bluuebunny/crossref_metadata_2025 huggingface dataset:
p- and m-Phenylenebis[trifluoro(phenyl)silicates] and Related Monosilicates
Authors: Kira Mitsuo , Hoshi Takashi , Kabuto Chizuko , Sakurai Hideki
Published: April 2006

Novel anionic pentacoordinate silicates, p-and m-phenylenebis[trifluoro(phenyl)silicates] and related mono-silicates were synthesized and their structures were determined by means of X-ray crystallography and NMR spectroscopy. Addition of a fluoride ion to a difluoro(phenyl)silyl group caused the significant decrease of the σP+ value as determined by 13C NMR spectroscopy.
New Synthesis of 2-Alkoxy-5-methyl-1,4-benzoquinones by the Oxidation of 4-Methylcatechol with Copper(II) Chloride in Alcohols
Authors: Takizawa Yasuomi , Iwasa Yoshihito , Suzuki Toshiaki , Miyaji Hiroyuki
Published: April 2006

4-Methylcatechol was oxidized with copper(II) chloride in various alcohols under oxygen to give the corresponding 2-alkoxy-5-methyl-1,4-benzoquinones.
Structure of Adduct Formed from α-Trichlorostannyl Ketone and Trichloroethynyltin a Direct Evidence for the Carbostannylation of Alkynyl Metals
Authors: Hayashi Akio , Yamaguchi Masahiko , Hirama Masahiro , Kabuto Chizuko , Ueno Masako
Published: April 2006

An adduct formed from 2-trichlorostannyl-3-pentanone and phenylethynyltrichlorotin was isolated, and the structure was determined by spectroscopy and X-ray crystallography. It provides a direct evidence for the carbostannylation of alkynyl metals.
A New Synthetic Route to Prenylphenols. Synthesis of 4′,6′-Dihydroxy-2′-alkenyloxy-3′-(3-methyl-2-butenyl)acetophenones
Authors: Tsukayama Masao , Kikuchi Makoto , Yoshioka Syuji
Published: April 2006

The palladium-catalyzed coupling reaction of 4′,6′-bis(benzyloxy)-3′-iodo-2′-methoxyacetophenone with 2-methyl-3-butyn-2-ol gave 4′,6′-bis(benzyloxy)-3′-(3-hydroxy-3-methylbutynyl)-2′-methoxyacetophenone (5). Demethylation and bromination of the benzoate obtained from 5 with BBr3 gave 4′,6′-bis(benzoyloxy)-3′-(3-bromo-3-methylbutyl)-2′-hydroxyacetophenone (8). O-Prenylation of 8 with prenyl bromide, followed by hydrolysis of the resultant compound gave 4′,6′-dihydroxy-2′-prenyloxy-3′-prenylacetophenone. In a similar manner, 4′,6′-dihydroxy-2′-geranyloxy-3′-prenylacetophenone also was prepared from 8 and geranyl bromide.
Synthesis of Sm2Fe17Cx via the Arc Melting of Sm, SmC2, and Fe
Authors: Izumi Hirokazu , Machida Ken-ichi , Otsuka Daisuke , Adachi Gin-ya
Published: April 2006

An interstitial rare earth carbide Sm2Fe17Cx (x < 1) has been prepared from Sm metal, SmC2, and Fe by a cast method, and the magnetic property was investigated. The magnetization characteristics fairly agreed with those of the Sm2Fe17Cx compound obtained by the conventional method, and the result demonstrated that Sm metal can be partially replaced by SmC2. However, Sm2Fe17Cx hardly formed without some amounts of Sm metal and the sample with x > 1 was a mixture of α-Fe and an unknown phase.
Hafnium-Hydride Complexes Anchored to Silica. Catalysts of the Low Temperature Hydrogenolysis of Alkanes and Hydrogenation of Olefins
Authors: Ornelas Lindora d’ , Reyes Sheila , Quignard Françoise , Choplin Agnès , Basset Jean-Marie
Published: April 2006

Silica grafted hafnium hydride complexes were synthesized from tetra(neopentyl)hafnium and a partially dehydroxylated silica. These surface complexes are catalysts for hydrogenolysis of neopentane and butane and for hydrogenation of isobutene and propene, under mild conditions. Their catalytic properties are compared to the related supported Zr Hydride complexes.
Synthesis of Five-membered Heterocycles by Reactions of N-Substituted-2-aminomethyloxiranes with Heterocumulenes
Authors: Karikomi Michinori , Yamazaki Tohru , Toda Takashi
Published: April 2006

Various five-membered heterocyclic compounds were synthesized by the reactions of N-substituted-2-aminomethyloxiranes with several different heterocumulenes in good yields.
121Sb Mössbauer Spectra of Hexafluorocumyl Alcohol Complexes of Sb(V), and of Sb(III) with Negative Quadrupole Coupling Constants
Authors: Takeda Masuo , Takahashi Masashi , Yanagida Yasuo , Kojima Satoshi , Akiba Kin-ya
Published: April 2006

The antimony-121 Mössbauer spectra of antimony(V) complexes of hexafluorocumyl alcohol show that the oxygen atoms of the ligand attract 5s electrons of antimony atoms more than do chlorine atoms, but that the reverse is true for the 5pz electrons of the antimony atoms. The antimony(III) complexes of the same ligand exhibit large negative values of e2qQ, being only the second example of this negative sign.
Metal Vibration in an Ionophoric Biscalix[4]arene
Authors: Ohseto Fumio , Shinkai Seiji
Published: April 2006

