St. Joseph's Hospital

Cavernous malformations are congenital abnormalities of the cerebral vessels that affect 0.5% to 0.7% of the population. They occur in two forms: a sporadic form characterized by isolated lesions, and a familial form characterized by multiple lesions with an autosomal dominant mode of inheritance. The management of patients with cavernous malformations, particularly those with the familial form of the disease, remains a challenge because little is known regarding the natural history. The authors report the results of an ongoing study in which six families afflicted by familial cavernous malformations have been prospectively followed with serial interviews, physical examinations, and magnetic resonance (MR) imaging at 6- to 12-month intervals. A total of 59 members of these six families were screened for protocol enrollment; 31 (53%) had MR evidence of familial cavernous malformations. Nineteen (61%) of these 31 patients were symptomatic, with seizures in 12 (39%), recurrent headaches in 16 (52%), focal sensory/motor deficits in three (10%), and visual field deficits in two (6%). Twenty-one of these 31 patients underwent at least two serial clinical and MR imaging examinations. A total of 128 individual cavernous malformations (mean 6.5 +/- 3.8 lesions/patient) were identified and followed radiographically. During a mean follow-up period of 2.2 years (range 1 to 5.5 years), serial MR images demonstrated 17 new lesions in six (29%) of the 21 patients; 13 lesions (10%) showed changes in signal characteristics, and five lesions (3.9%) changed significantly in size. The incidence of symptomatic hemorrhage was 1.1% per lesion per year. The results of this study demonstrate that the familial form of cavernous malformations is a dynamic disease; serial MR images revealed changes in the number, size, and imaging characteristics of lesions consistent with acute or resolving hemorrhage. It is believed that the de novo development of new lesions in this disease has not been previously reported. These findings suggest that patients with familial cavernous malformations require careful follow-up monitoring, and that significant changes in neurological symptoms warrant repeat MR imaging. Surgery should be considered only for lesions that produce repetitive or progressive symptoms. Prophylactic resection of asymptomatic lesions does not appear to be indicated.

As men age, serum testosterone concentrations decrease, the percentage of body mass that is fat increases, the percentage of lean body mass decreases, and muscle strength decreases. Because these changes are similar to those that occur in hypogonadal men, we hypothesized that increasing the serum testosterone concentration of men over 65 yr of age to that in young men would decrease their fat mass, increase their lean mass, and increase their muscle strength. We randomized 108 men over 65 yr of age to wear either a testosterone patch or a placebo patch in a double blind study for 36 months. We measured body composition by dual energy x-ray absorptiometry and muscle strength by dynamometer before and during treatment. Ninety-six men completed the entire 36-month protocol. Fat mass decreased (-3.0+/-0.5 kg) in the testosterone-treated men during the 36 months of treatment, which was significantly different (P = 0.001) from the decrease (-0.7+/-0.5 kg) in the placebo-treated men. Lean mass increased (1.9+/-0.3 kg) in the testosterone-treated men, which was significantly different (P < 0.001) from that (0.2+/-0.2 kg) in the placebo-treated men. The decrease in fat mass in the testosterone-treated men was principally in the arms (-0.7+/-0.1 kg; P < 0.001 compared to the placebo group) and legs (-1.1+/-0.2 kg; P < 0.001), and the increase in lean mass was principally in the trunk (1.9+/-0.3 kg; P < 0.001). The change in strength of knee extension and flexion at 60 degrees and 180 degrees angular velocity during treatment, however, was not significantly different between the two groups. We conclude that increasing the serum testosterone concentrations of normal men over 65 yr of age to the midnormal range for young men decreased fat mass, principally in the arms and legs, and increased lean mass, principally in the trunk, but did not increase the strength of knee extension and flexion, as measured by dynamometer.

