A heated rock crack captures and polymerizes primordial DNA and RNA.

Life is based on informational polymers such as DNA or RNA. For their polymerization, high concentrations of complex monomer building blocks are required. Therefore, the dilution by diffusion poses a major problem before early life could establish a non-equilibrium of compartmentalization. Here, we explored a natural non-equilibrium habitat to polymerize RNA and DNA. A heat flux across thin rock cracks is shown to accumulate and maintain nucleotides. This boosts the polymerization to RNA and DNA inside the crack. Moreover, the polymers remain localized, aiding both the creation of longer polymers and fostering downstream evolutionary steps. In a closed system, we found single nucleotides concentrate 104-fold at the bottom of the crack compared to the top after 24 hours. We detected enhanced polymerization for 2 different activation chemistries: aminoimidazole-activated DNA nucleotides and 2',3'-cyclic RNA nucleotides. The copolymerization of 2',3'-cGMP and 2',3'-cCMP in the thermal pore showed an increased heterogeneity in sequence composition compared to isothermal drying. Finite element models unravelled the combined polymerization and accumulation kinetics and indicated that the escape of the nucleotides from such a crack is negligible over a time span of years. The thermal non-equilibrium habitat establishes a cell-like compartment that actively accumulates nucleotides for polymerization and traps the resulting oligomers. We argue that the setting creates a pre-cellular non-equilibrium steady state for the first steps of molecular evolution.

P2X7 receptor-mediated release of microglial prostanoids and miRNAs correlates with reversal of neuropathic hypersensitivity in rats.

BACKGROUND: P2X7 receptor antagonists have potential for treating various central nervous system (CNS) diseases, including neuropathic pain, although none have been approved for clinical use. Reasons may include insufficient understanding of P2X7 receptor signalling in pain, and the lack of a corresponding preclinical mechanistic biomarker. METHODS: Lu AF27139 is a highly selective and potent small molecule antagonist at rat, mouse and human forms of the P2X7 receptor, with excellent pharmacokinetic and CNS permeability properties. In the current experiments, we probed the utility of previously characterized and novel signalling cascades exposed to Lu AF27139 using cultured microglia combined with release assays. Subsequently, we assessed the biomarker potential of identified candidate molecules in the rat chronic constriction injury (CCI) model of neuropathic pain; study design limitations precluded their assessment in spared nerve injury (SNI) rats. RESULTS: Lu AF27139 blocked several pain-relevant pathways downstream of P2X7 receptors in vitro. At brain and spinal cord receptor occupancy levels capable of functionally blocking P2X7 receptors, it diminished neuropathic hypersensitivity in SNI rats, and less potently in CCI rats. Although tissue levels of numerous molecules previously linked to neuropathic pain and P2X7 receptor function (e.g. IL-6, IL-1ß, cathepsin-S, 2-AG) were unaffected by CCI, Lu AF27139-mediated regulation of spinal PGE2 and miRNA (e.g. rno-miR-93-5p) levels increased by CCI aligned with its ability to diminish neuropathic hypersensitivity. CONCLUSIONS: We have identified a pain-relevant P2X7 receptor-regulated mechanism in neuropathic rats, which could hold promise as a translatable biomarker and by association enhance the clinical progression of P2X7 receptor antagonists in neuropathic pain. SIGNIFICANCE: Sub-optimal translation of preclinical molecules has hindered the clinical development of novel mechanism of action analgesics. We have undertaken a comprehensive in vitro analysis of migroglial signalling mechanisms recruited upon P2X7 receptor activation, a number of which were shown to be modulated by a selective P2X7 receptor antagonist in a well characterized animal model of neuropathic pain. Subject to further confirmation in other neuropathic models, this opens up the possibility to investigate their clinical utility as potential pain biomarkers in patients.

MR-based in vivo follow-up study of Achilles tendon volume and hydration state after ankle-loading activity.

