A three-year follow-up study of the development of joint contractures in 131 patients with systemic sclerosis.

OBJECTIVES: To analyse the correlation between the number of joint-contractures and other major clinical findings in a follow-up study of 131 patients with systemic sclerosis (SSc). METHODS: The range of motion of joints (ROM), HAQ-DI, and the major clinical characteristics were assessed. RESULTS: A high frequency of contractures (ROM<75% of the normal) were present at baseline in small joints of the hand (82%), wrists (75%), and shoulders (50%). ROM of the dominant side hand was significantly more decreased compared to the non-dominant side. The number of the upper extremity contractures correlated positively with ESR (p<0.01), CRP (p<0.01), HAQ-DI (p<0.01), and negatively with forced vital capacity (FVC) (p<0.05). The number of contractures was not significantly different in cases with early (≤ 4 years) and late disease duration in both the limited and diffuse subgroups. During the three-year follow-up period, an increase in the number of joint contractures (ROM<75%) was associated with an increase of ESR, modified Rodnan's skin score, and the European Scleroderma Study Group Activity Index by multiple linear regression analysis. Univariate analysis over a six-year period demonstrated poor outcome in patients with more than ten contractures, or more than four contractures of unilateral hand-joints. CONCLUSIONS: Contractures predominantly develop during the early years following disease onset in both SSc subgroups. Inflammation and skin-involvement are significant contributing factors for the development of contractures. The dominant hand may be more pronouncedly impaired compared to the non-dominant side. A high number of joint-contractures might be an unfavourable prognostic factor in SSc.

Cross-cultural adaptation of the disabilities of the arm, shoulder, and hand (DASH) questionnaire into Hungarian and investigation of its validity in patients with systemic sclerosis.

OBJECTIVE: To adapt and validate the Hungarian version of the DASH and the shorter QuickDASH Outcome Measures and to establish their validity in patients with systemic sclerosis (SSc). METHODS: The Hungarian adaptation of the questionnaires was performed using forward/backward translations, expert and lay reviews. 128 patients completed the DASH, the Health Assessment Questionnaire (HAQ-DI), the Modified HAQ-DI for patients with SSc (SSc-HAQ), and the Short Form Health Survey (SF-36) questionnaire. 76 patients participated in a 12-month follow-up examination. Sensitivity to change was estimated using the standardized response mean (SRM). RESULTS: Cronbach alpha in the DASH sections were between 0.94-0.97. The intraclass correlation coefficient for the test-retest reliability of DASH was 0.89. DASH scores showed a correlation with both SSc-HAQ and the physical dimensions of the SF-36 (Spearman's rho: 0.89, -0.77 and -0.42, respectively). The SRM of DASH was 0.64 among the scleroderma patients with worsening HAQ-DI status. CONCLUSIONS: The Hungarian version of the DASH and QuickDASH demonstrated equivalent reproducibility, internal consistency and validity to the originals. The strong correlations of the DASH and QuickDASH with the HAQ-DI, and with the physical dimensions of the SF-36 show that the disability of the patient with SSc is predominantly caused by the functional impairment of the upper limb. Because both questionnaires were valuable tools for measuring upper extremity function and joint damage in SSc patients, we recommend the shorter and simpler QuickDASH for everyday clinical use.

The effect of extracts from ginger rhizome on inflammatory mediator production.

Compounds from rhizomes of Zingiber officinale, commonly called ginger, have been purported to have anti-inflammatory actions. We have used an in vitro test system to test the anti-inflammatory activity of compounds isolated from ginger rhizome. U937 cells were differentiated and exposed to lipopolysaccharide (LPS) from Escherichia coli (1 microg/ml) in the presence or absence of organic extracts or standard compounds found in ginger (6-, 8-, 10-gingerol or 6-shogaol) for 24 h. Supernatants were collected and analyzed for the production of prostaglandin E(2) (PGE(2)) and tumor necrosis factor alpha (TNF-alpha) by standard ELISA assays. Predominant compounds in the organic extracts were identified as 6-, 8- 10-gingerols and 6-, 8-, 10-shogaols. Organic extracts or standards containing gingerols were not cytotoxic, while extracts or standards containing predominantly shogaols were cytotoxic at concentrations above 20 microg/ml. Crude organic extracts of ginger were capable of inhibiting LPS induced PGE(2) (IC(50)<0.1 microg/ml) production. However, extracts were not nearly as effective at inhibiting TNF-alpha (IC(50)>30 microg/ml). Thirty three fractions and subfractions, prepared by column chromatography, were analyzed for bioactivity. Extracts containing either predominantly gingerols or shogaols (identified by HPLC) were both highly active at inhibiting LPS-induced PGE(2) production (IC(50)<0.1 microg/ml), while extracts that contained unknown compounds were less effective (IC(50)<3.2 microg/ml). Extracts or standards containing predominantly gingerols were capable of inhibiting LPS-induced COX-2 expression while shogaol containing extracts had no effect on COX-2 expression. These data demonstrate that compounds found in ginger are capable of inhibiting PGE(2) production and that the compounds may act at several sites.

