Use of complementary and alternative medicine in an urban county hospital epilepsy clinic.

We examined self-reported complementary and alternative medicine (CAM) use among a largely indigent population with epilepsy. Overall CAM use was 70%, with the most frequently reported complementary and alternative medicines (CAMs) being medical marijuana (33%), prayer/spirituality (31%), meditation (19%), vitamins (19%), and stress management (16%). Forty-four percent of patients reported improved seizure control with CAMs. Stress management accounted for perceived seizure reduction in 74%, followed by marijuana (54%), prayer (49%), and yoga (42%). Among the most commonly used and helpful CAMs, stress management was not associated with specific demographic or clinical variables; marijuana use was significantly associated with lower age (users=35.2±10 years vs. nonusers=41.6±12; p<0.01) and lower income (under $15,000 40% use vs. 14% over $15,000; p<0.05); and prayer was significantly associated with female gender (male=21% vs. female=45%; p<0.01) and Black ethnicity (Black=55% vs. Hispanic=30% vs. White=23%; p<0.05). Taken together, our study was notable for the high rate of CAM utilization in a largely indigent population, with high rates of perceived efficacy among several CAM modalities.

A pilot study investigating the use of at-home, web-based questionnaires compiling patient-reported outcome measures following total hip and knee replacement surgeries.

Patient-reported outcome measures (PROMs) are used routinely in NHS. Traditional pen-and-paper questionnaire collection can be time-consuming for both patients and clinic staff. The purpose of the current study was to determine whether a web-based PROMs system has the potential to provide satisfactory patient compliance and whether compiled data are equivalent to pen-and-paper PROMs data. A series of 82 patients who had joint replacement surgery was identified. Each patient was contacted by letter to register on the myClinicalOutcomes.co.uk website and to follow the instructions to render an Oxford score. A second request was sent to those failing to initially register. Telephone contact was then made with non-responders to identify the reason for failed registration. Successfully collated online Oxford scores were compared with previously recorded pen-and-paper scores for each patient from a prospectively updated database. Of the 82 patients identified, 61 (74%) received a letter or were otherwise contacted by telephone. Of these, 27 (44%) patients confirmed that they had access to the Internet. A total of 21 complete sets of data were collected. On review, the available secure online Oxford outcome scores demonstrated a mean of 30.1 (SD 11.4, range: 9-47). This mean score was comparable to the pen-and-paper database mean score of 29.1 (SD 11.8, range: 9-48) for the respective patients. Of the 27 respondents with Internet access, 21 (78%) produced complete scores that were available for real-time review. Available online scores were comparable to those collected via traditional means. With increased Internet availability and improved communication, remote web-based collection of patient reported outcomes may facilitate enhanced and efficient follow-up of patients.

Hip pain and pseudo-lengthening of the leg due to iliopsoas haematoma following implantation of an uncemented component in acetabular cotyloplasty technique.

We report early symptomatic (groin pain and apparent limb lengthening) findings in our 12 consecutive patients who underwent total hip replacements using a cementless acetabular cotyloplasty technique. This report is the first in the literature to mention such an early complication in a large number of patients and also to describe early detection and treatment in these cases. During the period of January 2007 to December 2010, 12 patients (seven female, five male) with dysplastic hip underwent total hip arthroplasty. The mean age of the patients was 57 years (range 52-61 years) and the mean follow-up time was 18 months (12-36 months). A cotyloplasty technique was performed and uncemented acetabular and femoral components were implanted in all these 12 patients. All patients were reviewed postoperatively for clinical and radiographic assessment at six weeks, three months, six months, and one year, and then annually thereafter. During the first one to two months (mean time 22 ± 16 days), all patients complained of a constant pain in the groin that started in the early postoperative period. A pseudo lengthening of the operated hip and pelvic tilt was found on clinical examination at the three-month follow-up. The True length did not reveal a significant leg length discrepancy. Hip pain, pseudo lengthening, and pelvic tilt resolved within 123 ± 17 days post-op. A cotyloplasty technique using an uncemented acetabular implant can cause an intrapelvic hematoma of the iliopsoas muscle giving rise to temporary groin pain, pseudo lengthening on the operated side, and gait disturbances to the patient in the early postoperative period. Symptoms resolved completely in all of our cases. Iliopsoas physiotherapy could be useful and should be encouraged during the symptomatic period. Patients have to be informed during consenting and reassured about this symptomatology. Awareness of this likely complication would help surgeons to detect the problem and initiate treatment early.

