Topically applied novel TRPV1 receptor antagonist, ACD440 Gel, reduces evoked pain in healthy volunteers, a randomized, double-blind, placebo-controlled, crossover study.

BACKGROUND: The TRPV1 receptor is a key molecule in pain generation. Previous development of oral TRPV1-antagonists was halted due to systemic heat insensitivity and body temperature alterations. The present Phase 1b study investigated the efficacy, safety and plasma exposure of a topically administered TRPV1-antagonist (ACD440 Gel) in healthy subjects. METHODS: The study comprised two parts. In part 1, 24 healthy subjects were included in this randomized double-blind, placebo-controlled, crossover trial. ACD440 Gel or Placebo was applied once daily and wiped off after 1 h, for 5 consecutive days. Assessments were done in normal skin, skin optimized for penetration (by stripping and occlusive gel application) and UVB-irradiated skin. Pain induced by thermo-nociceptive CO2 laser impulses generated laser-evoked potentials (LEPs), with readouts of peak-to-peak (PtP) amplitude in vertex-EEG and pain assessments by VAS (0-100). Endpoints include effects at 1 hour post-dose, AUC(Days 1-5) and AUC(0-24, Day 4). In UVB-irradiated skin, also pain on pinprick and skin redness were assessed. Part 2 explored the plasma pharmacokinetics of ACD440. RESULTS: ACD440 Gel reduced LEP PtP amplitude and VAS pain, p < 0.001, in all skin conditions, versus placebo. In UVB-irradiated skin, pinprick pain was also reduced, p = 0.047. Effects were significant after 1 h, maintaining for at least 9 h. There were no adverse events or drug-induced erythema. Plasma exposures of ACD440 were too low to establish an elimination half-life of ACD400. CONCLUSIONS: Topical ACD440 Gel demonstrated a significant analgesic effect on LEP, VAS score and pinprick pain, with low systemic exposures, supporting further clinical development. SIGNIFICANCE: This study demonstrates that the topical administration of a TRPV1-antagonist, ACD440 Gel, has potential as a new treatment for painful conditions affecting the skin, such as chronic peripheral neuropathic pain, without any local or systemic side effects.

Safety, Tolerability, Pharmacokinetics and Quantitative Electroencephalography Assessment of ACD856, a Novel Positive Allosteric Modulator of Trk-Receptors Following Multiple Doses in Healthy Subjects.