The purpose of this study was to evaluate temporal alterations of the Achilles tendon volume and hydration state after cross-country-running. Achilles tendons of six untrained participants were examined on a 3T MR-scanner before running, immediately afterwards, and in the following 24, 48, and 72 h. Using a 3D-UTE sequence, caudal (CA) and cranial (CR) mid-portion tendon areas were examined with off-resonance saturation ratios (OSR) and T2* relaxation times. Tendon volume was measured with a self-written Matlab-based automated contour detection algorithm (AVAT) in submillimeter T2-weighted MR images. A significant influence of running in caudal (P = 0.017) and cranial OSR values (P = 0.001), tendon volume (P = 0.024), and cranial T2* measurements (P = 0.046), but not in caudal T2* values (P = 0.298) were found. In detail, mean individual OSR and tendon volume measurements demonstrated a similar but inverted course in their values after exercise: initially, OSR values increased after running (and tendon volume decreased), while subsequently a decrease of OSR values (with an increase of tendon volume) could be observed. OSR and tendon volume measurements are able to detect a physiological response of tendons to a mechanical stimulus. After a transient decrease of free water in the Achilles tendon, an increase with a maximum free water content 48 h after ankle loading and a tendency toward normalization after 72 h was found.

Intradiurnal Fluctuations of Off-Resonance Saturation Effects in Healthy Human Achilles Tendons Assessed with a 3D Ultrashort Echo Time MRI Sequence at 3 Tesla.

PURPOSE: The purpose of this study was to evaluate whether gravitational interstitial fluid accumulation in healthy subjects has an impact on off-resonance saturation ratios (OSR) or the volume of the Achilles tendon after a prolonged time of reduced levels of physical activity. MATERIALS AND METHODS: 7 healthy volunteers were repeatedly investigated on 3 consecutive days on a 3 T whole body MR scanner using an ultrashort echo time (UTE) imaging sequence with a Gaussian off-resonance saturation pulse at a frequency offset of 2000 Hz to calculate OSR values. For accurate volumetric quantification of the Achilles tendon, a newly developed contour detection snake algorithm was applied on high-resolution isotropic T2-weighted SPACE sequence datasets. Single-measure intraclass correlation coefficients (ICC) were calculated to estimate test-retest reliability. RESULTS: For OSR and tendon volume measurements on three consecutive days, excellent reproducibility could be achieved with ICC values above 0.96 and 0.97, respectively. Comparing the results of all three days, a statistically significant mean individual percentage decrease (- 4.1  ±â€Š1.5 %; p = 0.001) of calculated tendon OSR values was found for the evening measurements. No statistically significant difference between tendon volumes in the morning and the evening could be detected (p = 0.589). CONCLUSION: The results of this in-vivo study demonstrate a significant influence of gravitational interstitial fluid accumulation after reduced physical activity on OSR values in the Achilles tendon, but not on tendon volume. Taken together with the demonstrated excellent reproducibility, these findings are important for future studies investigating temporal changes of the Achilles tendon microstructure.

Chemical biology of mGlu4 receptor activation: dogmas, challenges, strategies and opportunities.

Drug design necessitates a clear understanding of the phenotypic response to be elicited by a given ligandtarget interaction. This relationship is relatively well understood for classical biological targets of drug action, but for some novel targets, notably those amenable to allosteric modulation, developing such understanding may represent a more challenging task. In order to gain knowledge on the nature of the functional response derived from mGlu4 receptor activation, its molecular and cell biology are reviewed, including signalling pathways involved, receptor localization in central nervous system and beyond, and potential genetic links to disease. Broadly held views for both, orthosteric agonists as well as allosteric modulators, are compared with specific observations for the case of mGlu4 receptor activation via orthosteric and allosteric mechanisms. First, sub-type selectivity and brain penetration of amino acid mGlu4 receptor agonists are discussed, followed by the quantification of functional allosteric effects, the potential role of heterodimers in the functional response, and the observation of supra-physiological efficacy of mGlu4 receptor PAMs. We show that, in our analysis, these attributes differ from those that may be expected by extrapolating from broad knowledge. In addition, recent progress with mGlu4 receptor radioligands and PET ligands is summarized.

Qualitative and quantitative performance of ¹8F-FDG-PET/MRI versus ¹8F-FDG-PET/CT in patients with head and neck cancer.