The incidence of infrapatellar plicae in the elderly Welsh population.

There are several studies reporting the incidence of suprapatellar, medial, and lateral plicae, but there is very limited information regarding the incidence of the infrapatellar plica. The purpose of our study was to record the incidence of infrapatellar plicae in the elderly Welsh population suffering from knee osteoarthritis. A prospective study was performed and 90 knees with severe osteoarthritis of the knee joint (Kellgren-Lawrence type III and IV) were investigated during total knee arthroplasty surgery. Documentation was performed at every total knee replacement surgery for the length of the study. Knee replacement was performed by one senior surgeon. Infrapatellar plica was investigated by a medial parapatellar approach and was classified into five types according to Kim's classification. The overall incidence of infrapatellar plicae was 37.7%. The most common type of plicae was the separate type (23.3%). There was no significant difference found between male and female patients. The fenestra type was the least common (2.22%). The incidence of infrapatellar plicae in the elderly Welsh population suffering from knee osteoarthritis was significantly lower when compared to a study that recorded the incidence of infrapatellar plica in young patients. Possibly, the degenerative changes of the knee joint can cause the resorption of the infrapatellar plica, thus decreasing its incidence in the elderly population.

Inhibitors of cyclin-dependent kinases induce features of replicative senescence in early passage human diploid fibroblasts.

After a limited number of population doublings (PDs), cultures of normal mammalian diploid cells undergo an irreversible growth arrest known as replicative senescence [1]. As well as contributing to cellular ageing, senescence is viewed as an important mechanism of tumour suppression by preventing the emergence of immortal cell clones [2-4]. Senescent cells have a number of characteristics that distinguish them from cycling or quiescent cells including elevated levels of two cyclin-dependent kinase (Cdk) inhibitors, p16INK4a and p21CIP1 [5-11]. Here, we demonstrate that both of these Cdk inhibitors, as well as other members of their protein families (the INK4 and CIP/KIP families, respectively [12]), induce several facets of the senescent phenotype when ectopically expressed in young human diploid fibroblasts. These include a reduced proliferative capacity, an altered size and shape, the presence of underphosphorylated retinoblastoma protein (pRb), increased expression of plasminogen activator inhibitor (PAI-1) and the appearance of senescence-associated beta-galactosidase (SA-beta-gal) activity [2,3,13-15]. A 20 amino acid peptide from p16INK4a that inhibits Cdks active in the G1 phase of the cell cycle [16] produces similar effects in a dose-dependent manner suggesting that, in primary fibroblasts, inhibition of G1-specific Cdk activity is sufficient to induce phenotypic changes that normally occur at the end of their finite lifespan.

An abnormal Ca(2+) response in mutant sarcomere protein-mediated familial hypertrophic cardiomyopathy.

Dominant-negative sarcomere protein gene mutations cause familial hypertrophic cardiomyopathy (FHC), a disease characterized by left-ventricular hypertrophy, angina, and dyspnea that can result in sudden death. We report here that a murine model of FHC bearing a cardiac myosin heavy-chain gene missense mutation (alphaMHC(403/+)), when treated with calcineurin inhibitors or a K(+)-channel agonist, developed accentuated hypertrophy, worsened histopathology, and was at risk for early death. Despite distinct pharmacologic targets, each agent augmented diastolic Ca(2+) concentrations in wild-type cardiac myocytes; alphaMHC(403/+) myocytes failed to respond. Pretreatment with a Ca(2+)-channel antagonist abrogated diastolic Ca(2+) changes in wild-type myocytes and prevented the exaggerated hypertrophic response of treated alphaMHC(403/+) mice. We conclude that FHC-causing sarcomere protein gene mutations cause abnormal Ca(2+) responses that initiate a hypertrophic response. These data define an important Ca(2+)-dependent step in the pathway by which mutant sarcomere proteins trigger myocyte growth and remodel the heart, provide definitive evidence that environment influences progression of FHC, and suggest a rational therapeutic approach to this prevalent human disease.