To examine the local actions of IGF signaling in skeletal tissue in a physiological context, we have used Cre-mediated recombination to disrupt selectively in mouse osteoblasts the gene encoding the type 1 IGF receptor (Igf1r). Mice carrying this bone-specific mutation were of normal size and weight but, in comparison with normal siblings, demonstrated a striking decrease in cancellous bone volume, connectivity, and trabecular number, and an increase in trabecular spacing. These abnormalities correlated with a striking decrease in the rate of mineralization of osteoid that occurred despite an unexpected osteoblast and osteoclast hyperactivity, detected from the significant increments in both osteoblast and erosion surfaces. Our findings indicate that IGF1 is essential for coupling matrix biosynthesis to sustained mineralization. This action is likely to be particularly important during the pubertal growth spurt when rapid bone formation and consolidation are required. To examine the local actions of IGF signaling in skeletal tissue in a physiological context, we have used Cre-mediated recombination to disrupt selectively in mouse osteoblasts the gene encoding the type 1 IGF receptor (Igf1r). Mice carrying this bone-specific mutation were of normal size and weight but, in comparison with normal siblings, demonstrated a striking decrease in cancellous bone volume, connectivity, and trabecular number, and an increase in trabecular spacing. These abnormalities correlated with a striking decrease in the rate of mineralization of osteoid that occurred despite an unexpected osteoblast and osteoclast hyperactivity, detected from the significant increments in both osteoblast and erosion surfaces. Our findings indicate that IGF1 is essential for coupling matrix biosynthesis to sustained mineralization. This action is likely to be particularly important during the pubertal growth spurt when rapid bone formation and consolidation are required. Body size and linear bone growth in mammals is affected by cellular signaling pathways controlled by growth factors and hormones (1Efstratiadis A. Int. J. Dev. Biol. 1998; 42: 955-976PubMed Google Scholar). In this regard, a major growth-promoting signaling system consisting of the insulin-like growth factors (IGF, 1The abbreviations used are: IGF, insulin-like growth factor; PBS, phosphate-buffered saline; X-gal, 5-bromo-4-chloro-3-indolyl-β-d-galactopyranoside; AP, alkaline phosphatase IGF1 and IGF2) and the type 1 IGF receptor (IGF1R) regulates embryonic growth, as shown by gene knockout experiments in mice (1Efstratiadis A. Int. J. Dev. Biol. 1998; 42: 955-976PubMed Google Scholar). IGF1 acting through IGF1R also plays central roles in postnatal growth either independently or by mediating growth hormone functions (2Lupu F. Terwilliger J.D. Lee K. Segre G.V. Efstratiadis A. Dev. Biol. 2001; 229: 141-162Crossref PubMed Scopus (643) Google Scholar). Signaling through the IGF1R tyrosine kinase receptor not only promotes cell proliferation, but also mediates anti-apoptotic actions (3Baserga R. Resnicoff M. D'Ambrosio C. Valentinis B. Vitam. Horm. 1997; 53: 65-98Crossref PubMed Scopus (61) Google Scholar, 4Nakae J. Kido Y. Accili D. Endocr. Rev. 2001; 22: 818-835Crossref PubMed Scopus (357) Google Scholar). The IGF system includes a second receptor (IGF2R) devoid of signaling properties, but serving IGF2 turnover, and at least six IGF-binding proteins (IGFBPs) of obscure functional significance (single and also some double mouse mutations ablating IGFBPs have not revealed as yet significant consequences in growth impairment). 2J. Pintar, personal communication. The IGFs are produced locally in various tissues, including bones, and exert autocrine/paracrine functions, but they are also present in serum, mostly associated with IGFBPs. Whether the circulating IGFs act systemically as hormones is currently controversial (5Yakar S. Liu J.L. Stannard B. Butler A. Accili D. Sauer B. LeRoith D. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 7324-7329Crossref PubMed Scopus (1191) Google Scholar, 6D'Ercole A.J. Calikoglu A.S. Growth Horm. IGF Res. 2001; 11: 261-265Crossref PubMed Scopus (21) Google Scholar). A number of in vitro and in vivo studies are progressively unraveling the significance of the IGF system for skeletal development and metabolic control (for a review see Ref. 7Conover C.A. Growth Horm. IGF Res. 2000; 10 Suppl. B: S107-S110Crossref PubMed Scopus (46) Google Scholar). IGF1, by stimulating the proliferation of chondrocytes in the growth plate, plays an essential role in longitudinal bone growth (2Lupu F. Terwilliger J.D. Lee K. Segre G.V. Efstratiadis A. Dev. Biol. 2001; 229: 141-162Crossref PubMed Scopus (643) Google Scholar) and is also involved in the formation of trabecular bone. In fact, chondrocytes and bone cells produce IGFs and express IGF1R (see for example Refs. 8Shinar D.M. Endo N. Halperin D. Rodan G.A. Weinreb M. Endocrinology. 1993; 132: 1158-1167Crossref PubMed Scopus (88) Google Scholar and 9Wang E. Wang J. Chin E. Zhou J. Bondy C.A. Endocrinology. 1995; 136: 2741-2751Crossref PubMed Google Scholar). Studies using osteoblast culture systems have shown that IGF1 stimulates osteoblast proliferation, accelerates their differentiation, and enhances bone matrix production (10Canalis E. Bone. 1993; 14: 273-276Crossref PubMed Scopus (95) Google Scholar, 11Birnbaum R.S. Bowsher R.R. Wiren K.M. J. Endocrinol. 1995; 144: 251-259Crossref PubMed Scopus (55) Google Scholar). In addition, IGF1 is being recognized as a critical factor for bone cell survival (12Parfitt A.M. Mundy G.R. Roodman G.D. Hughes D.E. Boyce B.F. J. Bone Miner. Res. 1996; 11: 150-159Crossref PubMed Scopus (292) Google Scholar, 13Hughes D.E. Boyce B.F. Mol. Pathol. 1997; 50: 132-137Crossref PubMed Scopus (90) Google Scholar, 14Hill P.A. Tumber A. Meikle M.C. Endocrinology. 1997; 138: 3849-3858Crossref PubMed Scopus (186) Google Scholar). Finally, IGF1 also appears to regulate bone resorption, either directly or through its action on osteoblasts that stimulate in turn the formation and function of osteoclasts (15Hill P.A. Reynolds J.J. Meikle M.C. Endocrinology. 1995; 136: 124-131Crossref PubMed Google Scholar). Because of complex relationships in the signaling processes of the IGF regulatory system (1Efstratiadis A. Int. J. Dev. Biol. 1998; 42: 955-976PubMed Google Scholar) on one hand, and intricacies in bone development (16Olsen B.R. Reginato A.M. Wang W. Annu. Rev. Cell Dev. Biol. 2000; 16: 191-220Crossref PubMed Scopus (780) Google Scholar, 17Karsenty G. Wagner E.F. Dev. Cell. 2002; 2: 389-406Abstract Full Text Full Text PDF PubMed Scopus (1204) Google Scholar) on the other, it has been quite difficult to define individualin vivo aspects of the skeletal actions of IGF1, especially those brought about by local (autocrine/paracrine) mechanisms. Nevertheless, progress is being made with the use of genetically modified mice. For example, mice with targeted overexpression of IGF1 in osteoblasts exhibited an increased bone formation rate and increased trabecular and cortical bone volume (18Zhao G. Monier-Faugere M.C. Langub M.C. Geng Z. Nakayama T. Pike J.W. Chernausek S.D. Rosen C.J. Donahue L.R. Malluche H.H. Fagin J.A. Clemens T.L. Endocrinology. 2000; 141: 2674-2682Crossref PubMed Scopus (271) Google Scholar). Remarkably, these changes occurred without an increase in the total number of osteoblasts, suggesting that locally produced IGF1 could exert its anabolic effects primarily by increasing the performance of resident osteoblasts. Nevertheless, firm establishment of causal relationships necessitates complete ablation of IGF signaling by elimination of IGF1R function. In this regard, however, the invariable neonatal lethality ofIgf1r nullizygous mice (19Liu J.P. Baker J. Perkins A.S. Robertson E.J. Efstratiadis A. Cell. 1993; 75: 59-72Abstract Full Text PDF PubMed Scopus (2597) Google Scholar) precluded an examination of the skeletal role of IGF1 during postnatal growth and development. To circumvent this problem, we have now disrupted selectively theIgf1r gene in mouse osteoblasts using thecre/loxP recombination system, and evaluated the bone phenotype. As we report here, this site-specific ablation of IGF signaling impairs the rate of bone formation and severely retards mineralization of osteoid resulting in decreased cancellous bone volume and altered trabecular structure. A DNA fragment representing the human osteocalcin (OC) promoter (20Clemens T.L. Tang H. Maeda S. Kesterson R.A. DeMayo F. Pike J.W. Gundberg C.M. J. Bone Miner. Res. 1997; 12: 1570-1576Crossref PubMed Scopus (83) Google Scholar) was cloned into the pBluescript SK(−) vector to create pOC. A plasmid containing a cDNA encoding cre, which was modified to include a nuclear localization sequence and the human β-actin 3′-untranslated region (provided by Dr. Thomas Doetschman, University of Cincinnati), was cloned into the pKBpA plasmid (18Zhao G. Monier-Faugere M.C. Langub M.C. Geng Z. Nakayama T. Pike J.W. Chernausek S.D. Rosen C.J. Donahue L.R. Malluche H.H. Fagin J.A. Clemens T.L. Endocrinology. 2000; 141: 2674-2682Crossref PubMed Scopus (271) Google Scholar) downstream from a sequence representing the rabbit β-globin second intron flanked by remnants of truncated exons. The derived fused (globin-cre) sequences were then subcloned into pOC downstream from the osteocalcin promoter, to create pOC-cre (Fig. 1 A). The insert of this plasmid (OC-cre) was excised and microinjected into fertilized eggs (FVB-N mouse strain). Transgenic lines were established from 11 founders that were identified by Southern analysis of genomic DNA. Two of the transgenic lines (4 and 6) were analyzed in detail and used in our experiments (see “Results”). Differences in the level and specificity of transgenic expression between the two lines were not detected. Expression of cre mRNA was determined by Northern analysis of total RNA (10 μg per lane) using acre cDNA probe. All animals received humane care in compliance with the local Institutional Animal Care and Use Committee. OC-cre mice were mated with homozygous conditional mutants carrying modified Igf1ralleles (with loxP sites flanking exon 3; (21Dietrich P. Dragatsis I. Xuan S. Zeitlin S. Efstratiadis A. Mamm. Genome. 2000; 11: 196-205Crossref PubMed Scopus (104) Google Scholar), to generate OC-cre/Igf1rflox/+ progeny, which were used in subsequent crosses (see “Results”). The OC-cre mice were also crossed with Z/AP reporter mice (22Lobe C.G. Koop K.E. Kreppner W. Lomeli H. Gertsenstein M. Nagy A. Dev. Biol. 1999; 208: 281-292Crossref PubMed Scopus (452) Google Scholar), to estimate the efficiency of Cre-mediated recombination (see “Results”). For routine genotyping of progeny, thecre transgene was detected by PCR (1 min at 94 °C, 1 min at 53 °C, and 1 min at 72 °C, for 30 cycles) using the primers: 5′-CAAATAGCCCTGGCAGATTC-3′ (forward) and 5′-TGATACAAGGGACATCTTCC-3′ (reverse) to generate a 260-bp to a of the promoter and the rabbit β-globin The was detected by PCR (1 min at 94 °C, 1 min at °C, and 1 min at 72 °C, for 30 cycles) with the and (see (forward) and which generate a from the or a from the To the was used in with to generate a was used to the Z/AP reporter as To the specificity and efficiency of Cre-mediated OC-cre mice from two lines and 6) were crossed with the Z/AP mice G. Wagner E.F. Dev. Cell. 2002; 2: 389-406Abstract Full Text Full Text PDF PubMed Scopus (1204) Google Scholar) carrying a transgene (see A and “Results”). recombination the is and the downstream human gene is Mice were and were in PBS, and with in on for For was in one was used for and the for as (22Lobe C.G. Koop K.E. Kreppner W. Lomeli H. Gertsenstein M. Nagy A. Dev. Biol. 1999; 208: 281-292Crossref PubMed Scopus (452) Google Scholar). For the were for min in in was in (1 X-gal, and in at for to with and from were with PBS, in and in for 10 with PBS, and then with to in at For alkaline phosphatase the were with for and then in at for 30 min to were in PBS, in for 10 and with in for at least min or was were in and and in were and in were at 10 and were to were in for min and in in for 1 at and then in in at were then in and to were in containing for 10 For were for min in and then in for at °C, from were in PBS, (see through a and For were in for min and was by in at for 30 were then with PBS, in for 10 and with for min at were in PBS, through an and then The of the was evaluated using a system P. B. R. Int. 1996; PubMed Scopus Google Scholar). were the cortical bone in the and in the For of the and cortical the bone was using a per For of the in the the bone was using a at the growth and for A region of including only cancellous bone was to the growth and for were and as I. S. R. T. G. M. M. D. M. J. Bone Miner. Res. 2001; 16: PubMed Scopus Google Scholar). The were in with an size of either (for the or (for the were using a that not on about the is either or J. F. B. T. R. J. 1995; 96: PubMed Scopus Google Scholar). For the we the total bone volume and the volume as the of tissue volume by the total volume by the bone I. S. R. T. G. M. M. D. M. J. Bone Miner. Res. 2001; 16: PubMed Scopus Google Scholar). For the cortical the bone volume bone volume and cortical were in a region at the For the cancellous bone region in the bone volume trabecular trabecular trabecular number and were and were in bone were in H.H. M.C. of Bone Scholar), and were with a C. This analysis of the in for and bone were using the modified J. J. Pathol. 1997; 14: Scholar), and to the were for and of bone and were using a (18Zhao G. Monier-Faugere M.C. Langub M.C. Geng Z. Nakayama T. Pike J.W. Chernausek S.D. Rosen C.J. Donahue L.R. Malluche H.H. Fagin J.A. Clemens T.L. Endocrinology. 2000; 141: 2674-2682Crossref PubMed Scopus (271) Google Scholar, H.H. D. W. Int. PubMed Scopus Google Scholar). In were to the of the to that only sites were In were made in the to the of trabecular bone in the For and animals were with on 1 and and or All with the of the of the of Bone and A.M. J.A. Malluche H. R.R. J. Bone Miner. Res. 2: PubMed Scopus Google Scholar). are as All were significance level of was of the two at was using the of from a at was using the All were using the for conditional crosses between and of mice. used in this in which exon of theIgf1r gene is by loxP sites in have been (21Dietrich P. Dragatsis I. Xuan S. Zeitlin S. Efstratiadis A. Mamm. Genome. 2000; 11: 196-205Crossref PubMed Scopus (104) Google Scholar). To expression in the osteoblasts of we used the osteocalcin (OC) gene promoter and mice (see and Northern analysis demonstrated that the transgene encoding the was in and in of the For the of our it was important to the specificity and efficiency of Cre-mediated recombination in osteoblasts. the could not as a reporter for this the of skeletal tissue precluded an of the level of DNA by Southern analysis only a bone were but difficult for bone as in and could not be For these we used an and crossed OC-cre with Z/AP mice G. Wagner E.F. Dev. Cell. 2002; 2: 389-406Abstract Full Text Full Text PDF PubMed Scopus (1204) Google Scholar) carrying a which of a sequence encoding and a flanked by sites that is by a human alkaline phosphatase gene A). The gene is Cre-mediated of the efficiency of action be by in various the in and the of for alkaline To the of of the expression during from were for As shown in cells were detected in at the of from these revealed that the were osteoblasts and were also for X-gal, to estimate the efficiency of Cre-mediated cells and cells the of for and were (Fig. In derived from double exhibited a in and the of in the cells of the osteoblast the was that for X-gal, to of the into the In the double transgenic cells the representing of to for To also an estimate for the of Cre-mediated DNA brought about by the we the of osteoblasts and in from mice (4 that of the cells being of were for expression in the control the in the double transgenic was only of the in osteoblasts and was or including and skeletal from the mice for and for (Fig. PCR analysis using DNA from of that Cre-mediated recombination occurred in bone the that a of the for in osteoblasts and is not we that a level of by from the with the Z/AP reporter the performance of the OC-cre is on the of the the was used in with various cre to including a S. Liu J.L. Stannard B. Butler A. Accili D. Sauer B. LeRoith D. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 7324-7329Crossref PubMed Scopus (1191) Google Scholar), a I. Zeitlin S. 2000; PubMed Scopus Google Scholar), a 2000; PubMed Google Scholar), and a T. P. Efstratiadis A. 2001; PubMed Scopus Google Scholar), complete Cre-mediated recombination has been Xuan and A. the of crosses between animals with an were for a of effects using the as a bone as The abnormalities were but in animals not Because of the expression of the cre transgene from osteoblasts for the in the of an For these animals be to as in cells osteoblasts the of the gene by the genetically but normal mice be as from To bone and turnover, and were on and control at and of when the skeletal in the mouse is C. S. N. Donahue L.R. Rosen C.J. S. J. Bone Miner. Res. 2001; 16: PubMed Scopus Google Scholar). these the and normal animals were in size and in were detected at in with a and for and control with for of and of the gene in osteoblasts not to the postnatal growth in the the were on the of the the analysis at was on the at this is a of bone at this These which were with of the trabecular bone in the and revealed that the rate of bone formation for bone was in mice of and significant in osteoblast and osteoclast per bone of were and between mutants and in trabecular bone volume or were not detected at this are shown as per at per at to control as are shown only for significant to control as are shown only for significant volume number volume rate formation are shown as per at per at to control as are shown only for significant in a on mice demonstrated in comparison with the the rate was in the with a increase in mineralization and were made in the not however, the of as by the was increased in the and this was by an increase in osteoclast erosion and In comparison with the normal the mineralization in the mutants were in in trabecular bone volume trabecular and number by an increase in trabecular and is that the cortical was also in the mice of the total number of and the not from the in not To examine bone from and control mice were by using in the of the the cancellous bone volume was normal in the mutants and a decrease in the number of the of which was increased and A). In addition, in trabecular was normal In cortical bone volume and cortical at the of the were not between the two analysis and volume are shown as volume volume number volume are shown as in a in the of to normal between the by or the two of are in the that be from the with a trabecular by was in the was detected by This is to in in that could to in factor to between the two was the use of in the a bone was for a was used for of by have for the that IGF signaling in cells of the is essential for of the mineralization at a normal significant the roles of the IGFs in bone formation and C.A. Growth Horm. IGF Res. 2000; 10 Suppl. B: S107-S110Crossref PubMed Scopus (46) Google Scholar), this be on the about the that we In the mice that we have and of the IGF system have with the of osteoblasts, in which the function of the receptor mediating the signaling of IGF was selectively In fact, of the of Cre-mediated recombination at at least as in of the by using Z/AP reporter we that of cells IGF1R were to to from the during their subsequent In this regard, the of our is of the of action of the IGFs and of the of either one of these growth which roles that are not both embryonic and postnatal IGF2 only during J. Liu J.P. Robertson E.J. Efstratiadis A. Cell. 1993; 75: Full Text PDF PubMed Scopus Google Scholar). These the establishment of a the of in the IGF1R signaling with the of the as in the and functional bone that were evaluated by and the aspects of our are currently and a of be to at a level functional relationships and their to the of R. J.P. J. Mol. Endocrinol. 2001; PubMed Scopus Google Scholar), the mouse that we have as it has brought into downstream from the of which be from the of the of bone in mice at and at a when growth has and the animals are a a be evaluated with a Nevertheless, our in the of bone at IGF signaling is for in osteoblasts anti-apoptotic at normal as by a in osteoblast and a in bone formation In addition, of coupling of and the number of osteoclasts is also this not and at of significant in were not between mutants and fact, the cell were in the a about an unexpected in the of osteoid was detected that was by a in mineralization. In addition, the skeletal representing bone the of bone which were revealed as in the number, and of of with increase in trabecular and normal bone as however, the of as tissue that the bone processes were not in mice. the in with mineralization by signaling the detected changes consequences of the of IGF signaling at the of when the has been is in this regard, that cortical bone volume was not affected in the the effects on trabecular bone could be by the that this skeletal is to the rate of particularly the of the Our indicate despite a of the processes of osteoid production on one and mineralization on the are and be as of two bone osteoblasts not only and and proteins of the matrix but also in the mineralization which to 1995; Google Scholar, Res. 1996; PubMed Scopus Google Scholar, N. R. E. Growth Scholar). and of matrix containing from the of osteoblasts, the are by of the that and are then progressively in the is that the is controlled by the osteoblasts through an of the The for a mineralization is an increase in the between osteoid and This which is increased normal in the is for some of the osteoid to for of mineralization. the normal between the of osteoid and mineralization appears to be in the of IGF as is an in some the between the that this a between the of resulting in and mineralization. to be suggesting that IGF1 could bone mineralization is to our was for example, that IGF1 in of osteoblasts in vitro in with bone formation R.S. Bowsher R.R. Wiren K.M. J. Endocrinol. 1995; 144: 251-259Crossref PubMed Scopus (55) Google Scholar), of an complex into in a of the in bone with Rosen C.J. C.M. J. Bone Miner. Res. 2001; 16: Scopus Google Scholar). is also that is to of the matrix and to be in the of the J. J.P. Int. 1996; Full Text PDF PubMed Scopus (88) Google Scholar). In this regard, it is that IGF1 has been shown to stimulate in human cells by the expression of a A. G. J.P. J. Bone. 2001; PubMed Scopus Google Scholar). is that IGF1 is for by osteoblasts. of the that we have is likely to have important it is that IGF1 is critical for both linear bone growth and skeletal our findings that IGF1 is essential for coupling matrix biosynthesis to sustained mineralization. This action could be particularly important during the pubertal growth spurt when rapid bone formation and consolidation are required. Langub and for in the

