Observational Study of the Association between Hyponatremia and Rhabdomyolysis in Patients Presenting to Hospital.

Hyponatremia may be a risk factor for rhabdomyolysis, but the association is not well defined and may be confounded by other variables. The aims of this study were to determine the prevalence and strength of the association between hyponatremia and rhabdomyolysis and to profile patients with hyponatremia. In a cross-sectional study of 870 adults admitted to hospital with rhabdomyolysis and a median peak creatine kinase of 4064 U/L (interquartile range, 1921−12,002 U/L), glucose-corrected serum sodium levels at presentation showed a U-shape relationship to log peak creatine kinase. The prevalence of mild (130−134 mmol/L), moderate (125−129 mmol/L), and severe (<125 mmol/L) hyponatremia was 9.4%, 2.5%, and 2.1%, respectively. We excluded patients with hypernatremia and used multivariable linear regression for analysis (n = 809). Using normal Na+ (135−145 mmol/L) as the reference category, we estimated that a drop in Na+ moving from one Na+ category to the next was associated with a 25% higher creatine kinase after adjusting for age, alcohol, illicit drugs, diabetes, and psychotic disorders. Multifactorial causes of rhabdomyolysis were more common than single causes. The prevalence of psychotic and alcohol use disorders was higher in the study population compared to the general population, corresponding with greater exposure to psychotropic medications and illicit drugs associated with hyponatremia and rhabdomyolysis. In conclusion, we found an association between hyponatremia and the severity of rhabdomyolysis, even after allowing for confounders.

Pain in patients with equal radiographic grades of osteoarthritis in both knees: the value of gray scale ultrasound.

OBJECTIVES: To investigate the association of ultrasound (US) features with pain and the functional scores in patients with equal radiographic grades of osteoarthritis (OA) in both knees. METHODS: Fifty-six consecutive patients with knee OA: 85 symptomatic knees (81 knees with medial pain) and 27 asymptomatic knees, and 10 healthy patients without knee OA as a control were enrolled. US was done by two ultrasonographers blinded to patient diagnoses. US features were semiquantitatively scored (0-3) when appropriate. RESULTS: In the OA group, common US findings were marginal osteophyte, suprapatellar synovitis, suprapatellar effusion (SPE), medial meniscus protrusion, medial compartment synovitis (MCS), lateral compartment synovitis, and Baker's cyst. Only SPE and MCS were significantly associated with knee pain. Visual analog pain scale (VAS) scores on motion were positively linearly associated with SPE and MCS (P < 0.01). Only MCS was degree-dependently associated with VAS scores at rest, the Western Ontario and McMaster Universities pain subscale, and the presence of medial knee pain (P < 0.01) after adjustments for age, gender, body mass index (BMI), radiographic grade, and other US features. In the control group, no US features were associated with knee pain. CONCLUSIONS: US inflammation features, including SPE and MCS, were positively linearly associated with knee pain in motion. MCS was also degree-dependently associated with pain at rest and the presence of medial knee pain. These findings show that synovitis was one important predictive factor of pain. Further studies to confirm the association of US features and pain are warranted.

Foot pressure and center of pressure in athletes with ankle instability during lateral shuffling and running gait.

This study evaluates foot pressure and center of pressure (COP) patterns in individuals with ankle instability during running and lateral shuffling. Eleven participants with ankle instability (AI) and 11 normal subjects (Normal) performed running and lateral shuffling tasks. The outcome measures were foot progression angle, peak pressure, and displacement of COP during stance phase. During running, the foot progression angle, that is, the angle of foot abduction, was lower in the AI group (Normal: 13.46° ± 4.45°; AI: 8.78° ± 3.91°), and the 1st metatarsal contact pressure (Normal: 0.76 ± 0.47 N/cm(2)·kg; AI: 1.05 ± 0.70 N/cm(2)·kg) and the 3rd metatarsal peak pressure were higher in the AI (Normal: 0.96 ± 0.60 N/cm(2)·kg; AI: 1.54 ± 0.68 N/cm(2)·kg). The medial-lateral (M-L) COP in the late-stance phase of running for the AI group transferred faster from lateral to medial foot than the Normal group. For lateral shuffling, the AI group had greater peak pressure at the 1st (Normal: 0.76 ± 0.67 N/cm(2)·kg; AI: 1.49 ± 1.04 N/cm(2)·kg), 2nd (Normal: 0.57 ± 0.39 N/cm(2)·kg; AI: 0.87 ± 0.68 N/cm(2)·kg), 3rd (Normal: 0.70 ± 0.54 N/cm(2)·kg; AI: 1.42 ± 0.87 N/cm(2)·kg), and 4th (Normal: 0.52 ± 0.38 N/cm(2)·kg; AI: 1.12 ± 0.78 N/cm(2)·kg) metatarsal areas than the Normal group. The M-L COP located more laterally from the early to mid-stance phase in the AI compared with the Normal group. The findings suggest that COP displacement during lateral shuffle may be a factor in ankle instability while the foot progression angle during running may be a compensatory strategy.

