bluuebunny/crossref_metadata_2025 huggingface dataset:
Successful treatment of multicentric reticulohistiocytosis with alendronate: Evidence for a direct effect of bisphosphonate on histiocytes
Authors: Goto Hitoshi , Inaba Masaaki , Kobayashi Keisuke , Imanishi Yasuo , Kumeda Yasuro , Inui Kentaro , Okada Fumihiko , Nishizawa Yoshiki
Published: December 2003

We describe the case of a 44‐year‐old Japanese woman with severe nodular erythematous skin lesions and arthritis mutilans who was admitted for further treatment of multicentric reticulohistiocytosis. Skin and synovial biopsies showed heavy infiltration with tartrate‐resistant acid phosphatase–positive histiocytes and multinucleated giant cells. Immunohistochemical analysis showed that some of the mononuclear cells in the skin were positive for RANKL. After 1 month of Alendronate, an aminobisphosphonate, given at a dosage of 10 mg once a week intravenously for the first 6 weeks and then once a month thereafter, the arthritis and skin nodules improved, and the remission has continued for more than 2 years. The findings in this patient suggest that osteoclast‐like multinucleated giant cells differentiate locally in the skin from infiltrating histiocytes with the help of RANKL‐positive stromal cells and that alendronate acts directly on cells of monocyte/macrophage lineage in humans. Thus, alendronate should be added to the list of drugs for the treatment of multicentric reticulohistiocytosis.
Efficacy and safety of tacrolimus in patients with rheumatoid arthritis: A double‐blind trial
Authors: Yocum David E. , Furst Daniel E. , Kaine Jeffrey L. , Baldassare Andrew R. , Stevenson Jon T. , Borton Mary Ann , Mengle‐Gaw Laurel J. , Schwartz Benjamin D. , Wisemandle Wayne , Mekki Qais A.
Published: December 2003

Objective

To evaluate the efficacy and safety of tacrolimus as monotherapy in controlling the signs and symptoms of patients with rheumatoid arthritis (RA).

Methods

This was a 6‐month, phase III, double‐blind, multicenter study. Patients with active RA who had discontinued all disease‐modifying antirheumatic drugs (DMARDs) for an appropriate washout period (at least 1 month) and who, after the washout period, had a stable joint count (at least 10 tender/painful joints and 7 swollen joints) were stratified according to DMARD intolerance or DMARD resistance, and randomized to receive a single daily oral dose of placebo, tacrolimus 2 mg, or tacrolimus 3 mg.

Results

A total of 464 patients received at least 1 dose of study drug. Baseline characteristics were similar among the 3 treatment groups. American College of Rheumatology 20% improvement (ACR20) success (defined as completion of 6 months of treatment and an ACR20 response at the month 6 visit) for the placebo, tacrolimus 2 mg, and tacrolimus 3 mg groups was 10.2%, 18.8% (P < 0.05 versus placebo), and 26.8% (P < 0.0005 versus placebo), respectively. At the end of treatment, the ACR20 and ACR50 response rates in the 3‐mg group were 32.0% (P < 0.005 versus placebo) and 11.8% (P < 0.05 versus placebo), respectively. DMARD‐intolerant patients had better ACR response rates than did DMARD‐resistant patients. Although serum creatinine levels increased by ≥40% from baseline at some time during the trial in 20% and 29% of patients receiving tacrolimus 2 mg/day and 3 mg/day, respectively, the serum creatinine level remained within the normal range throughout the trial in ∼90% of patients.

Conclusion

Tacrolimus, at dosages of both 2 mg/day and 3 mg/day, is efficacious and safe as monotherapy for patients with active RA, but treatment with the 3‐mg dose of tacrolimus resulted in generally better ACR response rates.
Stem cell therapy in a caprine model of osteoarthritis
Authors: Murphy J. Mary , Fink David J. , Hunziker Ernst B. , Barry Frank P.
Published: December 2003

Objective

To explore the role that implanted mesenchymal stem cells may play in tissue repair or regeneration of the injured joint, by delivery of an autologous preparation of stem cells to caprine knee joints following induction of osteoarthritis (OA).

Methods

Adult stem cells were isolated from caprine bone marrow, expanded in culture, and transduced to express green fluorescent protein. OA was induced unilaterally in the knee joint of donor animals by complete excision of the medial meniscus and resection of the anterior cruciate ligament. After 6 weeks, a single dose of 10 million autologous cells suspended in a dilute solution of sodium hyaluronan was delivered to the injured knee by direct intraarticular injection. Control animals received sodium hyaluronan alone.

Results

In cell‐treated joints, there was evidence of marked regeneration of the medial meniscus, and implanted cells were detected in the newly formed tissue. Degeneration of the articular cartilage, osteophytic remodeling, and subchondral sclerosis were reduced in cell‐treated joints compared with joints treated with vehicle alone without cells. There was no evidence of repair of the ligament in any of the joints.

Conclusion

Local delivery of adult mesenchymal stem cells to injured joints stimulates regeneration of meniscal tissue and retards the progressive destruction normally seen in this model of OA.
Longitudinal analysis of cartilage atrophy in the knees of patients with spinal cord injury
Authors: Vanwanseele B. , Eckstein F. , Knecht H. , Spaepen A. , Stüssi E.
Published: December 2003

Objective

A previous cross‐sectional study indicated that the morphology of patellar and tibial cartilage is subject to change after spinal cord injury (SCI). The aim of this study was to perform a longitudinal analysis of cartilage atrophy in all knee compartments, including the femoral condyles, in SCI patients over 12 months.

Methods

The right knees of 9 patients with complete, traumatic SCI were examined shortly after the injury (mean ± SD 9 ± 4 weeks) and at 6 and 12 months postinjury. Three‐dimensional morphology of the patellar, tibial, and femoral cartilage (mean and maximum thickness, volume, and surface area) was determined from coronal and transversal magnetic resonance images (fat‐suppressed gradient‐echo sequences) using validated postprocessing techniques.

