Early diagnosis of osteoporosis using radiogrammetry and texture analysis from hand and wrist radiographs in Indian population.

We propose an automated low cost tool for early diagnosis of onset of osteoporosis using cortical radiogrammetry and cancellous texture analysis from hand and wrist radiographs. The trained classifier model gives a good performance accuracy in classifying between healthy and low bone mass subjects. INTRODUCTION: We propose a low cost automated diagnostic tool for early diagnosis of reduction in bone mass using cortical radiogrammetry and cancellous texture analysis of hand and wrist radiographs. Reduction in bone mass could lead to osteoporosis, a disease observed to be increasingly occurring at a younger age in recent times. Dual X-ray absorptiometry (DXA), currently used in clinical practice, is expensive and available only in urban areas in India. Therefore, there is a need to develop a low cost diagnostic tool in order to facilitate large-scale screening of people for early diagnosis of osteoporosis at primary health centers. METHODS: Cortical radiogrammetry from third metacarpal bone shaft and cancellous texture analysis from distal radius are used to detect low bone mass. Cortical bone indices and cancellous features using Gray Level Run Length Matrices and Laws' masks are extracted. A neural network classifier is trained using these features to classify healthy subjects and subjects having low bone mass. RESULTS: In our pilot study, the proposed segmentation method shows 89.9 and 93.5% accuracy in detecting third metacarpal bone shaft and distal radius ROI, respectively. The trained classifier shows training accuracy of 94.3% and test accuracy of 88.5%. CONCLUSION: An automated diagnostic technique for early diagnosis of onset of osteoporosis is developed using cortical radiogrammetric measurements and cancellous texture analysis of hand and wrist radiographs. The work shows that a combination of cortical and cancellous features improves the diagnostic ability and is a promising low cost tool for early diagnosis of increased risk of osteoporosis.

The thyrotropin-releasing hormone (TRH)-immune system homeostatic hypothesis.

Decades of research have established that the biological functions of thyrotropin-releasing hormone (TRH) extend far beyond its role as a regulator of the hypothalamic-pituitary-thyroid axis. Gary et al. [Gary, K.A., Sevarino, K.A., Yarbrough, G.G., Prange, A.J. Jr., Winokur, A. (2003). The thyrotropin-releasing hormone (TRH) hypothesis of homeostatic regulation: implications for TRH-based therapeutics. J Pharmacol Exp Ther 305(2):410-416.] and Yarbrough et al. [Yarbrough, G.G., Kamath, J., Winokur, A., Prange, A.J. Jr. (2007). Thyrotropin-releasing hormone (TRH) in the neuroaxis: therapeutic effects reflect physiological functions and molecular actions. Med Hypotheses 69(6):1249-1256.] provided a functional framework, predicated on its global homeostatic influences, to conceptualize the numerous interactions of TRH with the central nervous system (CNS) and endocrine system. Herein, we profer a similar analysis to interactions of TRH with the immune system. Autocrine/paracrine cellular signaling motifs of TRH and TRH receptors are expressed in several tissues and organs of the immune system. Consistent with this functional distribution, in vitro and in vivo evidence suggests a critical role for TRH during the developmental stages of the immune system as well as its numerous interactions with the fully developed immune system. Considerable evidence supports a pivotal role for TRH in the pathophysiology of the inflammatory process with specific relevance to the "cytokine-induced sickness behavior" paradigm. These findings, combined with a number of documented clinical actions of TRH strongly support a potential utility of TRH-based therapeutics in select inflammatory disorders. Similar to its global role in behavioral and energy homeostasis a homeostatic role for TRH in its interactions with the immune system is consonant with the large body of available data. Recent advances in the field of immunology provide a significant opportunity for investigation of the TRH-immune system homeostatic hypothesis. Moreover, this hypothesis may provide a foundation for the development of TRH-based therapeutics for certain medical and psychiatric disorders involving immune dysfunction.

Thyrotropin-releasing hormone can relieve cancer-related fatigue: hypothesis and preliminary observations.