BACKGROUND: ACD856 is a positive allosteric modulator of tropomyosin receptor kinase (Trk) receptors which has shown to have pro-cognitive and anti-depressant-like effects in various animal models. It is currently in clinical development for the treatment of Alzheimer's disease and other disorders where cognition is impaired and is also considered for indications such as depression or other neuropsychiatric diseases. ACD856 has a novel mechanism of action modulating the activity of the Trk-receptors, resulting in increased stimulation of the neurotrophin signaling pathways. Previous studies applying single intravenous and oral doses of ACD856 indicate that ACD856 is safe and well-tolerated by healthy volunteer subjects, and that it has suitable safety and pharmacokinetic properties for further clinical development. OBJECTIVES: To investigate the safety and tolerability of 7 days of treatment with multiple ascending oral doses of ACD856 in healthy subjects, and to characterize its pharmacokinetic (PK) properties. In addition, pharmacodynamic effects of ACD856 using quantitative electroencephalography (qEEG) as an indicator for central target engagement were assessed. DESIGN: This was a prospective, phase I, double-blind, parallel-group, placebo-controlled, randomized study of the safety, tolerability, PK and pharmacodynamics of multiple ascending oral doses of ACD856 in healthy subjects. ACD856 or placebo were administered in 3 ascending dose cohorts of 8 subjects. Within each cohort, subjects were randomized to receive either ACD856 (n=6) or placebo (n=2). SETTING: The study was conducted at a First-in-Human unit in Sweden. PARTICIPANTS: Twenty-four healthy male and female subjects. INTERVENTION: The study medication was administered as an oral solution, with ACD856 or the same contents without the active ingredient (placebo). The dose levels ranged from 10 mg to 90 mg. ACD856 was administered once daily for 7 days, targeting steady state. MEASUREMENTS: Safety and tolerability assessments included adverse events, laboratory, vital signs, 12-lead electrocardiogram (ECG), physical examination, assessment of stool frequency and questionnaires to assess symptoms of anxiety, depression, as well as suicidal ideation and behavior. In addition, cardiodynamic ECGs were extracted to evaluate cardiac safety. PK parameters were calculated based on measured concentrations of ACD856 in plasma, urine, and cerebrospinal fluid (CSF) samples. Metabolite profiling, characterization and analysis was performed based on and urine samples. qEEG was recorded for patients in the two highest dose cohorts (30 and 90 mg/day) as a pharmacodynamic assessment to explore central target engagement. RESULTS: Treatment with ACD856 was well tolerated with no serious adverse events. No treatment emergent or dose related trends were observed for any of the safety assessments. ACD856 was rapidly absorbed and reached maximum plasma exposure at 30 to 45 minutes after administration. Steady state was reached before Day 6, with an elimination half-life at steady state of approximately 20 hours. At steady state, ACD856 exhibited accumulation ratios for Cmax and AUC of approximately 1.6 and 1.9 respectively. The exposure, Cmax and AUC0-24, increased proportionally with the dose. There was no unchanged ACD856 detected in urine. The metabolic pattern in urine and plasma was similar, and in alignment with the metabolites observed in preclinical toxicology studies. The level of ACD856 measured in CSF at steady state increased with dose, indicating Central Nervous System (CNS) exposure at relevant levels for pharmacodynamic effects. ACD856 demonstrated significant dose-dependent treatment-associated changes on qEEG parameters. Specifically, increase of the relative theta power and decrease of the fast alpha and beta power was observed, leading to an acceleration of the delta+theta centroid and an increase in the theta/beta ratio. CONCLUSIONS: ACD856 was well tolerated at the tested dose levels (10-90 mg/daily for 7 days) in healthy subjects. The compound has a robust pharmacokinetic profile, with rapid absorption and dose-dependent exposure. ACD856 was shown to pass the blood-brain-barrier, reach relevant exposure in the CNS and to induce dose-dependent treatment-related changes on qEEG parameters, indicating central target engagement.

A multicentre, randomized, placebo-controlled trial establishing the treatment effect of TDT 068, a topical formulation containing drug-free ultra-deformable phospholipid vesicles, on the primary features of erythematotelangiectatic rosacea.

BACKGROUND: Rosacea subtype 1 (erythematotelangiectatic) is an inflammatory skin disease with limited treatment options. TDT 068, a topical drug-free gel containing ultra-deformable Sequessome vesicles, is registered for use in inflammatory skin conditions, but has not been investigated in rosacea. OBJECTIVE: This postmarketing study aimed to substantiate the effects of TDT 068 in rosacea subtype 1. METHODS: Patients aged 18-85 scoring 6-15/30 for the primary and secondary features of the rosacea standard grading system (RSGS) were enrolled. Following stratification (four females/one male) patients were randomized (2:1) to receive TDT 068 or vehicle gel for 4 weeks. Efficacy was evaluated using the patient-rated rosacea-specific quality of life (R-QOL) instrument and investigator-rated RSGS. Adverse events (AEs) were monitored throughout. RESULTS: Of the 61 randomized patients, 58 were eligible for the full analysis set per protocol. Baseline characteristics were balanced across the groups. R-QOL symptom construct scores improved slightly from baseline to Week 4 in both groups (-0.04 ± 0.51 TDT 068 vs. -0.22 ± 0.59 vehicle; P = 0.1990). Changes in R-QOL total, function and emotion construct scores at Week 4 were similar with TDT 068 and vehicle, but TDT 068 yielded numerically greater increases in total RSGS scores (-1.55 ± 1.83 vs. -0.75 ± 2.38 vehicle; P = 0.105). Non-transient erythema improved significantly with TDT 068 at Week 4 (-0.34 ± 0.63 vs. -0.05 ± 0.51 vehicle; P = 0.044), with ≥1 grade improvement in 35% of patients (vs. 15% vehicle; P = 0.039). Numerically greater improvements in transient erythema and telangiectasia were also seen with TDT 068. Three treatment-related AEs were reported but no serious AEs occurred. CONCLUSION: These data, based on investigator assessment, provide evidence for the good tolerability of drug-free TDT 068 as well as modest improvements in the symptoms of erythematotelangiectatic rosacea.