Results

The mean thickness of knee joint cartilage decreased significantly during the first 6 months after injury (range 5–7%; P < 0.05). The mean change at 12 months was 9% in the patella, 11% in the medial tibia, 11% in the medial femoral condyle, 13% in the lateral tibia, and 10% in the lateral femoral condyle (P < 0.05 for all compartments).

Conclusion

This is the first report of a longitudinal analysis of cartilage atrophy in patients with SCI. These data show that human cartilage atrophies in the absence of normal joint loading and movement after SCI, with a rate of change that is higher than that observed in osteoarthritis (OA). A potential clinical implication is that cartilage thinning after SCI may affect the stress distribution in the joint and render it vulnerable to OA. Future studies should focus on whether specific exercise protocols and rehabilitation programs can prevent cartilage thinning.
Fatigue fractures suggesting clinical monarthritis
Authors: Garcia‐Porrua Carlos , Armesto Victor , Mañana Paula , Gonzalez‐Gay Miguel A.
Published: December 2003

Objective

To examine etiologic factors, clinical features, and outcome in a series of consecutive patients with fatigue fractures diagnosed at a rheumatology division for a defined population over a 14‐month period.

Methods

A prospective study of the patients diagnosed with fatigue fracture at the rheumatology division of the Hospital Xeral‐Calde (Lugo, Spain) between July 2000 and August 2001 was conducted. Hormonal status, body mass index, lifestyle, job, underlying diseases, and drug intake, which might be attributable risk factors for the stress fracture, were assessed. In all the patients a followup of at least 6 months was required.

Results

Six consecutive patients (4 women) fulfilled the inclusion criteria. All of them were younger than 65 years (median 45 years; range 36–64 years) and had a body mass index lower than 25. In this series no distinctive occupation was found. The delay to diagnosis since the onset of symptoms ranged from 0.5 to 6 months (median 1.5). All patients but 1 were sent to the rheumatology division because of a clinical diagnosis of monarthritis. Pain and swelling were the presenting symptoms. Conventional radiographs were normal and fine needle aspiration of the joints yielded negative results for microcrystals and organisms. Magnetic resonance imaging disclosed the presence and site of fracture in all the cases. Sequelae of mechanical pain and subsequent osteoarthritis were observed in the 3 cases with longer delay to diagnosis.

Conclusion

Fatigue fractures are not exceptional in unselected adults. Rheumatologists should consider this diagnosis in patients presenting with monarthritis. Physician awareness is required to prevent the development of sequelae.
Spirituality, well‐being, and quality of life in people with rheumatoid arthritis
Authors: Bartlett Susan J. , Piedmont Ralph , Bilderback Andrew , Matsumoto Alan K. , Bathon Joan M.
Published: December 2003

Objective

To evaluate spirituality, well‐being, and quality of life (QOL) among people with rheumatoid arthritis (RA).

Methods

Questionnaires assessing positive and negative affect, depression, QOL and spirituality were completed. Disease activity was assessed by rheumatologic examination.

Results

Women (n = 62) had a mean (± SD) age of 53.0 (± 13.0) years with 12 (± 13) swollen and tender joints (STJ). Men (n = 15) were 61.9 (± 13.0) years with 7 (± 11) STJ. Disease activity was associated (P< 0.05) positively with depression (r = 0.23), pain (r = 0.26), poorer self‐ratings of health (r = 0.29) and physical role limitations (r = 0.26). Spirituality was associated directly with positive affect (r = 0.26) and higher health perceptions (r = 0.29). In multiple regression, spirituality was an independent predictor of happiness and positive health perceptions, even after controlling disease activity and physical functioning, for age and mood.

Conclusion

Spirituality may facilitate emotional adjustment and resilience in people with RA by experiencing more positive feelings and attending to positive elements of their lives.
Management of depression in rheumatoid arthritis: A combined pharmacologic and cognitive‐behavioral approach
Authors: Parker Jerry C. , Smarr Karen L. , Slaughter James R. , Johnston Sandra K. , Priesmeyer Marydeth L. , Hanson Kathleen Donovan , Johnson Gail E. , Hewett James E. , Hewett John E. , Irvin William S. , Komatireddy Geetha R. , Walker Sara E.
Published: December 2003

Objective

To examine the effectiveness of cognitive‐behavioral and pharmacologic treatment of depression in rheumatoid arthritis (RA).

Methods

Subjects (n = 54) with confirmed diagnoses of both major depression and RA were randomly assigned to 1 of 3 groups: 1) cognitive‐behavioral/pharmacologic group (CB‐PHARM), 2) attention‐control/pharmacologic group, or 3) pharmacologic control group. Measures of depression, psychosocial status, health status, pain, and disease activity were collected at baseline, posttreatment (10 weeks), 6‐month followup, and 15‐month followup. Data were analyzed to compare the treatment effectiveness of the groups; data also were aggregated to examine the effects of antidepressive medication over time. Lastly, a no‐treatment control group was defined from a cohort of persons who declined participation.

Results

Baseline comparisons on demographic and dependent measures revealed a need to assess covariates on age and education; baseline scores on dependent measures also were entered as covariates. Analyses of covariance revealed no statistically significant group differences at postintervention, 6‐month followup, or 15‐month followup, except higher state and trait anxiety scores for the CB‐PHARM group at the 15‐month followup. In the longitudinal analyses of the effects of antidepressive medication, significant improvement in psychological status and health status were found at posttreatment, 6‐month followup, and 15‐month followup, but no significant improvements were shown for pain or disease activity. In addition, the comparison of the aggregated pharmacologic group with a no‐treatment group revealed a statistically significant benefit for the 3 groups that received the antidepressive medication.