A biscalix[4]arene linked with two poly(oxyethylene) groups was synthesized. It was spectrometrically detected by temperature-dependent 1H-NMR spectroscopy that alkali metal cations such as Na+ or K+ really “vibrates” between two metal-binding sites in the NMR time-scale.
Synthesis of Novel Rhenium(I) Enolate Complexes as Active Key Intermediates in the Catalytic Aldol Type Reaction
Authors: Hirano Masafumi , Ito Yuji , Hirai Miwa , Fukuoka Atsushi , Komiya Sanshiro
Published: April 2006

Rhenium(I) dinitrogen complex cis-ReH(N2)(PMe2Ph)4 catalyzes an aldol type reaction of ethyl cyanoacetate with benzaldehyde under moderate conditions. Rhenium enolate complexes Re(NCCRCO2R′)(NCCHRCO2R′)(PMe2Ph)4 (R = H, R′ = Me; R = H, R′ = Et; R = H, R′ = n-Bu; R = Me, R′ = Et) and Re(NCCHCO2Et)[NC(EtO2C)C=CHPh](PMe2Ph)4 as active intermediates of the aldol type reactions have been isolated.
Efficient and Regioselective Preparation of an Eight-membered Interglycosidic Benzylidene Derivative of β-Cyclodextrin
Authors: Sakairi Nobuo , Kuzuhara Hiroyoshi
Published: April 2006

Heptakis(6-O-pivaloyl)-β-cyclodextrin, prepared in high yield by pivaloylation of β-cyclodextrin (β-CD), was treated with α,α-dimethoxytoluene in the presence of (+)-10-camphorsulfonic acid to give a 46% yield of eight-membered interglycosidic benzylidene acetal, 31,22-O-benzylidene-61,62,63,64,65,66,67-hepta-O-pivaloylcyclomaltoheptaose. Further reductive ring-opening reaction or acid hydrolysis of the benzylidene group gave versatile intermediates for regioselective modification of β-CD.
Physicochemical Properties of 2-Methylthio-4-methylphenol, a Model Compound of the Novel Cofactor of Galactose Oxidase
Authors: Itoh Shinobu , Hirano Keisuke , Furuta Akihiro , Komatsu Mitsuo , Ohshiro Yoshiki , Ishida Akito , Takamuku Setsuo , Kohzuma Takamitsu , Nakamura Nobuhumi , Suzuki Shinnichiro
Published: April 2006

Physicochemical properties of 2-methylthio-4-methylphenol (1) were examined in order to obtain information about the nature of the newly found cofactor of galactose oxidase. Electrochemical studies and theoretical calculations indicated that the methylthio group works as an electron-withdrawing substituent to stabilize the radical species (one-electron oxidation state) of 1. The absorption spectrum obtained by the pulse radiolysis of 1 was very close to that of the oxidized apoenzyme.
Glucose Sensitivity of Thiol-modified Gold Electrodes Having Immobilized Glucose Oxidase and 2-Aminoethylferrocene
Authors: Kajiya Yoshio , Okamoto Tsuyoshi , Yoneyama Hiroshi
Published: April 2006

A novel amperometric glucose sensor was fabricated in which glucose oxidase and 2-aminoethylferrocene as an electron mediator were chemically bound to self-assembled 4-aminothiophenol monolayer on gold electrode with use of glutaraldehyde as a cross linking agent. The glucose sensor prepared under optimal conditions showed sensitivities more than 30 μA cm−2 for 20 mM of glucose.
Reduction of Chromium(VI) by Water-Extracts from Withered Oak Leaves
Authors: Arakawa Hirohumi , Tsushima Masato , Kishi Masami , Watanabe Norimoto
Published: April 2006

Introduction of water-extracts from withered oak leaves into potassium chromate readily diminished Cr(VI) to give water soluble chromium species which are presumably composed of tannin and Cr(III). Thus, this method is useful for treatment of potential hazards like Cr(VI).
Facile C-Se and C-S Bond Cleavages in Diorganyl Selenides and Sulfides by Iodine
Authors: Nakanishi Warô
Published: April 2006

The C-Se and C-S bonds in ArSeCH2SeAr, PhCH2SeCH2SeCH2Ph, (p-t-BuC6H4SeCH2)2, 1,8-(MeSe)2C10H6, PhCH2SeMe, PhSCH2SPh, and PhCH2SCH2SCH2Ph are easily cleaved by iodine, while those of PhSe(CH2)3SePh, 1-MeSeC10H7, PhSeCH2I, and PhCH2SMe are not. The driving force of the reaction is also discussed.
Preparation of Chiral 1,2-Alkanediols with Baker’s Yeast-Mediated Oxidation
Authors: Kometani Tadashi , Morita Yasufumi , Furui Hideyuki , Yoshii Hidefumi , Matsuno Ryuichi
Published: April 2006

(S)-1,2-Alkanediols, which were the opposite configuration to those produced by baker’s yeast-mediated bioreduction of corresponding 1-hydroxy-2-alkanones, were prepared by baker’s yeast-mediated oxidation. Treatment of racemic 1,2-alkanediols with baker’s yeast under the aerobic condition followed by removal of the corresponding 1-hydroxy-2-alkanones, which were produced by enantioselective oxidation of (R)-1,2-alkanediols, afforded (S)-1,2-alkanediols.
Catalytic Stereoselective Synthesis of 2-Amino-2-Deoxy-α-D-Glucopyranosides and Galactopyranosides
Authors: Matsubara Koki , Mukaiyama Teruaki
Published: April 2006

In the presence of a catalyst generated from SnCl4 and a silver salt, various 2-amino-2-deoxy-α-D-glucopyranosides or galactopyranosides are stereoselectively synthesized in good yields with high stereoselectivities through anomerization step starting from 1,3,4,6-tetra-O-acetyl-2-deoxy-2-(2,2,2-trichloroethoxycarbonylamino)-β-D-glucopyranose or galactopyranose and alkyl trimethylsilyl ethers, respectively.
Reaction of C60 with Chlorophenyldiazirine. Spectral and Electronic Properties of the C60-Chlorophenylcarbene 1:1 Adduct
Authors: Komatsu Koichi , Kagayama Akifumi , Murata Yasujiro , Sugita Nobuyuki , Kobayashi Kaoru , Nagase Shigeru , Wan Terence S M
Published: April 2006

