An angiotensin-converting enzyme (ACE) polymorphism may mitigate the effects of angiotensin-pathway medications on posttraumatic stress symptoms.

Angiotensin, which regulates blood pressure may also act within the brain to mediate stress and fear responses. Common antihypertensive medication classes of angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) have been associated with lower PTSD symptoms. Here we examine the rs4311 SNP in the ACE gene, previously implicated in panic attacks, in the relationship between ACE-I/ARB medications and PTSD symptoms. Participants were recruited from outpatient wait rooms between 2006 and March 2014 (n= 803). We examined the interaction between rs4311 genotype and the presence of blood pressure medication on PTSD symptoms and diagnosis. PTSD symptoms were lower in individuals taking ACE-Is or ARBs (N = 776). The rs4311 was associated with PTSD symptoms and diagnosis (N = 3803), as the T-carriers at the rs4311 SNP had significantly greater likelihood of a PTSD diagnosis. Lastly, the rs4311 genotype modified the effect of ACE-Is or ARBs on PTSD symptoms (N = 443; F1,443 = 4.41, P < 0.05). Individuals with the CC rs4311 genotype showed lower PTSD symptoms in the presence of ACE-Is or ARBs. In contrast, T- carriers showed the opposite, such that the presence of ACE-Is or ARBs was associated with higher PTSD symptoms. These data suggest that the renin-angiotensin system may be important in PTSD, as ACE-I/ARB usage associates with lower symptoms. Furthermore, we provide genetic evidence that some individuals are comparatively more benefitted by ACE-Is/ARBs in PTSD treatment. Future research should examine the mechanisms by which ACE-Is/ARBs affect PTSD symptoms such that pharmaco-genetically informed interventions may be used to treat PTSD.

External urethral sphincter dilation for the management of high risk myelomeningocele: 15-year experience.

PURPOSE: We investigate the long-term outcome using external urethral sphincter dilation for high risk myelomeningocele. MATERIALS AND METHODS: Since 1984 external urethral sphincter dilation was performed in 25 patients with myelomeningocele who demonstrated passive leak point pressure greater than 40 cm. H2O and/or poor bladder compliance. Mean followup from the first dilation was 8.4 years. Overall 2.4 dilations were performed per patient (range 1 to 8). Cystometrography, imaging study and continence status were evaluated retrospectively. RESULTS: Overall external urethral sphincter dilation produced durable improvements in mean leak point pressure (60.9 versus 34.4 cm. H2O), capacity (119.8 versus 233.3 ml.), initial compliance (11.5 versus 28.4 ml./cm. H2O) and terminal compliance (1.1 versus 7.7 ml./cm. H2O). Categorical analysis revealed 3 groups in terms of outcome. Group 1 consisted of 11 patients (44%) who demonstrated durable improvements in urodynamic parameters as well as preservation of the upper tracts. These patients demonstrated a 2-step compliance pattern on pre-dilation cystometrography, in which elevated leak point pressure was associated with excellent initial compliance. Group 2 consisted of 5 patients (20%) who failed to maintain safe leak point pressure and whose upper tracts deteriorated, including 4 who eventually underwent augmentation cystoplasty. This group demonstrated a 1-step hypertonicity in which elevated leak point pressure was associated with a steep pressure increase during early filling. Group 3 consisted of 9 patients (36%) who responded minimally in terms of leak point pressure reduction but whose upper tracts remained well preserved. They demonstrated a high pressure instability pattern associated with excellent baseline compliance. CONCLUSIONS: External urethral sphincter dilation provides an effective long-term solution for select high risk myelomeningocele cases. Those who demonstrate elevated leak point pressure and poor bladder compliance at the time of external urethral sphincter dilation are less likely to respond, suggesting that the bladder may have already undergone irreversible changes due to high outlet resistance. Patients who demonstrate instability patterns are less likely to respond to external urethral sphincter dilation in terms of leak point pressure reduction but the upper tracts appear to be well preserved.

Renal transplantation in children with severe lower urinary tract dysfunction.