Conclusion

In persons with RA, cognitive‐behavioral approaches to the management of depression were not found to be additive to antidepressant medication alone, but antidepressant intervention was superior to no treatment.
Thyroid dysfunction in primary Sjögren's syndrome: A long‐term followup study
Authors: d'Arbonneau Frédérique , Ansart Séverine , Berre Rozenn Le , Dueymes Maryvonne , Youinou Pierre , Pennec Yvon‐Louis
Published: December 2003

Objective

To evaluate the prevalence of thyroid dysfunction and related autoantibodies in patients with primary Sjögren's syndrome (pSS), and to determine whether these abnormalities develop over time.

Methods

pSS patients (n = 137) and controls (n = 120) were investigated for thyroid dysfunction and for the presence of anti–thyroid peroxidase antibody (anti‐TPO) and antithyroglobulin antibody (ATG). Followup time for patients was 1–16 years, and 72 of the 120 controls were reevaluated 3 years after initial evaluation.

Results

Thyroid disease was more frequent in the pSS patients than in the controls (30% versus 4%; P < 10‐4), as were anti‐TPO and ATG (11% versus 3%; P < 0.02, and 3% versus 1%, not significant). Ten of 107 euthyroid pSS patients dropped out of the study, and thyroid dysfunction became apparent at followup in 12 of the remaining 97. Most of the patients with thyroid‐related autoantibodies at entry developed autoimmune thyroid disease thereafter.

Conclusion

Thyroid dysfunction is frequent in pSS patients, and those prone to develop thyroid disorders are identified by thyroid‐related autoantibodies, or by rheumatoid factor and anti‐Ro/SSA activity.
Domains of health‐related quality of life important to patients with giant cell arteritis
Authors: Hellmann David B. , Uhlfelder Misty L. , Stone John H. , Jenckes Mollie W. , Cid Maria C. , Guillevin Loic , Moreland Larry , Dellaripa Paul F. , Hoffman Gary S. , Merkel Peter A. , Spiera Robert , Brown Lin , Hernández‐Rodríguez José , Rubin Haya R.
Published: December 2003

Objective

To determine aspects of quality of life (QOL) important to people with giant cell arteritis (GCA).

Methods

We explored the domains of QOL affected by GCA in audiotaped focus groups. We then created an Importance Rating Questionnaire (IRQ) by constructing questions related to the domains most frequently mentioned. Of 214 GCA patients to whom the IRQ was sent, 145 (68%) responded. We calculated frequencies of responses and then ranked items by the proportion selecting the top category of importance and also according to a mean item rank. We compared the domains of QOL covered by the IRQ with those in the Short Form 12 (SF‐12).

Results

The highest rated QOL item was “losing sight in both eyes permanently.” Of the top 20 items, 12 were in domains not covered directly by the SF‐12.

Conclusion

We have identified aspects of QOL important to GCA patients. Assessment of QOL in GCA should include vision and other domains that are not included in standard QOL questionnaires.
Effects of concurrent strength and endurance training in women with early or longstanding rheumatoid arthritis: Comparison with healthy subjects
Authors: Häkkinen A. , Hannonen P. , Nyman K. , Lyyski T. , HÄkkinen K.
Published: December 2003

Objective

To investigate the effects of a 21‐week concurrent strength and endurance training protocol on physical fitness profile in women with early or longstanding rheumatoid arthritis (RA) compared with healthy subjects.

Methods

Twenty‐three female patients with RA volunteered for the study. Twelve had early RA and eleven had longstanding RA. Twelve healthy women served as controls. Maximal strength of different muscle groups was measured by dynamometers, walking speed with light cells, and vertical squat jump on the force platform to mirror explosive force. Maximal oxygen uptake was measured by gas analyzer. Six training sessions (3 strength training and 3 endurance training) were carried out in a 2‐week period for 21 weeks.

Results

The training led to large gains in maximal strength both in women with RA and in healthy women (P < 0.043–0.001). The strength gains were accompanied by increases in walking speed (P < 0.034–0.001) and vertical squat jump (P < 0.034–0.001). Significant improvements also occurred in maximal aerobic capacity in all groups (P < 0.023–0.014).

Conclusions

Both early and longstanding RA patients with stable disease can safely improve all characteristics of their physical fitness profile using a progressive concurrent strength and endurance training protocol.
Investigation of quality of life, mood, pain, disability, and disease status in primary systemic vasculitis
Authors: Koutantji Maria , Harrold Emma , Lane Suzanne E. , Pearce Shirley , Watts Richard A. , Scott David G. I.
Published: December 2003

Objective

To assess quality of life (QOL) and psychological adjustment in primary systemic vasculitis (PSV), and to assess their relationship to disease‐related measures.

Methods

Fifty‐one PSV patients completed questionnaires assessing QOL (Short Form 36 [SF‐36]), disability (Health Assessment Questionnaire [HAQ]), and mood (Hospital Anxiety and Depression Scale [HADS]). Illness‐related measures, disease activity, and permanent damage scores (the Birmingham Vasculitis Damage Index [BVDI] modified, and the Birmingham Vasculitis Activity Scale modified) were collected. Aspects of the HAQ's psychometric properties were evaluated.

Results

PSV patients' SF‐36 scores, except for mental health, were significantly lower than the norms, indicating poorer QOL. Using the HADS, 43.2% of patients reported increased anxiety symptoms and 25.5% increased depressive symptoms. Patients with increased pain when compared with those with little or no pain had significantly impaired scores in all SF‐36 subscales, except for mental health; and they scored significantly worse on depression, fatigue, problems with sleep, and symptom severity. Patients with neuropathic symptoms and those taking high levels of steroids had significantly impaired scores on some of the relevant measures. There were no significant correlations between the modified BVDI scores with the SF‐36 subscales or with the other self‐report disease‐related measures. The HAQ showed high internal consistency and high concurrent and discriminant validity.