Successful treatment of erlotinib-induced acute hepatitis and acute interstitial pneumonitis with high-dose corticosteroid: a case report and literature review.

Erlotinib, a kind of epidermal growth factor receptor tyrosine kinase inhibitor, is a target therapy and approved for the treatment of metastatic non-small cell lung cancer (NSCLC) and advanced pancreatic cancer. Among these EGFR-TKI agents, including gefitinib and erlotinib, the common dose-limiting toxicities are diarrhea, mucositis and skin rash (Acneform eruptions). In addition to the above adverse effects, infrequent but potentially fatal and lethal entity complications include acute interstitial lung disease (ILD) and acute hepatitis. The incidence of EGFR-TKI agents (gefitinib and erlotinib) induced acute hepatitis is rare and hepatotoxicity of EGFR-TKI agent was rarely discussed. The treatment of EGFR-TKI agents induced acute hepatitis remains uncertain and cessation medication is current policy. Here we reported a case of erlotinib induced interstitial pneumonitis and acute hepatitis with clinical appearance of hypoxemia and general weakness, treated with high dose pulse therapy and showed good recovery.

Model-based segmentation of flexor tendons from magnetic resonance images of finger joints.

Trigger finger is a common hand disease, causing swelling, painful popping and clicking in moving the affected finger joint. To better evaluate patients with trigger finger, segmentation of flexor tendons from magnetic resonance (MR) images of finger joints, which can offer detailed structural information of tendons to clinicians, is essential. This paper presents a novel model-based method with three stages for automatically segmenting the flexor tendons. In the first stage, a set of tendon contour models (TCMs) is initialized from the most proximal cross-sectional image via two-step ellipse estimation. Each of the TCMs is then propagated to its distally adjacent image by affine registration. The propagation is sequentially performed along the proximal-distal direction until the most distal image is reached, as the second stage of segmentation. The TCMs on each cross-sectional image are refined in the last stage with the snake deformation. MR volumes of three subjects were used to validate the segmentation accuracy. Compared with the manual results, our method showed good accuracy with small average margins of errors (within 0.5 mm) and large overlapping ratio (dice similarity coefficient above 0.8). Overall, the proposed method has great potential for morphological change assessment of flexor tendons and pulley-tendon system modeling for image guided surgery.

Jar-opening challenges. Part 2: estimating the force-generating capacity of thumb muscles in healthy young adults during jar-opening tasks.

This study discusses the force-generating capacity of thumb muscles during jar-opening tasks using two grip patterns: the power grip and the precision grip. This study develops a three-dimensional biomechanical model of the thumb to predict muscle forces in jar-opening activities based on external forces measured by a custom-designed jar device. Ten healthy subjects participated in the study. Each participant turned a jar lid of 66 mm diameter counterclockwise with maximal effort and preferred speed using both grip patterns. The average normal and tangential forces applied by the thumb to the jar lid show that the normal force is the primary contributive force for opening a jar. This normal force is approximately three times the tangential force. Muscular force-generating capacity measurements show that the major active muscles during a jar-opening activity for both grips include the flexor pollicis longus, flexor pollicis brevis, abductor pollicis brevis, adductor pollicis, and opponens pollicis. The total muscle force ratios for the precision grip and power grip with respect to externally applied forces are 5.6 and 4.7 respectively. These ratios indicate that the power grip pattern produces less muscle force per unit of external applied load. The technique proposed in this study provides a proper apparatus and model for measuring three-dimensional loads and estimating the force-generating capacity of each muscle and tendon of the thumb during jar-opening tasks.

Effects of age and gender on the movement workspace of the trapeziometacarpal joint.

While researchers have suggested that joint mobility would probably be affected by age and gender, research findings often present discrepancies. Little research has been performed on the factors which effect mobility of the trapeziometacarpal (TMC) joint. The purpose of this study was to address the effects of age and gender on the ranges of motion of the normal TMC joint. Eighty normal subjects divided into four age groups participated in this study. The TMC joint motions were recorded using an electromagnetic tracking system. In order to achieve a maximal range of TMC joint motion which was defined as the maximal workspace, each subject was asked to perform actively maximal circumduction, flexion-extension, and abduction-adduction of the TMC joint. Numerical and statistical methods were used to compute the TMC workspace and to detect significant differences. A workspace-to-length ratio was determined as an index to examine the effects of the age and gender on the joint mobility. The results demonstrated that age and gender had significant influences on the TMC workspace among the groups studied. The understanding of TMC joint mobility under different age and gender conditions is achieved through this study. The findings can be used to report clinical measures in the determination of the extent of impairment of osteoarthritis as well as the outcomes between pre- and post-surgical (or non-surgical) interventions.