PURPOSE: Renal transplantation in children with end stage renal disease due to congenital urological malformations has traditionally been associated with a poor outcome compared to transplantation in those with a normal urinary tract. In addition, the optimal urological treatment for such children remains unclear. To address these issues, we retrospectively reviewed our experience with renal transplantation in this population. MATERIALS AND METHODS: Between 1986 and 1998, 12 boys and 6 girls a mean age of 8.4 years with a severe dysfunctional lower urinary tract underwent a total of 15 living related and 6 cadaveric renal transplantations. Urological anomalies included posterior urethral valves in 8 cases, urogenital sinus anomalies in 4, the prune-belly syndrome in 2, and complete bladder duplication, ureterocele, lipomeningocele and the VATER syndrome in 1 each. In 11 children (61%) bladder augmentation or continent urinary diversion was performed, 2 (11%) have an intestinal conduit and 5 (28%) have a transplant into the native bladder. RESULTS: In this group patient and overall allograft survival was 100 and 81%, respectively. These values were the same in all children who underwent renal transplantation at our center during this era. In the 17 children with a functioning transplant mean serum creatinine was 1.4 mg./dl. Technical complications occurred in 4 patients (22%), including transplant ureteral obstruction in 2 as well as intestinal conduit stomal stenosis and Mitrofanoff stomal incontinence. CONCLUSIONS: Renal transplantation may be successfully performed in children with end stage renal disease due to severe lower urinary tract dysfunction. Bladder reconstruction, which may be required in the majority of these cases, appears to be safe when performed before or after the transplant. A multidisciplinary team approach to surgery is advantageous.

A novel dye-linked formaldehyde dehydrogenase with some properties indicating the presence of a protein-bound redox-active quinone cofactor.

Dye-linked formaldehyde dehydrogenase from methylamine-grown Hyphomicrobium zavarzinii ZV 580, a tetramer of M(r) 210,000 with subunits of M(r) 54,000, was purified to homogeneity in five steps with 10% yield. The enzyme shows optimal affinity for, and activity with, formaldehyde (Km 67 microM) compared with other aldehydes. Pyridoxal phosphate, pyrroloquinoline quinone and other cofactors that would give the enzyme a distinctive absorption spectrum are absent. Slight changes are observed in the spectrum at 300-550 nm on oxidation of the enzyme with Wurster's Blue (WB) and reduction with formaldehyde. Titration of the native reduced enzyme with WB accounts for 2 mol of electrons per mol of tetrameric enzyme. The circumstantial evidence supporting the presence of a redox-active quinone cofactor bound to the polypeptide chain comprises a signal at g = 2.0049 in the X-band e.p.r. spectrum of the enzyme oxidized with WB, which disappears on reduction with formaldehyde, and a positive reaction of the native as well as the denatured and dialysed enzyme in the redox-cycling assay with glycinate and NitroBlue Tetrazolium (quinone staining). The oxidized enzyme is inhibited by equimolar amounts of phenylhydrazine, which is also a reductant. Hydrazone formation was absent with completely inhibited enzyme, according to photometric evidence. Likewise, the glycinate-dependent reduction of NitroBlue Tetrazolium was not affected by the inhibitor. It is concluded that an oxidation product of the hydrazine is the actual inhibitor which reacts with an amino acid residue of the active site rather than with the prospective quinone cofactor.

Participation of proteinase yscA in the in vitro formation of the smaller subunit of glycogen phosphorylase in extracts of Saccharomyces cerevisiae.

Analyses by sodium dodecyl sulphate-polyacrylamide gradient-gel electrophoresis and Western blotting of the proteins from boiled cell samples from all growth phases of yeast cultures, and from all stages of extract preparation indicate that the smaller subunit (s-monomer), which is found in purified glycogen phosphorylase (EC 2.4.1.1) from baker's yeast, is not present in the living cell. It is observed in extracts of Saccharomyces carlsbergensis and S. cerevisiae after incubation at ambient temperatures or even after storage in the frozen state at -25 degrees C. Its formation is sensitive towards pepstatin A, and it is absent from extracts of several mutants of S. cerevisiae that do not contain active proteinase yscA (EC 3.4.33.6). When purified proteinase yscA is added to the extracts of these mutants, the formation of s-monomer is restored. When the proteinase yscA-deficient strains are grown with a reduced amount of complex nitrogen compounds, the slightly smaller sc-monomer is formed in their extracts. This event must be attributed to a different proteinase, since it is sensitive towards p-hydroxymercuriphenylsulphonate, but not towards pepstatin A. The N-terminal amino acid of the sc-monomer was found to be blocked, as in the case of the native l-monomer, but not the s-monomer.

Ophthalmic evaluation of long-term survivors of childhood acute lymphoblastic leukemia.