Conclusion

Many aspects of QOL are significantly impaired in PSV. Self‐reported pain and disease symptoms, SF‐36 scores, and depression and anxiety levels are significant indicators of the adverse impact of vasculitis on patients' lives that need to be assessed and managed.
Validation of a rheumatoid arthritis health‐related quality of life instrument, the CSHQ‐RA
Authors: Russak S. M. , Sherbourne C. D. , Lubeck D. P. , Paulus H. D. , Chiou C. F. , Sengupta N. , Borenstein J. , Ofman J. , Moadel A. , Weisman M. H.
Published: December 2003

Objective

To test the validity and reliability of a newly developed disease‐specific multidimensional quality of life instrument: the Cedars‐Sinai Health‐Related Quality of Life Instrument (CSHQ‐RA).

Methods

A total of 350 rheumatoid arthritis (RA) patients were asked to complete the CSHQ‐RA at 2 time points (4 weeks apart). Patients also completed the Medical Outcomes Study Short Form 36 (SF‐36) and the Stanford Health Assessment Questionnaire (HAQ) Disability Index (DI) at the second time point. Construct validity was tested, using Pearson's correlations, by comparing subscale scores on the CSHQ‐RA to those obtained from the mental component summary (MCS) and physical component summary (PCS) of the SF‐36. HAQ DI scores were used to assess the discriminant validity of the CSHQ‐RA. Intraclass correlation coefficients (ICCs) were used to assess test–retest reliability.

Results

Response rates for the first and second survey were 83% (291) and 93% (276), respectively; 84% of respondents were women, and mean age was 57 years. Mean scores ± SDs on instruments were: HAQ 0.73 ± 0.69; MCS 49 ± 12; and PCS 33 ± 11. Pearson's correlations between the CSHQ‐RA subscale scores and the SF‐36 scores ranged from 0.55 to 0.76 (P < 0.001). Analysis of variance indicate that scores on the CSHQ‐RA discriminated between levels of physical disability as measured by the HAQ (P < 0.001). Test–retest reliability was demonstrated in the instrument's subscale scores (ICC 0.70–0.90).

Conclusion

These results support the construct validity, discriminant validity, and reliability of the CSHQ‐RA as a measure that captures the impact of RA on patients' health‐related quality of life.
Mortality of large‐artery complication (aortic aneurysm, aortic dissection, and/or large‐artery stenosis) in patients with giant cell arteritis: A population‐based study over 50 years
Authors: Nuenninghoff Dirk M. , Hunder Gene G. , Christianson Teresa J. H. , McClelland Robyn L. , Matteson Eric L.
Published: December 2003

Objective

To determine the mortality of giant cell arteritis (GCA) with large‐artery complication compared with that of GCA without large‐artery complication.

Methods

An inception cohort of 168 residents of Olmsted County, Minnesota, in whom GCA was diagnosed between January 1, 1950, and December 31, 1999, was followed up. Mortality in patients with incident large‐artery complication (aortic aneurysm, aortic dissection, and large‐artery stenosis) was determined and compared with that in patients in whom large‐artery complication did not develop.

Results

No difference in survival was observed between the total group of patients with any type of large‐artery complication and patients without large‐artery complication or the general population. However, mortality was markedly increased in the 9 patients in whom thoracic aortic dissection developed (median survival 1.1 years [interquartile range 0.2–7.8 years]) compared with that in all other patients with GCA (P< 0.001). No difference in survival was observed between the group of patients with either aortic aneurysm and/or dissection (thoracic and/or abdominal aorta) and the group with GCA without large‐artery complication. Survival of patients with GCA and large‐artery stenosis was not different from that of patients with GCA without large‐artery complication.

Conclusion

Thoracic aortic dissection in GCA is associated with markedly increased mortality. Overall, mortality in the whole group of patients with GCA with large‐artery complication was similar to that in patients with GCA without large‐artery complication.
Tests for an Epidemic Change in a Sequence of Exponentially Distributed Random Variables
Authors: Ramanayake Asoka , Gupta Arjun K.
Published: December 2003

Consider a sequence of independent exponential random variables that is susceptible to a change in the means. We would like to test whether the means have been subjected to an epidemic change after an unknown point, for an unknown duration in the sequence. The likelihood ratio statistic and a likelihood ratio type statistic are derived. The distribution theories and related properties of the test statistics are discussed. Percentage points and powers of the tests are tabulated for selected values of the parameters. The powers of these two tests are then compared to the two statistics proposed by Aly and Bouzar. The tests are applied to find epidemic changes in the set of Stanford heart transplant data and air traffic arrival data.
Tests for Genetic Differentiation
Authors: Neuhäuser Markus
Published: December 2003

When testing for genetic differentiation the joint null hypothesis that there is no allele frequency difference at any locus is of interest. Common approaches to test this hypothesis are based on the summation of χ2 statistics over loci and on the Bonferroni correction, respectively. Here, we also consider the Simes adjustment and a recently proposed truncated product method (TPM) to combine P‐values. The summation and the TPM (using a relatively large truncation point) are powerful when there are differences in many or all loci. The Simes adjustment, however, is powerful when there are differences regarding one or a few loci only. As a compromise between the different approaches we introduce a combination between the Simes adjustment and the TPM, i.e. the joint null hypothesis is rejected if at least one of the two methods, Simes and TPM, is significant at the α/2‐level. Simulation results indicate that this combination is a robust procedure with high power over the different types of alternatives.
Novel Synthetic Approach for Optical Resolution of Cryptophanol‐A: A Direct Access to Chiral Cryptophanes and Their Chiroptical Properties
Authors: Brotin Thierry , Barbe Romain , Darzac Magali , Dutasta Jean‐Pierre
Published: December 2003

