We have recently found that GPR120, which is abundantly expressed in intestine, functions as a receptor for unsaturated long-chain free fatty acids (FFAs) and that GPR120 stimulation promotes the secretion of glucagons-like peptide-1 (GLP-1) in the mouse (Hirasawa et al., Nat Med 11:90-94, 2005). In this study, we cloned and characterized rat GPR120 (rGPR120), and then we examined the in vivo effects of acute and long-term administration of the natural ligand alpha-linolenic acid (alpha-LA). The cloned rat GPR120 complimentary DNA had a seven transmembrane structure, and a homology comparison of human, mouse, and rat GPR120 revealed that the rat GPR120 (rGPR120) shares 85 and 98% sequence identity with the human and mouse GPR120 proteins, respectively. The tissue distribution and ligand properties of rGPR120 were similar to those of mouse GPR120. In addition, alpha-LA provoked a transient increase in [Ca2+]i levels in HEK293 cells expressing rGPR120. Furthermore, administration of alpha-LA to the rat increased plasma GLP-1 levels, and long-term administration of alpha-LA led to proliferation of pancreatic beta cells, probably because of the enhanced GLP-1 secretion. These results show that rat GPR120 is a G-protein-coupled receptor whose ligand is a free fatty acid, and it may play an important role in the FFA-associated physiological responses.

Data in the biological, chemical, and clinical domains are accumulating at ever-increasing rates and have the potential to accelerate and inform drug development in new ways. Challenges and opportunities now lie in developing analytic tools to transform these often complex and heterogeneous data into testable hypotheses and actionable insights. This is the aim of computational pharmacology, which uses in silico techniques to better understand and predict how drugs affect biological systems, which can in turn improve clinical use, avoid unwanted side effects, and guide selection and development of better treatments. One exciting application of computational pharmacology is drug repurposing-finding new uses for existing drugs. Already yielding many promising candidates, this strategy has the potential to improve the efficiency of the drug development process and reach patient populations with previously unmet needs such as those with rare diseases. While current techniques in computational pharmacology and drug repurposing often focus on just a single data modality such as gene expression or drug-target interactions, we argue that methods such as matrix factorization that can integrate data within and across diverse data types have the potential to improve predictive performance and provide a fuller picture of a drug's pharmacological action. WIREs Syst Biol Med 2016, 8:186-210. doi: 10.1002/wsbm.1337 For further resources related to this article, please visit the WIREs website.

The mechanism of the progressive loss of CD4+ T lymphocytes, which underlies the development of AIDS in human immunodeficiency virus (HIV-1)-infected individuals, is unknown. Animal models, such as the infection of Old World monkeys by simian-human immunodeficiency virus (SHIV) chimerae, can assist studies of HIV-1 pathogenesis. Serial in vivo passage of the nonpathogenic SHIV-89.6 generated a virus, SHIV-89.6P, that causes rapid depletion of CD4+ T lymphocytes and AIDS-like illness in monkeys. SHIV-KB9, a molecularly cloned virus derived from SHIV-89.6P, also caused CD4+ T-cell decline and AIDS in inoculated monkeys. It has been demonstrated that changes in the envelope glycoproteins of SHIV-89.6 and SHIV-KB9 determine the degree of CD4+ T-cell loss that accompanies a given level of virus replication in the host animals (G. B. Karlsson et. al., J. Exp. Med. 188:1159-1171, 1998). The envelope glycoproteins of the pathogenic SHIV mediated membrane fusion more efficiently than those of the parental, nonpathogenic virus. Here we show that the minimal envelope glycoprotein region that specifies this increase in membrane-fusing capacity is sufficient to convert SHIV-89.6 into a virus that causes profound CD4+ T-lymphocyte depletion in monkeys. We also studied two single amino acid changes that decrease the membrane-fusing ability of the SHIV-KB9 envelope glycoproteins by different mechanisms. Each of these changes attenuated the CD4+ T-cell destruction that accompanied a given level of virus replication in SHIV-infected monkeys. Thus, the ability of the HIV-1 envelope glycoproteins to fuse membranes, which has been implicated in the induction of viral cytopathic effects in vitro, contributes to the capacity of the pathogenic SHIV to deplete CD4+ T lymphocytes in vivo.