A reaction of C60 with an equimolar amount of chlorophenyldiazirine in refluxing toluene afforded the C60-chlorophenylcarbene 1:1 adduct in 37% yield. The adduct was shown to have the cyclopropane structure by 13C NMR and exhibited reversible reduction waves at the potential about 0.1 V more negative and an irreversible oxidation peak at nearly the same potential as compared with those of C60 itself.
Infrared External Reflection Spectra of Langmuir Films of Stearic Acid and Cadmium Stearate
Authors: Sakai Hiroshi , Umemura Junzo
Published: April 2006

In situ FT-IR external reflection spectra of spread monolayers (Langmuir films) of stearic acid and Cd stearate on the water surface were recorded at various surface areas. In the stearic acid monolayer, the trans-gauche conformational change upon monolayer compression was observed, while only the all-trans conformer was observed in the Cd stearate monolayer. Even in largely expanded monolayers of Cd stearate, present is the rigid crsytalline island instead of the rather flexible island in the acid monolayer.
Anormaly of 35Cl NMR Spin-Lattice Relaxation Rate for the Chloride Anion in the Capsular Complex with Macrotricyclic Quaternary Ammonium Ion
Authors: Ichikawa Kazuhiko , Yamamoto Akira , Hossain MD Alamgir
Published: April 2006

The inclusion of chloride ion into homemade macrotricyclic tetra-quaternary ammonium cation MQA4+ has been characterized from the measurement of 35Cl NMR spin-lattice relaxation rate R1. The observed anormaly in the R( = [Cl−]t/[MQA4+]t) dependence of R1 was simulated by a model of the chemical exchange reaction betwen the capsulated Cl− in a intramolecular cavity of MQA4+ and the Cl− outside it. The R1,c for the former is faster than that for the aqueous Cl− complex by about three times. Thus, R1 plays a significant role as a quantitative prove of the types of the local environment around chloride ions in solution.
Efficient Hg(II) Ion Transport through Liquid Membranes by Diamide Derivatives of Methionine with a 8-Quinolyl Group
Authors: Kasuga Kazuyuki , Hirose Takuji , Takahashi Toshikazu , Hiratani Kazuhisa
Published: April 2006

Several new diamide compounds with a 8-quinolyl group were synthesized from methionine and their metal ion transport abilities as carriers through liquid membranes were investigated. Hg(II) ion was transported most effectively by these carriers. The selectivity for Hg(II) over Cu(II) was improved by the introduction of a bulky p-toluoyl group as the acyl group on the 2-acylamino substituent.
Ring Opening of Epoxides with Acetone Cyanohydrin Catalyzed by Lanthanoid(III) Alkoxides
Authors: Ohno Hiroshi , Mori Atsunori , Inoue Shohei
Published: April 2006

Ring opening of epoxide and aziridine with acetone cyanohydrin is promoted by a catalytic amount of lanthanoid(III) alkoxide to provide β-hydroxy nitrile and β-amino nitrile, respectively.
Fractures of the acetabulum in osteogenesis imperfecta
Authors: Darmanis S. , Bircher M.
Published: April 2006

We describe two patients aged 16 and 25 years with osteogenesis imperfecta who sustained displaced fractures of the acetabulum following minor trauma. The femoral heads were deformed by impact against the acetabular margin and both cases underwent surgical reconstruction. The quality of the bone and soft tissues made the operations challenging. There were potential complications specific to osteogenesis imperfecta, including bleeding, the creation of secondary fracture lines and shredding of the soft-tissue. The cases provide useful guidelines for addressing these difficulties.
Constrained total hip arthroplasty in a paediatric patient with cerebral palsy and painful dislocation of the hip
Authors: Blake S. M. , Kitson J. , Howell J. R. , Gie G. A. , Cox P. J.
Published: April 2006

We describe a patient with cerebral palsy, of normal intelligence, who could not walk but who by the age of 16 had been successfully managed with a staged bilateral total hip arthroplasty using a constrained liner.
The role of the dorsal vertebral cortex in the stability of transpedicular screws
Authors: Karataglis D. , Kapetanos G. , Lontos A. , Christodoulou A. , Christoforides J. , Pournaras J.
Published: April 2006

The aim of this biomechanical study was to investigate the role of the dorsal vertebral cortex in transpedicular screw fixation. Moss transpedicular screws were introduced into both pedicles of each vertebra in 25 human cadaver vertebrae. The dorsal vertebral cortex and subcortical bone corresponding to the entrance site of the screw were removed on one side and preserved on the other. Biomechanical testing showed that the mean peak pull-out strength for the inserted screws, following removal of the dorsal cortex, was 956.16 N. If the dorsal cortex was preserved, the mean peak pullout strength was 1295.64 N. The mean increase was 339.48 N (26.13%; p = 0.033). The bone mineral density correlated positively with peak pull-out strength.

