Migration and chemical modification of silicone in women with breast prostheses

Studies using magnetic resonance spectroscopy in human volunteers to evaluate their livers in vivo and to analyze their blood in vitro suggest that there are measurable amounts of silicon compounds in the blood of some women with implants and that there is migration of silicone to other organs such as the liver.     

Accelerated 3D echo-planar spectroscopic imaging at 4 Tesla using modified blipped phase-encoding.

Whole-brain echo-planar spectroscopic imaging (EPSI) often substantially lengthens MRI/MRSI (magnetic resonance spectroscopic imaging) protocols. To halve acquisition time, application of a blipped phase-encoding (PE) gradient during the EPSI readout (RO) was previously suggested by PE of the even RO echoes in k-space at an interstitial location along k(PE), separated from the odd RO echoes, effectively reducing the number of PEs by a factor of 2. However, the approach is very susceptible to phase inconsistencies between even and odd RO echoes in the presence of B(0) inhomogeneities and gradient imbalance, leading to ghosting in the PE direction. In this work, the blipped PE gradient is placed in between pairs of even/odd RO gradient lobes to avoid these problems. This approach is demonstrated in a phantom and in normal human brain in vivo at 4T. While the proposed method allows substantial reduction in metabolite ghosting, it may be limited by the presence of a relatively large spurious signal at the Nyquist frequency.     

CHARACTERISTICS OF MEMBRANE TRANSPORT PROCESSES OF MACULA DENSA CELLS

1. Macula densa (MD) cells are located within the thick ascending limb (TAL) and have their apical surface in contact with tubular fluid and their basilar region in contact with the glomerulus. These cells sense changes in luminal fluid sodium chloride concentration ([NaCl]) and transmit signals resulting in changes in vascular resistance (tubuloglomerular feedback) and renin release. 2. Current efforts have focused on understanding the cellular transport mechanisms of MD cells. Progress in this area has benefited from the use of the isolated perfused TAL-glomerular preparation, which permits direct access to MD cells. 3. Using microelectrodes to measure basolateral membrane potential (V_BL) of MD cells, it was found that VBL was very sensitive to changes in luminal fluid [NaCl]. As [NaCl] was elevated from 20 to 150mmol/L, V_BL was found to depolarize by over 30 mV. 4. Basolateral membrane potential measurements were also used to identify an apical Na⁺: 2CI^?: K⁺ cotransport pathway in MD cells that is the major pathway for NaCl entry into these cells. 5. Other work identified a basolateral chloride channel that is presumed to be responsible for changes in V_BL during alterations in luminal [NaCl]. This channel, which is the predominant conductance across the basolateral membrane, may be regulated by intracellular Ca²⁺ and cAMP. 6. An apical Na⁺: H⁺ exchanger in MD cells was detected by measuring changes in intracellular pH using the fluorescent probe 2′,7′-bis-(2-carboxyethyl)-5(and-6) carboxyfluorescein. 7. Using patch-clamp techniques, a high density of pH- and Ca²⁺-sensitive K⁺ channels was observed at the apical membrane of MD cells. 8. Other studies found that, at the normal physiological conditions prevailing at the end of the TAL (luminal [NaCl] of 20–60 mmol/L), reabsorption mediated by MD cells is very sensitive to changes in luminal [NaCl].     

EFFECT OF SOME TRICYCLIC AND NONTRICYCLIC ANTIDEPRESSANTS ON [3H]IMIPRAMINE BINDING AND SEROTONIN UPTAKE IN RAT CEREBRAL CORTEX AFTER PROLONGED TREATMENT

Chronic administration of different antidepressant drugs reduced the number of [3H]imipramine [( 3H]IMI) binding sites in rat cerebral cortex. In the same experimental conditions, fluvoxamine and dothiepin, as well as desmethylimipramine, induced an increase in the maximal velocity of high affinity serotonin (5HT) uptake in cortical slices, whereas citalopram and viloxazine were ineffective in this regard. Our results indicate that even if 5HT uptake and [3H]IMI binding sites are located on the same nerve terminals, they are differently modulated. Increased Vmax of the 5HT uptake process could be due to a rebound phenomenon after withdrawal from drugs that acutely inhibit 5HT uptake. The effect on [3H]IMI sites might be explained through either the agonist properties of the drugs towards these sites or the involvement of mechanisms still unknown.     