Jar-opening challenges. Part 1: an apparatus for assessing hand and finger torques and forces in a jar-opening activity.

A simulated jar apparatus was developed to record hand kinetics and torque contribution of a digit during jar-opening activities. The design of the apparatus, namely a jar body and a lid, is similar to a commercial jam jar that is regularly seen in daily living. One six-axis force-torque transducer and a torque cell were mounted inside the jar lid to detect the external force exerted from the digit and fixed on to the jar body to record the overall torque generated by the hand and wrist respectively. The applications of the apparatus were used to test the twisting torque of the hand and to measure the applied forces of the digit, which are both important factors in opening a jar. The contribution of each digit relative to the total twisting torque of the hand could be obtained via the apparatus. The intraclass correlation coefficient of the repeated measurements of the obtained forces and moments for different counterweights was approximately 0.96-1.00, which indicates that the reliability of the measured components of the apparatus is high. The high coefficient of determination (r2 > 0.99) indicates high accuracy of prediction of the measured values with respect to the expected loads. The validation outcomes support the design rationale and actual body part of the simulated jar. In addition, understanding the contribution of a single digit in opening a jar was also achieved via the apparatus and model.

Multidrug-resistant Acinetobacter baumannii bacteraemia: clinical features, antimicrobial therapy and outcome.

Nosocomial infections caused by Acinetobacter baumannii have increased in recent years. Isolates of multidrug-resistant A. baumannii (MDRAB) have been recovered in Taiwan since 1999. The characteristics of 55 patients with MDRAB bacteraemia infections occurring between January 2003 and February 2005 were analysed retrospectively. The overall 30-day mortality rate was 49%. The portal of entry was identified in 80% of patients, with the respiratory tract being implicated most frequently. Among the different antimicrobial regimens prescribed, the combination of a carbapenem and ampicillin-sulbactam was associated with a better outcome than the combination of a carbapenem and amikacin, or a carbapenem alone.

Photonic logic NOR gate based on two symmetric microring resonators.

We demonstrate an all-optical NOR logic gate based on symmetric GaAs-AlGaAs microring resonators whose resonances are closely matched. Two input pump data streams are tuned close to one resonance of the symmetric microrings to switch a probe beam tuned to another resonance by two-photon absorption. The switching energy of the gate is 20 pJ/pulse, and the switching window is 40 ps, limited by the carrier lifetime. The use of two rings provides for better cascading in photonic logic circuits because of the higher number of available ports.

Familial risk of allergic rhinitis and atopic dermatitis among Chinese families in Singapore.

INTRODUCTION: This study aims to determine the familial risk of atopic dermatitis (AD) and allergic rhinitis (AR) in Chinese children. MATERIALS AND METHODS: A cross-sectional study was conducted in a housing estate in Singapore. Data was collected using an interviewer-administered questionnaire. Participants included 257 Chinese families. Prevalence rate ratios (PRRs) and 95% confidence interval (CI) were calculated. RESULTS: For AD in all children, an increasing trend was found with PRRs of 1.9 (95% CI, 0.3 to 11.8) and 1.5 (95% CI, 0.4 to 5.5) for only father and only mother affected, respectively, to 2.3 (95% CI, 0.4 to 13.7) for both parents affected. In AR, a PRR of 2.7 (95% CI, 1.8 to 3.9) and 2.2 (95% CI, 1.5 to 3.2) for only father and only mother affected, respectively, and 4.5 (95% CI, 3.3 to 6.1) for both affected was found. The PRR (2.2; 95% CI, 1.4 to 3.7) of the first child developing AR when paternal or maternal history was positive was similar. This rose to 3.4 (95% CI, 2.2 to 5.1) when both parents also had AR. The PRR of the second child developing AR was 3.9 (95% CI, 1.7 to 8.9) when the first child alone was positive for AR and 7.0 (95% CI, 3.5 to 13.9) when both parents and the eldest child had AR. CONCLUSION: A positive family history increases the risk of developing AD and AR with increasing risk dependent on number of relatives affected. The second child's risk of AR is also associated with AR in the first child, suggesting mechanisms of incomplete penetrance.