The effect of turmeric extracts on inflammatory mediator production.

Major compounds of several commonly used botanicals, including turmeric, have been purported to have anti-inflammatory actions. In order to test the anti-inflammatory activity of compounds isolated from rhizomes of Curcuma longa L. (Zingiberaceae), we have established an in vitro test system. HL-60 cells were differentiated and exposed to lipopolysaccharide (LPS) from Escherichia coli (1 microg/ml) in the presence or absence of botanical compounds for 24 h. Supernatants were collected and analyzed for the production of tumor necrosis factor alpha (TNF-alpha) and prostaglandin E2 (PGE2) using standard ELISA assays. Water-soluble extracts were not cytotoxic and did not exhibit biological activity. Organic extracts of turmeric were cytotoxic only at concentrations above 50 microg/ml. Crude organic extracts of turmeric were capable of inhibiting LPS-induced TNF-alpha (IC50 value = 15.2 microg/ml) and PGE2 (IC50 value = 0.92 microg/ml) production. Purified curcumin was more active than either demethoxy- or bisdemethoxycurcumin. Fractions and subfractions of turmeric extracts collected via preparative HPLC had differing biological activity, ranging from no activity to IC50 values of < 1 microg/ml. For some fractions, subfractionation resulted in a loss of activity, indicating interaction of the compounds within the fraction to produce an anti-inflammatory effect. A combination of several of the fractions that contain the turmeric oils was more effective than the curcuminoids at inhibiting PGE2. While curcumin inhibited COX-2 expression, turmeric oils had no effect on levels of COX-2 mRNA.

Absorption and elimination of D and C Red No. 28 in male F-344 rats.

D and C Red No. 28 (Red 28) is a US certified color additive used in drugs and cosmetics. Little is known about the extent of systemic absorption and pharmacokinetic behavior of Red 28. Therefore, these studies were performed to determine oral bioavailability and pharmacokinetic parameters of Red 28 in male F-344 rats following single and repeated oral dosing. Rats were administered either a single i.v. dose (50 mg/kg), a low oral gavage dose (50 mg/kg), or a high oral gavage dose (500 mg/kg) of Red 28. Plasma, urine and feces samples were subjected to solid phase extraction (SPE) and analyzed by HPLC for Red 28. Regardless of the dose or route of administration, the terminal t(1/2) of Red 28 was 2.5 h. The major route of elimination was fecal excretion, with 88% (i.v.) and 98% (50 mg/kg p.o.) of the dose recovered by 96 h. Urinary excretion of Red 28 accounted for 1% of the dose following i.v. administration. No Red 28 was detected in urine after p.o. administration. Biliary excretion was determined experimentally to be the primary route of elimination for systemically available Red 28. Bioavailability following p.o. administration was very low (1-2%) and was not altered significantly by 14 days of dietary pretreatment with Red 28.

Analogues of amonafide and azonafide with novel ring systems.

Three new types of amonafide and azonafide analogues were synthesized and screened in a panel of human solid tumor cells and murine L1210 leukemia cells. The structural types included tetrahydroazonafides, which have the naphthalene chromophore of amonafide within the anthracene nucleus of azonafide; phenanthrene analogues, in which the linear anthracene nucleus is replaced by the bent phenanthrene nucleus; and azaphenanthrenes. The tetrahydroazonafides were generally intermediate in potencies between amonafide and azonafide against the tumor cells, but some of them had high potencies against the L1210 cells and were more potent against the MDR strain than the sensitive strain. The phenanthrene and azaphenanthrene analogues showed no improvement on the potencies of the anthracenes.

1,4-disubstituted anthracene antitumor agents.

Three different types of 1,4-disubstituted anthracenes were synthesized, and their cytotoxicity in a panel of tumor cells was compared with that of the corresponding 9,10-disubstituted anthracenes. The panel contained human myeloma, melanoma, colon, and lung cancer cells and sensitive and multidrug-resistant murine L1210 leukemia cells. These compounds had [[(dimethylamino)ethyl]amino]methyl, N-[(dimethylamino)ethyl]carbamoyl, and carboxaldehyde (4,5-dihydro-1H-imidazol-2-yl)hydrazone side chains. The 1,4-diamide was more potent across the tumor panel than the corresponding 9,10-isomer, but the 1,4-diamine and the 1,4-hydrazone were less potent than their 9,10-isomers. Although the 1,4-hydrazone was active against P388 leukemia in mice, it was inactive against L1210 leukemia. Within each pair of compounds, the one with greater average potency against tumor cells gave a greater increase in the transition melt temperature of DNA.