Fatigue in cancer patients is highly prevalent, predominantly idiopathic, difficult to manage, and has a significant negative impact on quality of life. Thyrotropin-releasing hormone (TRH) exerts normotrophic, state-dependent therapeutic effects in a variety of experimental and clinical situations. To evaluate TRH as a treatment for cancer-related fatigue, an ongoing randomized, placebo-controlled, crossover pilot study of breast cancer patients has been initiated and this report presents preliminary observations conducted with three of these patients over 4 consecutive weeks, thereby involving a total of six TRH treatments and six saline controls. Global assessment using both subjective and objective parameters showed that TRH exerted clear anti-fatigue effects in four of the six TRH treatments. These responses were rapid in onset and persisted through the 24 h observation period. No anti-fatigue responses were seen in five of the six saline controls. No unexpected side-effects were seen with TRH administration. These initial findings support the proposal that TRH can ameliorate cancer-related fatigue.

Histamine and thrombin modulate endothelial focal adhesion through centripetal and centrifugal forces.

We examined the contribution of actin-myosin contraction to the modulation of human umbilical vein endothelial cell focal adhesion caused by histamine and thrombin. Focal adhesion was measured as the electrical resistance across a cultured monolayer grown on a microelectrode. Actin-myosin contraction was measured as isometric tension of cultured monolayers grown on a collagen gel. Histamine immediately decreased electrical resistance but returned to basal levels within 3-5 min. Histamine did not increase isometric tension. Thrombin also immediately decreased electrical resistance, but, however, resistance did not return to basal levels for 40-60 min. Thrombin also increased isometric tension, ML-7, an inhibitor of myosin light chain kinase, prevented increases in myosin light chain phosphorylation and increases in tension development in cells exposed to thrombin. ML-7 did not prevent a decline in electrical resistance in cells exposed to thrombin. Instead, ML-7 restored the electrical resistance to basal levels in a shorter period of time (20 min) than cells exposed to thrombin alone. Also, histamine subsequently increased electrical resistance to above basal levels, and thrombin initiated an increase in resistance during the time of peak tension development. Hence, histamine and thrombin modulate endothelial cell focal adhesion through centripetal and centrifugal forces.

Thyrotropin-releasing hormone (TRH) in the neuroaxis: therapeutic effects reflect physiological functions and molecular actions.

Nearly four decades of research have yielded thousands of publications on the physiology, pharmacology and therapeutic effects of TRH and TRH mimetic analogs. This work addresses both the neuroendocrine and the extrahypothalamic actions and functions of the tripeptide. The many reports of clinical effects of TRH in diverse medical conditions, unrelated to pituitary or thyroid function, can appear bewildering, as can its widespread involvement in a plethora of neuronal and physiological processes. Herein, we hypothesize that a logical and causal interrelationship exists between the fundamental molecular and cellular actions of TRH, its broader physiological functions and the therapeutic effects that attend the administration of exogenous TRH and TRH analogs. When viewed from this perspective, the basic neurobiological actions and functions of TRH provide a rational basis for understanding its diverse therapeutic effects. We posit: that the fundamental excitatory actions of TRH throughout the neuroaxis result from blocking various K+ channels linked to G-protein coupled TRH receptors in neurons and pituitary cells in distinct TRH-innervated anatomical pathways; that the functional consequences of blockade of these K+ channels are to enhance neuronal and secretory outputs in TRH regulatory circuits to modulate behavioral and energy homeostasis, and; that in clinical situations the resultant broad and useful therapeutic effects following administration of TRH reflect the state-dependent normalizing effects of activation of these regulatory circuits. In this light, the spectrum of reported clinical effects of TRH agonism remains unique and impressive but is less enigmatic. With the understanding that the neurobiological actions of TRH underlie and are rationally antecedent to its documented, extensive clinical 'normotrophic' effects, continued empirical efforts to assess the medical uses of TRH and related drugs seem rational and warranted. We predict that the range of disorders whose symptoms are alleviated by TRH therapy will continue to expand and that TRH agonism could conceivably become a near-universal therapeutic adjunct, particularly in the practice of neuropsychiatric medicine.

Three-dimensional magnetic resonance-based morphometrics and ventricular dysmorphology in schizophrenia.

BACKGROUND: Recent methodological refinements in magnetic resonance (MR) imaging have led to brain averaging and morphometric approaches that are sensitive to subtle anatomical distinctions in schizophrenia. METHODS: Using a novel morphometric technique for surface analysis, 48 selected landmarks of the rendered ventricular system were extracted and compared between the ventricles of 20 patients with schizophrenia and 20 normal subjects. RESULTS: There was no significant difference in ventricular shape between groups, but significant (p = .015) and highly localized shape deformity was detected at the foramen of Monro and at the proximal temporal horn of the lateral ventricle of male (but not female) patients relative to controls. CONCLUSIONS: Three-dimensional MR-based morphometrics complements established volumetric approaches and can detect minute shape deformities that may be associated with schizophrenia.