Thirty-four long-term survivors of childhood acute lymphoblastic leukemia (ALL) underwent comprehensive ophthalmic examinations to detect retinopathy or other ocular sequelae. Sixteen of the 34 patients received whole brain radiation (greater than or equal to 2400 rad). All 18 patients in the non-radiated group had normal eye examinations, while 4 of 16 in the radiated group had ocular abnormalities. None of the ocular abnormalities could be definitely attributed to radiation and all patients had normal visual acuity. No radiation retinopathy was found in either group.

Neurological recovery after cardiac arrest: clinical feasibility trial of calcium blockers.

In order to determine whether the calcium blockers verapamil and/or magnesium sulfate decrease neurological morbidity after cardiac arrest, all out-of-hospital cardiac arrests (290) occurring during a nine-month period in five participating hospitals were retrospectively studied. Twenty-nine patients met the criteria for inclusion in this study. Each had an unwitnessed, out-of-hospital cardiac arrest and was comatose (no purposeful response to pain) 20 minutes after the restoration of spontaneous circulation (ROSC). Eighteen patients (calcium blocker group) received verapamil and/or magnesium sulfate at some point after ROSC, while eleven patients received standard ACLS therapy (control group). Age, arrest time, cardiopulmonary resuscitation (CPR) time, and cerebral ischemic time were comparable in the two groups. In the calcium blocker group, seven of 18 patients regained consciousness, and six of these seven survived. All six survivors appeared neurologically normal upon discharge and at three and six months of follow-up. While no demonstrably adverse effects were seen after the administration of magnesium sulfate, 56% of the patients who received verapamil had a significant drop in blood pressure. In the control group, three of 11 patients regained consciousness and two of the three left the hospital alive. Both survivors were disabled--one severely and one moderately. Follow-up after three and six months revealed no significant improvement in their disability. Overall, six of 18 patients experienced clinically complete neurological recovery in the calcium blocker group, while none of the 11 patients in the control group made a complete neurological recovery (P = 0.06).

Cavernous hemangioma of the retina, cutaneous angiomas, and intracranial vascular lesion by computed tomography and nuclear magnetic resonance imaging.

In a 32-year-old man with a right-sided retinal cavernous hemangioma and cutaneous angiomas, computed tomography and nuclear magnetic resonance imaging confirmed the presence of cerebrovascular lesions. This supports the inclusion of cavernous hemangioma of the retina in the established group of neuro-oculo-cutaneous phacomatoses.

Respiratory ubiquinone-9 from Hyphomicrobium spec. Strain ZV 580.

Ubiquinone-9, an ubiquinone with a side-chain containing 9 prenyl residues, was purified from Hyphomicrobium spec. strain ZV 580, and identified by thin-layer chromatography, UV spectroscopy, and mass spectrometry. The participation of the quinone in the reactions of the respiratory chain was established by observing its increasing reduction in a membrane fraction upon the addition of NADH, the exhaustion of oxygen, and in the presence of NADH plus cyanide. The degrees of reduction in these states matched those of the cytochromes b and c.

Degradation of pyrimidine bases in Clostridium sticklandii.

Resting cells of Clostridium sticklandii took up thymine or uracil, when grown in a medium containing 40 mM serine and 20 mM thymine or uracil. The uptake was much lower, when the cells had been grown in a complex medium. Cell-free extracts from cells grown in the complex medium reduced the two bases to the dihydro compounds and decomposed dihydrothymine to beta-ureidoisobutyrate, as indicated by thin-layer chromatography. Uptake and degradation were stimulated by both NADH and NADPH. Further breakdown did not occur, as 14CO2 was not evolved from C-2-labelled thymine or uracil. The rates of pyrimidine uptake and breakdown of C. sticklandii were lower than those reported for C. sporogenes (Hilton et al., 1975).

NADH-dependent reduction of D-proline in Clostridium sticklandii. Reconstitution from three fractions containing NADH dehydrogenase, D-proline reductase, and a third protein factor.

The enzyme system from Clostridium sticklandii catalyzing the NADH-dependent reduction of D-proline was co-purified by chromatography on DEAE-cellulose at pH 8.2 and ammonium sulfate fractionation, and resolved into fractions containing three different protein components, NADH dehydrogenase, D-proline reductase and a third protein factor, by chromatography on DEAE-cellulose at pH 7.0. Upon recombination of the fractions containing the three different protein components, the NADH-dependent reduction of D-proline was successfully reconstituted. The NADH dehydrogenase fractions oxidized NADH in the presence of artificial electron acceptors, and were inhibited by p-hydroxymercuriphenylsulfonate (50% at 80 nM). They contained 3--4 different enzyme bands as revealed by polyacrylamide-gel electropherograms stained with the NADH-dependent reduction of 2,3,5-triphenyltetrazolium chloride. D-Proline reduction was also coupled to a leuco-methylene blue-generating system containing D-glucose and glucose-oxidase (EC 1.1.3.4). Circumstantial evidence indicated that, among the clostridial proteins, only D-proline reductase and the third protein factor were needed for this reaction.