The purpose of this study was to determine the effects of different volumes of high-intensity resistance training on isometric torque and muscle thickness. Training was conducted three times per week using one set (low volume, EX-1, N = 18) or three sets (high volume, EX-3, N = 20) of dynamic variable resistance exercise. Ten subjects acted as nontraining controls (CONT). Bilateral knee extension (KEXT) and flexion (KFLEX) exercise was performed to fatigue within 8-12 repetitions for 14 wk. Maximal isometric KEXT and KFLEX torque was tested at 6 degrees, 24 degrees, 42 degrees, 60 degrees, 78 degrees, 96 degrees, and 108 degrees of KFLEX using a MedX (Ocala, FL) KEXT/KFLEX ergometer. The anterior (ANT), lateral (LAT), and posterior (POST) right thigh, the medialis muscle (MED), and the lateralis muscle (LATER) were assessed for thickness by B-mode ultrasound (ULTRA). Both training groups improved torque output at most angles, but there was no difference between EX-1 and EX-3 (P>> or = 0.05). ULTRA detected increases in muscle thickness for EX-1 at 60% LAT and 40% and 60% POST. EX-3 increased muscle thickness at the MED, and 40% and 60% POST. In conclusion, one set of high intensity resistance training was as effective as three sets for increasing KEXT and KFLEX isometric torque and muscle thickness in previously untrained adults.

CONCLUSIONS

Successful hearing preservation is possible in individuals with excellent low frequency hearing. This is possible due to the partial insertion of an atraumatic electrode using an atraumatic round window surgical technique.

OBJECTIVE

This paper describes the round window surgical technique used to preserve excellent low frequency hearing in patients receiving partially inserted MED-EL cochlear implant electrodes. Results of preserved low frequency hearing in partial deafness cochlear implantation (PDCI) are reported.

METHODS

The surgical approach is described in detail. Ten subjects received a partial insertion of a standard electrode, using the round window approach. Pure tone audiometry was conducted in the implanted and non-implanted ear preoperatively, at implant fitting and then at 1, 3, 6 and 12 months after initial device fitting.

RESULTS

Results show hearing preservation in 9 of the 10 subjects. One subject lost all hearing 2 weeks after cochlear implantation. Hearing has remained essentially stable up to the 1 year postoperative period. Eight of the nine subjects use the cochlear implant together with their natural low frequency hearing; one subject uses a hearing aid in the implanted ear to amplify the low frequencies.

Uncoupling protein-3 (UCP3) is a mitochondrial inner membrane protein expressed most abundantly in skeletal muscle and to a lesser extent in heart and brown adipose tissue. Evidence supports a role for UCP3 in fatty acid oxidation (FAO); however, the underlying mechanism has not been explored. In 2001 we proposed a role for UCP3 in fatty acid export, leading to higher FAO rates (Himms-Hagen, J., and Harper, M. E. (2001) Exp. Biol. Med. (Maywood) 226, 78-84). Specifically, this widely held hypothesis states that during elevated FAO rates, UCP3 exports fatty acid anions, thereby maintaining mitochondrial co-enzyme A availability; reactivation of exported fatty acid anions would ultimately enable increased FAO. Here we tested mechanistic aspects of this hypothesis as well as its functional implications, namely increased FAO rates. Using complementary mechanistic approaches in mitochondria from wild-type and Ucp3(-/-) mice, we find that UCP3 is not required for FAO regardless of substrate type or supply rate covering a 20-fold range. Fatty acid anion export and reoxidation during elevated FAO, although present in skeletal muscle mitochondria, are independent of UCP3 abundance. Interestingly, UCP3 was found to be necessary for the fasting-induced enhancement of FAO rate and capacity, possibly via mitigated mitochondrial oxidative stress. Thus, although our observations indicate that UCP3 can impact FAO rates, the mechanistic basis is not via an integral function for UCP3 in the FAO machinery. Overall our data indicate a function for UCP3 in mitochondrial adaptation to perturbed cellular energy balance and integrate previous observations that have linked UCP3 to reduced oxidative stress and FAO.