STUDY DESIGN: A prospective, randomized, multicenter, Food and Drug Administration-regulated Investigational Device Exemption clinical trial. OBJECTIVES: The purpose of this study was to compare the safety and effectiveness of lumbar total disc replacement, using the CHARITE artificial disc (DePuy Spine, Raynham, MA), with anterior lumbar interbody fusion, for the treatment of single-level degenerative disc disease from L4-S1 unresponsive to nonoperative treatment. SUMMARY OF BACKGROUND DATA: Reported results of lumbar total disc replacement have been favorable, but studies have been limited to retrospective case series and/or small sample sizes. METHODS: Three hundred four (304) patients were enrolled in the study at 14 centers across the United States and randomized in a 2:1 ratio to treatment with the CHARITE artificial disc or the control group, instrumented anterior lumbar interbody fusion. Data were collected pre- and perioperatively at 6 weeks and at 3, 6, 12, and 24 months following surgery. The key clinical outcome measures were a Visual Analog Scale assessing back pain, the Oswestry Disability Index questionnaire, and the SF-36 Health Survey. RESULTS: Patients in both groups improved significantly following surgery. Patients in the CHARITE artificial disc group recovered faster than patients in the control group. Patients in the CHARITE artificial disc group had lower levels of disability at every time interval from 6 weeks to 24 months, compared with the control group, with statistically lower pain and disability scores at all but the 24 month follow-up (P < 0.05). At the 24-month follow-up period, a significantly greater percentage of patients in the CHARITE artificial disc group expressed satisfaction with their treatment and would have the same treatment again, compared with the fusion group (P < 0.05). The hospital stay was significantly shorter in the CHARITE artificial disc group (P < 0.05). The complication rate was similar between both groups. CONCLUSIONS: This prospective, randomized, multicenter study demonstrated that quantitative clinical outcome measures following lumbar total disc replacement with the CHARITE artificial disc are at least equivalent to clinical outcomes with anterior lumbar interbody fusion. These results support earlier reports in the literature that total disc replacement with the CHARITE artificial disc is a safe and effective alternative to fusion for the surgical treatment of symptomatic disc degeneration in properly indicated patients. The CHARITE artificial disc group demonstrated statistically significant superiority in two major economic areas, a 1-day shorter hospitalization, and a lower rate of reoperations (5.4% compared with 9.1%). At 24 months, the investigational group had a significantly higher rate of satisfaction (73.7%) than the 53.1% rate of satisfaction in the control group (P = 0.0011). This prospective randomized multicenter study also demonstrated an increase in employment of 9.1% in the investigational group and 7.2% in the control group.