Preservation of the dorsal vertebral cortex at the site of insertion of the screw offers a significant increase in peak pull-out strength. This may result from engagement by the final screw threads in the denser bone of the dorsal cortex and the underlying subcortical area. Every effort should be made to preserve the dorsal vertebral cortex during insertion of transpedicular screws.
The Management of Incisional Hernia
Authors: Kingsnorth Andrew
Published: April 2006

Many thousand laparotomy incisions are created each year and the failure rate for closure of these abdominal wounds is between 10–15%, creating a large problem of incisional hernia. In the past many of these hernias have been neglected and treated with abdominal trusses or inadequately managed with high failure rates. The introduction of mesh has not had a significant impact because surgeons are not aware of modern effective techniques which may be used to reconstruct defects of the abdominal wall. This review will cover recent advances in incisional hernia surgery which affect the general surgeon, and also briefly review advanced techniques employed by specialist surgeons in anterior abdominal wall surgery.
Improving Hand-Washing Performance – A Crossover Study of Hand-Washing in the Orthopaedic Department
Authors: Macdonald Duncan JM , McKillop Elisabeth CA , Trotter Sylvia , Gray Alastair JR
Published: April 2006

INTRODUCTION

Effective hand-washing is essential for reducing the spread of infection in hospitals. We aimed to evaluate hand-washing performance of hospital personnel and to determine if this could be improved by education.

MATERIALS AND METHODS

A total of 55 personnel working in the orthopaedic department were asked to clean their hands using an alcohol gel containing a clear fluorescent substance. They were unaware of the assessment method. Performance was assessed by examining their hands under UV light to identify areas that had been neglected. Subjects could visualise which areas they had missed and were then educated regarding hand-washing technique and retested after 7 days.

RESULTS

Of the 55 subjects, 53 completed the study. Individual performance varied widely. Following a simple educational intervention, 49 out of 53 subjects improved from an average of 7.8% to 2.3% area missed (P < 0.001).

CONCLUSIONS

We suggest that hand-washing effectiveness needs to be improved and that a simple educational intervention can be effective.
Mammography in Symptomatic Women Attending a Rapid Diagnosis Breast Clinic: A Prospective Study
Authors: Biggs MJP , Ravichandran D
Published: April 2006

INTRODUCTION

We determined whether it is safe to avoid mammograms in a group of symptomatic women with a non-suspicious history and clinical examination.

PATIENTS AND METHODS

Symptomatic women aged 35 years or over newly referred to a rapid-diagnosis breast clinic underwent mammography on arrival in the clinic. A breast radiologist reported on the mammograms. An experienced clinician who was unaware of the mammogram findings examined patients and decided whether a mammogram was indicated or not. If not, a management plan was formulated. Mammogram findings were then provided to the clinician and any change to the original management plan as a result of mammography was recorded.

RESULTS

In two-thirds (67%) of 218 patients, the clinician felt a mammogram was indicated. Half (46%) of these mammograms showed an abnormality; of these abnormal mammograms, 41% were breast cancer. Among the third (n = 71) of mammograms felt not to be indicated, 3 showed abnormalities of which 2 were breast cancer. One cancer was not suspected clinically or mammographically but was diagnosed on cyto/histopathological assessment.

CONCLUSIONS

A significant proportion of patients attending a symptomatic breast clinic have a non-suspicious history and normal clinical findings on examination. However, even in this group avoiding mammograms risks missing clinically occult breast cancers. It would appear sensible to offer mammograms to all symptomatic women over 35 years of age.
Letters and Notes in Orthopaedic Surgery
Authors: Hook Samantha E , Banister Gordon C , Topliss Claire , Webb Jonathan
Published: April 2006

INTRODUCTION

Accurate written communication is essential in orthopaedic surgery. Incomplete and poorly structured letters can lead to poor knowledge of a patient's diagnosis.

MATERIALS AND METHODS

Structured and traditional letter formats were compared for speed of reading and preference by general practitioners (GPs), consultants, registrars and out-patient nursing staff. In addition, out-patient clinic letters and notes were analysed and compared for speed of reading and ease of assimilating information and content.

RESULTS

There was overwhelming preference for the structured letter format. This style of letter could be read significantly more quickly with information better assimilated and relevant data included more frequently. However, only 26% of letters generated contained a complete set of information sought by GPs and hospital staff.

CONCLUSIONS

Structured letters are better in orthopaedics because it is easier to access the contents. The structured format disciplines medical staff to address essential information. Even with a structured format the majority of letters omitted essential information. Training in letter writing is necessary. A structured letter format next to dictating machines might improve the quality of letters generated.
PSA Testing: Are Patients Aware of What Lies Ahead?
Authors: Lamplugh Marc , Gilmore Paul , Quinlan Timothy , Cornford Philip
Published: April 2006

INTRODUCTION

Screening for prostate cancer with serum prostate specific antigen (PSA) remains a controversial topic. The UK NHS Executive has issued extensive guidance stressing the importance of adequate counselling prior to performing this test. This study aims to assess men's knowledge of the PSA test at the time of their referral and their attitude towards screening.

PATIENTS AND METHODS

A total of 219 men referred to urology via the ‘fast track’ prostate cancer service were recruited into the study. Of these, 191 were referred from primary care and 28 from secondary care. All men completed a questionnaire regarding their knowledge and expectation of the test.

RESULTS

The response rate for completed questionnaires was 100%. Overall, 91 (41.5%) men were aware that their PSA had been performed prior to referral and only 79 (36%) men understood why the test was being done. Patients referred from secondary care appeared to be better informed. Despite these figures, 175 (80%) men said they would recommend PSA testing to a friend or colleague, and 196 (89%) men said the test should be broadly publicised.

CONCLUSIONS

Nearly two-thirds of the men referred to urology with an elevated PSA were unaware that they had even had their PSA done. Information about the limitations of PSA testing and the consequence of a positive test result had been deficient. Informed counselling for the PSA test should form part of the consultation of any physician intending to undertake this test whether for lower urinary tract symptoms or for prostate cancer screening.
The Effects of 1α,25-Dihydroxyvitamin D3 on the Expression of DNA Replication Genes
Authors: Eelen Guy , Verlinden Lieve , Van Camp Mark , Van Hummelen Paul , Marchal Kathleen , De Moor Bart , Mathieu Chantal , Carmeliet Geert , Bouillon Roger , Verstuyf Annemieke
Published: April 2006

To identify key genes in the antiproliferative action of 1,25(OH)2D3, MC3T3-E1 mouse osteoblasts were subjected to cDNA microarray analyses. Eleven E2F-driven DNA replication genes were downregulated by 1,25(OH)2D3. These results were confirmed by quantitative RT-PCR in different cell types, showing the general nature of this action of 1,25(OH)2D3.