In the cellular immune response, recognition by CTL-TCRs of viral antigens presented as peptides by HLA class I molecules, triggers destruction of the virally infected cell (Townsend, A.R.M., J. Rothbard, F.M. Gotch, G. Bahadur, D. Wraith, and A.J. McMichael. 1986. Cell. 44:959-968). Altered peptide ligands (APLs) which antagonise CTL recognition of infected cells have been reported (Jameson, S.C., F.R. Carbone, and M.J. Bevan. 1993. J. Exp. Med. 177:1541-1550). In one example, lysis of antigen presenting cells by CTLs in response to recognition of an HLA B8-restricted HIV-1 P17 (aa 24-31) epitope can be inhibited by naturally occurring variants of this peptide, which act as TCR antagonists (Klenerman, P., S. Rowland Jones, S. McAdam, J. Edwards, S. Daenke, D. Lalloo, B. Koppe, W. Rosenberg, D. Boyd, A. Edwards, P. Giangrande, R.E. Phillips, and A. McMichael. 1994. Nature (Lond.). 369:403-407). We have characterised two CTL clones and a CTL line whose interactions with these variants of P17 (aa 24-31) exhibit a variety of responses. We have examined the high resolution crystal structures of four of these APLs in complex with HLA B8 to determine alterations in the shape, chemistry, and local flexibility of the TCR binding surface. The variant peptides cause changes in the recognition surface by three mechanisms: changes contributed directly by the peptide, effects transmitted to the exposed peptide surface, and induced effects on the exposed framework of the peptide binding groove. While the first two mechanisms frequently lead to antagonism, the third has more profound effects on TCR recognition.

METHODS

A retrospective review involving 873 consecutive cases of lumbar disc herniation treated by microendoscopic discectomy (MED) was conducted and a mean 28-month follow-up was performed.

OBJECTIVE

The purpose of this study was to describe the MED technique for lumbar disc herniation and report long-time outcome and complications.

BACKGROUND

The conception of MED was introduced in 1997. Long-time outcome has not been described.

METHODS

A total of 873 consecutive patients with lumbar disc herniation were treated with the METRx system. Oswestry Disability Index (ODI) was used to quantify pain relief. The degree of pain and disability was also measured by visual analog scale (VAS) and modified MacNab criteria. A control group of 358 patients treated with standard open discectomy was used for comparison.

RESULTS

There was significant improvement in the mean preoperative and postoperative VAS and ODI score for the MED and open groups, and there was no statistical difference of the pain improvement between the two groups. For the MED group, average length of hospital stay was 4.8 days; mean time to return to work or normal activities was 15 days; average operative blood loss per level was 44 mL. These were significantly less than open group.

CONCLUSIONS

MED is an effective microendoscopic system with fine long-term outcome in treating lumbar disc herniation. The endoscopic approach allows smaller incisions and less tissue trauma, compared with standard open microdiscectomy. Strict adherence to well-defined preoperative selection criteria could ensure optimal postoperative outcome.

There is evidence indicating that density of 5-HT2A receptors is altered in brain regions of depressed suicide victims and in platelets of suicidal subjects with major depression or schizophrenia. Recent studies have also shown an association between the allele C of 102T/C polymorphism in the 5-HT2A receptor gene and schizophrenia. The present investigation tested the hypothesis that the observed changes in 5-HT2A receptor density in platelets of patients with major depression are a trait rather than state phenomenon and are associated with the 102 C allele in 5-HT2A receptor gene in a sample of 120 patients with major depression and a group of 131 control subjects comparable with respect to age, sex, and ethnic background. The allele and genotype frequencies of 102T/C polymorphism in 5-HT2A receptor gene were compared between patients and control subjects and between suicidal and non-suicidal patient groups. The major finding of this study was a significant association between the 102 C allele in 5-HT2A receptor gene and major depression, chi(2) = 4.5, df = 1, P = 0.03, particularly in patients with suicidal ideation, chi(2) = 8.5, df = 1, P < 0.005. Furthermore, we found that patients with a 102 C/C genotype had a significantly higher mean HAMD item 3 score (indication of suicidal ideation) than T/C or T/T genotype patients. Our results suggest that the 102T/C polymorphism in 5-HT2A receptor gene is primarily associated with suicidal ideation in patients with major depression. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:56-60, 2000.

Caveolae are 50-100 nm invaginations that represent an appendage or subcompartment of the plasma membrane. They are found in most cell types but are abundant in fibroblasts, adipocytes, endothelial cells, type I pneumocytes, epithelial cells, and smooth and striated muscle cells. Functionally, caveolae have been implicated in three major processes: endothelial transcytosis, potocytosis, and signal transduction. Caveolin, a 21-24 kD integral membrane protein, is a principal component of the caveolar membrane in vivo. Within caveolar microdomains, caveolin functions as a multivalent docking site for recruiting and sequestering signaling molecules. More specifically, caveolin interacts directly in a regulated manner with multiple lipid-modified signaling molecules (such as Src-tyrosine kinases, Gα subunits, and H-Ras), preferring the inactive conformation of these molecules. Here, we present a general overview of our current knowledge of caveolae and caveolin functioning and possible implications for treatment of human disease. (Trends Cardiovasc Med 1997;7:103-110). © 1997, Elsevier Science Inc.

