An update on cardiac implantable electronic devices for the general physician.

Cardiac electronic device implantation is a common and important intervention for patients with tachy-and bradyarrhythmia. An increasing number of patients are receiving more complex devices such as cardiac resynchronisation therapy or devices with a defibrillation function. Over the last 5 years, two new models of cardiac device have emerged, subcutaneous defibrillators and leadless pacemakers. With an ageing population and data demonstrating 2000 per 100,000 of the population aged over 75 years have a cardiac device, it is essential that the general physician remains updated on the common pacemaker indications and available therapies.

Reducing thermal crosstalk in ten-channel tunable slotted-laser arrays.

Given the tight constraints on the wavelength stability of sources in optical networks, the thermal crosstalk between operating devices in a ten-channel thermally-tunable slotted laser array for DWDM applications has been investigated. It was found experimentally the current standard thermal solution with the laser array chip mounted on an AlN carrier does not allow for wavelength stability of ± 25 GHz ( ± 2 K) with a temperature rise of 5 K measured in a device with 100 mA (CW) applied to a neighbouring laser (device spacing = 360 µm). A combined experimental/numerical approach revealed solid state submounts comprising diamond or highly ordered pyrolytic graphite are inadequate to reduce crosstalk below an allowable level. Numerical simulations of advanced cooling technologies reveal a microfluidic enabled substrate would reduce thermal crosstalk between operational devices on the chip to acceptable levels. Critically our simulations show this reduced crosstalk is not at the expense of device tunability as the thermal resistance of individual lasers remains similar for the base and microfluidic cases.

Heightened locomotor-activating effects of amphetamine administered into the nucleus accumbens in adolescent rats.

There is a shift in sensitivity to systemically administered psychostimulants in adolescence, as evidenced by less amphetamine-induced locomotor activity in adolescent compared to adult rodents. Locomotor activating effects of amphetamine are dependent on drug actions in the core of the nucleus accumbens (NAc), but the contribution of this region to age differences in amphetamine sensitivity has not been studied directly. In the present study, we investigated the development of the NAc using targeted injections of amphetamine (0, 3, or 6 µg/side) directly into the NAc core in early (postnatal day 30; P30) or late (P45) adolescence, or in adulthood (P75). Locomotor activity was recorded during two 1h sessions, 48 h apart. Amphetamine increased locomotor activity at all ages. P45 rats were more active than adults only at the 3 µg/side dose, but this difference was not significant when baseline activity was taken into account. In contrast, P30 rats were more active than adults at the 6 µg/side dose, indicating that the magnitude of the locomotor response is highest in early adolescence. Results of the present study are the first to directly show a developmental difference in the sensitivity of the NAc to amphetamine under conditions in which the influence of pharmacokinetic factors and regulatory brain regions is minimized.

Chronic social stress in adolescence influenced both amphetamine conditioned place preference and locomotor sensitization.

We previously reported that chronic social stress (SS) in adolescence, but not in adulthood, increased the locomotor-activating effects of nicotine in females, and not males, when tested in adulthood. However, SS rats had decreased locomotor response to nicotine when tested in adolescence. Here, we investigated age-related changes in the effects of SS on both conditioned place preference (CPP) and locomotor sensitization to amphetamine. In the CPP experiment, SS females tested in adolescence had increased preference for the 1.0 mg/kg dose of amphetamine, whereas SS rats of both sexes showed a decrease in CPP for the 0.5 mg/kg dose when tested as adults. Irrespective of time of testing, SS males and females had enhanced locomotor sensitization compared to controls. Thus, adolescent SS produced both immediate and enduring effects on behavioral responses to amphetamine, likely by altering the development of the mesocorticolimbic dopamine system, which holds implications for vulnerability to addiction.

Effects of chronic social stress in adolescence on anxiety and neuroendocrine response to mild stress in male and female rats.

Using a rat model of adolescent social stress (SS, daily 1 h isolation and change of cage partner, 30-45 days of age), we have reported sex-specific effects on neuroendocrine function over the course of SS, and enduring effects of SS in females, and not males, on drug-related behaviour. Here, we investigated both the immediate and enduring impact of SS in adolescence on anxiety-like behaviour in the elevated plus maze (EPM) and determined the temporal pattern of corticosterone release after confinement to the open arm of the EPM. When tested as adolescents, SS decreased anxiety-like behaviour in females and had no effect in males. When tested as adults several weeks after the chronic stress, overall, SS tended to increase anxiety-like behaviour in both sexes. However, estrous cycle moderated the effect in females, in that reduced anxiety-like behaviour was observed for SS females in the estrous group. Confinement to the open arm of the EPM increased plasma corticosterone concentrations, which declined markedly upon return to home cage for all except adolescent control males for which corticosterone concentrations at 45 and 90 min were elevated compared other groups. Among controls, anxiety-like behaviour decreased in females and increased in males with age, and confinement to the open arm of the EPM led to a greater increase in corticosterone concentrations in adult males compared to adolescent males. In sum, modest effects of adolescent social stress were observable several weeks after the stress exposure, indicating that sex-specific developmental trajectories and vulnerability to anxiety may be shaped by experiences in adolescence.

The structural basis for substrate specificity and inhibition of human S-adenosylmethionine decarboxylase.