Introduction: 1α,25-Dihydroxyvitamin D3 [1,25(OH)2D3] has a potent antiproliferative action characterized by a blocked transition from the G1- to the S-phase of the cell cycle. This study aims to identify genes whose expression is markedly altered after 1,25(OH)2D3 treatment in parallel with or preceding the observed G1-arrest.

Materials and Methods: The cDNA microarray technique was used, and the expression of approximately 4600 genes in MC3T3-E1 mouse osteoblasts was studied 6 and 12 h after treatment with 10−8 M 1,25(OH)2D3. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analyses were performed on MC3T3-E1 cells and on wildtype and vitamin D receptor (VDR) knockout primary murine epidermal keratinocytes (VDRwtMEKs, VDR−/−MEKs) and murine mammary tumor cells (GR) to confirm the microarray data.

Results and Conclusions: After 12 h of treatment, in parallel with the 1,25(OH)2D3-induced G1 arrest, a particular set of DNA replication genes including a cell division cycle 6 homolog, a DNA polymerase alpha subunit, proliferating cell nuclear antigen, two DNA polymerase delta subunits, and flap-structure specific endonuclease 1, was downregulated at least 2-fold. These genes are known targets of the E2F family of transcription factors, which are probably the central mediators of this action of 1,25(OH)2D3. Indeed, as shown by transfection assays with an E2F reporter construct, 12- and 24-h treatment of MC3T3-E1 cells with 1,25(OH)2D3 reduced E2F activity by 49% and 73%, respectively. Quantitative RT-PCR analyses confirmed the downregulation of these DNA replication genes by 1,25(OH)2D3 in MC3T3-E1, GR, and VDRwtMEKs cells, but not in VDR−/−MEKs cells, showing that this 1,25(OH)2D3-driven antiproliferative action is of a general nature and depends on a functional VDR.
Umbilical Venous IGF-1 Concentration, Neonatal Bone Mass, and Body Composition
Authors: Javaid MK , Godfrey KM , Taylor P , Shore SR , Breier B , Arden NK , Cooper C
Published: April 2006

IGF-1 is a key growth factor during fetal life. Using DXA, we found that the concentration of IGF-1 in umbilical cord serum is strongly related to neonatal whole body bone mineral content, lean mass, and fat mass. However IGF-1 did not explain the relationships of maternal smoking, fat mass, and physical activity with neonatal bone mass. The study supports a direct role for circulating IGF-1 in growth of the fetal skeleton.

Introduction: Evidence is accumulating that the risk of osteoporosis in later life may be determined in part by environmental influences during intrauterine and early postnatal life. We previously reported that maternal birthweight, smoking, fat stores, and physical activity during pregnancy predict neonatal bone mass. While the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis is an important determinant of postnatal skeletal growth, there are few data relating the concentration of growth factors in umbilical cord blood to bone mineral content (BMC) and other indices of body composition in the newborn infant.

Materials and Methods: We conducted a population-based study in a cohort of full-term, newborn infants whose mothers were characterized for lifestyle, body composition, and nutrition through their normal pregnancies. In a sample of 119 infants from the cohort, we related cord serum IGF-1 and insulin-like growth factor binding protein (IGFBP)-3 concentrations to neonatal body composition measured by DXA and evaluated the extent to which this cytokine mediates the previously reported effects of maternal diet and lifestyle on neonatal bone mass.

Results: There were strong positive associations between cord serum IGF-1 concentration and whole body BMC (r = 0.38, p < 0.001), whole body lean mass (r = 0.40, p < 0.001), and whole body fat mass (r = 0.50, p < 0.001) after adjusting for gestational age and sex. There was no association between cord serum IGF-1 and BMC adjusted for bone size. Neither cord serum IGF-1 nor IGFBP-3 explained the relationships that we previously reported between maternal influences and neonatal bone mass.

Conclusions: Cord serum IGF-1 is more closely related to the size of the neonatal skeleton than to its degree of mineralization. Documented maternal determinants of neonatal bone mass seem to mediate their effects independently of variations in cord serum IGF-1 in healthy pregnancies.
Vignettes in Osteoporosis: A Road Map to Successful Therapeutics
Authors: Rosen Clifford J , Black Dennis M , Greenspan Susan L
Published: April 2006

The diagnosis and management of osteoporosis have become increasingly more complex as new drugs enter the marketplace and meta-analyses of randomized trials with “other” agents become more prolific. We describe five common clinical scenarios encountered in the practice of osteoporosis medicine and various road maps that could lead to successful therapy.

Introduction: The diagnosis and treatment of osteoporosis have changed dramatically in the last decade. Advances in diagnostic technologies and a range of newer treatment options have provided the clinician with a wide array of choices for treating this chronic disease. Despite the issuance of several “guidelines” and practice recommendations, there still remains confusion among clinicians about basic approaches to the management of osteoporosis. This paper should be used as a case-based approach to define optimal therapeutic choices.

Materials and Methods: Five representative cases were selected from two very large clinical practices (Bangor, ME; Pittsburgh, PA). Diagnostic modalities and treatment options used in these cases were selected on an evidence-based analysis of respective clinical trials. Subsequent to narrative choices by two metabolic bone disease specialists (SG and CR), calculation of future fracture risk and selection of potential alternative therapeutic regimens were reviewed and critiqued by an epidemiologist (DB).