Neonatal cardiomyopathy in mice homozygous for the Arg403Gln mutation in the alpha cardiac myosin heavy chain gene.

Heterozygous mice bearing an Arg403Gln missense mutation in the alpha cardiac myosin heavy chain gene (alpha-MHC403/+) exhibit the histopathologic features of human familial hypertrophic cardiomyopathy. Surprisingly, homozygous alpha-MHC403/403 mice die by postnatal day 8. Here we report that neonatal lethality is caused by a fulminant dilated cardiomyopathy characterized by myocyte dysfunction and loss. Heart tissues from neonatal wild-type and alpha-MHC403/403 mice demonstrate equivalent switching of MHC isoforms; alpha isoforms in each increase from 30% at birth to 70% by day 6. Cardiac dimensions and function, studied for the first time in neonatal mice by high frequency (45 MHz) echocardiography, were normal at birth. Between days 4 and 6, alpha-MHC403/403 mice developed a rapidly progressive cardiomyopathy with left ventricular dilation, wall thinning, and reduced systolic contraction. Histopathology revealed myocardial necrosis with dystrophic calcification. Electron microscopy showed normal architecture intermixed with focal myofibrillar disarray. We conclude that 45-MHz echocardiography is an excellent tool for assessing cardiac physiology in neonatal mice and that the concentration of Gln403 alpha cardiac MHC in myocytes influences both cell function and cell viability. We speculate that variable incorporation of mutant and normal MHC into sarcomeres of heterozygotes may account for focal myocyte death in familial hypertrophic cardiomyopathy.

Dilated cardiomyopathy in homozygous myosin-binding protein-C mutant mice.

To elucidate the role of cardiac myosin-binding protein-C (MyBP-C) in myocardial structure and function, we have produced mice expressing altered forms of this sarcomere protein. The engineered mutations encode truncated forms of MyBP-C in which the cardiac myosin heavy chain-binding and titin-binding domain has been replaced with novel amino acid residues. Analogous heterozygous defects in humans cause hypertrophic cardiomyopathy. Mice that are homozygous for the mutated MyBP-C alleles express less than 10% of truncated protein in M-bands of otherwise normal sarcomeres. Homozygous mice bearing mutated MyBP-C alleles are viable but exhibit neonatal onset of a progressive dilated cardiomyopathy with prominent histopathology of myocyte hypertrophy, myofibrillar disarray, fibrosis, and dystrophic calcification. Echocardiography of homozygous mutant mice showed left ventricular dilation and reduced contractile function at birth; myocardial hypertrophy increased as the animals matured. Left-ventricular pressure-volume analyses in adult homozygous mutant mice demonstrated depressed systolic contractility with diastolic dysfunction. These data revise our understanding of the role that MyBP-C plays in myofibrillogenesis during cardiac development and indicate the importance of this protein for long-term sarcomere function and normal cardiac morphology. We also propose that mice bearing homozygous familial hypertrophic cardiomyopathy-causing mutations may provide useful tools for predicting the severity of disease that these mutations will cause in humans.

Induced expression of p16(INK4a) inhibits both CDK4- and CDK2-associated kinase activity by reassortment of cyclin-CDK-inhibitor complexes.