Francisella tularensis, the etiological agent of the inhalation tularemia, multiplies in a variety of cultured mammalian cells. Nevertheless, evidence for its in vivo intracellular residence is less conclusive. Dendritic cells (DC) that are adapted for engulfing bacteria and migration towards lymphatic organs could serve as potential targets for bacterial residence and trafficking. Here, we focus on the in vivo interactions of F. tularensis with DC following airway infection of mice. Lethal airway infection of mice with the live vaccine strain (LVS) results in trafficking of a CD11b(high)/CD11c(med)/autofluorescence(low) DC subset from the respiratory tract to the draining mediastinal lymph node (MdLN). Simultaneously, a rapid, massive bacterial colonization of the MdLN occurs, characterized by large bacterial foci formation. Analysis of bacteria in the MdLN revealed a major population of extracellular bacteria, which co-exists with a substantial fraction of intracellular bacteria. The intracellular bacteria are viable and reside in cells sorted for DC marker expression. Moreover, in vivo vital staining experiments indicate that most of these intracellular bacteria ( approximately 75%) reside in cells that have migrated from the airways to the MdLN after infection. The correlation between DC and bacteria accumulation in the MdLN was further demonstrated by manipulating DC migration to the MdLN through two independent pathways. Impairment of DC migration to the MdLN, either by a sphingosine-1-phosphate receptor agonist (FTY720) or by the D prostanoid receptor 1 agonist (BW245C), resulted in reduced bacterial colonization of MdLN. Moreover, BW245C treatment delayed the onset of morbidity and the time to death of the infected mice. Taken together, these results suggest that DC can serve as an inhabitation niche for F. tularensis in the early stages of infection, and that DC trafficking plays a role in pathogen dissemination. This underscores the therapeutic potential of DC migration impairing drugs in tularemia treatment.

BACKGROUND

Epidemiologic studies link Mediterranean-type diets to a low incidence of cardiovascular disease; however, few dietary intervention studies have been undertaken, especially in primary prevention.

OBJECTIVE

In the Mediterranean Diet, Cardiovascular Risks and Gene Polymorphisms (Medi-RIVAGE) study, the effects of a Mediterranean-type diet (Med group) or a low-fat diet (low-fat group) on risk factors were evaluated in 212 volunteers (men and women) with moderate risk factors for cardiovascular disease.

METHODS

After the 3-mo dietary intervention, changes in many risk factors were evaluated. Dietary questionnaires and plasma nutritional markers were used to test compliance.

RESULTS

Although the dietary goals were only partially reached, changes in dietary habits were observed in both groups (n = 169): protein, carbohydrate, and fiber intakes increased and fat quality (decreased saturated fat and increased monounsaturated or polyunsaturated fat) improved. BMI, total and triacylglycerol-rich lipoprotein (TRL) cholesterol, triacylglycerols, TRL triacylglycerols, apolipoproteins A-I and B, insulinemia, glycemia, and the homeostasis model assessment score were significantly lower after 3 mo. The reductions in total cholesterol, triacylglycerols, and insulinemia remained significant after adjustment for BMI. There was a trend for a diet-by-time interaction for LDL cholesterol (P = 0.09). Our data predicted a 9% reduction in cardiovascular disease risk with the low-fat diet and a 15% reduction with this particular Mediterranean diet.

CONCLUSIONS

After a 3-mo intervention, both diets significantly reduced cardiovascular disease risk factors to an overall comparable extent.

We have previously shown that c-MYC-induced mammary tumorigenesis in mice proceeds via a preferred secondary pathway involving spontaneous activating mutations in Kras2 (C. M. D'Cruz, E. J. Gunther, R. B. Boxer, J. L. Hartman, L. Sintasath, S. E. Moody, J. D. Cox, S. I. Ha, G. K. Belka, A. Golant, R. D. Cardiff, and L. A. Chodosh, Nat. Med. 7:235-239, 2001). In contrast, we now demonstrate that Wnt1-induced mammary tumorigenesis proceeds via a pathway that preferentially activates Hras1. In addition, we find that expression of oncogenic forms of Kras2 and Hras1 from their endogenous promoters has markedly different consequences for the progression of tumors to oncogene independence. Spontaneous activating Kras2 mutations occurring in either MYC- or Wnt1-induced tumors were strongly associated with oncogene-independent tumor growth following MYC or Wnt1 downregulation. In contrast, Hras1-mutant Wnt1-induced tumors consistently remained oncogene dependent. Additionally, Kras2-mutant tumors exhibited substantially higher levels of ras-GTP, phospho-Erk1/2, and phospho-Mek1/2 compared to Hras1-mutant tumors, suggesting the involvement of the ras/mitogen-activated protein kinase (MAPK) pathway in the acquisition of oncogene independence. Consistent with this, by use of carcinogen-induced ras mutations as well as knock-in mice harboring a latent activated Kras2 allele, we demonstrate that Kras2 activation strongly synergizes with both c-MYC and Wnt1 in mammary tumorigenesis and promotes the progression of tumors to oncogene independence. Together, our findings support a model for tumorigenesis in which c-MYC and Wnt1 select for the outgrowth of cells harboring mutations in specific ras isoforms and that these secondary mutations, in turn, determine the extent of ras/MAPK pathway activation and the potential for oncogene-independent growth.