Radiographic image guidance has emerged as the new paradigm for patient positioning, target localization, and external beam alignment in radiotherapy. Although widely varied in modality and method, all radiographic guidance techniques have one thing in common--they can give a significant radiation dose to the patient. As with all medical uses of ionizing radiation, the general view is that this exposure should be carefully managed. The philosophy for dose management adopted by the diagnostic imaging community is summarized by the acronym ALARA, i.e., as low as reasonably achievable. But unlike the general situation with diagnostic imaging and image-guided surgery, image-guided radiotherapy (IGRT) adds the imaging dose to an already high level of therapeutic radiation. There is furthermore an interplay between increased imaging and improved therapeutic dose conformity that suggests the possibility of optimizing rather than simply minimizing the imaging dose. For this reason, the management of imaging dose during radiotherapy is a different problem than its management during routine diagnostic or image-guided surgical procedures. The imaging dose received as part of a radiotherapy treatment has long been regarded as negligible and thus has been quantified in a fairly loose manner. On the other hand, radiation oncologists examine the therapy dose distribution in minute detail. The introduction of more intensive imaging procedures for IGRT now obligates the clinician to evaluate therapeutic and imaging doses in a more balanced manner. This task group is charged with addressing the issue of radiation dose delivered via image guidance techniques during radiotherapy. The group has developed this charge into three objectives: (1) Compile an overview of image-guidance techniques and their associated radiation dose levels, to provide the clinician using a particular set of image guidance techniques with enough data to estimate the total diagnostic dose for a specific treatment scenario, (2) identify ways to reduce the total imaging dose without sacrificing essential imaging information, and (3) recommend optimization strategies to trade off imaging dose with improvements in therapeutic dose delivery. The end goal is to enable the design of image guidance regimens that are as effective and efficient as possible.

Abstract Variants of UNC13A , a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia 1–3 , two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-43 4,5 . Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in UNC13A , resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic UNC13A polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These polymorphisms potentiate cryptic exon inclusion, both in cultured cells and in brains and spinal cords from patients with these conditions. Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which UNC13A variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies.

Uterine microbiota have been reported under various conditions and populations; however, it is uncertain the level to which these bacteria are residents that maintain homeostasis, tourists that are readily eliminated or invaders that contribute to human disease. This review provides a historical timeline and summarizes the current status of this topic with the aim of promoting research priorities and discussion on this controversial topic. Discrepancies exist in current reports of uterine microbiota and are critically reviewed and examined. Established and putative routes of bacterial seeding of the human uterus and interactions with distal mucosal sites are discussed. Based upon the current literature, we highlight the need for additional robust clinical and translational studies in this area. In addition, we discuss the necessity for investigating host-microbiota interactions and the physiologic and functional impact of these microbiota on the local endometrial microenvironment as these mechanisms may influence poor reproductive, obstetric, and gynecologic health outcomes and sequelae.

Potential and documented interactions between alternative therapy agents and warfarin are discussed. An estimated one third of adults in the United States use alternative therapies, including herbs. A major safety concern is potential interactions of alternative medicine products with prescription medications. This issue is especially important with respect to drugs with narrow therapeutic indexes, such as warfarin. Herbal products that may potentially increase the risk of bleeding or potentiate the effects of warfarin therapy include angelica root, arnica flower, anise, asafoetida, bogbean, borage seed oil, bromelain, capsicum, celery, chamomile, clove, fenugreek, feverfew, garlic, ginger ginkgo, horse chestnut, licorice root, lovage root, meadowsweet, onion, parsley, passionflower herb, poplar, quassia, red clover, rue, sweet clover, turmeric, and willow bark. Products that have been associated with documented reports of potential interactions with warfarin include coenzyme Q10, danshen, devil's claw, dong quai, ginseng, green tea, papain, and vitamin E. Interpretation of the available information on herb-warfarin interactions is difficult because nearly all of it is based on in vitro data, animal studies, or individual case reports. More study is needed to confirm and assess the clinical significance of these potential interactions. There is evidence that a wide range of alternative therapy products have the potential to interact with warfarin. Pharmacists and other health care professionals should question all patients about use of alternative therapies and report documented interactions to FDA's MedWatch program.

Importance: Catheter ablation of persistent atrial fibrillation (AF) has limited success. Procedural strategies beyond pulmonary vein isolation have failed to consistently improve results. The vein of Marshall contains innervation and AF triggers that can be ablated by retrograde ethanol infusion. Objective: To determine whether vein of Marshall ethanol infusion could improve ablation results in persistent AF when added to catheter ablation. Design, Setting, and Participants: The Vein of Marshall Ethanol for Untreated Persistent AF (VENUS) trial was an investigator-initiated, National Institutes of Health-funded, randomized, single-blinded trial conducted in 12 centers in the United States. Patients (N = 350) with persistent AF referred for first ablation were enrolled from October 2013 through June 2018. Follow-up concluded in June 2019. Interventions: Patients were randomly assigned to catheter ablation alone (n = 158) or catheter ablation combined with vein of Marshall ethanol infusion (n = 185) in a 1:1.15 ratio to accommodate for 15% technical vein of Marshall ethanol infusion failures. Main Outcomes and Measures: The primary outcome was freedom from AF or atrial tachycardia for longer than 30 seconds after a single procedure, without antiarrhythmic drugs, at both 6 and 12 months. Outcome assessment was blinded to randomization treatment. There were 12 secondary outcomes, including AF burden, freedom from AF after multiple procedures, perimitral block, and others. Results: Of the 343 randomized patients (mean [SD] age, 66.5 [9.7] years; 261 men), 316 (92.1%) completed the trial. Vein of Marshall ethanol was successfully delivered in 155 of 185 patients. At 6 and 12 months, the proportion of patients with freedom from AF/atrial tachycardia after a single procedure was 49.2% (91/185) in the catheter ablation combined with vein of Marshall ethanol infusion group compared with 38% (60/158) in the catheter ablation alone group (difference, 11.2% [95% CI, 0.8%-21.7%]; P = .04). Of the 12 secondary outcomes, 9 were not significantly different, but AF burden (zero burden in 78.3% vs 67.9%; difference, 10.4% [95% CI, 2.9%-17.9%]; P = .01), freedom from AF after multiple procedures (65.2% vs 53.8%; difference, 11.4% [95% CI, 0.6%-22.2%]; P = .04), and success achieving perimitral block (80.6% vs 51.3%; difference, 29.3% [95% CI, 19.3%-39.3%]; P < .001) were significantly improved in vein of Marshall-treated patients. Adverse events were similar between groups. Conclusions and Relevance: Among patients with persistent AF, addition of vein of Marshall ethanol infusion to catheter ablation, compared with catheter ablation alone, increased the likelihood of remaining free of AF or atrial tachycardia at 6 and 12 months. Further research is needed to assess longer-term efficacy. Trial Registration: ClinicalTrials.gov Identifier: NCT01898221.