The validity of using a video-based motion analysis system for measuring maximal area of fingertip motion and angular variation.

The aim of the study was to verify the application of a three-dimensional video motion analysis system to evaluate maximal fingertip motion area and angular variation of the hand by comparison and correlation with videofluoroscopic analysis. Eight normal subjects were recruited in this study. The maximal motion area of the fingertip and the angles of the metacarpal phalangeal (MP), proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints in performing five sequential postures for functional evaluation of the hand were measured using a video motion analysis system and a fluoroscopy system respectively. The results indicated that the intraclass correlation coefficient (ICC) of the calculated maximal fingertip motion area between the two methods was 0.9597. The ICC for total active motion (TAM) measurements of three finger joints was 0.940 between the surface and bony landmarks by fluoroscopy, 0.952 between the surface landmarks from fluoroscopy and motion analysis, and 0.927 between the bony landmark from fluoroscopy and surface markers from motion analysis. The ICC for angular measurements between three different paired assessments was 0.9650, 0.8896 and 0.8799 for the MP, PIP and DIP joints respectively. The results indicate that motion analysis is a practical method for assessing impairment of the hand.

Host cell factor requirement for hepatitis C virus enzyme maturation.

The cellular chaperone, HSP90, is identified here as an essential factor for the activity of NS2/3 protease of hepatitis C virus. The cleavage activity of NS2/3 protease synthesized in reticulocyte lysate is ATP-dependent, as evidenced by ATP depletion experiments and inhibition with nonhydrolyzable ATP analogs. Geldanamycin and radicicol, ATP-competitive inhibitors of the chaperone HSP90, also inhibit the cleavage of in vitro-synthesized NS2/3. Furthermore, these HSP90 inhibitors prevent NS2/3 cleavage when the protease is expressed in mammalian cells. The physical association of NS2/3 with HSP90 is demonstrated by immunoprecipitation. Thus, by way of a chaperone/folding activity, an HSP90-containing complex is required for maturation of the polyprotein that encodes the enzymes essential for hepatitis C virus replication.

Identification of MK-944a: a second clinical candidate from the hydroxylaminepentanamide isostere series of HIV protease inhibitors.

Recent results from human clinical trials have established the critical role of HIV protease inhibitors in the treatment of acquired immune-deficiency syndrome (AIDS). However, the emergence of viral resistance, demanding treatment protocols, and adverse side effects have exposed the urgent need for a second generation of HIV protease inhibitors. The continued exploration of our hydroxylaminepentanamide (HAPA) transition-state isostere series of HIV protease inhibitors, which initially resulted in the identification of Crixivan (indinavir sulfate, MK-639, L-735,524), has now yielded MK-944a (L-756,423). This compound is potent, is selective, and competitively inhibits HIV-1 PR with a K(i) value of 0.049 nM. It stops the spread of the HIV(IIIb)-infected MT4 lymphoid cells at 25.0-50.0 nM, even in the presence of alpha(1) acid glycoprotein, human serum albumin, normal human serum, or fetal bovine serum. MK-944a has a longer half-life in several animal models (rats, dogs, and monkeys) than indinavir sulfate and is currently in advanced human clinical trials.

Only a small fraction of purified hepatitis C RNA-dependent RNA polymerase is catalytically competent: implications for viral replication and in vitro assays.

The enzymatic activity of a C-terminally truncated form of the RNA-dependent RNA polymerase, termed NS5B(Delta21), of the hepatitis C virus (strain BK) has been investigated using both homopolymeric and heteropolymeric RNA templates. Incorporation of nucleotides into a heteropolymeric RNA template as catalyzed by NS5B(Delta21) is characterized by biphasic reaction time courses. At high concentrations of nucleoside triphosphate in reactions allowing a preincubation of NS5B(Delta21) and RNA template, an initial rapid phase of the reaction is followed by a slower linear phase. The amplitude of the first phase of the reaction varies directly with the concentration of the enzyme in the reaction. It is shown here that full-length copies of the template are produced during the first phase of the reaction. Our results reveal that NS5B(Delta21) is processive but only a small fraction, less than 1%, of the purified enzyme present participates productively in the reaction. Most importantly, the turnover number for the hepatitis C NS5B(Delta21) is comparable to those observed for other polymerases such as the HIV-1 reverse transcriptase. The combined results reconcile in part the apparent discrepancy of the low, observed specific activity of the purified enzyme and the rapid generation of HCV in vivo.

Combinatorial diversification of indinavir: in vivo mixture dosing of an HIV protease inhibitor library.