Results: A narrative about each case and possible management choices for each of the five cases are presented with references to justify selection of the various therapeutic options. Alternatives are considered and discussed based on literature and references through July 2003. The disposition of the individual patient is noted at the end of each case.

Conclusions: A case-based approach to the management of osteoporosis provides a useful interface between guidelines, evidence-based meta-analyses, and clinical practice dilemmas.
Adipogenic Differentiation of Human Adult Stem Cells From Bone Marrow Stroma (MSCs)
Authors: Sekiya Ichiro , Larson Benjamin L , Vuoristo Jussi T , Cui Jian-Guo , Prockop Darwin J
Published: April 2006

We assayed gene expressions during adipogenesis of human MSCs. Microarray assays demonstrated time-dependent increases in expression of 67 genes, including 2 genes for transcription factors that were not previously shown to be expressed during adipogenesis.

Introduction: Increased numbers of bone marrow adipocytes have been observed in patients with osteoporosis and aplastic anemia, but the pathological mechanisms remain unknown. Recently, microarray assays for mRNAs were used to follow adipogenic differentiation of the preadipocytic cell line, 3T3-L1, but adipogenic differentiation has not been examined in primary cells from bone marrow. Here we defined the sequence of gene expression during the adipogenesis ex vivo of human cells from bone marrow referred to as either mesenchymal stem cells or marrow stromal cells (MSCs).

Materials and Methods: MSCs were plated at extremely low densities to generate single-cell derived colonies, and adipogenic differentiation of the colonies assayed by accumulation of fat vacuoles, time-lapse photomicroscopy, microarrays, and reverse transcriptase-polymerase chain reaction (RT-PCR) assays.

Results and Conclusions: About 30% of the colonies differentiated to adipocytes in 14 days and about 60% in 21 days. Cell proliferation was inhibited by approximately 50% in adipogenic medium. The differentiation occurred primarily at the center of the colonies, and a few adipocytes that formed near the periphery migrated toward the centers. RT-PCR assays demonstrated that the differentiation was accompanied by increases in a series of genes previously shown to increase with adipogenic differentiation: peroxisome proliferator activated receptor γ, CCAAT enhancer-binding protein α, acylCoA synthetase, lipoprotein lipase, and fatty acid binding protein 4. We also followed differentiation with microarray assays. Sixty-seven genes increased more than 10-fold at day 1 and 20-fold at day 7, 14, or 21. Many of the genes identified were previously shown to be expressed during adipocytic differentiation. However, others, such as zinc finger E-box binding protein and zinc finger protein 145, were not. This study should serve as a basis for future study to clarify the mechanisms of adipocyte differentiation of MSCs.
Deficiency of Insulin Receptor Substrate-1 Impairs Skeletal Growth Through Early Closure of Epiphyseal Cartilage
Authors: Hoshi Kazuto , Ogata Naoshi , Shimoaka Takashi , Terauchi Yasuo , Kadowaki Takashi , Kenmotsu Shin-Ichi , Chung Ung-Il , Ozawa Hedehiro , Nakamura Kozo , Kawaguchi Hiroshi
Published: April 2006

Morphological analyses in and around the epiphyseal cartilage of mice deficient in insulin receptor substrate-1 (IRS-1) showed IRS-1 signaling to be important for skeletal growth by preventing early closure of the epiphyseal cartilage and maintaining the subsequent bone turnover at the primary spongiosa.

Introduction: IRS-1 is an essential molecule for intracellular signaling by IGF-I and insulin, both of which are potent anabolic regulators of cartilage and bone metabolism. To clarify the role of IRS-1 signaling in the skeletal growth, morphological analyses were performed in and around the epiphyseal cartilage of mice deficient in IRS-1 (IRS-1−/−), whose limbs and trunk were 20–30% shorter than wildtype (WT) mice.

Materials and Methods: The epiphyseal cartilage and the primary spongiosa at proximal tibias of homozygous IRS-1−/− and WT male littermates were compared using histological, immunohistochemical, enzyme cytohistochemical, ultrastructural, and bone histomorphometrical analyses.

Results: In and around the WT epiphyseal cartilage, IRS-1 and insulin-like growth factor (IGF)-I receptors were widely expressed, whereas IRS-2 was weakly localized in bone cells. Chronological observation revealed that height of the proliferative zone and the size of hypertrophic chondrocytes were decreased in WT mice as a function of age, and these decreases were accelerated in the IRS-1−/− cartilage, whose findings at 12 weeks were similar to those of WT at 24 weeks. In the IRS-1−/− cartilage, proliferating chondrocytes with positive proliferating cell nuclear antigen (PCNA) or parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor immunostaining had almost disappeared by 12 weeks. Contrarily, TUNEL+ apoptotic cells were increased in the hypertrophic zone, at the bottom of which most of the chondrocytes were surrounded by the calcified matrix, suggesting the closure of the cartilage. In the primary spongiosa, bone volume, alkaline phosphatase (ALP)+ osteoblasts, TRACP+ osteoclasts, and the osteopontin-positive cement line were markedly decreased. Bone histomorphometrical parameters for both bone formation and resorption were significantly lower in IRS-1−/− mice, indicating the suppression of bone turnover.

Conclusion: The IRS-1−/− epiphyseal cartilage exhibited insufficient proliferation of chondrocytes, calcification of hypertrophic chondrocytes, acceleration of apoptosis, and early closure of the growth plate. Thus, the data strongly suggest that IRS-1 signaling is important for the skeletal growth by preventing early closure of the epiphyseal cartilage and by maintaining the subsequent bone turnover at the primary spongiosa.
Estrogen Regulates the Production of VEGF for Osteoclast Formation and Activity in op/op Mice
Authors: Kodama Ichiro , Niida Shumpei , Sanada Mitsuhiro , Yoshiko Yuji , Tsuda Mikio , Maeda Norihiko , Ohama Koso
Published: April 2006

op/op mice have a severe deficiency of osteoclasts because of lacking functional M-CSF that is an essential factor of osteoclast differentiation and function. We now report that OVX induces osteoclast formation and cures osteopetrosis by increasing the VEGF that regulates osteoclast formation in these mice.