STUDY DESIGN: A prospective, randomized, multicenter, Food and Drug Administration-regulated, investigational device exemption clinical trial. OBJECTIVES: To compare the safety and effectiveness of lumbar total disc replacement (TDR) with the CHARITE artificial disc (DePuy Spine, Raynham, MA) to anterior lumbar interbody fusion for the treatment of single-level degenerative disc disease from L4-S1 unresponsive to nonoperative treatment. In addition, to evaluate the radiographic outcomes of lumbar artificial disc replacement at either L4-L5 or L5-S1 with the CHARITE artificial disc as compared to anterior lumbar interbody fusion with cylindrical cages and iliac crest bone graft; and to determine if a correlation exists between clinical outcomes and surgical accuracy of TDR placement within the disc space. SUMMARY OF BACKGROUND DATA: Prior investigators have reported excellent radiographic results with the CHARITE artificial disc for the treatment of lumbar degenerative disc disease. These encouraging results are the product of retrospective reviews without a control. Very few studies have reported on the segmental motion of an intervertebral level implanted with an artificial disc, and no studies have reported a correlation of radiographic and clinical outcomes. METHODS: A prospective, randomized, multicenter, US Food and Drug Administration, investigational device exemption study with 24-month follow-up was performed at 14 centers throughout the United States. A total of 304 subjects were randomized in a 2:1 ratio, with 205 in the investigational group (TDR with the CHARITE artificial disc) and 99 in the control group (anterior lumbar interbody fusion with BAK cages and iliac crest bone graft). A total of 71 TDR training cases were performed (up to 5 at each site) before randomization beginning at each site. Plain radiographs were analyzed for each subject in both groups regarding range of motion (ROM) in flexion/extension, restoration of disc space height, and subsidence. Prosthesis placement in the coronal and midsagittal planes was analyzed for the 276 patients with TDR. Correlations were performed between prosthesis placement and clinical outcomes. RESULTS: Patients in the investigational group had a 13.6% mean increase, and those in the control group an 82.5% decrease in mean flexion/extension ROM at 24 months postoperatively compared to baseline. Patients in the investigational group had significantly better restoration of disc height than the control group (P < 0.05). There was significantly less subsidence in the investigational group compared to the control group (P < 0.05). The surgical technical accuracy of CHARITE artificial disc placement was divided into 3 groups: I, ideal (83%); II, suboptimal (11%); and III, poor (6%), and correlated with clinical outcomes. The flexion/extension ROM and prosthesis function improved with the surgical technical accuracy of radiographic placement (P = 0.003). CONCLUSIONS: Preoperative ROM in flexion/extension was restored and maintained in patients receiving a TDR. TDR with the CHARITE artificial disc resulted in significantly better restoration of disc space height, and significantly less subsidence than anterior interbody fusion with BAK cages. Clinical outcomes and flexion/extension ROM correlated with surgical technical accuracy of CHARITE artificial disc placement. In the majority of cases, placement of the CHARITE artificial disc was ideal.