Strategies of sequential therapies in unresectable metastatic colorectal cancer: a meta-analysis.

BACKGROUND: Before the emergence of first-line combination chemotherapy, the standard of care for unresectable metastatic colorectal cancer (mcrc) was first-line monotherapy with modulated 5-fluorouracil. Several large phase iii randomized controlled trials, now completed, have assessed whether a planned sequential chemotherapy strategy-beginning with fluoropyrimidine monotherapy until treatment failure, followed by another regimen (either monotherapy or combination chemotherapy) until treatment failure-could result in the same survival benefit produced with an upfront combination chemotherapy strategy, but with less toxicity for patients. METHODS: The medline and embase databases, and abstracts from meetings of the American Society for Clinical Oncology and the European Society for Medical Oncology, were searched for reports comparing a sequential strategy of chemotherapy with an upfront combination chemotherapy in adult patients with mcrc. Publications that reported efficacy or toxicity data (or both) were included. RESULTS: The five eligible trials that were identified included 4532 patients. A meta-analysis of those trials demonstrates a statistically significant survival advantage for combination chemotherapy (hazard ratio: 0.92; 95% confidence interval: 0.86 to 0.99). However, the median survival advantage (3-6 weeks in most trials) is small and of questionable clinical significance. Three trials reported first-line toxicities. Upfront combination chemotherapy results in significantly more neutropenia, febrile neutropenia, thrombocytopenia, diarrhea, nausea, vomiting, and sensory neuropathy. Sequential chemotherapy results in significantly more hand-foot syndrome. CONCLUSIONS: Given the small survival advantage associated with upfront combination chemotherapy, planned sequential chemotherapy and upfront combination chemotherapy can both be considered treatment strategies. Treatment should be chosen on an individual basis considering patient and tumour characteristics, toxicity of each strategy, and patient preference.

Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer.

BACKGROUND: The Panitumumab Randomized trial In combination with chemotherapy for Metastatic colorectal cancer to determine Efficacy (PRIME) demonstrated that panitumumab-FOLFOX4 significantly improved progression-free survival (PFS) versus FOLFOX4 as first-line treatment of wild-type (WT) KRAS metastatic colorectal cancer (mCRC), the primary end point of the study. PATIENTS AND METHODS: Patients were randomized 1:1 to panitumumab 6.0 mg/kg every 2 weeks + FOLFOX4 (arm 1) or FOLFOX4 (arm 2). This prespecified final descriptive analysis of efficacy and safety was planned for 30 months after the last patient was enrolled. RESULTS: A total of 1183 patients were randomized. Median PFS for WT KRAS mCRC was 10.0 months [95% confidence interval (CI) 9.3-11.4 months] for arm 1 and 8.6 months (95% CI 7.5-9.5 months) for arm 2; hazard ratio (HR) = 0.80; 95% CI 0.67-0.95; P = 0.01. Median overall survival (OS) for WT KRAS mCRC was 23.9 months (95% CI 20.3-27.7 months) for arm 1 and 19.7 months (95% CI 17.6-22.7 months) for arm 2; HR = 0.88; 95% CI 0.73-1.06; P = 0.17 (68% OS events). An exploratory analysis of updated survival (>80% OS events) was carried out which demonstrated improvement in OS; HR = 0.83; 95% CI 0.70-0.98; P = 0.03 for WT KRAS mCRC. The adverse event profile was consistent with the primary analysis. CONCLUSIONS: In WT KRAS mCRC, PFS was improved, objective response was higher, and there was a trend toward improved OS with panitumumab-FOLFOX4, with significant improvement in OS observed in an updated analysis of survival in patients with WT KRAS mCRC treated with panitumumab + FOLFOX4 versus FOLFOX4 alone (P = 0.03). These data support a positive benefit-risk profile for panitumumab-FOLFOX4 for patients with previously untreated WT KRAS mCRC. KRAS testing is critical to select appropriate patients for treatment with panitumumab.