To investigate the mode of action of the p16(INK4a) tumor suppressor protein, we have established U2-OS cells in which the expression of p16(INK4a) can be regulated by addition or removal of isopropyl-beta-D-thiogalactopyranoside. As expected, induction of p16(INK4a) results in a G1 cell cycle arrest by inhibiting phosphorylation of the retinoblastoma protein (pRb) by the cyclin-dependent kinases CDK4 and CDK6. However, induction of p16(INK4a) also causes marked inhibition of CDK2 activity. In the case of cyclin E-CDK2, this is brought about by reassortment of cyclin, CDK, and CDK-inhibitor complexes, particularly those involving p27(KIP1). Size fractionation of the cellular lysates reveals that a substantial proportion of CDK4 participates in active kinase complexes of around 200 kDa. Upon induction of p16(INK4a), this complex is partly dissociated, and the majority of CDK4 is found in lower-molecular-weight fractions consistent with the formation of a binary complex with p16(INK4a). Sequestration of CDK4 by p16(INK4a) allows cyclin D1 to associate increasingly with CDK2, without affecting its interactions with the CIP/KIP inhibitors. Thus, upon the induction of p16(INK4a), p27(KIP1) appears to switch its allegiance from CDK4 to CDK2, and the accompanying reassortment of components leads to the inhibition of cyclin E-CDK2 by p27(KIP1) and p21(CIP1). Significantly, p16(INK4a) itself does not appear to form higher-order complexes, and the overwhelming majority remains either free or forms binary associations with CDK4 and CDK6.

Comparison of two murine models of familial hypertrophic cardiomyopathy.

Although sarcomere protein gene mutations cause familial hypertrophic cardiomyopathy (FHC), individuals bearing a mutant cardiac myosin binding protein C (MyBP-C) gene usually have a better prognosis than individuals bearing beta-cardiac myosin heavy chain (MHC) gene mutations. Heterozygous mice bearing a cardiac MHC missense mutation (alphaMHC(403/+) or a cardiac MyBP-C mutation (MyBP-C(t/+)) were constructed as murine FHC models using homologous recombination in embryonic stem cells. We have compared cardiac structure and function of these mouse strains by several methods to further define mechanisms that determine the severity of FHC. Both strains demonstrated progressive left ventricular (LV) hypertrophy; however, by age 30 weeks, alphaMHC(403/+) mice demonstrated considerably more LV hypertrophy than MyBP-C(t/+) mice. In older heterozygous mice, hypertrophy continued to be more severe in the alphaMHC(403/+) mice than in the MyBP-C(t/+) mice. Consistent with this finding, hearts from 50-week-old alphaMHC(403/+) mice demonstrated increased expression of molecular markers of cardiac hypertrophy, but MyBP-C(t/+) hearts did not demonstrate expression of these molecular markers until the mice were >125 weeks old. Electrophysiological evaluation indicated that MyBP-C(t/+) mice are not as likely to have inducible ventricular tachycardia as alphaMHC(403/+) mice. In addition, cardiac function of alphaMHC(403/+) mice is significantly impaired before the development of LV hypertrophy, whereas cardiac function of MyBP-C(t/+) mice is not impaired even after the development of cardiac hypertrophy. Because these murine FHC models mimic their human counterparts, we propose that similar murine models will be useful for predicting the clinical consequences of other FHC-causing mutations. These data suggest that both electrophysiological and cardiac function studies may enable more definitive risk stratification in FHC patients.

Activation of a caspase-9-mediated apoptotic pathway by subcellular redistribution of the novel caspase recruitment domain protein TMS1.

Genetic and epigenetic alterations affecting proteins involved in apoptosis can contribute to the establishment and progression of cancer. Recently, our laboratory has isolated a novel gene, TMS1, that is aberrantly methylated and silenced in a significant proportion of human breast cancers. TMS1 contains a caspase recruitment domain (CARD), suggesting a role in caspase-mediated cell death. In the present study, we characterize the participation of TMS1 in apoptosis and examine the subcellular localization of the protein. Inducible expression of TMS1 inhibited cellular proliferation and induced DNA fragmentation in a time-dependent manner. These apoptotic events were blocked by the general caspase inhibitor, Z-VAD-fmk. The ability of TMS1 to trigger apoptosis was also suppressed by a dominant negative form of caspase-9 but not by a dominant negative form of caspase-8, indicating that TMS1 functions through activation of caspase-9. Unlike a number of other CARD-containing proteins, TMS1 did not activate nuclear factor kappaB-dependent transcription, consistent with a proapoptotic role for TMS1 in death signaling pathways. Timed localization studies revealed that TMS1-induced apoptosis was accompanied by the redistribution of TMS1 from the cytoplasm to perinuclear spherical structures. Whereas the apoptotic activity of TMS1 was blocked by caspase inhibition, the formation of TMS1-containing subcellular structures was not, suggesting that the redistribution of TMS1 precedes caspase activation. Both the proapoptotic activity of TMS1 and aggregate formation were dependent on the CARD. In summary, the data indicate that TMS1-induced apoptosis proceeds through a CARD-dependent aggregation step followed by activation of a caspase-9-mediated pathway.