The separation by crystallization of the pair of cryptophane diastereomers 1 a and 1 b, obtained in 1:1 ratio by treating racemic anti cryptophanol‐A (2) with (−)‐camphanic acid chloride, provided a substantial amount of optically pure material (diastereomeric excess>98 %). Subsequent hydrolysis afforded the optically pure cryptophanol‐A enantiomers (+)‐2 and (−)‐2, which were submitted to nucleophilic substitution reactions to provide cryptophane‐A (+)‐3 and cryptophane monoester (−)‐4 in optically pure form. The chiroptical properties of the new cryptophanes 1–4 were investigated by using circular dichroism spectroscopy, and the absolute configuration of the molecules was clearly established. These new cryptophanes represent additional interesting examples for studying the Cotton effect of interacting multichromophoric systems. Moreover, this novel approach presents numerous advantages over the other methods developed so far to obtain optically pure cryptophanes, and compounds (−)‐2, (+)‐2, and (−)‐4 can give access to new enantiopure functionalized cryptophanes with host–guest properties similar to those of cryptophane‐A.
Comparison of Micro‐ and Mesoporous Inorganic Materials in the Uptake and Release of the Drug Model Fluorescein and Its Analogues
Authors: Fisher Karen A. , Huddersman Katherine D. , Taylor M. Joan
Published: December 2003

The uptake of the three species of the drug model fluorescein (fluorescein sodium salt (FNa), fluorescein free acid (F), and fluorescein diacetate (FDA)) by zeolite NaX and the mesoporous zeotype MCM‐41 was investigated as well as their release rates into solutions at pH 7 and pH 4.5. UV/Vis analysis was carried out at a wavelength of 490 nm. Uptakes of the sodium salt of 9 % for zeolite X and 14 % for MCM suggest little penetration of the pores. The use of ethanol as the loading solvent for F resulted in little uptake for both zeolitic materials due to the successful competition of the ethanol for binding sites. Use of acetone (weaker proton acceptor) as loading solvent significantly improved the uptake of F to 17 % and 12 % for zeolite X and MCM, respectively, whilst the uptake of FDA in acetone increased still further to 22 % and 17 % for zeolite X and MCM, respectively. Generally there was a large initial release of the fluorescein analogues from the surface of the zeolites with very little further increase over time. The prescence of an esterase enzyme in the release medium of FDA tripled the release from MCM to 15 % but left the release from zeolite X unaffected at 6 %. The results obtained show that uptake of fluorescein and its analogues is dependent on the loading solvent used, the amount released is influenced by not only the solvent but the pH and the presence of enzymes in the release medium.
(9Z)‐ and (11Z)‐8‐Methylretinals for Artificial Visual Pigment Studies: Stereoselective Synthesis, Structure, and Binding Models
Authors: Alvarez Rosana , Domínguez Marta , Pazos Yolanda , Sussman Fredy , de Lera Angel R.
Published: December 2003

Artificial visual pigment formation was studied by using 8‐methyl‐substituted retinals in an effort to understand the effect that alkyl substitution of the chromophore side chain has on the visual cycle. The stereoselective synthesis of the 9‐cis and 11‐cis isomers of 8‐methylretinal, as well as the 5‐demethylated analogues is also described. The key bond formations consist of a thallium‐accelerated Suzuki cross‐coupling reaction between cyclohexenylboronic acids and dienyliodides (C6C7), and a highly stereocontrolled Horner–Wadsworth–Emmons or Wittig condensation (C11C12). The cyclohexenylboronic acid was prepared by trapping the precursor cyclohexenyllithium species with B(OiPr)3 or B(OMe)3. The cyclohexenyllithium species is itself obtained by nBuLi‐induced elimination of a trisylhydrazone (Shapiro reaction), or depending upon the steric hindrance of the ring, by iodine–metal exchange. In binding experiments with the apoprotein opsin, only 9‐cis‐5‐demethyl‐8‐methylretinal yielded an artificial pigment; 9‐cis‐8‐methylretinal simply provided residual binding, while evidence of artificial pigment formation was not found for the 11‐cis analogues. Molecular‐mechanics‐based docking simulations with the crystal structure of rhodopsin have allowed us to rationalize the lack of binding displayed by the 11‐cis analogues. Our results indicate that these isomers are highly strained, especially when bound, due to steric clashes with the receptor, and that these interactions are undoubtedly alleviated when 9‐cis‐5‐demethyl‐8‐methylretinal binds opsin.
Novel Heterotopic Colloids of Anionic Porphyrins Entangled in Cationic Amphiphilic Cyclodextrins: Spectroscopic Investigation and Intracellular Delivery
Authors: Mazzaglia Antonino , Angelini Nicola , Darcy Raphael , Donohue Ruth , Lombardo Domenico , Micali Norberto , Sciortino Maria Teresa , Villari Valentina , Scolaro Luigi Monsù
Published: December 2003

The entanglement process between water‐soluble 5,10,15,20‐tetrakis(4‐sulfonatophenyl)‐21H,23H‐porphine and the amphiphilic cyclodextrin (CD) heptakis(2‐ω‐amino‐O‐oligo(ethylene oxide)‐6‐hexylthio)‐β‐CD and the occurrence of various species at different porphyrin:CD ratios were studied by a combination of UV/Vis absorption, fluorescence anisotropy, time‐resolved fluorescence, resonance light scattering, and circular dichroism. The effect of the entanglement process on the mean vesicle diameter was investigated over a wide concentration range by quasielastic light‐scattering techniques. The experimental results indicate that the presence of porphyrins in this colloidal system promotes some structural rearrangements, essentially driven by charge interaction, which are responsible for a sensitive change of vesicle dimensions. In the range of porphyrin:CD molar ratios between 1:10 and 1:50, the porphyrin is solubilized in monomeric form (τ1=11.5 ns) and photosensitizes the production of singlet oxygen (1O2). At the same molar ratio the ability of this amphiphilic cyclodextrin to transport porphyrins into tumor cells indicates specificity at the nuclear‐compartment level. These findings may be of potential interest for the of development agents for photodynamic therapy of tumors.
Theoretical Studies on the Mode of Inhibition of Ribonucleotide Reductase by 2′‐Substituted Substrate Analogues
Authors: Fernandes Pedro Alexandrino , Ramos Maria João
Published: December 2003

