Moulds and yeasts in fruit salads and fruit juices.

Thirty-eight fruit salad samples including cantaloupe, citrus fruits, honeydew, pineapple, cut strawberries and mixed fruit salads, and 65 pasteurized fruit juice samples (apple, carrot, grapefruit, grape and orange juices, apple cider, and soy milk) were purchased from local supermarkets in the Washington, DC area and tested for fungal contamination. The majority of fruit salad samples (97%) were contaminated with yeasts at levels ranging from <2.0 to 9.72 log10 of colony forming units per gram (cfu/g). Frequently encountered yeasts were Pichia spp., Candida pulcherrima, C. lambica, C. sake, Rhodotorula spp., and Debaryomyces polymorphus. Low numbers of Penicillium spp. were found in pineapple salads, whereas Cladosporium spp. were present in mixed fruit and cut strawberry salads. Twenty-two per cent of the fruit juice samples tested showed fungal contamination. Yeasts were the predominant contaminants ranging from <1.0 to 6.83 log10 cfu/ml. Yeasts commonly found in fruit juices were C. lambica, C. sake, and Rhodotorula rubra. Geotrichum spp. and low numbers of Penicillium and Fusarium spp. (1.70 and 1.60 log10 cfu/ml, respectively) were present in grapefruit juice.

Improving QSAR models for the biological activity of HIV Reverse Transcriptase inhibitors: Aspects of outlier detection and uninformative variable elimination.

The goal of this study is to derive a methodology for modeling the biological activity of non-nucleoside HIV Reverse Transcriptase (RT) inhibitors. The difficulties that were encountered during the modeling attempts are discussed, together with their origin and solutions. With the selected multivariate techniques: robust principal component analysis, partial least squares, robust partial least squares and uninformative variable elimination partial least squares, it is possible to explore and to model the contaminated data satisfactory. It is shown that these techniques are versatile and valuable tools in modeling and exploring biochemical data.

Classification and regression trees--studies of HIV reverse transcriptase inhibitors.

In this paper, the application of Classification And Regression Trees (CART) is presented for the analysis of biological activity of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs). The data consist of the biological activities, expressed as pIC50, of 208 NNRTIs against wild-type HIV virus (HIV-1) and four mutant strains (181C, 103N, 100I, 188L) and the computed interaction energies with the Reverse Transcriptase (RT) binding pocket. CART explains the observed biological activity of NNRTIs in terms of interactions with individual amino acids in the RT binding pocket, i.e., the original data variables.

In vitro and in vivo activities of the novel azole antifungal agent r126638.

R126638 is a new triazole agent with potent antifungal activity in vitro against various dermatophytes, Candida spp., and Malassezia spp. Its activity against Malassezia spp. in vitro was superior to that of ketoconazole, the agent currently used for the treatment of Malassezia-related infections. R126638 showed activity comparable to or lower than that of itraconazole against dermatophytes in vitro; however, in guinea pig models of dermatophyte infections, R126638 given orally consistently showed antifungal activity superior to that of itraconazole, with 50% effective doses (ED(50)s) three- to more than eightfold lower than those of itraconazole, depending on the time of initiation and the duration of treatment. The ED(50) of R126638 in a mouse dermatophytosis model was more than fivefold lower than that of itraconazole. These data indicate that if the effects of R126638 seen when it is used to treat animals can be extrapolated to humans, the novel compound would be expected to show effects at doses lower than those of existing drugs and, hence, present a lower risk for side effects.

Inhibition and substrate recognition--a computational approach applied to HIV protease.

We have developed a computational approach in which an inhibitor's strength is determined from its interaction energy with a limited set of amino acid residues of the inhibited protein. We applied this method to HIV protease. The method uses a consensus structure built from X-ray crystallographic data. All inhibitors are docked into the consensus structure. Given that not every ligand-protein interaction causes inhibition, we implemented a genetic algorithm to determine the relevant set of residues. The algorithm optimizes the q2 between the sum of interaction energies and the observed inhibition constants. The best possible predictive model resulting has a q2 of 0.63. External validation by examining the predictivity for compounds not used in derivation of the model leads to a prediction accuracy between 0.9 and 1.5 log10 unit. Out of 198 residues in the whole protein, the best internally predictive model defines a subset of 20 residues and the best externally predictive model one of 9 residues. These residues are distributed over the subsites of the enzyme. This approach provides insight in which interactions are important for inhibiting HIV protease and it allows for quantitative prediction of inhibitor strength.

Evolution of anti-HIV drug candidates. Part 2: Diaryltriazine (DATA) analogues.

A synthesis program directed toward improving the stability of imidoyl thiourea based non-nucleoside reverse transcriptase inhibitors (NNRTIs) led to the discovery of diaryltriazines (DATAs), a new class of potent NNRTIs. The synthesis and anti-HIV structure-activity relationship (SAR) studies of a series of DATA derivatives are described.

Evolution of anti-HIV drug candidates. Part 3: Diarylpyrimidine (DAPY) analogues.