TMS1, a novel proapoptotic caspase recruitment domain protein, is a target of methylation-induced gene silencing in human breast cancers.

Gene silencing associated with aberrant methylation of promoter region CpG islands is an acquired epigenetic alteration that serves as an alternative to genetic defects in the inactivation of tumor suppressor and other genes in human cancers. The hypothesis that aberrant methylation plays a direct causal role in carcinogenesis hinges on the question of whether aberrant methylation is sufficient to drive gene silencing. To identify downstream targets of methylation-induced gene silencing, we used a human cell model in which aberrant CpG island methylation is induced by ectopic expression of DNA methyltransferase. Here we report the isolation and characterization of TMS1 (target of methylation-induced silencing), a novel CpG island-associated gene that becomes hypermethylated and silenced in cells overexpressing DNA cytosine-5-methyltransferase-1. We also show that TMS1 is aberrantly methylated and silenced in human breast cancer cells. Forty percent (11 of 27) of primary breast tumors exhibited aberrant methylation of TMS1. TMS1 is localized to chromosome 16p11.2-12.1 and encodes a 22-kDa predicted protein containing a COOH-terminal caspase recruitment domain, a recently described protein interaction motif found in apoptotic signaling molecules. Ectopic expression of TMS1 induced apoptosis in 293 cells and inhibited the survival of human breast cancer cells. The data suggest that methylation-mediated silencing of TMS1 confers a survival advantage by allowing cells to escape from apoptosis, supporting a new role for aberrant methylation in breast tumorigenesis.

Accumulation of p16INK4a in mouse fibroblasts as a function of replicative senescence and not of retinoblastoma gene status.

Viral transformation of mouse and human fibroblasts has very different effects on the composition of cyclin-dependent kinase (Cdk) complexes. In human cells transformed by the large T-antigen of simian virus 40 (SV40 T-Ag) and human tumour cell lines that lack a functional retinoblastoma gene product (pRb) no cyclin D1-Cdk4 complexes can be detected because all the available Cdk4 is associated with the Cdk-inhibitor p16INK4a. In contrast, SV40-transformed mouse cells and fibroblasts from Rh1-nullizygous mouse embryos contain normal levels of cyclin D1-Cdk4 complexes. To investigate this species difference, we have compared the biochemical properties and expression of mouse p16INK4a with that of its human counterpart. There is a marked increase in p16 RNA and protein levels as primary embryo fibroblasts approach their finite lifespan in culture, but mouse p16 expression does not appear to be influenced by the status of pRb. Transformed or spontaneously immortalized mouse cells therefore do not achieve the very high levels of p16 characteristic of pRb-negative human cell lines. We suggest that these differences may be related to the different frequencies with which mouse and human cells can be immortalized in culture.

Two new mutations in the human E1 beta subunit of branched chain alpha-ketoacid dehydrogenase associated with maple syrup urine disease.