S-Adenosylmethionine decarboxylase belongs to a small class of amino acid decarboxylases that use a covalently bound pyruvate as a prosthetic group. It is an essential enzyme for polyamine biosynthesis and provides an important target for the design of anti-parasitic and cancer chemotherapeutic agents. We have determined the structures of S-adenosylmethionine decarboxylase complexed with the competitive inhibitors methylglyoxal bis(guanylhydrazone) and 4-amidinoindan-1-one-2'-amidinohydrazone as well as the irreversible inhibitors 5'-deoxy-5'-[N-methyl-N-[(2-aminooxy)ethyl]amino]adenosine, 5'-deoxy-5'-[N-methyl-N-(3-hydrazinopropyl)amino]adenosine, and the methyl ester analogue of S-adenosylmethionine. These structures elucidate residues important for substrate binding and show how those residues interact with both covalently and noncovalently bound inhibitors. S-Adenosylmethionine decarboxylase has a four-layer alphabeta betaalpha sandwich fold with residues from both beta-sheets contributing to substrate and inhibitor binding. The side chains of conserved residues Phe7, Phe223, and Glu247 and the backbone carbonyl of Leu65 play important roles in binding and positioning the ligands. The catalytically important residues Cys82, Ser229, and His243 are positioned near the methionyl group of the substrate. One molecule of putrescine per monomer is observed between the two beta-sheets but far away from the active site. The activating effects of putrescine may be due to conformational changes in the enzyme, to electrostatic effects, or both. The adenosyl moiety of the bound ligand is observed in the unusual syn conformation. The five structures reported here provide a framework for interpretation of S-adenosylmethionine decarboxylase inhibition data and suggest strategies for the development of more potent and more specific inhibitors of S-adenosylmethionine decarboxylase.

Three-dimensional structure of a hyperthermophilic 5'-deoxy-5'-methylthioadenosine phosphorylase from Sulfolobus solfataricus.

The structure of 5'-deoxy-5'-methylthioadenosine phosphorylase from Sulfolobus solfataricus (SsMTAP) has been determined alone, as ternary complexes with sulfate plus substrates 5'-deoxy-5'-methylthioadenosine, adenosine, or guanosine, or with the noncleavable substrate analog Formycin B and as binary complexes with phosphate or sulfate alone. The structure of unliganded SsMTAP was refined at 2.5-A resolution and the structures of the complexes were refined at resolutions ranging from 1.6 to 2.0 A. SsMTAP is unusual both for its broad substrate specificity and for its extreme thermal stability. The hexameric structure of SsMTAP is similar to that of purine-nucleoside phosphorylase (PNP) from Escherichia coli, however, only SsMTAP accepts 5'-deoxy-5'-methylthioadenosine as a substrate. The active site of SsMTAP is similar to that of E. coli PNP with 13 of 18 nearest residues being identical. The main differences are at Thr(89), which corresponds to serine in E. coli PNP, and Glu(163), which corresponds to proline in E. coli PNP. In addition, a water molecule is found near the purine N-7 position in the guanosine complex of SsMTAP. Thr(89) is near the 5'-position of the nucleoside and may account for the ability of SsMTAP to accept either hydrophobic or hydrophilic substituents in that position. Unlike E. coli PNP, the structures of SsMTAP reveal a substrate-induced conformational change involving Glu(163). This residue is located at the interface between subunits and swings in toward the active site upon nucleoside binding. The high-resolution structures of SsMTAP suggest that the transition state is stabilized in different ways for 6-amino versus 6-oxo substrates. SsMTAP has optimal activity at 120 degrees C and retains full activity after 2 h at 100 degrees C. Examination of the three-dimensional structure of SsMTAP suggests that unlike most thermophilic enzymes, disulfide linkages play a key in role in its thermal stability.

Gelatinous transformation of bone marrow following chemotherapy for myeloma.

Gelatinous transformation of the marrow (GTBM) has been associated with various conditions. We present a unique case of GTBM in a patient with myeloma following treatment with Melphalan.

X-ray structure of Escherichia coli pyridoxine 5'-phosphate oxidase complexed with FMN at 1.8 A resolution.

BACKGROUND: Escherichia coli pyridoxine 5'-phosphate oxidase (PNPOx) catalyzes the terminal step in the biosynthesis of pyridoxal 5'-phosphate (PLP), a cofactor used by many enzymes involved in amino acid metabolism. The enzyme oxidizes either the 4'-hydroxyl group of pyridoxine 5'-phosphate (PNP) or the 4'-primary amine of pyridoxamine 5'-phosphate (PMP) to an aldehyde. PNPOx is a homodimeric enzyme with one flavin mononucleotide (FMN) molecule non-covalently bound to each subunit. A high degree of sequence homology among the 15 known members of the PNPOx family suggests that all members of this group have similar three-dimensional folds. RESULTS: The crystal structure of PNPOx from E. coli has been determined to 1.8 A resolution. The monomeric subunit folds into an eight-stranded beta sheet surrounded by five alpha-helical structures. Two monomers related by a twofold axis interact extensively along one-half of each monomer to form the dimer. There are two clefts at the dimer interface that are symmetry-related and extend from the top to the bottom of the dimer. An FMN cofactor that makes interactions with both subunits is located in each of these two clefts. CONCLUSIONS: The structure is quite similar to the recently deposited 2.7 A structure of Saccharomyces cerevisiae PNPOx and also, remarkably, shares a common structural fold with the FMN-binding protein from Desulfovibrio vulgaris and a domain of chymotrypsin. This high-resolution E. coli PNPOx structure permits predictions to be made about residues involved in substrate binding and catalysis. These predictions provide testable hypotheses, which can be answered by making site-directed mutants.