We have recently reported that the inhibition of endothelial cell COX-2 by non-steroidal anti-inflammatory drugs suppresses alpha(V)beta(3)- (but not alpha(5)beta(1)-) dependent Rac activation, endothelial cell spreading, migration, and angiogenesis (Dormond, O., Foletti, A., Paroz, C., and Ruegg, C. (2001) Nat. Med. 7, 1041-1047). Here we investigated the role of the COX-2 metabolites PGE(2) and TXA2 in regulating human umbilical vein endothelial cell (HUVEC) adhesion and spreading. We report that PGE(2) accelerated alpha(V)beta(3)-mediated HUVEC adhesion and promoted Rac activation and cell spreading, whereas the TXA2 agonist retarded adhesion and inhibited spreading. We show that the cAMP level and the cAMP-regulated protein kinase A (PKA) activity are critical mediators of these PGE(2) effects. alpha(V)beta(3)-mediated adhesion induced a transient COX-2-dependent rise in cAMP levels, whereas the cell-permeable cAMP analogue 8-brcAMP accelerated adhesion, promoted Rac activation, and cell spreading in the presence of the COX-2 inhibitor NS-398. Pharmacological inhibition of PKA completely blocked alpha(V)beta(3)-mediated adhesion. A constitutively active Rac mutant (L61Rac) rescued alpha(V)beta(3)-dependent spreading in the presence of NS398 or, but did not accelerate adhesion, whereas a dominant negative Rac mutant (N17Rac) suppressed spreading without affecting adhesion. alpha(5)beta(1)-mediated HUVEC adhesion, Rac activation, and spreading were not affected by PGE(2), 8-brcAMP, or the inhibition of PKA. In conclusion, these results demonstrate that PGE(2) accelerates alpha(V)beta(3)-mediated endothelial cell adhesion through cAMP-dependent PKA activation and induces alpha(V)beta(3)-dependent spreading via cAMP- and PKA-dependent Rac activation and may contribute to the further understanding of the regulation of vascular integrins alpha(V)beta(3) by COX-2/PGE(2) during tumor angiogenesis and inflammation.

Quantification of cerebral perfusion using dynamic susceptibility contrast MRI generally relies on the assumption of an intact blood-brain barrier. The present study proposes a method to correct the tissue response function that does not require this assumption, thus, allowing perfusion studies in, for example, high-grade brain tumors. The correction for contrast extravasation in the tissue during the bolus passage is based on a two-compartment kinetic model. The method separates the intravascular hemodynamic response and the extravascular component and returns the corrected tissue response function for perfusion quantification as well as the extravasation rate constant of the vasculature. Results of simulation experiments with different degrees of contrast extravasation are presented. The clinical potential is illustrated by determination of the perfusion and extravasation of a glioblastoma multiforme. The correction scheme proves to be fast and reliable even in cases of low signal-to-noise ratio. It is applicable whether extravasation occurs or not. When extravasation is present, application of the proposed method is mandatory for accurate cerebral blood volume measurements. Magn Reson Med 43:820-827, 2000.