BACKGROUND AND PURPOSE: MR imaging and PET/CT are integrated in the work-up of head and neck cancer patients. The hybrid imaging technology (18)F-FDG-PET/MR imaging combining morphological and functional information might be attractive in this patient population. The aim of the study was to compare whole-body (18)F-FDG-PET/MR imaging and (18)F-FDG-PET/CT in patients with head and neck cancer, both qualitatively in terms of lymph node and distant metastases detection and quantitatively in terms of standardized uptake values measured in (18)F-FDG-avid lesions. MATERIALS AND METHODS: Fourteen patients with head and neck cancer underwent both whole-body PET/CT and PET/MR imaging after a single injection of (18)F-FDG. Two groups of readers counted the number of lesions on PET/CT and PET/MR imaging scans. A consensus reading was performed in those cases in which the groups disagreed. Quantitative standardized uptake value measurements were performed by placing spheric ROIs over the lesions in 3 different planes. Weighted and unweighted κ statistics, correlation analysis, and the Wilcoxon signed rank test were used for statistical analysis. RESULTS: κ statistics for the number of head and neck lesion lesions counted (pooled across regions) revealed interreader agreement between groups 1 and 2 of 0.47 and 0.56, respectively. Intrareader agreement was 0.67 and 0.63. The consensus reading provided an intrareader agreement of 0.63. For the presence or absence of metastasis, interreader agreement was 0.85 and 0.70. The consensus reading provided an intrareader agreement of 0.72. The correlations between the maximum standardized uptake value in (18)F-FDG-PET/MR imaging and (18)F-FDG-PET/CT for primary tumors and lymph node and metastatic lesions were very high (Spearman r = 1.00, 0.93, and 0.92, respectively). CONCLUSIONS: In patients with head and neck cancer, (18)F-FDG-PET/MR imaging and (18)F-FDG-PET/CT provide comparable results in the detection of lymph node and distant metastases. Standardized uptake values derived from (18)F-FDG-PET/MR imaging can be used reliably in this patient population.

Fused thiazolyl alkynes as potent mGlu5 receptor positive allosteric modulators.

A new series of potent fused thiazole mGlu5 receptor positive allosteric modulators (PAMs) (10, 11 and 27-31) are disclosed and details of the SAR and optimization are described. Optimization of alkynyl thiazole 9 (Lu AF11205) led to the identification of potent fused thiazole analogs 10b, 27a, 28j and 31d. In general, substituted cycloalkyl, aryl and heteroaryl carboxamides, and carbamate analogs are mGlu5PAMs, whereas smaller alkyl carboxamide, sulfonamide and sulfamide analogs tend to be mGlu5 negative allosteric modulators (NAMs).

Discovery and structure-activity relationship of 1,3-cyclohexyl amide derivatives as novel mGluR5 negative allosteric modulators.

A novel series of trans-1,3-cyclohexyl diamides was discovered and characterized as mGluR5 negative allosteric modulators (NAMs) lacking an alkyne moiety. Conformational constraint of one of the amide bonds in the diamide template led to a spirooxazoline template. A representative compound (24d) showed good in vitro potency, high CNS penetration and, upon subcutaneous dosing, demonstrated efficacy in the mouse marble burying test, generally used as indicative of potential anxiolytic activity.

Azetidinyl oxadiazoles as potent mGluR5 positive allosteric modulators.

A novel series of aryl azetidinyl oxadiazoles are identified as mGluR5 positive allosteric modulators (PAMs) with improved physico-chemical properties. N-substituted cyclohexyl and exo-norbornyl carboxamides, and carbamate analogs of azetidines are moderate to potent mGluR5 PAMs. The aryl, lower alkyl carboxamides analogs and sulfonamide analogs of azetidines are moderate mGluR5 negative allosteric modulators (NAMs). In the aryl oxadiazole moiety, substituents such as fluoro, chloro and methyl are well tolerated at the meta position while para substituents led to either inactive compounds or NAMs. A tight pharmacophore and subtle 'PAM to NAM switching' with close analogs makes the optimization of the series extremely challenging.

N-Aryl pyrrolidinonyl oxadiazoles as potent mGluR5 positive allosteric modulators.

A novel series of N-aryl pyrrolidinonyl oxadiazoles were identified as mGluR5 positive allosteric modulators (PAMs). Optimization of the initial lead compound 6a led to the identification of the 12c (-) enantiomer as a potent compound with acceptable in vitro clearance, CYP, hERG and PK properties. Para substituted N-aryl pyrrolidinonyl oxadiazoles are mGluR5 PAMs while the meta and ortho substituted N-aryl pyrrolidinonyl oxadiazoles are negative allosteric modulators (NAMs). Para fluoro substitution on the N-aryl group and meta chloro or methyl substituents on the aryl oxadiazole moiety are optimal for mGluR5 PAM efficacy. The existence of an exquisitely sensitive 'PAM to NAM switch' within this chemotype making it challenging for simultaneous optimization of potency and drug-like properties.