Several 2′‐substituted‐2′‐deoxyribonucleotides are potent time‐dependent inactivators of the enzyme ribonucleotide reductase (RNR), which function by destructing its essential tyrosil radical and/or by performing covalent addition to the enzyme. The former leads to inhibition of the R2 dimer of RNR and the latter to inhibition of the R1 dimer. Efforts to elucidate the mechanism of inhibition have been undertaken in the last decades, and a general mechanistic scheme has emerged. Accordingly, two alternative pathways lead either to the inhibition of R1 or R2, for which the 2′‐chloro‐2′‐deoxynucleotides serve as the model for the inhibition of R1 and the 2′‐azido‐2′‐deoxynucleotides the model for the inhibition of R2. However, the underlying reason for the different behavior of the inhibitors has remained unknown until now. Moreover, a fundamental mechanistic alternative has been proposed, based on results from biomimetic reactions, in which the 2′‐substituents would be eliminated as radicals, and not as anions, as previously assumed. This would lead to further reactions not predicted by the existing mechanistic scheme. To gain a better understanding we have performed high‐level theoretical calculations on the active site of RNR. Results from this work support the general Stubbe's paradigm, although some changes to that mechanism are necessary. In addition, a rational explanation of the factors that determine which of the dimers (R1 or R2) will be inactivated is provided for the first time. It has been demonstrated also that the 2′‐substituents are indeed eliminated as anions, and not as radicals. Biomimetic experiments have led to different results because they lack a basic group capable of deprotonating the 3′‐HO group of the substrate. It has been found here that the chemical character of the leaving group (radical or anionic) can be manipulated by controlling the protonation state of the 3′‐HO group.
Calenzanane Sesquiterpenes from the Red Seaweed Laurencia microcladia from the Bay of Calenzana, Elba Island: Acid‐Catalyzed Stereospecific Conversion of Calenzanol into Indene‐ and Guaiazulene‐Type Sesquiterpenes
Authors: Guella Graziano , Skropeta Danielle , Mancini Ines , Pietra Francesco
Published: December 2003

It is shown here that calenzanane sesquiterpenes (1 and 6) can be isolated from organic extracts from the red seaweed Laurencia microcladia Kützing from the Bay of Calenzana, Elba Island, provided contact with acidic media is minimized. Such contact induces rearrangements of 1 in dry solvents to indene‐type 5 and the blue‐colored guaiazulenium‐type ion 17, via spectrometrically (NMR) characterized indene‐type transient intermediates 10, 14, and 12. Addition of NEt3 to the reaction mixture at appropriate stages allowed the isolation of 12 (and 8 on workup on SiO2), and guaiazulene (18). Prolonged contact with silica gel led to complete degradation of 1, giving calenzanane‐type epimeric enones 20 a/20 b as well as indene‐type epimeric carbinols 22 a/22 b and fulvene 7. The latter was also formed during silica‐gel flash chromatography of the algal extracts. A unifying mechanistic view of these branching and cascade transformations may have both heuristic value, suggesting possible artefact origin of azulenoids, and synthetic applications.
A Phthalocyanine Dendrimer Capable of Forming Spherical Micelles
Authors: Uchiyama Takamichi , Ishii Kazuyuki , Nonomura Taro , Kobayashi Nagao , Isoda Seiji
Published: December 2003

A novel and intrinsically spherical micelle has been prepared by utilizing a silicon phthalocyanine ((WG3)SiPc) that has a thin hydrophobic alkyl chain and a bulky hydrophilic poly(aryl ether) dendrimer with terminal carboxyl groups, as its two axial ligands. Gel‐permeation chromatography and cryo‐transmission electron microscopic experiments indicate that (WG3)SiPcs self‐assemble to form a spherical micelle at very low concentrations in aqueous solution. Depending on the pH of the aqueous phase, (WG3)SiPc shuttles between aqueous and organic phases. In the presence of hydrophobic molecules, this transfer is accompanied by the inclusion of these (guest) molecules, indicating that the micelle acts as a molecular capsule with a nanospace surrounded by functional phthalocyanine planes.
Molecular Dynamics Simulations of Small Peptides: Can One Derive Conformational Preferences from ROESY Spectra?
Authors: Peter Christine , Rueping Magnus , Wörner Hans Jakob , Jaun Bernhard , Seebach Dieter , van Gunsteren Wilfred F.
Published: December 2003

Folding properties of β‐peptides were investigated by means of NMR experiments and MD simulations of β‐dipeptides, which serve as small test systems to study the influence of stereocenters and side chains on hydrogen‐bond and consequently on secondary‐structure formation. Two stereoisomers, SR and SS, of a Val‐Phe dipeptide, and of the corresponding Ala‐Ala dipeptide, and a Gly‐Gly dipeptide were simulated in methanol for 40 ns. In agreement with experiment, the isomers of the Val‐Phe dipeptide adopt quite different conformers at 298 K, the differences being reduced at 340 K. Interestingly, the SR isomer shows enhanced hydrogen bonding at the higher temperature. The adopted conformations are primarily determined by the R or S side chain substitution, and less by the type of side chain. Back‐calculation of 1H ROESY spectra and 3J coupling constants from the MD simulations and comparison with the experimental data for the Val‐Phe dipeptides shows good agreement between simulation and experiment, and reveals possible problems and pitfalls, when deriving structural properties of a small and extremely flexible molecule from NMR data only. Inclusion of all aspects of internal dynamics is essential to the correct prediction of the NMR spectra of these small molecules. Cross comparison of calculated with experimental spectra for both isomers shows that only a few out of many ROESY peaks reflect the sizeable conformational differences between the isomers at 298 K.
LaSeTe2—Temperature Dependent Structure Investigation and Electron Holography on a Charge‐Density‐Wave‐Hosting Compound
Authors: Doert Thomas , Fokwa Boniface Polequin Tsinde , Simon Paul , Lidin Sven , Söhnel Tilo
Published: December 2003