Eastern Canadian Colorectal Cancer Consensus Conference: standards of care for the treatment of patients with rectal, pancreatic, and gastrointestinal stromal tumours and pancreatic neuroendocrine tumours.

The annual Eastern Canadian Colorectal Cancer Consensus Conference was held in Halifax, Nova Scotia, October 20-22, 2011. Health care professionals involved in the care of patients with colorectal cancer participated in presentation and discussion sessions for the purposes of developing the recommendations presented here. This consensus statement addresses current issues in the management of rectal cancer, including pathology reporting, neoadjuvant systemic and radiation therapy, surgical techniques, and palliative care of rectal cancer patients. Other topics discussed include multidisciplinary cancer conferences, treatment of gastrointestinal stromal tumours and pancreatic neuroendocrine tumours, the use of folfirinox in pancreatic cancer, and treatment of stage ii colon cancer.

Randomized, double-blind, placebo-controlled study of safety and efficacy of miltefosine in antihistamine-resistant chronic spontaneous urticaria.

BACKGROUND: Chronic spontaneous urticaria (CSU), a mast cell-driven condition, is debilitating, common, and hard to treat. Miltefosine, a lipid raft modulator, can inhibit mast cell responses in vivo. OBJECTIVE: To study the safety and efficacy of systemic miltefosine treatment in CSU patients resistant to standard-dosed antihistamines. METHODS: In this investigator-initiated multicentre, randomized, double-blind, placebo-controlled study, CSU patients were treated for 4 weeks with daily doses of up to 150-mg miltefosine (n = 47) or placebo (n = 26). Disease activity was assessed using the urticaria activity score. Safety and tolerability of miltefosine were also assessed. RESULTS: After 4 weeks of treatment, Urticaria Activity Score (UAS7) levels were substantially more reduced in miltefosine-treated patients (-6.3 vs. -3.5 in placebo-treated patients; P = 0.05). Also, the number of weals, but not the intensity of pruritus, was significantly reduced in miltefosine-treated patients vs. placebo-treated patients (P = 0.02). In general, adverse events were frequent in both groups (miltefosine: 88%, placebo: 65% of patients) but mostly mild to moderate in severity. We did not observe any serious adverse events. CONCLUSIONS: The results of this study indicate that miltefosine is an effective and safe treatment option for CSU patients who do not respond to standard-dosed antihistamines.

Eastern Canadian colorectal cancer consensus conference: application of new modalities of staging and treatment of gastrointestinal cancers.

The annual Eastern Canadian Colorectal Cancer Consensus Conference was held in Ottawa, Ontario, October 22-23, 2010. Health care professionals involved in the care of patients with colorectal cancer participated in presentation and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses current issues in the management of colorectal cancer, such as the use of epidermal growth factor inhibitors in metastatic colon cancer, the benefit of calcium and magnesium with oxaliplatin chemotherapy, the role of microsatellites in treatment decisions for stage II colon cancer, the staging and treatment of rectal cancer, and the management of colorectal and metastatic pancreatic cancers.

Eastern Canadian Colorectal Cancer Consensus Conference: setting the limits of resectable disease.

The annual Eastern Canadian Colorectal Cancer Consensus Conference was held in Montreal, Quebec, October 22-24, 2009. Health care professionals involved in the care of patients with colorectal cancer participated in presentation and discussion sessions for the purposes of developing the recommendations presented here. This consensus statement addresses current issues in the management colorectal cancer, such as the management of hepatic and pulmonary metastases, the role of monoclonal antibodies to the epidermal growth factor receptor, and the benefits and safety of chemotherapy in elderly patients. The management of gastrointestinal neuroendocrine tumours and gastric cancer are also discussed.