Efficacy switching SAR of mGluR5 allosteric modulators: highly potent positive and negative modulators from one chemotype.

A series of metabotropic glutamate 5 receptor (mGluR5) allosteric ligands with positive, negative or no modulatory efficacy is described. The ability of this series to yield both mGluR5 PAMs and NAMs with single-digit nanomolar potency is unusual, and the underlying SAR is detailed.

Novel heterocyclic compounds as mGlu5 antagonists: WO2009015897.

Metabotropic glutamate receptor 5 (mGlu5) negative allosteric modulators (NAMs) have previously been implicated in a number of pathophysiological conditions, based on preclinical, and to some extent clinical, proof of concept for migraine, gastroesophageal reflux disease, Parkinson's disease and anxiety. In the past, the potential use of known mGlu5 antagonists for the treatment of lower urinary tract disorders was disclosed. In the patent evaluated herein, novel derivatives of 4-(prop-2-ynylidene)piperidine are described and claimed by Recordati Ireland Ltd, Ireland, as NAMs at mGlu5 for the treatment of lower urinary tract disorders. Selected compounds reported in this application were efficacious in the cystometry model of bladder dysfunction in conscious rats, and mGlu5 NAMs are, therefore, suggested to have potential for the treatment of lower urinary tract disorders.

Discovery of a potent and brain penetrant mGluR5 positive allosteric modulator.

This Letter describes the discovery of a novel series of mGluR5 positive allosteric modulators (PAMs). The lead compound, 11c, exhibits excellent potency (EC(50)=30 nM) in vitro, and reaches high brain levels in both rats and mice after oral administration.

Identification and characterization of NDT 9513727 [N,N-bis(1,3-benzodioxol-5-ylmethyl)-1-butyl-2,4-diphenyl-1H-imidazole-5-methanamine], a novel, orally bioavailable C5a receptor inverse agonist.

The complement system represents an innate immune mechanism of host defense that has three effector arms, the C3a receptor, the C5a receptor (C5aR), and the membrane attack complex. Because of its inflammatory and immune-enhancing properties, the biological activity of C5a and its classical receptor have been widely studied. Because specific antagonism of the C5aR could have therapeutic benefit without affecting the protective immune response, the C5aR continues to be a promising target for pharmaceutical research. The lack of specific, potent and orally bioavailable small-molecule antagonists has limited the clinical investigation of the C5aR. We report the discovery of NDT 9513727 [N,N-bis(1,3-benzodioxol-5-ylmethyl)-1-butyl-2,4-diphenyl-1H-imidazole-5-methanamine], a small-molecule, orally bioavailable, selective, and potent inverse agonist of the human C5aR. NDT 9513727 was discovered based on the integrated use of in vitro affinity and functional assays in conjunction with medicinal chemistry. NDT 9513727 inhibited C5a-stimulated responses, including guanosine 5'-3-O-(thio)triphosphate binding, Ca(2+) mobilization, oxidative burst, degranulation, cell surface CD11b expression and chemotaxis in various cell types with IC(50)s from 1.1 to 9.2 nM, respectively. In C5a competition radioligand binding experiments, NDT 9513727 exhibited an IC(50) of 11.6 nM. NDT 9513727 effectively inhibited C5a-induced neutropenia in gerbil and cynomolgus macaque in vivo. The findings suggest that NDT 9513727 may be a promising new entity for the treatment of human inflammatory diseases.

Aminopyrazine CB1 receptor inverse agonists.

A series of 5,6-diaryl-2-amino-pyrazines were prepared and found to have antagonist-like properties at the CB1 receptor. Subsequent SAR studies optimized both receptor potency and drug-like properties including solubility and Cytochrome-P450 inhibition potential. Optimized compounds were demonstrated to be inverse agonists and compared in vivo with rimonabant for their ability to inhibit food intake, to occupy central CB1 receptors and to influence hormonal markers associated with obesity.

Predictors of Outpatient Mental Health Service Use by American Youth.