Discovery of a novel series of potent and selective substrate-based inhibitors of p60c-src protein tyrosine kinase: conformational and topographical constraints in peptide design.

On the basis of the efficient substrate for p60c-src protein tyrosine kinase (PTK) YIYGSFK-NH2 (1) (Km = 55 microM) obtained by combinatorial methods, we have designed and synthesized a series of conformationally and topographically constrained substrate-based peptide inhibitors of this enzyme, which showed IC50 values in the low-micromolar range (1-3 microM). A "rotamer scan" was performed by introducing the four stereoisomers of beta-Me(2')Nal in the postulated interaction site of the peptide inhibitor 23(IC50 = 1.6 microM). This substitution led to selective and potent inhibitors of p60c-src PTK; however, no substantial difference in potency was observed among them. This and the results of the "stereochemical scan" performed at residues 2 and 7 of 3 (peptides 19-21), which form the disulfide bond, may suggest that the enzyme active site does not have rigid topographic requirements and thus is able to achieve important conformational changes to bind the ligand as long as the pharmacophore pattern in the inhibitor is conserved. Two new potent iodo-containing nonphosphorylatable tyrosine analogues were also incorporated into our lead inhibitory sequence 23, producing the most potent inhibitors for p60c-src PTK identified thus far in our studies. Compounds 29 and 30 exhibit IC50 values of 0.13 and 0.54 microM, respectively. Peptide 29 is 420-fold more potent than the parent peptide 1. Selectivity studies of peptides 23-30 toward p60c-src, Lyn, and Lck PTK showed in general high Lyn/Src and moderate Lck/Src selectivity ratios. We found that the chi1 space constraints of the specialized amino acids, introduced at position 3 of the peptide lead 23, were not as important as the configuration of the Calpha of that residue to recognize the subtle chemical environment surrounding the active site of Src and Lck PTK, as reflected on the obtained Lck/Src selectivity ratios.

Validation of object-induced MR distortion correction for frameless stereotactic neurosurgery.

Spatial fidelity is a paramount issue in image guided neurosurgery. Until recently, three-dimensional computed tomography (3D CT) has been the primary modality because it provides fast volume capture with pixel level (1 mm) accuracy. While three-dimensional magnetic resonance (3D MR) images provide superior anatomic information, published image capture protocols are time consuming and result in scanner- and object-induced magnetic field inhomogeneities which raise inaccuracy above pixel size. Using available scanner calibration software, a volumetric algorithm to correct for object-based geometric distortion, and a Fast Low Angle SHot (FLASH) 3D MR-scan protocol, we were able to reduce mean CT to MR skin-adhesed fiducial marker registration error from 1.36 to 1.09 mm. After dropping the worst one or two of six fiducial markers, mean registration error dropped to 0.62 mm (subpixel accuracy). Three dimensional object-induced error maps present highest 3D MR spatial infidelity at the tissue interfaces (skin/air, scalp/skull) where frameless stereotactic fiducial markers are commonly applied. The algorithm produced similar results in two patient 3D MR-scans.

Benchmarking the communication of continuous improvement activities.

Communication of a continuous improvement program in a large medical center was assessed using a formal benchmarking process with four non-health care organizations. Results indicated that continuous improvement must be integrated with the corporate strategic plan, must focus on customer satisfaction, and have active leadership support. A common framework should link different continuous improvement methodologies. Ongoing, open, multimedia two-way communication is required. Continuous improvement activities need to be integrated into all employees' daily work.

Development and characterization of potent and specific peptide inhibitors of p60c-src protein tyrosine kinase using pseudosubstrate-based inhibitor design approach.