2-[2'-(Dimethylamino)ethyl]-1,2-dihydro- 3H-dibenz[de,h]isoquinoline-1,3-diones with substituents at positions 4, 8, 9, 10, and 11. Synthesis, antitumor activity, and quantitative structure-activity relationships.

New 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3- diones with substituents at the 4, 8, 9, 10, and 11 positions were synthesized. Diazonium salts prepared from aminoazonafides were key intermediates for many of the analogues. Six of the new compounds were more potent than azonafide in a panel of tumor cells including human melanoma and ovarian carcinoma and murine L1210 leukemias. Three of these compounds, the 10-OCH3, 10-OC2H5, and 10-F analogues, had better ratios of cardiotoxicity to tumor-cell toxicity than azonafide. Eight compounds were not cross-resistant with MDR L1210 leukemia, and the 10-CN analogue was more potent against solid tumor cells than leukemia cells. The 9-OH, 10-CN, and 10-F analogues had high potency against both sensitive and resistant cell lines of MFX 7 breast carcinoma and WiDr colon carcinoma and sensitivity A599 lung carcinoma. Advantages of the 10-Cl, 10-NH2, and 10-CN analogues over azonafide were apparent in P388 leukemia in mice, and the 10-CN analogue was more effective than doxorubicin in this assay. Quantitative structure-activity relationship studies revealed statistically significant correlations between DNA binding strength of 8- and 10-substituted azonafides, as measured by deltaTm, and toxicity to tumor cells. There also were correlations between substituent size, as measured by MR, and cytotoxicity for 9- and 10-substituted azonafides and between MR and deltaTm for 4- and 11-substituted azonafides. Lipophilicity of substituents (pi) correlated with cytotoxicity for 9-, 10-, and 11-substituted azonafides. These results lend support to a model in which DNA binding strength influences cytotoxic potency, and lipophilicity increases DNA binding whereas large substituents decrease it.

6- and 7-substituted 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h] isoquinoline-1,3-diones: synthesis, nucleophilic displacements, antitumor activity, and quantitative structure-activity relationships.

New 2-[2'-(dimethylamino)ethyl]-3H-dibenz[de,h]isoquinoline-1,3-diones with substituents at the 6- and 7-positions were prepared. Nucleophilic aromatic displacement was a key reaction in the syntheses. Ten of the new compounds were more potent than the unsubstituted compound, azonafide, in a panel of tumor cells including human melanoma and ovarian cancer and murine sensitive and MDR L1210 leukemia. They also were less cardiotoxic in cell culture. Four of these compounds were not cross-resistant with the MDR leukemia, and one of them, 6-ethoxyazonafide, was nearly as potent against solid tumor cells as leukemia cells. These compounds also had good potency against human breast, colon, and lung cancer cells, including doxorubicin and mitoxantrone resistant cell lines. Advantages of the new analogues over azonafide were less in vivo, but 6-ethoxyazonafide was more effective against L1210 leukemia and subcutaneous B16 melanoma in mice. Although correlations of antitumor potency in cells and physicochemical properties of substituents were not found, there were statistically significant correlations of DNA melt transition temperature (delta Tm) with potency in solid tumor cells and sensitive and MDR resistant L1210 leukemia cells for 6-substituted azonafides and with solid tumors for 7-substituted azonafides.

Amino-substituted 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H- dibenz[de,h]isoquinoline-1,3-diones. Synthesis, antitumor activity, and quantitative structure--activity relationship.

Sets of 2-[2-(dimethylamino)ethyl]-1,2-dihydro-3H- dibenz[de,h]isoquinoline-1,3-diones with amino and actylamino groups at each of the eight positions on the anthracene nucleus were synthesized from appropriately substituted anthracenes. Their evaluation in in vitro antitumor and cardiotoxicity assays revealed a very strong dependence of potency on the position of substitution. Certain compounds, including the 4-, 5-, 7-, and 9-amino derivatives, showed significantly higher potency than the unsubstituted parent compound, azonafide. Among them, 7-aminoazonafide had low cardiotoxicity relative to cytotoxicity. In general, the acetylamino analogues were less potent than the amino derivatives against tumor cells and neonatal rat heart myocytes; however, 5-(acetylamino)azonafide was highly cardiotoxic. 9-Aminoazonafide was more efficacious than azonafide or amonafide against P388 leukemia in mice. Statistically significant correlations were made between the ability of amino analogues to increase the transition melt temperature (delta Tm) of DNA and their potency against solid tumors, leukemia cells, or cardiac myocytes.

