. The endocrinologist needs to be aware of the pitfalls and advantages of the tests in use.

Thyroid hormone receptor orthologues from invertebrate species with emphasis on Schistosoma mansoni.

Background: Thyroid hormone receptors (TRs) function as molecular switches in response to thyroid hormone to regulate gene transcription. TRs were previously believed to be present only in chordates.

Results: We isolated two TR genes from the Schistosoma mansoni and identified TR orthologues from other invertebrates: the platyhelminths, S.

Type 1 von Willebrand disease.

Since its first description in 1926, the precise nature and indeed significance of von Willebrand factor (VWD) in the area of human bleeding has been unsure and often controversial. The recognition of VWD as a distinct entity in blood and the cloning of the von Willebrand factor (VWF) gene in the 1980s encouraged both phenotypic and genotypic studies, culminating in 1994 with the recognition, by the VWF subcommittee of the Scientific and Standardization Committee (SSC) of International Society of Thrombosis and Haemostasy (ISTH), of three types of VWD, characterized by severe plasma VWF deficiency (type 3), functionally deficient plasma VWF (type 2) and reduced (below normal) levels of plasma VWF, which is functionally essentially normal (type 1; 70% of all cases). Since then, whereas gene analysis has recognized VWF gene (VWF) mutations in most individuals with type 3 and type 2 disease, the latter mutations correlating well with recognized functional domains within the VWF protein, few mutations have been reported in cases with type 1 VWD.

Function, structure and therapeutic potential of complement C5a receptors.

Complement fragment (C)5a is a 74 residue pro-inflammatory polypeptide produced during activation of the complement cascade of serum proteins in response to foreign surfaces such as microorganisms and tissue damaged by physical or chemical injury. C5a binds to at least two seven-transmembrane domain receptors, C5aR (C5R1, CD88) and C5L2 (gpr77), expressed ubiquitously on a wide variety of cells but particularly on the surface of immune cells like macrophages, neutrophils and T cells. C5aR is a classical G protein-coupled receptor that signals through G alpha i and G alpha 16, whereas C5L2 does not appear to couple to G proteins and has no known signalling activity.

Mutational analysis of the von Willebrand factor gene in type 1 von Willebrand disease using conformation sensitive gel electrophoresis: a comparison of fluorescent and manual techniques.

Two versions of conformation sensitive gel electrophoresis, fluorescent (F-CSGE) and manual (M-CSGE) techniques, were compared for mutation analysis of the von Willebrand factor gene. 56 PCRs were used to amplify all 52 exons of the gene in seven type 1 von Willebrand disease cases, plus a healthy control. One hundred and ninety-two samples were analyzed on each F-CSGE gel, compared with 40 on M-CSGE.

mGluR5 is involved in dendrite differentiation and excitatory synaptic transmission in NTERA2 human embryonic carcinoma cell-derived neurons.

The pluripotent human embryonic carcinoma cell line NTERA2 readily differentiates into neurons when exposed to retinoic acid in vitro. These neurons show characteristic morphology with long processes and they express neuronal markers TUJ-1 and NeuN. NTERA2-derived neurons can regulate Ca2+ signalling through ionotropic glutamate (iGluR) and muscarinic receptors (mAChRs).

Relaxed cleavage specificity of an immunoglobulin A1 protease from Neisseria meningitidis.

Respiratory pathogens, such as Neisseria meningitidis, secrete site-specific proteases able to cleave human immunoglobulin A1 (IgA1), the first line of defense at mucosal membranes. Bacterial isolates show wide variability in IgA1 protease activity, and those isolated from patients with clinical infection possess the highest levels of activity. A feature of this enzyme is the self-cleavage required for secretion of the mature extracellular form.

Evolution of a novel subfamily of nuclear receptors with members that each contain two DNA binding domains.

Background: Nuclear receptors (NRs) are important transcriptional modulators in metazoans which regulate transcription through binding to the promoter region of their target gene by the DNA binding domain (DBD) and activation or repression of mRNA synthesis through co-regulators bound to the ligand binding domain (LBD). NRs typically have a single DBD with a LBD.

Results: Three nuclear receptors named 2DBD-NRs, were identified from the flatworm Schistosoma mansoni that each possess a novel set of two DBDs in tandem with a LBD.

Identification and characterization of a nuclear receptor subfamily I member in the Platyhelminth Schistosoma mansoni (SmNR1).

A cDNA encoding a nuclear receptor subfamily I member in the platyhelminth Schistosoma mansoni (SmNR1) was identified and characterized. SmNR1 cDNA is 2406 bp long and contains an open reading frame encoding a 715 residue protein. Phylogenetic analysis demonstrates that SmNR1 is a divergent member of nuclear receptor subfamily I with no known orthologue.

Evidence for genetic variation as a factor in maintaining health.

For many chronic diseases, the influence of genetics is subtle and complex and does not conform to simple Mendelian patterns of inheritance as is seen with single-gene disorders. Genetic variation can influence the propensity for the initiating event, the progression to a clinical disease state, and the trajectory of disease. One example of how genetic variations may affect complex diseases is provided by the interleukin 1 family of cytokines.