Introduction: We have found that estrogen deficiency induced by ovariectomy (OVX) upregulated osteoclast formation in op/op mice. We have recently demonstrated that vascular endothelial growth factor (VEGF) could substitute for macrophage colony-stimulating factor (M-CSF) in the support of osteoclastic bone resorption in these mice. Therefore, in this study, we wished to assess the effects of VEGF on bone loss induced by OVX in these mice.

Materials and Methods: Eight-week-old op/op mice were bilateral OVX or sham-operated. Mice were killed at 8, 10, and 12 weeks of age, and femurs were removed for preparations. Some OVX mice were treated with three consecutive injections of 120 μl/body of VEGF-neutralizing antibody at 12-h intervals starting from 36 h before death at 4 weeks after OVX. VEGFR-1/Fc chimeric protein (600 μg/kg/day) or 17β-estradiol (0.16 μg/day) was administered in a dorsal subcutaneous pocket of the mice at the time of OVX. These mice were killed 2 weeks after surgery. Changes of serum levels of VEGF were measured by ELISA. Changes of mRNA levels of VEGF, Flt-1, interleukin-6, and osteoclast differentiation factor (ODF/TRANCE/RANKL) in bone tissue were measured by reverse transcriptase-polymerase chain reaction.

Results: In OVX op/op mice, trabecular bone volume of the femur was decreased, and the number of osteoclasts was significantly increased. Serum levels of VEGF were demonstrated to be higher in OVX mice than in sham-operated mice. VEGF mRNA, Flt–1 mRNA, interleukin-6 mRNA, and RANKL mRNA levels in bone tissue were elevated in OVX mice over that in sham-operated mice. The increase in osteoclast number was inhibited by VEGF antagonist treatment in OVX mice.

Conclusions: In this study, we have demonstrated that the production of VEGF and RANKL stimulated by OVX results in increased osteoclast formation in op/op mice.
Vitamin D and Calcium Supplementation Prevents Osteoporotic Fractures in Elderly Community Dwelling Residents: A Pragmatic Population-Based 3-Year Intervention Study
Authors: Larsen Erik Roj , Mosekilde Leif , Foldspang Anders
Published: April 2006

This study of 9605 community-dwelling residents supports that vitamin D and calcium supplementation may prevent osteoporotic fractures in elderly in a northern European region known to be deficient in vitamin D, especially during winter periods.

Introduction: We evaluated the effect of two programs for the prevention of osteoporotic fractures leading to acute hospital admission in a population of elderly community-dwelling residents.

Materials and Methods: This was a factorial, cluster-randomized, pragmatic, intervention study. We included 9605 community-dwelling residents aged 66+ years. We offered a prevention program of a daily supplement of 1000 mg of elemental calcium as calcium carbonate and 400 IU (10 μg) of vitamin D3 to a total of 4957 participants. Another program with evaluation and suggestions for the improvement of the domestic environment was offered to a total of 5063 participants. Both programs included revision of the resident's current pharmaceutical treatment. We achieved information on osteoporotic fractures in the study population from the Danish Hospital Registration Database. We defined osteoporotic fractures as low energy fractures of the proximal humerus, distal forearm, vertebral column, pelvis, cervical femur, and intertrochanteric femur.

Results: Active participation was 50.3% in the Calcium and Vitamin D Program and 46.4% in the Environmental and Health Program. We observed a 16% reduction in fracture incidence rate (relative risk [RR], 0.84; CI, 0.72–0.98; p < 0.025) among male and female residents offered the Calcium and Vitamin D Program (intention-to-prevent analysis).

Conclusions: This study supports that vitamin D and calcium supplementation may prevent osteoporotic fractures in community-dwelling elderly people in a northern European region known to be deficient in vitamin D, especially during winter periods.
Relationship Between Changes in Biochemical Markers of Bone Turnover and BMD to Predict Vertebral Fracture Risk
Authors: Sarkar Somnath , Reginster Jean-Yves , Crans Gerald G , Diez-Perez Adolfo , Pinette Karen V , Delmas Pierre D
Published: April 2006

The change in BMD is a poor predictor of vertebral fracture risk after raloxifene treatment. One-year percent change in bone turnover and BMD was used to predict vertebral fracture risk. The percent change in osteocalcin was determined to be a better predictor of vertebral fracture risk than BMD.

Introduction: The association between baseline BMD and fracture risk is well understood. However, the relationship between changes in BMD and fracture risk is not well defined. It has previously been demonstrated that BMD change was a poor predictor of vertebral fracture risk in raloxifene-treated women, whereas bone turnover markers were significantly associated with fracture risk. In the current analysis, we explore the prediction of vertebral fracture risk using changes in both BMD and bone turnover.

Materials and Methods: The Multiple Outcomes of Raloxifene Evaluation (MORE) trial was a randomized, placebo-controlled trial of 7705 women with osteoporosis treated with raloxifene 60 or 120 mg/day for 3 years. Markers of bone turnover were measured in one-third of the study population (n = 2503), and the present analyses include these women. Logistic regression models were constructed using one-year percent changes in BMD and bone turnover and relevant baseline demographics to predict the risk of vertebral fracture with pooled raloxifene therapy at 3 years. All covariates were standardized before modeling to facilitate direct comparisons between changes in BMD and bone turnover.