Precise quantification of human in vivo short echo time (1)H spectra remains problematic at clinical field strengths due to broad peak linewidths and low signal-to-noise ratio (SNR). In this study, multiple STEAM spectra (TE = 20 ms, volume = 8 cm(3)) were acquired in a single individual at 1.5 T and 4 T to compare quantification precision. Test-retest STEAM spectra (volume = 1.5 cm(3)) were also acquired from the anterior cingulate and thalamus of 10 individuals at 4.0 T. Metabolite levels were quantified using automated software that incorporated field strength-specific prior knowledge. With the distinct methods of data acquisition, processing, and fitting used in this study, peak height SNR increased approximately 80% while peak linewidth increased by approximately 50% in the 8 cm(3) volumes at 4.0 T compared to 1.5 T, resulting in an average increase in quantification precision of 39%. Metabolite levels from test-retest data (1.5 cm(3) voxels at 4.0 T) were quantified with similar inter- and intraindividual variability. Magn Reson Med 44:185-192, 2000. Published 2000 Wiley-Liss, Inc.

OBJECTIVE

Emerging data demonstrate that injection of dextranomer/hyaluronic acid (Dx/HA) copolymer (Deflux, Q-Med Scandinavia, Uppsala, Sweden) is a safe and effective treatment for most patients with vesicoureteral reflux (VUR). We sought to determine the efficacy and factors predictive of outcome in patients treated with Dx/HA.

METHODS

A total of 180 children 7 months to 15 years old (mean age 4.6 years) underwent subureteral injection of Dx/HA for VUR between October 2001 and February 2003. Dx/HA was injected submucosally within or beneath the intramural ureter. The average volume of injected material was measured for each ureter. At 2 weeks and 3 months postoperatively bladder ultrasounds were performed to measure the volume of Dx/HA (mm3) in the trigone using the volume of an ellipsoid (V = 4/3pir(1)r(2)r(3)). Renal sonography was performed to determine whether hydronephrosis was present. At 3 months fluoroscopic voiding cystourethrograms were used to evaluate for the presence of VUR.

RESULTS

A total of 292 ureters in 180 children were treated (112 bilateral cases). There were 141 girls and 39 boys. Mean maximum grade per patient was 2.6 (out of 5). Average injected volume per ureter was 0.83 +/- 0.03 ml (830 +/- 30 mm3). At 2 weeks the average measured volume was 663 +/- 70 mm3 (18% decrease from original volume), which decreased an additional 1% by 3 months to 656 +/- 103 mm3. There were no cases of hydronephrosis at up to 12 months postoperatively.There were 134 patients with at least 3 months of followup. After 1 treatment 72% (96) were cured (grade 0), while 55% of the failures (21 of 38) were improved. New contralateral VUR was seen in 6 patients (4.5%) who had neither a history of VUR nor an abnormal appearing ureteral orifice at cystoscopy. A lower success rate (60%) was seen in the first 20 patients compared with the last 20 patients (80%). The cure rate per grade was 90% for grade I, 82% for grade II, 73% for grade III and 65% for grade IV reflux. Local migration of material caudal to the ureteral orifice was seen in 61% of patients (11 of 18) at the time of reinjection of Dx/HA after initial treatment failure. There was no statistically significant difference in age, grade, volume injected, bilaterality or gender when successes were compared with failures.

CONCLUSIONS

The majority of patients (72%) undergoing minimally invasive treatment of VUR with Dx/HA are cured after 1 treatment. Contralateral treatment of nonrefluxing ureters should be considered in view of the increased incidence of new reflux (4.5%) and absence of morbidity with Dx/HA injection. There is a definite learning curve with injection therapy. The location of injected material and experience with the technique appear to correlate with the outcome of the procedure.

Para-aminosalicylic acid (PAS), an FDA-approved anti-tuberculosis drug, has been used successfully in the treatment of severe manganese (Mn)-induced Parkinsonism in humans [Jiang Y-M, Mo X-A, Du FQ, Fu X, Zhu X-Y, Gao H-Y, et al. Effective treatment of manganese-induced occupational Parkinsonism with p-aminosalicylic acid: a case of 17-year follow-up study. J Occup Environ Med 2006;48:644-9]. This study was conducted to explore the capability of PAS in reducing Mn concentrations in body fluids and tissues of Mn-exposed animals. Sprague-Dawley rats received daily intraperitoneally (i.p.) injections of 6mg Mn/kg, 5 days/week for 4 weeks, followed by a daily subcutaneously (s.c.) dose of PAS (100 and 200mg/kg as the PAS-L and PAS-H group, respectively) for another 2, 3 or 6 weeks. Mn exposure significantly increased the concentrations of Mn in plasma, red blood cells (RBC), cerebrospinal fluid (CSF), brain and soft tissues. Following PAS-H treatment for 3 weeks, Mn levels in liver, heart, spleen and pancreas were significantly reduced by 25-33%, while 3 weeks of PAS-L treatment did not show any effect. Further therapy with PAS-H for 6 weeks reduced Mn levels in striatum, thalamus, choroid plexus, hippocampus and frontal cortex by 16-29% (p<0.05). Mn exposure greatly increased iron (Fe) and copper (Cu) concentrations in CSF, brain and liver. Treatment with PAS-H restored Fe and Cu levels comparable with control. These data suggest that PAS likely acts as a chelating agent to mobilize and remove tissue Mn. A high-dose and prolonged PAS treatment appears necessary for its therapeutic effectiveness.