Among American children and adolescents aged 1 to 17 years, the 12- to 17-year-olds represent the largest users of outpatient mental health services. This study utilizes a nationally representative sample of this age group from the 2005 National Survey on Drug Use and Health to illuminate predictors of services use from three treatment settings: day treatment programs, mental health clinics/centers, and private/in-home settings. Univariate analyses were used to calculate the percentages of the study sample that used mental health services in these settings. In bivariate analyses, the authors estimated the strength of the associations between available predisposing, need, and enabling factors and the outcomes. Multiple logistic regressions estimated the independent effects of each covariate on the outcomes. Lifetime depression, lifetime general anxiety, delinquent behaviors, drug dependence, and Medicaid were consistent predictors of services use in the three treatment settings. Several other factors were associated with services use in bivariate analyses but lost most of their statistical significance when the authors adjusted for other confounders. Interpreted in light of its potential limitations, this study has important research and policy significance.

Leukocyte effects of C5a-receptor blockade during simulated extracorporeal circulation.

BACKGROUND: Distinct pathways of leukocyte activation during simulated cardiopulmonary bypass are mediated by the complement C5a anaphylatoxin. We hypothesized that a human C5a receptor antagonist would specifically inhibit the inflammatory response of neutrophils to simulated extracorporeal circulation, while preserving the C5b-9 pathway for innate immunity. METHODS: An in vitro extracorporeal circuit recirculated fresh heparinized whole blood through a membrane oxygenator with and without addition of a small molecule human C5a receptor antagonist. Samples were periodically drawn over 90 minutes for complement and leukocyte activation studies. RESULTS: Addition of the C5a receptor antagonist to simulated extracorporeal circulation abrogated both neutrophil CD11b upregulation and interleukin 8 release (p < 0.01 for both), despite full generation of C3a and C5b-9; however, elastase release from neutrophils was unaffected. Although C5a receptor blockade only trended toward inhibiting monocyte CD11b upregulation (p = 0.09), circuit clearance of both monocytes (p = 0.04) and neutrophils (p = 0.01) was significantly decreased. In addition, the C5a receptor antagonist completely blocked both neutrophil-platelet and monocyte-platelet conjugate formation (p < 0.001 for both), without affecting platelet P-selectin expression. CONCLUSIONS: C5a receptor blockade during simulated extracorporeal circulation completely blocked neutrophil beta2 integrin upregulation and induction of plasma interleukin 8, suggesting an acute downregulatory effect on neutrophil chemotaxis-related pathways, while preserving terminal complement generation and neutrophil elastase release. Inhibition of leukocyte-platelet conjugate formation suggests a novel function for leukocyte adhesive receptors, possibly related to preservation of elastase generation.

Randomized comparison of ultrasound surveillance and clinical monitoring on arteriovenous graft outcomes.

Arteriovenous graft thrombosis is a frequent event in hemodialysis patients, and usually occurs in grafts with significant underlying stenosis. Regular surveillance for graft stenosis, with pre-emptive angioplasty of significant lesions, may improve graft outcomes. This prospective, randomized, clinical trial allocated 126 hemodialysis patients with grafts to either clinical monitoring alone (control group) or to regular ultrasound surveillance for graft stenosis every 4 months in addition to clinical monitoring (ultrasound group). The two randomized groups were closely matched with respect to demographic, clinical, and graft characteristics, with the exception of a lower frequency of diabetes in the ultrasound group. The primary outcome was graft survival, and the secondary outcome was thrombosis-free graft survival. The frequency of pre-emptive graft angioplasty was 64% higher in the ultrasound group than in the control group (1.05 vs 0.64 events per patient-year, P<0.001), whereas the frequency of thrombosis was not different (0.67 vs 0.78 per patient-year, P=0.37). The median time to permanent graft failure was similar between the two groups (38 vs 37 months, P=0.93). Likewise, the median time to graft thrombosis or failure did not differ (22 vs 25 months, P=0.33). There was no significant association between diabetes and time to graft failure (P=0.93) or time to graft thrombosis or failure (P=0.88). In conclusion, the addition of regular ultrasound surveillance for graft stenosis to clinical monitoring increases the frequency of pre-emptive angioplasty, but may not decrease the likelihood of graft failure or thrombosis.

Molecular characterization of the gerbil C5a receptor and identification of a transmembrane domain V amino acid that is crucial for small molecule antagonist interaction.