Diabetic foot ulcers are a significant health care problem. Complications of foot ulcers are a leading cause of hospitalization and amputation in patients with diabetes mellitus. In response to a request from the Wound Healing Society, a panel of advisers, including physicians from academia and private practice, nurses, a podiatrist, a pedorthist, and a representative from industry, was selected to develop guidelines for the treatment of diabetic ulcers of the lower extremity. The approach used to develop guidelines was similar to that used by the Venous Ulcer Panel, also convened at the request of the Wound Healing Society. Those guidelines were presented on October 3, 2005, at a conference at the National Institutes of Health (NIH). Previous guidelines, meta-analyses, PubMed, MEDLINE, EMBASE, The Cochrane Database of Systematic Reviews, recent reviews of diabetic ulcer treatment, and the Medicare/CMS consensus of usual treatment of chronic wounds were reviewed for evidence. Guidelines were formulated, the underlying principle(s) enumerated, and evidence references listed and coded. The code abbreviations for the evidence citations were as follows: There was a major difference between our approach to evidence citations and past approaches to evidence-based guidelines. Most past approaches relied only on publications regarding clinical human studies. Laboratory or animal studies were not cited. We have used well-controlled animal studies that present proof of principle, especially when a clinical series corroborated the laboratory results. Because of this variation, a different system was used to grade the weight of evidence supporting a given guideline. The strength of evidence supporting a guideline is listed as Level I, Level II, or Level III. The guideline levels are: Level I: Meta-analysis of multiple RCTs or at least two RCTs supporting the intervention of the guideline. Another route would be multiple laboratory or animal experiments with at least two clinical series supporting the laboratory results. Level II: Less than Level I, but at least one RCT and at least two significant clinical series or expert opinion papers with literature reviews supporting the intervention. Experimental evidence that is quite convincing, but not yet supported by adequate human experience. Level III: Suggestive data of proof of principle, but lacking sufficient data such as meta-analysis, RCT, or multiple clinical series. Note: The suggestion in the guideline can be positive or negative at the proposed level (e.g., meta-analysis and two RCTs stating intervention is not of use in treating diabetic ulcers). Guidelines have been formulated in eight categories for the treatment of diabetic ulcers of the lower extremities. The categories are: Diagnosis Offloading Infection control Wound bed preparation Dressings Surgery Adjuvant agents (topical, device, systemic) Prevention of recurrence Each of the separate guidelines is undergoing a Delphi consensus among the panel members. Not all panel members thought they had sufficient expertise to critique all of the separate sections of the guidelines. However, each set of guidelines was critically evaluated by at least ten panel members. Preamble: Ulcers of the lower extremity may be caused by a variety of conditions, including neuropathy, ischemia, venous hypertension, and pressure. Patients with diabetes develop wounds secondary to neuropathy with or without biomechanical abnormalities, peripheral vascular disease with ischemia, or both. There are 20 million people in the United States with diabetes, of whom 10–15% are at risk for ulceration. It is imperative that the etiology be established to provide for proper therapy. Guideline #1.1: Clinically significant arterial disease should be ruled out by establishing that pedal pulses are clearly palpable or that the ankle : brachial index (ABI) is >0.9. An ABI >1.3 suggests noncompressible arteries. In elderly patients or patients with an ABI >1.2, a normal Doppler-derived waveform, a toe : brachial index of >0.7, or a transcutaneous oxygen pressure of >40 mmHg may help to suggest an adequate arterial flow. Color duplex ultrasound scanning provides anatomic and physiologic data confirming an ischemic etiology for the leg wound. (Level I) Principle: Diabetic ulcers can result from arterial insufficiency or neuropathy. Although clinical history and physical examination can be very suggestive of an ischemic etiology of the lower extremity diabetic ulcers, a definitive diagnosis must be established. When significant arterial disease is present, successful treatment requires that arterial insufficiency be addressed. Evidence: Sahli D, Eliasson B, Svensson M, Blohme G, Eliasson M, Samuelsson P, Ojbrandt K, Eriksson J. Assessment of toe blood pressure is an effective screening method to identify diabetes patients with lower extremity arterial disease. Angiology 2004; 55: 641–51. [CLIN S] Teodorescu V, Chen C, Morrissey N, Faries P, Marin M, Hollier L. Detailed protocol of ischemia and the use of noninvasive vascular laboratory testing in diabetic foot ulcers. Am J Surg 2004; 187 (5A): 75S–80. [LIT REV] Hirsch A, Criqui M, Treat-Jacobson D, Regensteiner J, Creager M, Olin J, Krook S, Hunninghake D, Comerota A, Walsh M, McDermott M, Hiatt W. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA 2001; 286: 1317–24. [CLIN S] Ascher E, Hingorani A, Markevich N, Yorkovich W, Schutzer R, Hou A, Jacob T, Nahata S, Kallakuri S. Role of duplex arteriography as the sole preoperative imaging modality prior to lower extremity revascularization surgery in diabetic and renal patients. Ann Vasc Surg 2004; 18: 433–439. [CLIN S] Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL, Hiratzka LF, Murphy WRC, Olin JW, Puschett JB, Rosenfield KA, Sacks D, Stanley JC, Taylor LM Jr, White CJ, White J, White RA. ACC/AHA guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society for Vascular Medicine and Biology, and the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to develop guidelines for the management of patients with peripheral arterial disease). American College of Cardiology Web site. Available at: http://www.acc.org/clinical/guidelines/pad/index.pdf. [STAT] Padberg FT, Back TL, Thompson PN, Hobson RW. Transcutaneous oxygen (TcPO2) estimates probability of in the ischemic extremity. J Surg [CLIN S] Guideline The of significant neuropathy can be by testing with a (Level Principle: to foot with pressure on the especially the of in of pressure. neuropathy may the of Evidence: N, D, foot ulcers in patients with JAMA [LIT REV] N, K, S, T, K, R, M, of examination for diabetic peripheral neuropathy J Complications [CLIN S] K, S. of a for of foot in patients with J Surg 2004; [CLIN S] A, P, V, V, J. of patients at risk for diabetic a of noninvasive testing with at diabetes J Complications 2001; [CLIN S] J, J. The use of the and for foot and amputation in with J [LIT REV] D, C, J, to identify people at risk for diabetic foot a [CLIN S] M, D, D, E, J, examination for the of in the of diabetic patients. for J [CLIN S] S, D, A, E, M, a effective and screening for diabetic patients at risk of foot ulceration. [CLIN S] J, R, P, of pressure in diabetic peripheral neuropathy. J [CLIN S] TL, for screening patients at risk for diabetic foot ulceration. [CLIN S] J, of foot pressure as of a diabetes disease management [CLIN S] Preamble: Diabetic may result from an in pressure on the diabetic foot of foot and neuropathy. Offloading the of pressure been the to Guideline should be in at risk for amputation arterial significant neuropathy, ulcer foot evidence of (Level Principle: The of in diabetic patients at risk for can be by Evidence: The for for diabetic patients. [CLIN S] M, M, E, of American and Society. Guidelines for diabetic foot by the of the American and Society. [LIT REV] C, K, S, C, J. of on foot in patients with a JAMA C, S, of diabetic in 2004; [LIT REV] E, T, effective is in diabetic clinical [CLIN S] E, An of diabetic to [CLIN S] E, G, A, A, P, in the of diabetic foot ulcers. 18: Guideline of diabetic and and (Level I) Principle: pressure on the diabetic is to Evidence: I, A, B, D, J, M, of two in management of diabetic foot ulcers. D, C, A, L. the diabetic foot clinical 2001; R, R, The of on 2004; S] G, A, S, in the treatment of diabetic and [CLIN S] A, P, G, M, V, S. of the of the foot of pressure [CLIN S] J, P, in an 2004; [LIT REV] MA, of ulcer in patients with diabetes mellitus. Wound S] P, S, in diabetic patients with foot [CLIN S] Preamble: Infection when the : is in of the Infection in the and of diabetic ulcers. Guideline all or by or (Level of is in Wound Principle: is with the to and as a for Evidence: in of Wound in M, N, The of chronic a Health [STAT] D, D, M, and the Diabetic Ulcer of and treatment on the of diabetic foot ulcers. J Am Surg of and [LIT REV] Wound bed preparation and the of a for multiple of [LIT REV] W. of Ann Surg index and with of diabetic foot ulcers. Wound G, G, R, Taylor for chronic venous leg ulcers. J [LIT REV] Guideline is in a or from the is not two of and of the and level of in a diabetic ulcer by or by a (Level Principle: levels of of or a level of the and have been to and of diabetic ulcers. should be to and Evidence: Wound caused by Surg [LIT REV] Wound a of caused by an of Surg Am [LIT REV] M, in diabetic patients with ulcers of 2001; for diabetic foot ulcers. [LIT REV] of and Surg Am [LIT REV] on a Role in the of the The and a method for the of on J The a a Am J Surg [STAT] P, I, K, C, C, K, the of chronic wounds in J [CLIN S] in diabetic the of 20 [LIT REV] The of in chronic leg ulcers. Ann Surg [CLIN S] of chronic leg ulcers. Guideline ulcers with of or level of adequate the level with a in the use of the to to the or of to the (Level I) Principle: not levels in can be Evidence: Wound a of caused by an of Surg Am [LIT REV] I, C, P, C, The of in leg ulcer by a a of Am J Surg The of in chronic leg ulcers. Ann Surg [CLIN S] White R, Wound and the of J 2001; [LIT REV] of chronic leg ulcers. Guideline diabetic foot not to the are (Level Principle: have been in to be in treating diabetic foot Although the are to and are are in Evidence: on and the Diabetic a report from the consensus on and treating the diabetic 2004; 20 [STAT] S, N, M, Systematic reviews of care agents for chronic diabetic foot ulceration. Health [STAT] and of of diabetic foot [LIT REV] A, D, for diabetic foot Guideline and of the and to or the ulcer should be with (Level Principle: the of and the normal of the and to by and Evidence: E, with to the of the an J [LIT REV] K, and of the J 2001; [LIT REV] of and [LIT REV] W. of the J [LIT REV] S, T, of in patients with and therapy. Guideline is the with a and (Level Principle: underlying a diabetic ulcer is of the a definitive but can be in establishing a diagnosis with a of and Evidence: K, E, to in pedal ulcers. clinical of underlying in diabetic patients. JAMA [CLIN S] M, on the diagnosis and management of Surg [LIT REV] D, K, J, A, Systematic and meta-analysis of for and 2001; [STAT] The use of of Surg [CLIN S] Guideline is by of the by of However, when this is not underlying a diabetic ulcer can be with therapy. (Level Principle: underlying a diabetic is by of the When been a of is the is not a least is Evidence: D, K, J, Systematic and meta-analysis of for and 2001; [STAT] and of of diabetic foot [LIT REV] treatment of have from of clinical J [LIT REV] J. of and in the management of J Surg M, on the diagnosis and management of Surg [LIT REV] Guideline the level of to of with in the ulcer by or (Level Principle: with than of be as the of that is Evidence: of Surg [LIT REV] E, The of on the of in Ann Surg and Surg 18: Murphy The of on and J Surg of and Surg Am [LIT REV] M, in diabetic patients with ulcers of 2001; of and are in Infection Dressings and Adjuvant and Preamble: Wound bed preparation is as the management of the to or the of The of bed preparation is to the and of a chronic to that of an wound. The of bed preparation have been V, Wound bed a approach to Wound D, the and Guideline of the as a is to and of such and and and (Level I) Principle: including a help in and of The of a major or disease and such as and with by in and such as or can all and may or agents can Patients undergoing major surgery have a as chronic is with and risk of Evidence: D, R, G, and guidelines for of wounds and of [STAT] Healing of and in [LIT REV] R, S. M, of in of the T, major J Surg [CLIN S] A, of and on and of and Surgery 2004; chronic a on and for therapy. Am J Surg 2004; 187 (5A): [LIT REV] Principle: must be adequate to provide sufficient to the of The level recent and are in patients are the Although diabetic ulcer patients are and not at the of is an is Evidence: I, M, V, N, J, G, J. of the of in critically II: a in the management of J 2004; [LIT REV] and weight the of intervention in [LIT REV] Principle: in an that is to the be is and that such as or oxygen by peripheral must be or Evidence: N, W, management of and oxygen in patients. Ann Surg [CLIN S] B, as an of the of oxygen and on in Surg Wound and and can Surg Am [LIT REV] K, J, and in to in patients. Ann Surg Surg P, W, J, K, P, J, R, K, J. Wound oxygen the risk of in patients. Surg [CLIN S] in and J Surg 2004; [LIT REV] 2004; [LIT REV] R, E, A, oxygen to the of J Guideline is to the and of and is to the and of the bed for The health care can from a of including or than one method may be is Level Principle: and can all The method of may on the of the the of the health the of the and Evidence: D, and the Diabetic Ulcer of on the of diabetic foot ulcers. J Am Surg index and with of diabetic foot ulcers. Wound for A, of and for pressure ulcer Am J Surg 2004; 187 [LIT REV] the Wound 2004; [LIT REV] J. and Wound [LIT REV] D, K, D, D, the and [LIT REV] J, of of a Wound M, N, The of chronic a Health [STAT] The of on and in J Surg Wound bed preparation and the of a for multiple of the [LIT REV] in the treatment of and ulcers. J Am [CLIN S] The and of two J S] A, E, M, C, approach management for diabetic foot a Diabetic JL, J, Diabetic foot of two and Wound Guideline should be and at each a should be with a of (Level Principle: and the to or is should only be used the is Experimental data suggest that a may be as may by pressure. Evidence: Wound D, D, Wound for Health [LIT REV] S, clinical with in vascular care. J Wound [CLIN S] a Ann of Ann Surg Guideline There should be an and of and of the and to bed The of should be evaluated to treatment is (Level Principle: of bed preparation are the ulcer is not at the for bed preparation to be The the of the the is to an ulcer is or of and to be Evidence: and guidelines for of wounds and of [STAT] index and with of diabetic foot ulcers. Wound Wound Healing a Wound Wound as of of Surg [STAT] Guideline Patients to a in ulcer by or of should be and should be (Level Principle: in of diabetic foot ulcers of treatment is a of of and of Evidence: P, P, A, in of diabetic foot ulcers a is a of in a [CLIN S] Wound as of of Surg [CLIN S] Wound and approaches to Surg 2001; [LIT REV] L. leg and of Ulcer J [CLIN S] Guideline control (Level Principle: Wound is to be in the of diabetes levels also the of Evidence: A, of diabetic foot ulcers with a blood [CLIN S] M, M, of control on in diabetic J Wound [CLIN S] in to J Am [CLIN S] at diabetes and Am J Surg N, I, of diabetic on in diabetic J, S, in J 2004; The of blood control in the with diabetes mellitus. J of in diabetic requires preoperative blood J Surg N, G, M, D, T, on for diabetes 2001; Wound and diabetes mellitus. Surg [LIT REV] C, control and the risk of in a of with [CLIN S] Preamble: There is a of for treatment of diabetic ulcers. bed with Guidelines are to help the regarding the and use of care Most be used in with and of the Guideline a that a (Level Principle: and of wounds by also Evidence: of and on the of a wound. K, Eriksson E, P, Healing of wounds in a J Surg T, B, J, Eriksson of wounds in a Surg J, S, N, T, S, K, R, J, D, Eriksson Surg [CLIN S] Guideline clinical to a (Level Principle: are not are as effective as of in of Evidence: The of two on J Surg P, M, of J Surg J, S, S. Healing of J Wound M, N, M, T, Systematic reviews of care and agents used in the of chronic Health [STAT] of a in the management of diabetic foot ulcers. Wound [CLIN S] Guideline a that the and the (Level I) Principle: and with can the and Evidence: B, of by chronic Wound S, N, J, Murphy G, of the and chronic the of and Wound Wound from human pressure ulcers levels and to J J, S, S. Healing of J Wound R, P, V, S, G, G, J, S, J, J. and of in the treatment of diabetic foot Guideline a that in and and not cause (Level Principle: Wound and can all the of Evidence: D, D, from Am J [CLIN S] Guideline a that is (Level I) Principle: Because of are as the least However, when is to health care of and as as the of the Evidence: P, K, C, of leg ulcer treatment in primary care. of and treatment in a J Health K, P, B, and of and in the management of patients with chronic leg 2001; care a clinical Wound [LIT REV] Guideline use agents (topical, device, systemic) a and ulcer and when is a of in response to of are in Adjuvant Level Principle: and may and in selected patients or are quite and are in in the Adjuvant Evidence: references are in the Adjuvant P, for treatment of diabetic foot ulcers. Am J Surg 2004; 187 (5A): [LIT REV] Preamble: The of and are not successful in all diabetic ulcers. the multiple have been to diabetic ulcers with of clinical are but data are supporting surgery in selected patients. Guideline may of diabetic (Level Principle: the pressure on ulcers in patients with and may be of in diabetic foot ulcers. Evidence: M, D, M, M, J. of on ulcers. clinical J Surg G, C, the for the treatment of diabetic ulceration. Surg Am [LIT REV] S, L. of the in diabetic patients are at risk for of the J Surg [CLIN S] with of the ankle in diabetic the of and [CLIN S] for the treatment of ulcers a in pressure with in than ankle J 2004; [CLIN S] Guideline Patients with ischemia should be for a revascularization Principle: In patients with arterial in blood is with an in and Evidence: P, on Wound Healing and for with Diabetic 2004; [LIT REV] T, Vascular and of the diabetic Surg [LIT REV] K, and clinical of arterial in diabetic and of J Vasc Surg [CLIN S] E, M, M, use of peripheral in the treatment of diabetic foot clinical of a of diabetic J [CLIN S] D, extremity revascularization in Surg [CLIN S] A, arterial for foot ischemia in patients with diabetes mellitus. J Vasc Surg [CLIN S] Preamble: agents have been to be used as to and in the treatment of diabetic ulcers. agents can be agents to be to the at ulcer and to the of agents have evidence to guidelines regarding Guideline is effective in treating diabetic foot ulcers. (Level I) Principle: are in Evidence: D, Diabetic Ulcer of human for the treatment of lower extremity diabetic ulcers. J Vasc Surg J, J, and of a of human in patients with chronic diabetic a in patients with lower extremity ulcers. J, and of human in patients with lower extremity diabetic a of studies. Wound [STAT] J, V, D, the of clinical with the that is an effective to the treatment of diabetic foot ulcers. J [STAT] Guideline not yet have data on to of for treatment of diabetic ulcers, suggest (Level I) Principle: are in Evidence: in chronic diabetic foot ulcers. G, D, M, T, response of in diabetic S, J, D, of in of ulcers. Surgery D, K, V, and treatment of chronic ulcers Surg D, K, V, S, E, of in ulcers Surg JL, C, of on the of chronic diabetic ulcer of the 18: of on in diabetic foot ulcers. J of ulcers in patients with diabetes by treatment with Wound S, S, in foot ulcers. Diabetic [CLIN S] G, M, G, P, P, of as for diabetic foot 2001; A, M, N, J, of in diabetic foot W, G, C, of diabetic foot ulcers. Guideline pressure may be of in treating diabetic (Level I) Principle: treatment may by and the of the and should be when are not Evidence: M, K, G, J, of for diabetic foot Ann Vasc Surg S, C, J, M, J, L. in the of diabetic foot D, L. Diabetic negative pressure diabetic foot a M, T, S, R, D, L. with the negative pressure in the treatment of diabetic and S] D, C, A, R, R, J. Guidelines regarding negative in the diabetic 2004; [LIT REV] D, L. negative pressure for treating chronic Cochrane Database 2001; [STAT] Guideline may be of in diabetic foot ulcers. (Level I) Principle: in diabetic foot ulcers by of and that the Evidence: P, Diabetic Ulcer the and of in the of chronic diabetic foot of a A, V, Diabetic Ulcer a human is effective in the management of diabetic foot a clinical 2001; Healing of chronic foot ulcers in diabetic patients with a human J Surg J, P, K, The of treatment of diabetic foot ulcers. [STAT] J, T, Hollier L. Healing of diabetic foot ulcers and pressure ulcers with human a in Surg [CLIN S] a use in the treatment of venous leg ulcers and diabetic foot ulcers. [LIT REV] a human for the treatment of chronic diabetic foot ulcers. 2004; [LIT REV] Guideline may be of in diabetic foot ulcers. (Level I) Principle: of to wounds may and Evidence: for a of evidence from in animal and clinical J [LIT REV] P, C, M, K, D, M, of on chronic leg ulcer and T, Eriksson S, of diabetic ulcers. Ann Surg of on the of wounds in diabetic Wound 2001; as an to diabetic foot a clinical 2001; Guideline oxygen may be of in the amputation in patients with ischemic diabetic foot ulcers. (Level I) Principle: oxygen may the of oxygen to a in diabetic patients and Evidence: C, S, E, D, J. oxygen for treating a of the Surg [LIT REV] A, G, G, B, A, P, E, The of oxygen in ischemic diabetic lower extremity a J Vasc Surg A, G, G, B, Role of oxygen in a J Surg 2001; E, A, P, A, G, M, P, oxygen in treatment of ischemic diabetic foot T, Chen S, The vascular of oxygen in treatment of diabetic 2001; [CLIN S] C, oxygen of chronic leg a Surg P, C, R, D, M, the of chronic diabetic foot a P, M, I, S. oxygen for chronic Cochrane Database [STAT] oxygen lower extremity and the diabetic [LIT REV] Preamble: Diabetic ulcers of the lower extremity are a chronic problem. are must be for ulcers. Guideline Patients with diabetic ulcers should use to (Level Principle: Most not the underlying pressure on the is Evidence: M, G, D, C, S, of diabetic in 2004; [LIT REV] for people with 2004; 20 [LIT REV] and the diabetic clinical and Am J Surg 2004; 187 (5A): [LIT REV] management of the diabetic 2001; [LIT REV] R, R, G, K, W, of on foot as by in diabetic a 2001; 18: E, G, A, A, P, in the of diabetic foot ulcers. 18: S, V, Taylor L. of to in people with [CLIN S] A, in treatment of diabetic ulcers. clinical [CLIN S] Guideline foot care and of the the recurrence of diabetic ulceration. (Level Principle: foot care including proper and proper in diabetic Evidence: M, M, E, of American and Society. Guidelines for diabetic foot by the of the American and Society. [LIT REV] W, P, on Wound Healing and for with Diabetic Wound and for people with diabetic foot ulcers. 2004; 20 [LIT REV] The diabetic [LIT REV] foot in patients with diabetes mellitus. J [STAT] of foot in patients with [STAT] K, and lower extremity risk and in [CLIN S] was supported by the Wound Healing a to the Wound Healing Society.