Structure of a single sharp quantum Hall edge probed by momentum-resolved tunneling.

Momentum-resolved magnetotunneling spectroscopy is performed at a single sharp quantum Hall (QH) edge to probe the structure of integer QH edge modes. An epitaxially overgrown cleaved edge is shown to realize the sharp-edge limit with interchannel distances smaller than both the magnetic length and the Bohr radius where the Chklovskii soft-edge picture is no longer valid. The line shape of principal conductance peaks is explained, and an edge filling factor is determined from the peak position. A step in the dispersion is attributed to fluctuations in the QH ground energy.

Schmidt syndrome presenting as acute liver failure.

The Schmidt Syndrome (Type II Autoimmune-Syndrome) is characterised by an autoimmune adrenalitis in combination with a chronic lymphocellular thyreoiditis resulting in insufficiency of these organs in adulthood. Combination with diabetes is possible. The diagnosis is usually established by clinical examination and analysis of serum hormone levels (adrenocorticotropin hormone [ACTH], cortisol, thyroid stimulating hormone [TSH], triiodothyronine [fT3], thyroxine [fT4]). In the present case, initial diagnosis was rapid progressive liver failure of unknown origin with consecutive multiple organ dysfunction syndrome including dysfunction of heart, lungs, and kidneys. Frequent and less frequent causes of liver failure were ruled out, e.g. viral or autoimmune hepatitis, Budd-Chiari-syndrome, toxic, or drug induced liver failure. In retrospect, the multiple organ dysfunction syndrome was caused by hypoperfusion due to severe hypovolemia and hypoperfusion was induced by adrenocortical insufficiency proven by endocrinological testing. The clinical course of this case stresses the importance of the hormone balance in the critical ill patient. The guideline for treatment of patients with assumed hormonal dysregulation should include a full hormone status prior to substitution. The present case report also illustrates the importance of clinical signs and careful consideration of the medical history in detecting an autoimmune endocrine disease.

Non-functioning pituitary adenomas: endocrinological and clinical outcome after transsphenoidal and transcranial surgery.

AIM: To study improvement of anterior pituitary function after transsphenoidal and transcranial surgery of non-functioning (NF) pituitary macro- and microadenomas. METHODS: We retrospectively examined 155 patients with NF adenomas preoperatively and 3 months, 1 year and 2 years postoperatively. 130 patients harboured a macroadenoma, 109 underwent transsphenoidal (group one), 21 transcranial surgery (group two). 25 patients presented a microadenoma (transsphenoidal surgery, group three). Endocrine studies included basal serum levels and dynamic testing of anterior pituitary partial function. Clinical symptoms and hormone replacement therapy were documented. RESULTS: Preoperatively, in group one, two and three, somatotropic function was impaired in 85, 90 and 80 %, gonadotropic in 61, 57 and 24 %, corticotropic in 31, 38 and 28 %, thyreotropic in 32, 38 and 12 % and lactotropic in 22, 38 and 32 % cases, respectively. Pituitary functions did not improve significantly after transsphenoidal or transcranial surgery. Presurgically, 63, 62 and 0 % patients complained about visual impairments, 60, 48 and 40 % about headache, 53, 24 and 36 % about fatigue and 28, 33 and 20 % about disturbance of cycle or potency. After transsphenoidal surgery, impaired vision, headache and fatigue improved within 3 months; after transcranial surgery, only headache improved. Preoperatively, pituitary malfunctions were treated adequately. Postsurgically, more patients received adrenal and thyroid hormone substitution, less patients received sex hormones than examinations proved necessary. CONCLUSION: Anterior pituitary function of NF adenoma patients did not improve significantly after transsphenoidal or transcranial surgery. After transsphenoidal surgery, most clinical symptoms normalised within 3 months. In some of the patients, substitution was not optimally adjusted to hormonal impairments.

Improved risk-benefit ratio for topical triamcinolone acetonide in Transfersome in comparison with equipotent cream and ointment: a randomized controlled trial.