Angiogenesis of human melanomas has been the focus of intense interest since it was shown that the spread and prognosis of primary tumors is correlated with their vascularization (N. Weidner, J. P. Semple, W. R. Welch, and J. Folkman, N. Engl. J. Med., 324: 1-8, 1991). Basic fibroblast growth factor (bFGF) and its high-affinity receptor FGFR-1 have been implicated in melanoma growth and angiogenesis (R. Halaban, Y. Funasaka, J. Lee, J. Rubin, D. Ron, and D. Birnbaum, Fibroblast Growth Factors in Normal and Malignant Melanocytes, pp. 232-243. New York: The New York Academy of Sciences, 1991). We have studied the expression of the Tie endothelial cell receptor tyrosine kinase mRNA in skin and primary cutaneous melanomas as well as in their skin and brain metastases by in situ hybridization. The Tie probe hybridized very weakly with the vascular endothelium of capillaries of normal skin, while it was detected in larger arteries and veins as well as in capillaries around sweat glands. However, capillaries and medium-sized vessels within cutaneous and brain metastases of melanoma were strongly positive for Tie mRNA. In contrast, endothelial cells contained very little or no FGFR-1 transcripts, whereas abundant FGFR-1 mRNA was present in melanoma tumor cells and in fibrovascular stroma. In agreement with these findings, a Tie-specific amplified cDNA band was obtained by reverse transcription-polymerase chain reaction from melanoma metastases but not from normal skin. These results suggest a role for the Tie receptor in the angiogenesis associated with melanoma metastases.

OBJECTIVE

To evaluate various endometrial pathologies described in association with postmenopausal tamoxifen treatment, as well as the clinical aspects of these endometrial pathologies.

METHODS

A search was made in PUB MED for all studies published in English, up to the end of 2003, reporting on endometrial pathologies in association with postmenopausal tamoxifen treatment. Overall 106 studies were available, and all are included in this review. The types of studies included were mostly randomized clinical trials, non-randomized cohort studies, prospective and retrospective case controlled studies.

RESULTS

Endometrial polyps represent the most common endometrial pathology associated with postmenopausal tamoxifen exposure. A high rate of malignancy was reported in these polyps. Endometrial hyperplasia, endometrial polyps, endometrial cancer and malignant mixed mesodermal tumors and sarcoma are more commonly diagnosed in postmenopausal breast cancer tamoxifen-treated patients as compared to non-treated patients. Long-term tamoxifen users are more likely to succumb to endometrial cancer and endometrial sarcomas than non-users, due to the unfavorable histology of the endometrial malignancy, and an advanced stage of diagnosis.

CONCLUSIONS

The clinician should be alerted to these pathologies, which, in some cases, may potentially increase the mortality of these patients. Consequently, it is suggested that their supervision is of importance, especially if the patients experience any gynecological symptoms, including pelvic pain or pressure.

BACKGROUND

Opioid use and dosing for patients with chronic non-cancer pain have dramatically increased over the past decade, resulting in a national epidemic of mortality associated with unintentional overdose, and increased risk of disability among injured workers. We assessed changes in opioid dosing patterns and opioid-related mortality in the Washington State (WA) workers' compensation system following implementation of a specific WA opioid dosing guideline in April, 2007.

METHODS

Using detailed computerized billing data from WA workers' compensation, we report overall prevalence of opioid prescriptions, average morphine-equivalent dose (MED)/day, and proportion of workers on disability compensation receiving opioids and high-dose (≥120 mg/day MED) opioids over the past decade. We also report the trend of unintentional opioid deaths during the same time period.

RESULTS

Compared to before 2007, there has been a substantial decline in both the MED/day of long-acting DEA Schedule II opioids (by 27%) and the proportion of workers on doses ≥120 md/day MED (by 35%). There was a 50% decrease from 2009 to 2010 in the number of deaths.

CONCLUSIONS

The introduction in WA of an opioid dosing guideline appears to be associated temporally with a decline in the mean dose for long-acting opioids, percent of claimants receiving opioid doses ≥120 mg MED per day, and number of opioid-related deaths among injured workers.