Cytoprotective effect of epidermal growth factor on acid- and pepsininduced damage to rat gastric epithelial cells: Roles of Na+/H+ exchangers

We have previously established a cell damage model, with damage induced by either acid or pepsin treatment for 30 min, involving a rat gastric epithelial cell line (RGM1). In the present study, pretreatment of cells with epidermal growth factor (EGF; 0.1–10ng/mL) or sucralfate (0.1–3 mg/mL) for 4 h prevented such cell damage in a concentration-dependent manner. Protection of cells by these drugs was not affected by pretreatment with indomethacin (10⁻⁵ mol/L) for 4 h. Removal of Na⁻, but not Ca²⁺, from the acidified medium totally abolished the inhibitory effect of EGF, but not that of sucralfate. Genistein (a tyrosine kinase inhibitor) apparently reduced the inhibitory effect of EGF. DNA synthesis by RGM1 cells did not increase when cells were incubated with EGF for 4 h. We conclude that both EGF and sucralfate protect RGM1 cells from acid- and pepsin-induced damage and that the mechanism of protection by EGF against acid-induced damage seems to be via activation of Na⁺/H⁺ exchangers.     

Influence of peripheral afferents on cortical and spinal motoneuron excitability.

The objective of this study was to establish to what extent muscle, cutaneous, and joint afferents alter the excitability of spinal and cortical motor neurons. This question was examined by studying the impact of electrical stimulation of the second and third digits, the median nerve at the wrist, and the recurrent thenar motor branch on the F/H and magneto-electrical cortical motor responses (MEPs) of the thenar muscles. The firing frequencies of single F/H motor unit action potentials were unaltered by the foregoing conditioning peripheral stimuli. MEPs conditioned by motor threshold stimulation of the median nerve at the wrist or the recurrent motor branch were significantly increased in size at conditioning to test intervals of 50 to 80 milliseconds. No significant change in MEP size resulted from conditioning stimulation of the digital nerves. We conclude that muscle afferents were primarily responsible for the increase in MEP size. Conditioning stimuli may allow examiners to assess central motor conduction where it would otherwise be impossible.     

Down-regulation of rat β-adrenoceptors by clenbuterol or desipramine does not require chronic treatment: [H]CGP-12177 binding reveals rapid (24 hour) modulation

Desipramine (DMI, 15 mg/kg, s.c.) decreased [³H]CGP-12177-labelled cortical β-adrenoceptor density (B_max) by 30% upon chronic (14 day) treatment. However, even a single dose (in mg/kg) of DMI (15) or the β-adrenoceptor agonist, clenbuterol (20), induced a rapid (24 hour) and significant reduction of β-adrenoceptor B_max (−15%; p<0.01). Acute treatment with amitryptiline (10), clorgyline (1), fluoxetine (10), nomifensine (10) or maprotiline (20) had no significant effect on [³H]CGP-12177-labelled β-adrenoceptors, suggesting that rapid down-regulation may not be a general property of antidepressant drugs. None of the antidepressants altered the B_max of [³H]ketanserin-labelled 5-HT_2A receptors on acute treatment. These results show that β-adrenoceptor down-regulation by clenbuterol and DMI is not dependent on chronic treatment and may, therefore, be a poor correlate of the gradual onset of therapeutic efficacy seen clinically with antidepressant drugs.     

Investigation of the anti-complement agents, FUT-175 and K76COOH, in discordant xenotransplantation

Abstract: We examined whether hyperacute rejection (HAR) of a discordant xenograft in a nonhuman primate model could be inhibited by the anticomplement agents, FUT-175 (FUT) and K76COOH (K76). The inhibitory effect of FUT and K76 on baboon sera was studied in vitro by i) complement-mediated hemolysis of sheep erythrocytes (by measuring serum CH50) and ii) cytotoxicity to cultured pig kidney (PK15) cells. The in vivo administration of FUT (at 0.2–25 mg/kg/h i.v. continuously) and K76 (50 mg/kg i.v. bolus) allowed evaluation of the serum levels of these drugs. Both FUT and K76 inhibited serum CH50 in a concentration-dependent manner. An enhanced effect was obtained by combining K76 with FUT therapy. High concentrations of FUT (>10^-4 M) and K76 (>10³ μxg/ml) were necessary to suppress serum CH50 to <5% of the normal level. However, PK15 cytotoxicity remained at >50% in the presence of i) 10^-4 M of FUT, ii) 10³ μg/ml of K76, and iii) 10^-6 M of FUT + 10³ μg/ml of K76. Pig heart transplantation (HTX) was performed in two baboons receiving FUT (1 mg/kg/h i.v. continuously) and K76 (at 200 mg/kg ×1 or 400 mg/kg + 200 mg/kg × 2 i.v, respectively). Cytotoxicity of the serum to PK15 cells at the time of HTX showed 39% and 1% cell death, respectively, in these two baboons, and the CH50 level was 1% (of control level) and 0%, respectively. Graft survival was 4.5 hours and 10 hours (with death of the baboon), respectively (compared with a mean of 29 minutes in control experiments). Both excised grafts showed typical features of hyperacute rejection. Immunopathological studies revealed deposition of C1q, C3d, C6, properdin, and Factor B, demonstrating that complement activation was not fully inhibited by FUT and K76. We conclude that i) FUT and K76 are indeed potent complement inhibitors, ii) the dosages of FUT and K76 necessary to suppress complement-mediated injury cannot be extrapolated from previously reported data obtained from serum CH50 levels, and iii) higher (possibly toxic) dosages will be required to inhibit complement activation completely. It seems unlikely that HAR will be prevented by these drugs alone, although they may be beneficial when combined with other forms of therapy.     