Maple syrup urine disease (MSUD) is an autosomal recessive disorder caused by defective function of the mitochondrial branched chain alpha-ketoacid dehydrogenase (BCKD) complex. Mutations in both alleles of any of three genes for component proteins result in the clinical phenotype. Two discrete mutant alleles for the E1 beta subunit of the decarboxylase component in a proband with MSUD are defined and parental origin of each allele identified. The maternal mutation, an A to T transversion at nucleotide 526 in the coding sequence, potentiates an asparagine to tyrosine change at position 126 (N126Y). The paternal mutant allele contains a C to T transition at nucleotide 970 introducing a stop codon (R274 ). Western blot analysis revealed a 75% reduction in the E1 beta-N126Y protein and an absence of the R274* truncated protein in proband cells. Both mutant proteins could be synthesized, imported into mitochondria, and processed in vitro. Functional analysis of the mutant proteins provided new information on the role of E1 beta in the activity of BCKD. In vivo the E1 beta-N126Y protein associated into macromolecular complexes indistinguishable from those formed with the wild type E1 beta protein. However, catalytic activity of these complexes in proband cells was < 1% of wild type activity. Alignment comparisons with other thiamin pyrophosphate-requiring enzymes suggests the N126Y substitution could interfere with interactions of the protein with the cofactor causing inactivity. The truncated E1 beta-R274* protein is unstable and not found in mitochondria from the patient derived cells.

Ventricular arrhythmia vulnerability in cardiomyopathic mice with homozygous mutant Myosin-binding protein C gene.

BACKGROUND: Homozygous mutant mice expressing a truncated form of myosin-binding protein C (MyBP-C(t/t)) develop severe dilated cardiomyopathy, whereas the heterozygous mutation (MyBP-C(t/+)) causes mild hypertrophic cardiomyopathy. Adult male MyBP-C(t/t) and MyBP-C(t/+) mice were evaluated for arrhythmia vulnerability with an in vivo electrophysiology study. METHODS AND RESULTS: Surface ECGs were obtained for heart rate, rhythm, and conduction intervals. Atrial, atrioventricular, and ventricular conduction parameters and refractoriness were assessed in 22 MyBP-C(t/t), 10 MyBP-C(t/+), and 17 wild-type MyBP-C(+/+) mice with endocardial pacing and intracardiac electrogram recording. Arrhythmia induction was attempted with standardized programmed stimulation at baseline and with isoproterenol. Heart rate variability and ambient arrhythmia activity were assessed with telemetric ECG monitors. Quantitative histological characterization was performed on serial sections of excised hearts. MyBP-C(t/t) and MyBP-C(t/+) mice have normal ECG intervals and sinus node, atrial, and ventricular conduction and refractoriness. Ventricular tachycardia was reproducibly inducible in 14 of 22 MyBP-C(t/t) mice (64%) during programmed stimulation, compared with 2 of 10 MyBP-C(t/+) mice (20%) and 0 of 17 wild-type controls (P<0.001). Ventricular ectopy was present only in MyBP-C(t/t) mice during ambulatory ECG recordings. There were no differences in heart rate variability parameters. Interstitial fibrosis correlated with genotype but did not predict arrhythmia susceptibility within the MyBP-C(t/t) group. CONCLUSIONS: MyBP-C(t/t) mice, despite prominent histopathology and ventricular dysfunction, exhibit normal conduction and refractoriness, yet are vulnerable to ventricular arrhythmias. Somatic influences between genetically identical mutant mice most likely account for variability in arrhythmia susceptibility. A sarcomeric protein gene mutation leads to a dilated cardiomyopathy and ventricular arrhythmia vulnerability phenotype.

Correlation of nonspecific immune monitoring with rejection or impaired function of renal allografts.

Two nonspecific immunological assays were combined with radionuclide scanning to monitor 113 patients thrice weekly following allotransplantation. The nonspecific immune assays included measurement of the percentage of active T rosette-forming cells (% A-T RFCs) and spontaneous blastogenesis (SB). An increase in SB and decrease in % A-T RFCs (greater than 1 sd of normal controls) constituted an immune event. The immune parameters were correlated with thrice weekly radionuclide studies which were computer analyzed for glomerular and tubular function. Alteration of the immunological and radionuclide parameters significantly correlated (P less than 0.001) with 90 rejection episodes displayed by 72 nonantithymocyte globulin (ATG)-treated renal allograft recipients during the first 30 postoperative days. In the absence of clinically defined rejection, changes in immune parameters correlated with (1) decline of radionuclide parameters and (2) alterations in weight, temperature, creatinine clearance, and serum creatinine, suggesting subclinical events. As a result of the effects of ATG on lymphocytes, a similar comparison could not be made for 41 other patients treated with this immunosuppressive drug. The incidence of false positive tests was 12.7%. Thus, the combination of two nonspecific immune parameters, % A-T RFCs and SB, with computerized analysis of radionuclide scans may afford a reliable index to diagnose early rejection or impaired function of renal allografts.