The synthesis and anti-HIV-1 activity of a series of diarylpyrimidines (DAPYs) are described. Several members of this novel class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) are extremely potent against both wild-type and a panel of clinically significant single- and double-mutant strains of HIV-1.

Functional turbo spin echo magnetic resonance imaging versus tomography for evaluating cervical spine involvement in rheumatoid arthritis.

STUDY DESIGN: Comparison of findings in plain radiography and conventional tomography with findings in plain radiography and magnetic resonance imaging of the upper cervical spine in consecutive patients with rheumatoid arthritis and with known or suspected abnormalities of the cervical spine. OBJECTIVES: To determine whether plain radiography and magnetic resonance imaging provide enough information to dispense with tomography in investigations of cervical spine involvement in rheumatoid arthritis. SUMMARY OF BACKGROUND DATA: With the recent advances in magnetic resonance imaging technology and the proliferation of magnetic resonance imaging techniques for specific clinical conditions. METHODS: Twenty-eight patients with rheumatoid arthritis and with known or suspected abnormalities of the cervical spine underwent a clinical neurologic examination; plain radiography, including full flexion lateral radiography; anteroposterior and lateral tomography at C1-C2; and magnetic resonance imaging at the same level in neutral position and in flexion. Two radiologists evaluated one image set consisting of plain radiography and conventional tomographic images and another image set consisting of plain radiography and magnetic resonance images, for each patient. RESULTS: Compared with conventional tomography and plain radiography, magnetic resonance imaging and plain radiography showed cystic lesions and erosions of the odontoid process and vertical atlantoaxial subluxation more often, showed anterior subluxation as often, and showed lateral atlantoaxial subluxation less often. CONCLUSION: Magnetic resonance imaging produces sufficiently distinct images of destruction of the odontoid and subluxations for it to replace conventional tomography in investigations of upper cervical spine involvement in rheumatoid arthritis.

Changes in the carpal tunnel due to action of the flexor tendons: visualization with magnetic resonance imaging.

Successive cross-sectional areas (CSA) of the carpal tunnel were measured with the fingers in both extension and full flexion in 12 healthy volunteers using magnetic resonance imaging. During flexion, lumbrical muscles could be observed to move into the carpal tunnel up to different levels in all volunteers. For each of the volunteers, the level of the hook of hamate was used as the reference level. The mean CSA measured at this level was considerably larger in flexion than in extension: 191 mm2 (SD, +/- 26) and 169 mm2 (SD, +/- 15), respectively (p = .004). In three volunteers, no difference in CSA between extension and flexion was measured at the hamate level, despite the presence of lumbrical muscles, whereas in these same volunteers at levels more distal, the CSA clearly increased during flexion. The mean CSA for extension and flexion distal and just proximal to the smallest level differed significantly, but the absence of expansion was noticed only at the smallest level. Other changes that were frequently observed during flexion were fat compression, flattening and displacement of the median nerve, and pressure on the superficial and deep flexor tendons.

[Cervical myelopathy as complication of manual therapy in a patient with a narrow cervical canal]. / Cervicale myelopathie als complicatie van manuele therapie bij een patiënt met een nauw cervicaal kanaal.

A 31-year-old man had manipulative therapy because of pain in the neck, the left shoulder and the left arm. Immediately after cervical traction he developed neurological symptoms. Clinical investigation led to the diagnosis of cervical myelopathy. The patient had a rather narrow cervical canal. Six weeks after treatment with external fixation and corticosteroids the situation had improved markedly, with remaining hypesthesia in both hands and the right leg.

In vivo studies on the mechanism of action of the broad spectrum anticonvulsant loreclezole.

In animal models of epilepsy the anticonvulsant profile of loreclezole resembles that of barbiturates and benzodiazepines. We examined whether the increase in seizure threshold to pentylenetetrazole infusion produced by 10 mg/kg of loreclezole, pentobarbital or diazepam could be reversed by a spectrum of benzodiazepine partial inverse to full inverse agonists (FG-7142 beta-carboline carboxylate, CGS-8216, Ro-15-4513 and DMCM) or by a benzodiazepine neutral antagonist (Ro-15-1788). The doses of the benzodiazepine inverse agonists were chosen to produce a 20-40% decrease in seizure threshold. The seizure threshold increase produced by loreclezole and pentobarbital was reduced by all the benzodiazepine inverse agonists and potentiated by Ro-15-1788. Diazepam was antagonized by the benzodiazepine inverse agonists and by the neutral antagonist. The generality of this finding was examined in amygdala-kindled rats. The decrease in the duration of forepaw clonus and the reduction in behavioural stage34 produced by loreclezole, pentobarbital and diazepam was reversed by CGS-8216. Ro-15-1788, which itself showed anticonvulsant effects in this model, antagonized the effects of diazepam, but not loreclezole or pentobarbital. Thus loreclezole behaves more like a barbiturate than a benzodiazepine in these two in vivo models. This suggests a possible mechanism of action of loreclezole at a neuromodulatory site within the GABAA receptor complex, which is unlikely to be a benzodiazepine receptor.