Multiple-infusion dosing regimens for gentamicin were established for 84 patients with the use of individually calculated values of elimination kinetic parameters. Serum level-time data obtained after a single infusion were used to determine the patient's gentamicin half-life (t 1/2) and distribution volume. Patients with serum creatinine (Cr) less than 1.2 mg per 100 ml had t 1/2 (mean, 2.25 hr) and total body clearances (mean, 0.082 L/hr/kg) significantly different from those with Cr greater than or equal to 1.2 mg/100 ml (means, 5.3 and 0.039, respectively). Distribution volumes were not significantly different (means, 0.22 and 0.21 L/kg, respectively). Calculations of dosing intervals and infusion rates, based on each patient's kinetic parameters and desired steady-state peaks and nadirs, assumed a one-compartment model with first-order elimination and 1-hr constant-rate input at fixed intervals. Follow-up steady-state peak and nadir levels were measured in 63 of the regimens. Differences between predicted and measured peak levels averaged --0.05 mug/ml with 60% of the measured values falling within 1 mug/ml of that predicted. Predicted-measured nadir differences averaged --0.62 mug/ml (significantly different from zero) indicating slight bias in the model. Fifty-six percent of these nadirs were within 1 mug/ml of that predicted.

In response to growing U.S. interest, the Society for Coronary Angiography and Interventions recently formed a Transradial Committee whose purpose is to examine the utility, utilization, and training considerations related to transradial access for percutaneous coronary and peripheral procedures. With international partnership, the committee has composed a comprehensive overview of this subject presented here-with.

Background. Rickettsia parkeri rickettsiosis, a recently identified spotted fever transmitted by the Gulf Coast tick (Amblyomma maculatum), was first described in 2004. We summarize the clinical and epidemiological features of 12 patients in the United States with confirmed or probable disease attributable to R. parkeri and comment on distinctions between R. parkeri rickettsiosis and other United States rickettsioses.