The cytoplasmic protein p60c-src, an ubiquitous non-receptor protein tyrosine kinase (PTK) is a potential anticancer target as it is over-expressed and/or constitutively active in several cancer types. In addition, the phenotype of c-src knock-out mice is consistent with osteopetrosis, which suggests that inhibitors against this enzyme may also be therapeutic for osteoporosis. Using a known peptide substrate for c-src, MIYKYYF, as a template, we have developed a series of pseudosubstrate-based peptide inhibitors. Structure-activity relationship studies have been performed on one of these inhibitors, CIYKYYF. In a kinase assay using YIYGSFK as the substrate, CIYKYY has been demonstrated to inhibit p60c-src, with an IC50 of 0.6 microm. Further truncation has led to the determination that even the smaller peptide, CIYK, is a moderately potent inhibitor with IC50 of 15 microm. Some improvement in inhibitory potency (IC50 = 11.8 microm) has been observed with the replacement of Tyr3 in CIYK with beta-phenylalanine (beta-Phe). The tetrapeptide CI(beta-Phe)K will be used as a lead compound for future development of peptidomimetics and small molecule inhibitors that have the capacity to penetrate the plasma membrane of intact cells.

Pyocyanin from Pseudomonas aeruginosa inhibits prostacyclin release from endothelial cells.

Pseudomonas aeruginosa pneumonia causes a vasculitis of small pulmonary arteries. While the fully developed lesion demonstrates vessel wall necrosis, the early lesion is remarkable for preservation of viable endothelium despite vessel wall invasion by bacteria. Pyocyanin, an exoproduct of P. aeruginosa, markedly inhibited prostacyclin production by pulmonary artery endothelial cells without causing cell lysis. Pyocyanin might after vascular homeostasis in the absence of cytolysis.

Ionomycin and PDBU increase MDCK monolayer permeability independently of myosin light chain phosphorylation.

It has been hypothesized that modulation of epithelial paracellular permeability may be mediated by initiation of contraction of a band of actin and myosin located at the tight junction. Phosphorylation of myosin light chain (MLC) is an important determinant of actomyosin contraction. We asked if ionomycin (iono) and phorbol 12,13-dibutyrate (PDBU), which increase paracellular permeability of Madin-Darby canine kidney (MDCK) cell monolayers, increased MLC phosphorylation in MDCK cells. MDCK cell MLC was constitutively phosphorylated by myosin light chain kinase (MLCK), and after PDBU and iono > 99% of MLC continued to be phosphorylated by MLCK. Neither iono or PDBU, nor the combination of iono and PDBU, increased MLC phosphorylation. In contrast, the phosphatase inhibitor okadaic acid did increase MLC phosphorylation. Adenosine 3',5'-cyclic monophosphate (cAMP) and forskolin decreased MLC phosphorylation in control MDCK cells and in cells exposed to iono and PDBU. In contrast, cAMP and forskolin did not blunt the decrease in transepithelial resistance caused by iono and PDBU. Iono and PDBU increase MDCK monolayer permeability independently of an increase in MLC phosphorylation.

Retropharyngeal leiomyoma: case report and review of the literature.

An 8-year-old girl was initially seen with dyspnea, drooling of secretions, and loss of weight. A large mass was seen protruding through the posterior pharyngeal wall, which was found to be a leiomyoma after excision. No previous case report exists of a retropharyngeal leiomyoma.

Thrombin inhibits myosin light chain dephosphorylation in endothelial cells.

Histamine and thrombin increase myosin light-chain kinase-mediated phosphorylation of myosin light chain (MLC) in human umbilical vein endothelial cells (HUVEC). The increase in MLC phosphorylation caused by thrombin persists longer (330 min) than the increase caused by histamine (<5 min), although both increase cell calcium similarly. We hypothesized that some of the longer duration of the increase in MLC phosphorylation caused by thrombin was because of inhibition of myosin dephosphorylation by thrombin. Calyculin A, an inhibitor of type 1 and 2A protein phosphatases, caused a time-dependent increase in MLC phosphorylation in unstimulated HUVEC. As thrombin-stimulated phosphorylation approached its peak at 15 min, calyculin A caused progressively less of an increase in MLC phosphorylation in thrombin-stimulated HUVEC, and no increase at the peak of thrombin stimulation. In HUVEC in which cell calcium was maintained at 600 nM, thrombin increased MLC phosphorylation above the level caused by increased calcium alone at a time coinciding with the peak of thrombin stimulation. However, when phosphatase activity was already inhibited with calyculin A, thrombin did not further increase MLC phosphorylation in cells in which calcium was maintained at 600 nM calcium. Thrombin increases MLC phosphorylation in HUVEC not only by increasing cell calcium but also by inhibiting calyculin A-sensitive dephosphorylation of MLC.