Demonstration by radionuclide imaging of possible vascular steal from a renal transplant.

Radionuclide studies in a renal-transplant patient with congestive heart failure suggested vascular steal from the renal allograft by a contralateral femoral arteriovenous fistula. These reliable, noninvasive diagnostic procedures have potential use in similar settings to evaluate allograft perfusion and function. Correction by removal of the fistula was demonstrated.

Synthesis, characterization and mutagenicity of 2-nitroso-6,7-dimethoxytetrahydroisoquinoline.

The compound 6,7-dimethoxytetrahydroisoquinoline (Scheme 2, (ii] reacts with nitrous acid at ambient temperature and pH approximately 3.0 to give, in high yield the expected 2-nitroso-6,7-dimethoxytetrahydroisoquinoline (Scheme 2, (iii)). An unequivocal chemical structure of this nitroso derivative was established by high resolution mass spectrometry and 1H NMR spectrometry. Unlike many N-nitroso compounds, (iii) crystallizes in a single rotational isomer which spontaneously forms, in dimethylsulfoxide (DMSO) solution, an equilibrium mixture of the two E/Z isomeric forms with a t1/2 approximately 53 h. The compound is mutagenic to Salmonella tester strains TA98, TA100, TA1538, TA1535, and TA1537 but only in the presence of induced rat liver microsomes. The highest mutagenic activity of approximately 10 net revertants/nM was obtained with TA100 at a dose of 10 micrograms/plate. The compound (ii) is a close structural analog to the tetrahydroisoquinolines formed by endogenous condensation/cyclization reactions that can occur, between acetaldehyde and dopamine or norepinephrine, when alcohol is consumed.

Characterization and mutagenicity of 1-nitrosotryptophol and 6-nitrotryptophol possible genotoxic substances associated with smoking and alcohol consumption.

Tryptophol (Typ) is a minor product of tryptophane metabolism in humans which is increased with alcohol consumption. Typ can react rapidly with nitrite at pH 3.0 to form 1-nitrosotryptophol (NO-Typ) in high yield. This product is also formed in various organic solvents by the reaction of NO/NO2 mixtures with Typ. Under similar conditions, NO2 in the absence of NO will react with Typ to form 6-nitrotryptophol (NO2-Typ). Both products, NO-Typ and NO2-Typ, are mutagenic when tested in the absence of rat liver microsomes with a variety of Salmonella typhimurium tester strains.

Radionuclide diagnosis of diaphragmatic rupture with hepatic herniation.

Seven surgically proven cases of a traumatic rupture of the right hemidiaphragm with a hepatic herniation were preoperatively diagnosed by radionuclide liver-spleen imagings, and they were retrospectively analyzed. All injuries resulted from blunt traumatic injury including automobile accidents, and there were associated pelvic and rib fractures in five cases. All patients developed some degree of dyspnea in the relatively immediate phase. All chest radiographs showed an apparent elevation of right hemidiaphragm. Radionuclide liver-spleen imaging with 99mTc sulfur colloid characteristically demonstrated a distortion of liver configuration with superior and posterior displacement of the right lobe. Four patients had a large tear in the central tendon of the right hemidiaphragm, and none had a tear in the anterior part or in left lobe of the liver. The differential diagnosis of elevated right hemidiaphragm is briefly discussed. It is concluded that the correct preoperative diagnosis of the diaphragmatic rupture with liver hernia could be made with an awareness of this condition following trauma and radionuclide liver-spleen imaging.