There is no consensus on what test to use as the basis for sample size determination and power analysis. Some authors advocate the Wald test and some the likelihood-ratio test. We argue that the Wald test should be used because the Z-score is commonly applied for regression coefficient significance testing and therefore the same statistic should be used in the power function. We correct a widespread mistake on sample size determination when the variance of the maximum likelihood estimate (MLE) is estimated at null value. In our previous paper, we developed a correct sample size formula for logistic regression with single exposure (Statist. Med. 2007; 26(18):3385-3397). In the present paper, closed-form formulas are derived for interaction studies with binary exposure and covariate in logistic regression. The formula for the optimal control-case ratio is derived such that it maximizes the power function given other parameters. Our sample size and power calculations with interaction can be carried out online at www.dartmouth.edu/ approximately eugened.

Plasmodium falciparum is an obligate intracellular pathogen responsible for worldwide morbidity and mortality. This parasite establishes a parasitophorous vacuole within infected red blood cells wherein it differentiates into multiple daughter cells that must rupture their host cells to continue another infectious cycle. Using atomic force microscopy, we establish that progressive macrostructural changes occur to the host cell cytoskeleton during the last 15 h of the erythrocytic life cycle. We used a comparative proteomics approach to determine changes in the membrane proteome of infected red blood cells during the final steps of parasite development that lead to egress. Mass spectrometry-based analysis comparing the red blood cell membrane proteome in uninfected red blood cells to that of infected red blood cells and postrupture vesicles highlighted two temporally distinct events; (Hay, S. I., et al. (2009). A world malaria map: Plasmodium falciparum endemicity in 2007. PLoS Med. 6, e1000048) the striking loss of cytoskeletal adaptor proteins that are part of the junctional complex, including α/β-adducin and tropomyosin, correlating temporally with the emergence of large holes in the cytoskeleton seen by AFM as early ~35 h postinvasion, and (Maier, A. G., et al. (2008) Exported proteins required for virulence and rigidity of Plasmodium falciparum-infected human erythrocytes. Cell 134, 48-61) large-scale proteolysis of the cytoskeleton during rupture ~48 h postinvasion, mediated by host calpain-1. We thus propose a sequential mechanism whereby parasites first remove a selected set of cytoskeletal adaptor proteins to weaken the host membrane and then use host calpain-1 to dismantle the remaining cytoskeleton, leading to red blood cell membrane collapse and parasite release.

Unrestrained plethysmography (UP) has been widely used to measure airway reactivity in conscious mice. It is non-invasive, easy to use, suitable for longitudinal studies, and allows a large throughput of animals for screening purposes. A non-dimensional parameter based on a characteristic change in the expiratory waveshape of the UP box signal, Penh, has been used as an indicator of bronchconstriction. Hamelmann et al. [Non-invasive measurement of airway responsiveness in allergen mice using barometric plethysmography. Am J Respir Crit Care Med 1997;156:766-77] presented experimental data showing a correlation between Penh and intrapleural pressure, as well as lung resistance; and Dohi et al. [Non-invasive system for evaluating the allergen-specific airway response in a murine model of asthma. Lab Invest 1999;79:1559-71] showed that Penh tracked the bronchial response to allergen challenge. More recently, papers and letters to the editor have argued against the use of UP and Penh in resistance applications, presenting mathematical and theoretical arguments that the UP waveform, and parameters derived from it (Penh) are dominated by conditioning, and are essentially unrelated to resistance [Lundblad et al. A reevaluation of the validity of UP in mice. J Appl Physiol 2002;93:1198-207; Mitzner and Tankersley. Interpreting Penh in mice. J Appl Physiol 2003;94:828-32]. This paper discusses the mathematics of UP as applied to two types of whole body plethysmographs (WBPs): a sealed chamber (pressure plethysmograph, PWBP); and a chamber with a pneumotachograph in its wall (flow plethysmograph, FWBP). We show that the PWBP waveform is largely dominated by conditioning, and exhibits little effect due to resistance; thus supporting the claim that UP and Penh are unrelated to resistance, when applied to measurements at typical room temperatures. By contrast, the effects of resistance or specific airway resistance (sRaw) are evident in the FWBP waveform, even at room temperature. Penh is derived from the FWBP waveform. We show that the changes in the FWBP waveform which occur in response to methacholine challenge cannot be due to conditioning, and are not simply due to changes in respiratory timing. Finally, we describe how Penh quantifies those changes.