Anaphylatoxin C5a is a potent inflammatory mediator associated with pathogenesis and progression of several inflammation-associated disorders. Small molecule C5a receptor (C5aR) antagonist development is hampered by species-specific receptor biology and the associated inability to use standard rat and mouse in vivo models. Gerbil is one rodent species reportedly responsive to small molecule C5aR antagonists with human C5aR affinity. We report the identification of the gerbil C5aR cDNA using a degenerate primer PCR cloning strategy. The nucleotide sequence revealed an open reading frame encoding a 347-amino acid protein. The cloned receptor (expressed in Sf9 cells) bound recombinant human C5a with nanomolar affinity. Alignment of the gerbil C5aR sequence with those from other species showed that a Trp residue in transmembrane domain V is the only transmembrane domain amino acid unique to small molecule C5aR antagonist-responsive species (i.e. gerbil, human, and non-human primate). Site-directed mutagenesis was used to generate human and mouse C5aRs with a residue exchange of this Trp residue. Mutation of Trp to Leu in human C5aR completely eliminated small molecule antagonist-receptor interaction. In contrast, mutation of Leu to Trp in mouse C5aR enabled small molecule antagonist-receptor interaction. This crucial Trp residue is located deeper within transmembrane domain V than residues reportedly involved in C5a- and cyclic peptide C5a antagonist-receptor interaction, suggesting a novel interaction site(s) for small molecule antagonists. These data provide insight into the basis for small molecule antagonist species selectivity and further define sites critical for C5aR activation and function.

Changing impact of gastroesophageal reflux in medical and otolaryngology practice.

OBJECTIVES/HYPOTHESIS: A major trend in gastroesophageal reflux disease (GERD) is an observed increased prevalence of the problem, with an associated burden on health care resources. There are relatively few objective reports of increasing prevalence of this disease, and there are no epidemiologic reports that discuss changing practice strategies in managing the disease. The clinical problem is of critical importance to practicing otolaryngologists, who manage the impact of GERD on diseases affecting the ear, nose, and throat. The hypothesis of this thesis is that 1) GERD is an increasing problem affecting outpatient office visits over time, and 2) the disease is increasingly managed with prescription pharmacotherapy. STUDY DESIGN: Retrospective national medical database review using the National Ambulatory Medical Care Survey. METHODS: Twelve years of data (1990-2001) were examined with visits weighted to provide U.S. estimates of care. Average annual frequencies and visit rates were calculated for total visits and by age, sex, race, and physician specialty. Selected issues in GERD treatment were also examined, including prescriptions and physician/patient counseling regarding stress management, tobacco abuse, and diet modification. Trends were reported based on changes in care across three time periods to satisfy statistical significance: 1990 to 1993, 1994 to 1997, and 1998 to 2001. RESULTS: Between 1990 and 1993 and 1998 and 2001, there was a significant increase in U.S. ambulatory care visits for GERD, from a rate of 1.7 per 100 to 4.7 per 100. There were no significant changes in race, although there was a small trend toward increased GERD visits in the age group over 44 years old and in the male sex. Office visits to otolaryngologists increased from 89,000 to 421,000 between the time periods of 1990 to 1993 and 1998 to 2001. This also represented a percent increase in office encounters by otolaryngologists compared with visits by all specialties from 2.9% to 4.4%. Over the three time periods, there was a fall in prescriptions for histamine (H2) blockers from 58.1% to 20.7% of total prescriptions. Over the same three time periods, prescriptions of proton pump inhibitors increased from 13.2% to 64.6%. Physician recommendations for over the counter medications fell from 18.8% to 6.6%. Average annual counseling during ambulatory care visits for GERD was assessed for the period from 1998 to 2001 as follows: diet counseling was provided at 27.2% of encounters, tobacco cessation counseling was provided at 3.9%, and stress management was discussed at 3.9%. CONCLUSIONS: During the 1990s, there was a substantial increase in the use of ambulatory care services for GERD. Although much of this increase was among the primary care community, otolaryngologists appeared to have an increasingly prominent role in the management of this disease. There have also been dramatic changes in physician prescribing patterns for GERD, with the emergence of the predominant role of proton pump inhibitors. However, the use of physician counseling for lifestyle modification of factors known to affect GERD remains very low. The increasing impact of GERD on physician practice emphasizes the importance of both physician and patient education in the delivery of health care related to this disease.