Single crystals of LaSeTe2 have been prepared by reaction of the elements in a LiCl/RbCl flux at 970 K for seven days. Satellite reflections observed in diffraction experiments indicate the presence of an incommensurate lattice distortion, which is of the charge‐density‐wave (CDW) type. The modulated structure has been solved from X‐ray data at 173, 293, and 373 K. LaSeTe2 crystallizes in the 3+1‐dimensional orthorhombic superspace group Cmcm(00γ)s00 (No. 63.2) with lattice parameters of a=4.295(1), b=25.371(4), c=4.306(1) Å (173 K), a=4.297(1), b=25.408(4), c=4.309(1) Å (293 K), and a=4.309(1), b=25.481(6), c=4.321(1) Å (373 K). The modulation vector q=(0, 0, 0.288) does not change over the temperature interval. Electron holographic investigations confirm the existence of the modulation and help to visualize the charge‐density wave.
Lanthanide(III) Complexes of Novel Mixed Carboxylic‐Phosphorus Acid Derivatives of Diethylenetriamine: A Step towards More Efficient MRI Contrast Agents
Authors: Kotek Jan , Lebdušková Petra , Hermann Petr , Vander Elst Luce , Muller Robert N. , Geraldes Carlos F. G. C. , Maschmeyer Thomas , Lukeš Ivan , Peters Joop A.
Published: December 2003

Three novel phosphorus‐containing analogues of H5DTPA (DTPA = diethylenetriaminepentaacetate) were synthesised (H6L1, H5L2, H5L3). These compounds have a ‐CH2‐P(O)(OH)‐R function (R = OH, Ph, CH2NBn2) attached to the central nitrogen atom of the diethylenetriamine backbone. An NMR study reveals that these ligands bind to lanthanide(III) ions in an octadentate fashion through the three nitrogen atoms, a PO oxygen atom and four carboxylate oxygen atoms. The complexed ligand occurs in several enantiomeric forms due to the chirality of the central nitrogen atom and the phosphorus atom upon coordination. All lanthanide complexes studied have one coordinated water molecule. The residence times (τ${{298\hfill \atop {\rm M}\hfill}}$) of the coordinated water molecules in the gadolinium(III) complexes of H6L1 and H5L2 are 88 and 92 ns, respectively, which are close to the optimum. This is particularly important upon covalent and noncovalent attachment of these Gd3+ chelates to polymers. The relaxivity of the complexes studied is further enhanced by the presence of at least two water molecules in the second coordination sphere of the Gd3+ ion, which are probably bound to the phosphonate/phosphinate moiety by hydrogen bonds. The complex [Gd(L3)(H2O)]2− shows strong binding ability to HSA, and the adduct has a relaxivity comparable to MS‐325 (40 s−1 mM−1 at 40 MHz, 37 °C) even though it has a less favourable τM value (685 ns). Transmetallation experiments with Zn2+ indicate that the complexes have a kinetic stability that is comparable to—or better than—those of [Gd(dtpa)(H2O)]2− and [Gd(dtpa‐bma)(H2O)].
Spectroscopic and Computational Investigations of Stable Radical Anions of Triosmium Benzoheterocycle Clusters
Authors: Nervi Carlo , Gobetto Roberto , Milone Luciano , Viale Alessandra , Rosenberg Edward , Rokhsana Dalia , Fiedler Jan
Published: December 2003

The variable temperature 1H and 13C NMR and EPR spectra of the stable radical anions [Os3(CO)9(μ3‐η2‐L)(μ‐H)] (LH=phenanthridine, 1; 5,6‐benzoquinoline, 2), and [Os3(CO)10(μ3‐η2‐L)(μ‐H)] (LH=quinoxaline, 3) are reported. The radical anions 1−, 2−, and 3− can be prepared by both exhaustive electrolysis and partially by chemical reduction with cobaltocene and with sodium dispersion (only with sodium dispersion in the case of 3−). DFT calculations on 1–3 reveal that the LUMO for the electron‐deficient compounds 1 and 2 involves significant contributions from both the heterocyclic ligand and the two metal atoms bridged by the ligand and the μ‐hydride. The character of this orbital rationalizes the previously observed regioselective reactions of these complexes with nucleophiles. In contrast, the LUMO for the electron precise 3 involves only ligand‐based orbitals. Partial chemical reduction of 1 and 2 requires an excess of either cobaltocene or sodium, and their 1H and 13C NMR spectra reveal selective line broadening of those proton resonances that are predicted by DFT calculations to bear the greatest amount of free spin density. The variable temperature behavior of the partially chemically reduced species of 1 and 2 indicates that electron transfer between the reduced/unreduced cluster pair and between the cobaltocene/cobaltocenium pair occurs on the NMR timescale. The radical anions of 1 and 2 prepared by exhaustive electrolysis show an EPR signal at room temperature, while the NMR signals are uniformly broadened. Compound 3 appears to be partially reduced by sodium at room temperature and shows uniformly broadened 1H NMR resonances at room temperature that sharpen significantly at −80 °C. The temperature dependence of the spectra are discussed in terms of the effects of relative electron nuclear relaxation processes, chemical exchange, and the results of the DFT calculations.
Continuous Flow Techniques in Organic Synthesis
Authors: Jas Gerhard , Kirschning Andreas
Published: December 2003