Influence of the synthetic microtubule inhibitor erbulozole (P.I.N.N.) (R 55 104), a new tubulozole congener, and gamma irradiation on murine tumors in vivo.

Erbulozole (P.I.N.N.) (R 55 104) is a more water soluble congener of the synthetic microtubule inhibitor tubulozole (R 46 846) exhibiting a reversible antimicrotubular activity in vitro at a dose (1.56 x 10(-8) M) which is at least 10-fold lower. The compound also has an antiinvasive potential and shows antitumoral effects both in vitro and in vivo when administered appropriately. Eighty mg/kg R 55 104, given orally 6 h before or 3 h after radiotherapy, displays a prominent interactive effect with 10 Gy gamma irradiation in subcutaneous murine tumors which is similar to 160 mg/kg tubulozole administered 6 h before 10 Gy. The enhancing effect is also observed in a clinically relevant radiation dose fractionation schedule whereby eight fractions of 2 Gy each were pretreated 2 h before with 40 mg/kg R 55 104. Further study of this radiochemotherapeutic combination may lead to new clinical applications.

Geometry of the aortic bifurcation measured by computed tomography.

Apart from metabolic risk factors haemodynamic disturbances play a role in atherogenesis. The haemodynamic factors depend among other things on the geometry of vessels including the aortic bifurcation. The geometry of the aortic bifurcation can be expressed by the diameter of the distal abdominal aorta, the area ratio of the bifurcation and the convergence of the aorta. Data on the geometry have been reported of both post-mortem and in-vivo investigations by angiography and echography. Because of the disadvantages of angiographic and echographic measurements, the aortic bifurcation has been assessed by CT-scanning in a series of 50 patients. The mean diameter of the distal aorta measured 15.9 mm for men and 13.0 mm for women. The calculated area ratio was 0.74 for men and 0.81 for women. These data are in agreement with the angiographic measurements. A convergence was found of 30.6 percent for men and 45.4 percent for women. There is a discrepancy between these values and those reported in the literature.

Antimycotic azoles. 7. Synthesis and antifungal properties of a series of novel triazol-3-ones.

A series of novel triazol-3-ones have been synthesized, and their in vitro and in vivo antifungal properties are reported. Compound 68 (itraconazole), which displays a pronounced oral activity against vaginal candidosis in rats and against microsporosis in guinea pigs, has been selected for clinical evaluation.

The effects of tubulazole, a new synthetic microtubule inhibitor on experimental neoplasms.

Tubulazole, a new synthetic microtubule inhibitor in vitro, is tested in vivo upon three experimental neoplasms: MO4 sarcoma, L1210 leukemia and TA3 carcinoma. The compound is tested using different treatment schedules upon different inoculation routes of the cells. All trials show the compound to have distinct antineoplastic properties in vivo by prolonging the median survival time. The best treatment schedule seems to be an intermittent one, i.e. treatment every fourth day starting 1 day after tumor inoculation. Comparison with cyclophosphamide and vincristine is in favor of tubulazole for treating TA3 mammacarcinoma, while cyclophosphamide and vincristine give somewhat better results upon L1210 leukemia. The effects of tubulazole and cyclophosphamide upon MO4 fibrosarcoma are comparable, while vincristine has no effect in this system. Worthwhile noting is that all the in vivo, as well as in vitro, activity of tubulazole resides in the cis isomer, while the trans isomer has no effect at all.

Antimycotic azoles. 6. Synthesis and antifungal properties of terconazole, a novel triazole ketal.

The preparation and antifungal properties of cis-1-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1, 3-dioxolan-4-yl]methoxy]phenyl]-4-(1-methylethyl)piperazine are reported. Terconazole has a high topical in vivo activity against vaginal candidosis in rats and against dermatophytosis in guinea pigs.

Antimycotic imidazoles. 5. Synthesis and antimycotic properties of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles.

The synthesis of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles is described starting with phenylacetyl bromides or 1-(phenylacetyl)imidazoles. The compounds were generally obtained as cis/trans mixtures and and found to be active in vitro against dermatophytes, yeast, other fungi, and Gram-positive bacteria. Some also showed good activity against Candida albicans in vivo.

Antimycotic imidazoles. part 4. Synthesis and antifungal activity of ketoconazole, a new potent orally active broad-spectrum antifungal agent.

The preparation and antifungal properties of cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine (I) are described. Ketoconazole has, at low oral doses, a high in vivi activity against vaginal candidosis in rats and against cutaneous candidosis in guinea pigs.

Ketoconazole -- a new broad spectrum orally active antimycotic.

Oral treatment with ketoconazole prevented and cured artificial crop candidosis of the turkey, vaginal candidosis of the rat and skin candidosis of the guinea-pig. It was also highly effective against artificial systemic candidosis of the guinea-pig and chicken as well as against dermatophytoses of the guinea-pig.