The transverse abdominal island flap operation was the method of breast reconstruction after mastectomy and in chest wall reconstruction in 300 patients from September 1980 to July 1986. In 58% (221 of 383 breast reconstructions), the breast mound was formed in a single operation and required no further revision. Only 18 reconstructed breasts required modification after 1 year. Symmetry was achieved without altering the opposite breast in 113 (52% of the 217 unilateral reconstructions). Complications included one total flap loss (0.3%) and 18 partial flap losses (6%). There was one lower abdominal hernia (0.3%) and two small defects in the upper anterior rectus sheath (0.8%). Lower abdominal wall laxity occurred in two patients (0.8%), one requiring repair. As expected, there was some loss of abdominal wall strength after reconstruction but this did not affect sports or work performance in over 90% of patients. Ninety-eight per cent of respondents (272 or 278) judged the operation worth their time and effort. This major operative procedure is indicated only in healthy patients.

BACKGROUND: Most studies of urinary cytology have been research analyses designed to test the method itself, and many claim that the high diagnostic yields in these studies cannot be achieved in daily practice. The authors examined the clinical and pathologic records in three hospital pathology practice settings--academic, community, and cancer referral settings--to determine the diagnostic yield of urinary cytology under daily clinical conditions. METHODS: Records of consecutive urinary cytology specimens from 1672 patients reported from the years 1990-1994 were reviewed and correlated with histologic and clinical information. Initial analyses were based on the records themselves, without review of pathologic specimens. Subsequently, a subset of specimens was reviewed to determine reasons for noncorrelations. RESULTS: Results confirmed that the diagnostic sensitivity and specificity of urinary cytology for high grade transitional cell neoplasms, as reported in the daily practice of pathology, are very high (79% and >95%, respectively). Disaggregated cells from low grade transitional cell neoplasms usually lack recognizable features of neoplasia, and attempts to classify such lesions cytologically result in low diagnostic yield, with an overall sensitivity of 26%. Of these 1672 patients, 707 had insufficient clinical information for analysis, despite diligent and persistent efforts to acquire it. CONCLUSIONS: The diagnostic yield of consultations based on urinary cytology in the daily practice of pathology is high, regardless of whether the practice setting is referral-based or community-based. The available information indicates that in approximately 79% of patients with high grade transitional cell neoplasms, the neoplasms can be detected using urinary cytology. Conversely, a negative result is predictive of no cancer in more than 90% of cases. Sensitivity for detecting low grade urothelial lesions is low; however, most of these are easily detected cystoscopically. The authors' inability to acquire sufficient information to determine diagnostic yield in a large percentage of their cases was disturbing to them. Not only did this deficiency render their analyses incomplete, but lack of easily accessible follow-up and the apparent low priority for quality assurance activities among pathologists in all types of practice settings is likely to significantly reduce the feedback required for pathologists to acquire and maintain expertise in this very difficult area.

BACKGROUND: Chronic inflammation is a key player in pathogenesis. The inflammatory cytokine, tumor necrosis factor-alpha is a well known inflammatory protein, and has been a therapeutic target for the treatment of diseases such as Rheumatoid Arthritis and Crohn's Disease. Obesity is a well known risk factor for developing non-insulin dependent diabetes melitus. Adipose tissue has been shown to produce tumor necrosis factor-alpha, which has the ability to reduce insulin secretion and induce insulin resistance. Based on these observations, we sought to investigate the impact of unsaturated fatty acids such as oleic acid in the presence of TNF-alpha in terms of insulin production, the molecular mechanisms involved and the in vivo effect of a diet high in oleic acid on a mouse model of type II diabetes, KKAy. METHODS: The rat pancreatic beta cell line INS-1 was used as a cell biological model since it exhibits glucose dependent insulin secretion. Insulin production assessment was carried out using enzyme linked immunosorbent assay and cAMP quantification with competitive ELISA. Viability of TNF-alpha and oleic acid treated cells was evaluated using flow cytometry. PPAR-gamma translocation was assessed using a PPRE based ELISA system. In vivo studies were carried out on adult male KKAy mice and glucose levels were measured with a glucometer. RESULTS: Oleic acid and peanut oil high in oleic acid were able to enhance insulin production in INS-1. TNF-alpha inhibited insulin production but pre-treatment with oleic acid reversed this inhibitory effect. The viability status of INS-1 cells treated with TNF-alpha and oleic acid was not affected. Translocation of the peroxisome proliferator- activated receptor transcription factor to the nucleus was elevated in oleic acid treated cells. Finally, type II diabetic mice that were administered a high oleic acid diet derived from peanut oil, had decreased glucose levels compared to animals administered a high fat diet with no oleic acid. CONCLUSION: Oleic acid was found to be effective in reversing the inhibitory effect in insulin production of the inflammatory cytokine TNF-alpha. This finding is consistent with the reported therapeutic characteristics of other monounsaturated and polyunsaturated fatty acids. Furthermore, a diet high in oleic acid, which can be easily achieved through consumption of peanuts and olive oil, can have a beneficial effect in type II diabetes and ultimately reverse the negative effects of inflammatory cytokines observed in obesity and non insulin dependent diabetes mellitus.

Parathyroid hormone (PTH) is a potent anabolic agent for bone, but the mechanism(s) by which it works remains imperfectly understood. Previous studies have indicated that PTH stimulates insulin-like growth factor (IGF) I production, but it remains uncertain whether IGF-I mediates some or all of the skeletal actions of PTH. To address this question, we examined the skeletal response to PTH in IGF-I-deficient (knockout [k/o]) mice. These mice and their normal littermates (NLMs) were given daily injections of PTH (80 microg/kg) or vehicle for 2 weeks after which their tibias were examined for fat-free weight (FFW), bone mineral content, bone structure, and bone formation rate (BFR), and their femurs were assessed for mRNA levels of osteoblast differentiation markers. In wild-type mice, PTH increased FFW, periosteal BFR, and cortical thickness (C.Th) of the proximal tibia while reducing trabecular bone volume (BV); these responses were not seen in the k/o mice. The k/o mice had normal mRNA levels of the PTH receptor and increased mRNA levels of the IGF-I receptor but markedly reduced basal mRNA levels of the osteoblast markers. Surprisingly, these mRNAs in the k/o bones increased several-fold more in response to PTH than the mRNAs in the bones from their wild-type littermates. These results indicate that IGF-I is required for the anabolic actions of PTH on bone formation, but the defect lies distal to the initial response of the osteoblast to PTH.

A retrospective review with a mean follow-up time of 60 months was performed on 126 patients who had treatment of unicompartmental gonarthrosis with either abrasion arthroplasty plus arthroscopic debridement or arthroscopic debridement alone. Fifty-nine patients had abrasion arthroplasty and arthroscopic debridement, and 67 patients had arthroscopic debridement alone. All patient had stage II Ahlbäck changes roentgenographically, as well as Outerbridge stage IV changes arthroscopically in the involved compartment. All the knees were evaluated postoperatively at a minimum of 60 months, utilizing The Hospital For Special Surgery Knee Scoring System. In the group treated with abrasion arthroplasty, 51% had good to excellent results, 16% had fair results, and 33% had poor results. The conditions of ten of the patients who had poor results actually became worse subsequent to their abrasion arthroplasty. In the group that had arthroscopic debridement, 66% had good to excellent results, 13% had fair results, and 21% had poor results. The conditions of 12 of the patients who had poor results actually became worse subsequent to the arthroscopic debridement.

BACKGROUND: Obesity is a risk factor for the progression of chronic kidney disease (CKD). The impact of weight loss on proteinuria and renal function is less clear. We aimed to determine the effect of intentional weight loss on proteinuria and kidney function. METHODS: Three bibliographic databases including Medline, Cochrane and SCUPOS as well as reference list of articles were searched. We included randomized and non-randomized controlled trials as well as single-arm trials published in English through May 2009 which examined urinary protein among obese or overweight adults before and after weight loss interventions including dietary restriction, exercise, anti-obesity medications and bariatric surgery. Study characteristics and methodological quality of trials were assessed. RESULTS: Five hundred twenty-two subjects from five controlled and eight uncontrolled trials were included. Weight loss interventions were associated with decreased proteinuria and microalbuminuria by 1.7 g [95% confidence interval (95% CI), 0.7 to 2.6 g] and 14 mg (95% CI, 11 to 17 mg), respectively (P < 0.05). Meta-regression showed that, independent of decline in mean arterial pressure, each 1 kg weight loss was associated with 110 mg (95% CI, 60 to 160 mg, P < 0.001) decrease in proteinuria and 1.1 mg (95% CI, 0.5 to 2.4 mg, P = 0.011) decrease in microalbuminuria, respectively. The decrease was observed across different designs and methods of weight loss. Only bariatric surgery resulted in a significant decrease in creatinine clearance. CONCLUSIONS: Weight loss is associated with decreased proteinuria and microalbuminuria. There were no data evaluating the durability of this decrease or the effect of weight loss on CKD progression.