As part of the dramatic changes associated with the need for preparing compound libraries in pharmaceutical and agrochemical research laboratories, the search for new technologies that allow automation of synthetic processes has become one of the main topics. Despite this strong trend for automation high‐throughput chemistry is still carried out in batches, whereas flow‐through processes are rather restricted to production processes. This is far from understandable because the main advantages of that approach are facile automation, reproducibility, safety, and process reliability, because constant reaction parameters can be assured. Indeed, methods and technologies are missing that allow rapid transfer from the research level to process development without time‐consuming adaptation and optimization of methods from the laboratory scale to production plant scale. Continuous‐flow processes are considered as a universal lever to overcome these restrictions and, only recently, joint efforts between synthetic and polymer chemists and chemical engineers have resulted in the first continuous‐flow devices and microreactors; these allow rapid preparation of compounds with minimum workup. Many of these approaches use immobilized reagents and catalysts, which are embedded in a structured flow‐through reactor. It is generally accepted, that for achieving best reaction and kinetic parameters for convective‐flow processes monolithic materials are ideally suited as solid phases or polymer supports. In addition, immobilization techniques have to be developed that allow facile regeneration of the active species in the reactor.
Asymmetric Dearomatization of the Furan Ring Promoted by Conjugate Organolithium Addition to (Menthyloxy)(3‐furyl)carbene Complexes of Chromium
Authors: Barluenga José , Nandy Sandip K. , Laxmi Y. R. Santosh , Suárez José Ramón , Merino Isabel , Flórez Josefa , García‐Granda Santiago , Montejo‐Bernardo José
Published: December 2003

The sequential low‐temperature addition reaction of an organolithium compound and methyl triflate to (menthyloxy)(3‐furyl)carbene complexes of chromium and tungsten proceeded with excellent regioselectivity (1,4‐addition) and diastereoselectivity (2,3‐trans disposition of the nucleophile and electrophile groups) to afford new 2,3‐disubstituted (2,3‐dihydro‐3‐furyl)carbene complexes. In addition, a high degree of diastereofacial selectivity was achieved by employing alkenyllithium compounds. After detachment of both the metal fragment and the chiral auxiliary group, trisubstituted 2,3‐dihydrofuran derivatives containing a quaternary stereogenic center at the C3 position were obtained. The characterization, including X‐ray crystallography, of a novel type of stable four‐membered chelate (η2‐alkene)tetracarbonylcarbene complex of chromium is also reported.
Homo‐ and Heterometallic [2×2] Grid Arrays Containing RuII, OsII, and FeII Subunits and their Mononuclear RuII and OsII Precursors: Synthesis, Absorption Spectra, Redox Behavior, and Luminescence Properties
Authors: Bassani Dario M. , Lehn Jean‐Marie , Serroni Scolastica , Puntoriero Fausto , Campagna Sebastiano
Published: December 2003

The absorption spectra, redox behavior, and luminescence properties (both at 77 K in rigid matrices and at room temperature in fluid solution) of a series of [2×2] molecular grids have been investigated. The latter were prepared either by means of sequential self‐assembly, or by a stepwise protection/deprotection procedure, and are based on a ditopic hexadentate ligand 1 in which two terpyridine‐like binding sites are fused together in a linear arrangement. The molecular grids studied include the homometallic species [{Fe(1)}4]8+ (Fe2Fe2), and the heterometallic species [{Ru(1)}2{Fe(1)}2]8+ (Ru2Fe2) and [{Os(1)}2{Fe(1)}2]8+ (Os2Fe2). For comparison purposes, the properties of the mononuclear complexes [Ru(1)2]2+ (1‐Ru) and [Os(1)2]2+ (1‐Os) have been studied. All these compounds exhibit very intense absorption bands in the UV region (ε in the 105–106 M−1 cm−1 range, attributed to spin‐allowed ligand‐centered (LC) transitions), as well as intense metal‐to‐ligand charge‐transfer (MLCT) transitions (ε in the 104–105 M−1 cm−1 range) that extend to the entire visible region. The mononuclear species 1‐Ru and 1‐Os exhibit relatively intense luminescence, both in acetonitrile at room temperature (τ=59 and 18 ns, respectively) and in butyronitrile rigid matrices at 77 K. In contrast, the tetranuclear molecular grids do not exhibit any luminescence, either at room temperature or at 77 K. This is attributed to fast intercomponent energy transfer from the Ru‐ or Os‐based subunits to the low‐lying metal‐centered (MC) levels involving the FeII centers, which leads to fast radiationless decay. The redox behavior of the compounds is characterized by several metal‐centered oxidation and ligand‐centered reduction processes, most of them reversible in nature (as many as twelve for Fe2Fe2). Detailed assignment of each redox process has been made, and it is apparent that these systems can be viewed as multilevel molecular electronic species capable of reversibly exchanging a number of electrons at accessible and predetermined potentials. Furthermore, it is shown that the electronic interaction between specific subunits depends on their location in the structure and on the oxidation states of the other components.
Optimierung eines Fermentationsprozesses mit Data Mining‐Methoden
Authors: Rommel S. , Schuppert A.
Published: December 2003

No abstracts.
Einfluss der Gas/Feststoff‐Vermischung im Einlaufbereich eines Downers auf das globale Verweilzeitverhalten des Gases
Authors: Brust H. , Wirth K.‐E.
Published: December 2003

No abstracts.
„Controller Performance Assessment”︁ – Eine Möglichkeit zur Verbesserung der Prozessführung
Authors: Nohr M. , Boll M.
Published: December 2003

No abstracts.