Proteolytic Processing Mechanisms in the Biosynthesis of Neuroendocrine Peptides: The Subtilisin-like Proprotein Convertases

The recent discovery of a novel family of precursor processing endoproteases has greatly accelerated progress in understanding the complex mechanisms underlying the maturation of prohormones, neuropeptides, and many other precursor-derived proteins. At least six members of this family have been found thus far in mammalian species, several having alternatively spliced isoforms, and related enzymes have been identified in many invertebrates, including molluscs, insects, nematodes, and coelenterates. The proprotein convertases are all dependent on calcium for activity and all possess highly conserved subtilisin-like domains with the characteristic catalytic triad of this serine protease (ordered Asp, His, and Ser along the polypeptide chain). Two members of this family, PC2(SPC2) and PC1/PC3(SPC3), appear to play a preeminent role in neuroendocrine precursor processing. Both convertases are expressed only in the brain and in the extended neuroendocrine system, while another important family member—furin/PACE (SPC1)—is expressed more ubiquitously, in almost all tissues, and at high levels in liver. SPC2 and SPC3 exhibit acidic pH optima and other properties which enhance their activity in the acidic, calcium-enriched environment of the dense-core secretory granules of the regulated pathway in neuroendocrine cells, while furin has a neutral pH optimum and is localized predominantly to the trans Golgi network where it is retained by a C-terminal transmembrane domain. Furin processes a wide variety of precursors in the constitutive pathway, such as those of growth factors, receptors, coagulation factors, and viral glycoproteins. Recent findings on the processing of proopiomelanocortin, proinsulin, proglucagon, and several other neuroendocrine precursors by SPC2 and SPC3 are discussed, along with information on the structure, properties, evolution, developmental expression, and regulation or the convertases. An inherited defect in the fat/fat mouse which affects the processing of proinsulin, and probably also many other prohormones, due to a point mutation in carboxypeptidase E has recently been identified and has begun to provide new insights into the functional integration of the individual processing steps.     

Diagnostik und Therapie von Harnstoffzyklusdefekten

Zusammenfassung Fragestellung: Es werden die Verl?ufe von 8 Patienten mit St?rungen der Harnstoffsynthese [Carbamylphosphatsynthetasemangel (4), Citrullin?mie (2) und Argininosuccinatlyasemangel (2) ] beschrieben. Methode/Therapieprinzipien: Akuttherapie: Na-Benzoat und Arginin i. v., dazu Peritonealdialyse und/oder H?modiafiltration. Lanfristige Therapie: proteinreduzierte Ern?hrung, Substitution essentieller Aminos?uren, Na-Benzoat bzw. Na-Phenylbutyrat oral, Substitution von verzweigtkettigen Aminos?uren. Ergebnisse: Sp?testens 3 Tage post partum entwickelte sich nach initialer Alkalose ein hyperammon?misches Koma mit Hirn?dem, das zu deutlichen Residualsch?den führte. Vier Patienten verstarben zwischen der 2. Lebenswoche und dem 4. Lebensjahr aus unterschiedlichen Gründen. Hyperammon?mien traten bei allen Patienten auf und lie?en sich konservativ beherrschen. Na-Phenylbutyrat verursachte weniger gastrointestinale Nebenwirkungen als Na-Benzoat, verzweigtkettige Aminos?uren hatten einen positiven Effekt. Ein Patient wurde vom 1. Lebenstag an medikament?s behandelt, die Entwicklung verlief altersgerecht. Schlu?folgerung: Die Symptome Alkalose, respiratorische Insuffizienz und eine schnelle Verschlechterung des Allgemeinzustands bei Neugeborenen sollten an einen Harnstoffzyklusdefekt denken lassen. Medikament?se Therapie und die Kombination aus Peritoneal- und H?modiafiltration sind prim?r lebenserhaltend. Deutliche Residualsch?den sind die Regel, die überlebensprognose ist eingeschr?nkt. Na-Phenylbutyrat hat weniger Nebenwirkungen als Na-Benzoat. Therapiebeginn vor dem neonatalen Hirn?dem kann Komplikationen verhindern.