BACKGROUND: Transfersome is a drug delivery technology based on highly deformable, ultraflexible lipid vesicles which penetrate the skin when applied non-occlusively. OBJECTIVES: To assess the advantages of this carrier-based formulation in humans, the efficacy and the atrophogenic potential of triamcinolone acetonide (TAC) in Transfersome was compared with commercially available TAC-containing cream and ointment. METHODS: Healthy volunteers were enrolled in double-blind, placebo-controlled clinical trials with random study medication assignment to the test areas. RESULTS: A 10-fold lower dose of TAC in Transfersome(R) (2.5 micro g cm-2) was bioequivalent to 25 micro g cm-2 TAC in conventional formulations as measured by erythema suppression (cream: P = 0.01, ointment: P < 0.001). A skin blanching assay revealed different kinetics of the formulations, with a delayed onset of action of the Transfersome and ointment preparations. Ultrasonic measurements revealed a significantly reduced atrophogenic potential. There was a 12.1% reduction in skin thickness given by TAC in Transfersome compared with a 21.1% reduction given by a bioequivalent dose in TAC cream after a 6-week treatment period (P = 0.007). CONCLUSIONS: Transfersome may significantly improve the risk-benefit ratio of topically applied glucocorticosteroids.

[Model project on coding accuracy]. / Modellprojekt Kodierqualität.

First experiences with the external evaluation of coding accuracy in view of the German DRG-System are reported. 387 randomised inpatient cases of three departments of a municipal hospital were evaluated. 1.648 diagnosis codes and 946 procedure codes were evaluated with complete clinical data. Before and after correction by the reviewers the cases were grouped (AR-DRG 4.1) and the casemix index of the sample was calculated. 45.9% to 56.7% of primary diagnosis in the department samples were rated as correct. 25.2% to 37.5% of secondary diagnosis were rated as correct, 8.3% to 14.2% were corrected and 49.2% to 60.5% were rated as not relevant with regard to the German coding standards. 7.2% to 22.7% of secondary diagnosis had to be completed in the data. Evaluation of procedure codes resulted in 54.2% to 65.7% accepted codes, 5.9% to 12.1% corrected codes and 23.1% to 39.9% not accepted with regard to the German coding standards. 30.8% to 37.0% of procedure codes had to be completed in the data. After review, remarkable shift in DRGs was seen and casemix index increased 6.9% in average (0.25-12.1%). General and department-specific implications for improvement of coding accuracy could be evaluated. Consequences of potential coding errors in a prospective payment system on DRG basis were seen under conditions of daily hospital practice. External evaluation of coding accuracy used in this study could be the methodological basis for further investigations on this topic.

Selenoprotein synthesis in archaea.

The availability of the genome sequences from several archaea has facilitated the identification of the encoded selenoproteins and also of most of the components of the machinery for selenocysteine biosynthesis and insertion. Until now, selenoproteins have been identified solely in species of the genera Methanococcus (M.) and Methanopyrus. Apart from selenophosphate synthetase, they include only enzymes with a function in energy metabolism. Like in bacteria and eukarya, selenocysteine insertion is directed by a UGA codon in the mRNA and involves the action of a specific tRNA and of selenophosphate as the selenium donor. Major differences to the bacterial system, however, are that no homolog for the bacterial selenocysteine synthase was found and, especially, that the SECIS element of the mRNA is positioned in the 3' nontranslated region. The characterisation of a homolog for the bacterial SelB protein showed that it does not bind to the SECIS element necessitating the activity of at least a second protein. The use of the genetic system of M. maripaludis allowed the heterologous expression of a selenoprotein gene from M. jannaschii and will facilitate the elucidation of the mechanism of the selenocysteine insertion process in the future.

Droplet growth by coalescence in binary fluid mixtures.

The evolution of the drop-size distribution in immiscible fluid mixtures following well-specified shear histories is investigated by in situ microscopy, allowing determination of the shear-induced coalescence efficiency epsilon. At small capillary number Ca, epsilon is constant, whereas at larger values of Ca, epsilon decreases, in agreement with theory accounting for slight deformation of the drops in close approach. Coalescence causes the drop-size distribution to broaden in general, but greater deformation of the larger drops at high shear rates causes the drop-size distribution to remain narrow.