Results and Conclusion: Prevalent vertebral fracture status (p < 0.0001), baseline lumbar spine BMD (p < 0.0001), and number of years postmenopausal (p = 0.0005) were independent predictors of fracture risk in raloxifene-treated patients. Therapy-by-change in femoral neck BMD (p = 0.02) and therapy-by-change in osteocalcin (OC; p = 0.01) were also significant for all treatment groups, indicating that changes in BMD and OC have different effects on fracture risk for the placebo and pooled raloxifene groups. The final model included significant baseline variables and change in OC (p = 0.01), whereas change in femoral neck BMD was not significant. After adjustment of each significant baseline variable, the percent change in OC was better able to predict the reduction in vertebral fracture risk than the percent change in femoral neck BMD in patients treated with raloxifene.
Effect of 6-Month Whole Body Vibration Training on Hip Density, Muscle Strength, and Postural Control in Postmenopausal Women: A Randomized Controlled Pilot Study
Authors: Verschueren Sabine MP , Roelants Machteld , Delecluse Christophe , Swinnen Stephan , Vanderschueren Dirk , Boonen Steven
Published: April 2006

High-frequency mechanical strain seems to stimulate bone strength in animals. In this randomized controlled trial, hip BMD was measured in postmenopausal women after a 24-week whole body vibration (WBV) training program. Vibration training significantly increased BMD of the hip. These findings suggest that WBV training might be useful in the prevention of osteoporosis.

Introduction: High-frequency mechanical strain has been shown to stimulate bone strength in different animal models. However, the effects of vibration exercise on the human skeleton have rarely been studied. Particularly in postmenopausal women—who are most at risk of developing osteoporosis—randomized controlled data on the safety and efficacy of vibration loading are lacking. The aim of this randomized controlled trial was to assess the musculoskeletal effects of high-frequency loading by means of whole body vibration (WBV) in postmenopausal women.

Materials and Methods: Seventy volunteers (age, 58–74 years) were randomly assigned to a whole body vibration training group (WBV, n = 25), a resistance training group (RES, n = 22), or a control group (CON, n = 23). The WBV group and the RES group trained three times weekly for 24 weeks. The WBV group performed static and dynamic knee-extensor exercises on a vibration platform (35–40 Hz, 2.28–5.09g), which mechanically loaded the bone and evoked reflexive muscle contractions. The RES group trained knee extensors by dynamic leg press and leg extension exercises, increasing from low (20 RM) to high (8 RM) resistance. The CON group did not participate in any training. Hip bone density was measured using DXA at baseline and after the 6-month intervention. Isometric and dynamic strength were measured by means of a motor-driven dynamometer. Data were analyzed by means of repeated measures ANOVA.

Results: No vibration-related side effects were observed. Vibration training improved isometric and dynamic muscle strength (+15% and + 16%, respectively; p < 0.01) and also significantly increased BMD of the hip (+0.93%, p < 0.05). No changes in hip BMD were observed in women participating in resistance training or age-matched controls (−0.60% and −0.62%, respectively; not significant). Serum markers of bone turnover did not change in any of the groups.

Conclusion: These findings suggest that WBV training may be a feasible and effective way to modify well-recognized risk factors for falls and fractures in older women and support the need for further human studies.
CYP3A4 is a Human Microsomal Vitamin D 25-Hydroxylase
Authors: Gupta Ram P , Hollis Bruce W , Patel Shailendra B , Patrick Kennerly S , Bell Norman H
Published: April 2006

The human hepatic microsomal vitamin D 25-hydroxylase protein and gene have not been identified with certainty. Sixteen hepatic recombinant microsomal enzymes were screened for 25-hydroxylase activity; 11 had some 25-hydroxylase activity, but CYP3A4 had the highest activity. In characterized liver microsomes, 25-hydroxylase activity correlated significantly with CYP3A4 testosterone 6β-hydroxylase activity. Activity in pooled liver microsomes was inhibited by known inhibitors of CYP3A4 and by an antibody to CYP3A2. Thus, CYP3A4 is a hepatic microsomal vitamin D 25-hydroxylase.

Introduction: Studies were performed to identify human microsomal vitamin D-25 hydroxylase.

Materials and Methods: Sixteen major hepatic microsomal recombinant enzymes derived from cytochrome P450 cDNAs expressed in baculovirus-infected insect cells were screened for 25-hydroxylase activity with 1α-hydroxyvitamin D2 [1α(OH)D2], 1α-hydroxyvitamin D3 [1α(OH)D3], vitamin D2, and vitamin D3 as substrates. Activity was correlated with known biological activities of enzymes in a panel of 12 characterized human liver microsomes. The effects of known inhibitors and specific antibodies on activity also were determined.

Results: CYP3A4, the most abundant cytochrome P450 enzyme in human liver and intestine, had 7-fold greater activity than that of any of the other enzymes with 1α(OH)D2 as substrate. CYP3A4 25-hydroxylase activity was four times higher with 1α(OH)D2 than with 1α(OH)D3 as substrate, was much less with vitamin D2, and was not detected with vitamin D3. 1α(OH)D2 was the substrate in subsequent experiments. In a panel of characterized human liver microsomes, 25-hydroxylase activity correlated with CYP3A4 testosterone 6β-hydroxylase activity (r = 0.93, p < 0.001) and CYP2C91 diclofenac 4′-hydroxylase activity (r = 0.65, p < 0.05), but not with activity of any of the other enzymes. Activity in recombinant CYP3A4 and pooled liver microsomes was dose-dependently inhibited by ketoconazole, troleandomycin, isoniazid, and α-naphthoflavone, known inhibitors of CYP3A4. Activity in pooled liver microsomes was inhibited by antibodies to CYP3A2 that are known to inhibit CYP3A4 activity.

Conclusion: CYP3A4 is a vitamin D 25-hydroxylase for vitamin D2 in human hepatic microsomes and hydroxylates both 1α(OH)D2 and 1α(OH)D3.