Inhibition by glycine of the catabolic reduction of proline in Clostridium sticklandii: evidence on the regulation of amino acid reduction.

The growth of Clostridium sticklandii on the substrate pair L-alanine-L-proline (reductant-oxidant each 40 mM) in a medium containing 2 g/l yeast extract was completely inhibited by equimolar amounts of glycine, although glycine itself should be used as oxidant by the cells. The effect of glycine was the same, whether L-alanine, L-arginine, or L-serine wwere used as reductants. Performance of the growth experiments in media of high osmolarity excluded the possibility that the inhibition effected by glycine was caused by the synthesis of defective cell wall peptidoglycan. In cell-free extracts an inhibition of L-proline reduction by glycine was observed that did not belong to anyone of the known types of kinetic inhibition. It depended upon the presence of a functioning glycine-reducing enzyme system, besides glycine itself, and was lost after the purification of D-proline reductase. It was concluded from these results that a protein, besides glycine, participated in the inhibition of L-proline reduction. The regulatory implications of the inhibition for the energy metabolism of C. sticklandii are discussed.

Inhibition of acetate and propionate formation upon aeration of resting cells of the anaerobic Propionibacterium shermanii: evidence of the Pasteur reaction.

When resting cell suspensions of the anaerobic P. shermanii were brought to an oxygen concentration of 0.64 mumoles/ml, acid formation was completely inhibited. The cells started to respire on the propionic acid previously accumulated furing anaerobiosis. Glucose consumption was concomitantly decreased to about 60 percent of the rate during anaerobiosis. As the viability of the cells was not affected by the transition to aerobic conditions, the changes observed upon aeration were ascribed to the regulatory properties of the Pasteur reaction. Damage inflicted by oxygen was encountered in the rapid inactivation of propionate respiration. This damage outlived the time of oxygenation, and was manifested during the subsequent anaerobiosis in the decreased activity to form propionate. This indicates that oxygen may inactivate one (or more) enzyme(s) involved in the metabolism of propionate. The viability of cells in buffer, and glucose-containing buffer, was found to be only insignificantly decreased by oxygen in the range from 0 to 500 mumoles of oxygen per g of wet cells.

The electron transport system of the anaerobic Propionibacterium shermanii: cytochrome and inhibitor studies.

1. Electron transport particles obtained from cell-free extracts of Propionibacterium shermanii by centrifugation at 105000 times g for 3 hrs oxidized NADH, D,L-lactate, L-glycerol-3-phosphate and succinate with oxygen and, except for succinate, with fumarate, too. 2. Spectral investigation of the electron transport particles revealed the presence of cytochromes b, d and o, and traces of cytochrome alpha1 and a c-type cytochrome. Cytochrome b was reduced by succinate to about 50%, and by NADH, lactate or glycerol-3-phosphate to 80--90%. 3. The inhibitory effects of amytal and rotenone on NADH oxidation, but not on the oxidation of the other substrates, indicated the presence of the NADH dehydrogenase complex, or "site I region", in the electron transport system of P. shermanii. 4. NQNO inhibited substrate oxidations by oxygen and fumarate, as well as equilibration of the flavoproteins of the substrate dehydrogenases by way of menaquinone. The inhibition occurred at low concentrations of the inhibitor and reached 80--100%, depending on the substrate tested. The site of inhibition of the respiratory activity was located between menaquinone and cytochrome b. In addition, inhibition of flavoprotein equilibration suggested that NQNO acted upon the electron transfer directed from menaquinol towards the acceptor to be reduced, either cytochrome b or the flavoproteins, which would include fumarate reductase. 5. In NQNO-inhibited particles, cytochrome b was not oxidized by oxygen-free fumarate, but readily oxidized by oxygen. It was concluded from this and the above evidence that the branching-point of the electron transport chain towards fumarate reductase was located at the menaquinone in P. shermanii. It was further concluded that all cytochromes were situated in the oxygen-linked branch of the chain, which formed a dead end of the system under anaerobic conditions. 6. Antimycin A inhibited only oxygen-linked reactions of the particles to about 50% at high concentrations of the inhibitor. Inhibitors of terminal oxidases were inactive, except for carbon monoxide.