Determination of ammonia using carbon dioxide laser photoacoustic spectroscopy compared with conventional spectrophotometry.

The potential of carbon dioxide laser photoacoustic spectroscopy and the traditional Indophenol Blue colorimetric method for detecting gaseous ammonia have been compared. The results obtained with the two independent techniques are comparable in the range of concentrations studied.

Autotransplantation of superior cervical ganglion to the caudate nucleus in three patients with Parkinson's disease (preliminary report).

Striatal cervical ganglionic implants have been utilized for the first time for treatment of three patients suffering from Parkinson's disease. Tissue grafts from the superior cervical ganglion have been dissected and immediately transplanted into the head of the caudate nucleus. The grafted tissue placed in a cavity of the caudate nucleus remains in contact with the cerebrospinal fluid in the lateral ventricle. Three and six months after surgery, none of the patients has had any major complications and their lower score of Unified Parkinsonism Rating Scale (UPRS) points was associated with an improvement of the signs of Parkinson's disease. Present data have provided some optimism that grafting of superior cervical ganglion is a feasible approach in Parkinson's disease.

Some basic features of the pathological and normal motor system studied by chronic deep electrodes.

Our stereotactic experiences in agreement with the literature showed, that different target points could influence the same motor disturbance. To choose the best target point or target point combinations we generally implant the electrodes into VL, Vim, CM, P, dentate nucleus and motor cortex. To ensure the correct sequence of therapeutic lesions we developed an investigation system, taking into consideration the resting and the working state of the motor system. We elicited events centrally (stimulation of the different target points) and peripherally (reflexes) and recorded the evoked potentials at the non-stimulated sites along with the motor and motor modulation effects in the appropriate muscles. The elicited events depend on the site of stimulation and registration and on the state of muscle activity. The centrally and peripherally elicited events influence each other. With our technique the elicited events and their functional dependency is most explicit within the motor system. The results help to explain some basic motor functions and help to answer some of our therapeutic questions.

The rhythmic properties of the motor system.

The resonance properties of the motor control circuits are basic features of the motor system. From our results, it can be concluded that, when the normally existing suppression mechanism weakens, external stimuli or internal impulses may elicit oscillations in the circuits according to the resonant frequency, and tremor will appear. It seems that the resonant frequency is between 5 and 8 Hz, as demonstrated by rhythmic voluntary movement, rhythmic elicited reflex movement and rhythmic modulated voluntary movement modulated by the stimulation of the central motor system.

Determinants of altered anxiety after abnormal maternal serum alpha-fetoprotein screening.

With maternal serum alpha-fetoprotein testing, large numbers of previously "low-risk" patients are now considered high risk and are offered genetic testing. Anecdotally, these patients have been perceived as more highly anxious than other second-trimester patients referred for genetic testing because of advanced maternal age. Thus we have studied patient demographics, true genetic risks, the perceptions of risk, and state (situational) and trait (constitutional) anxiety for these patients and their partners. Significantly increased state anxiety was noted for mothers as compared with fathers both in the group of women referred for testing because of maternal serum alpha-fetoprotein levels and in those referred due to advanced maternal age. State anxiety was increased in the women referred for maternal serum alpha-fetoprotein levels as compared with women referred for advanced maternal age. True genetic risks were comparable between the groups. Some critics have argued that maternal serum alpha-fetoprotein screening engenders unnecessary anxiety. Our data show that patients undergoing genetic testing due to maternal serum alpha-fetoprotein levels have higher state anxiety than women undergoing testing because of advanced maternal age, but that indication is much less a factor than are partner differences. Therefore, increased anxiety after abnormal maternal serum alpha-fetoprotein testing results cannot be reasonably used as an argument against such testing.

Investigation of trigeminal SEP with scalp and deep electrodes.

A special technique for stimulating and recording trigeminal somatosensory evoked potential (SEP) is described. Eleven healthy subjects and seven patients with chronically implanted deep electrodes have been investigated. Characteristic polyphasic waves were repeatedly observed. The recording of somatosensory evoked potential following trigeminal stimulation is a more difficult technique. This paper describes data in control subjects with scalp electrodes and data on patients with electrodes in the nucleus ventralis posteromedialis and cortical white matter. Depth recording may provide useful information about the origin, nature, and properties of trigeminal SEP.

The spread of somatosensory-evoked potentials within the nervous system.

Four thalamic and cortical recordings were carried out in 5 patients. The thalamic-evoked potentials were typical and revealed a triphasic complex, but their latencies showed a relatively high standard deviation. They could be divided into two groups according to their latencies, both of which had low SD. These data suggested that there could be two types of latency of thalamic SEP, because the 4 patients' body sizes were very similar. More detailed surface, cortical and depth recordings are needed to resolve these questions.