Heterologous expression of archaeal selenoprotein genes directed by the SECIS element located in the 3' non-translated region.

Previous in silico analysis of selenoprotein genes in Archaea revealed that the selenocysteine insertion (SECIS) motif necessary to recode UGA with selenocysteine was not adjacent to the UGA codon as is found in Bacteria. Rather, paralogous stem-loop structures are located in the 3' untranslated region (3' UTR), reminiscent of the situation in Eukarya. To assess the function of such putative SECIS elements, the Methanococcus jannaschii MJ0029 (fruA, which encodes the A subunit of the coenzyme F420-reducing hydrogenase) mRNA was mapped in vivo and probed enzymatically in vitro. It was shown that the SECIS element is indeed transcribed as part of the respective mRNA and that its secondary structure corresponds to that predicted by RNA folding programs. Its ability to direct selenocysteine insertion in vivo was demonstrated by the heterologous expression of MJ0029 in Methanococcus maripaludis, resulting in the synthesis of an additional selenoprotein, as analysed by 75Se labelling. The selective advantage of moving the SECIS element in the untranslated region may confer the ability to insert more than one selenocysteine into a single polypeptide. Evidence for this assumption was provided by the finding that the M. maripaludis genome contains an open reading frame with two in frame TGA codons, followed by a stem-loop structure in the 3' UTR of the mRNA that corresponds to the archaeal SECIS element.

Quantum interference in artificial band structures.

Magnetotransport experiments on two-dimensional electron systems with an atomically precise, one-dimensional potential modulation reveal striking quantum interference oscillations. Within a semiclassical framework, they are recognized either as self-interference along closed orbits, many of them rendered possible by magnetic breakdown between Fermi contour segments of the artificial band structure, or as interference-enhanced backscattering. The known commensurability oscillations appear as a special case of the latter mechanism.

Selenium-dependent growth of Treponema denticola: evidence for a clostridial-type glycine reductase.

Assessment of the nutritional requirements of Treponema denticola disclosed a strict growth dependence on selenium. In vivo labeling of cells of this organism with (75)Se and electrophoretic analysis revealed three labeled bands, two of which were selenoproteins correlating in size with subunits A and B of glycine reductase. Antibodies directed against glycine- or betaine-reductase subunits of Eubacterium acidaminophilum specifically also reacted with proteins from cell lysates of T. denticola. Moreover, ORFs within the T. denticola genome sequence were found whose products display high sequence similarity to glycine-reductase subunits. These findings strongly support the notion that T. denticola ferments amino acids via the activity of glycine reductase, an enzyme previously thought to be restricted to gram-positive bacteria.

Identification and characterisation of the selenocysteine-specific translation factor SelB from the archaeon Methanococcus jannaschii.

Selenocysteine insertion into archaeal selenopolypeptides is directed through an mRNA structure (the SECIS element) situated in the 3' non-translated region like in eukaryotes. To elucidate the mechanism how this element affects decoding of an in-frame UGA with selenocysteine the open reading frames of the genome of Methanococcus jannaschii were searched for the existence of a homolog to the bacterial specialized translation factor SelB. The product of the open reading frame MJ0495 was identified as the archaeal SelB homolog on the basis of the following characteristics: (1) MJ0495 possesses sequence features characteristic of bacterial SelB; (2) purified MJ0495 displays guanine nucleotide binding properties like SelB; and (3) it preferentially binds selenocysteyl-tRNA(Sec). In contrast to bacterial SelB, however, no binding of MJ0495 protein to the SECIS element of the mRNA was found under the experimental conditions employed which correlates with the fact that MJ0495 lacks the C-terminal domain of the bacterial SelB protein known to bind the SECIS element. It is speculated that in Archaea the functions of bacterial SelB are distributed over at least two proteins, one, serving as the specific translation factor, like MJ0495, and another one, binding to the SECIS which interacts with the ribosome and primes it to decode UGA.