An efficient combination solution-phase/solid-phase route enabling the diversification of the P1', P2', and P3 subsites of indinavir has been established. The synthetic sequence can facilitate the rapid generation of HIV protease inhibitors possessing more favorable pharmacokinetic properties as well as enhanced potencies. Multiple compound dosing in vivo may also accelerate the identification of potential drug candidates.

An alternate binding site for the P1-P3 group of a class of potent HIV-1 protease inhibitors as a result of concerted structural change in the 80s loop of the protease.

Structures of the complexes of HIV protease inhibitor L--756,423 with the HIV-1 wild-type protease and of the inhibitors Indinavir, L-739,622 and Saquinavir with the mutant protease (9X) containing nine point mutations (Leu10Val, Lys20Met, Leu24Ile, Ser37Asp, Met46Ile, Ile54Val, Leu63Pro, Ala71Val, Val82Thr) have been determined. Comparative analysis of these structures reveals an alternate binding pocket for the P1-P3 group of Indinavir and L--756, 423. The alternate binding pocket is a result of concerted structural change in the 80s loop (residues 79-82) of the protease. The 80s loop is pulled away from the active site in order to accommodate the P1-P3 group, which is sandwiched between the flap and the 80s loop. This structural change is observed for the complexes of the wild type as well as the 9X mutant protease. The study reveals that the 80s loop is an intrinsically flexible loop in the wild-type HIV-1 protease and that mutations in this loop are not necessary to result in conformational changes. Conformation of this loop in the complex depends primarily upon the nature of the bound inhibitor and may be influenced by mutations in the protease. The results underscore the need to understand the intrinsic structural plasticity of the protease for the design of effective inhibitors against the wild-type and drug-resistant enzyme forms. In addition, the alternate binding pocket for the P1-P3 group of Indinavir and L--756,423 may be exploited for the design of potent inhibitors.

X-ray structure of simian immunodeficiency virus integrase containing the core and C-terminal domain (residues 50-293)--an initial glance of the viral DNA binding platform.

The crystal structure of simian immunodeficiency virus (SIV) integrase that contains in a single polypeptide the core and the C-terminal deoxyoligonucleotide binding domain has been determined at 3 A resolution with an R-value of 0.203 in the space group P2(1)2(1)2(1). Four integrase core domains and one C-terminal domain are found to be well defined in the asymmetric unit. The segment extending from residues 114 to 121 assumes the same position as seen in the integrase core domain of avian sarcoma virus as well as human immunodeficiency virus type-1 (HIV-1) crystallized in the absence of sodium cacodylate. The flexible loop in the active site, composed of residues 141-151, remains incompletely defined, but the location of the essential Glu152 residue is unambiguous. The residues from 210-218 that link the core and C-terminal domains can be traced as an extension from the core with a short gap at residues 214-215. The C(alpha) folding of the C-terminal domain is similar to the solution structure of this domain from HIV-1 integrase. However, the dimeric form seen in the NMR structure cannot exist as related by the non-crystallographic symmetry in the SIV integrase crystal. The two flexible loops of the C-terminal domain, residues 228-236 and residues 244-249, are much better fixed in the crystal structure than in the NMR structure with the former in the immediate vicinity of the flexible loop of the core domain. The interface between the two domains encompasses a solvent-exclusion area of 1500 A(2). Residues from both domains purportedly involved in DNA binding are narrowly distributed on the same face of the molecule. They include Asp64, Asp116, Glu152 and Lys159 from the core and Arg231, Leu234, Arg262, Arg263 and Lys264 from the C-terminal domain. A model for DNA binding is proposed to bridge the two domains by tethering the 228-236 loop of the C-terminal domain and the flexible loop of the core.

Inhibition of hepatitis C virus NS2/3 processing by NS4A peptides. Implications for control of viral processing.

The NS2/3 protease of hepatitis C virus is responsible for a single cleavage in the viral polyprotein between the nonstructural proteins NS2 and NS3. The minimal protein region necessary to catalyze this cleavage includes most of NS2 and the N-terminal one-third of NS3. Autocleavage reactions using NS2/3 protein translated in vitro are used here to investigate the inhibitory potential of peptides likely to affect the reaction. Peptides representing the cleaved sequence have no effect upon reaction rates, and the reaction rate is insensitive to dilution. Both results are consistent with prior suggestions that the NS2/3 cleavage is an intramolecular reaction. Surprisingly, peptides containing the 12-amino acid region of NS4A responsible for binding to NS3 inhibit the NS2/3 reaction with K(i) values as low as 3 microM. Unrelated peptide sequences of similar composition are not inhibitory, and neither are peptides containing incomplete segments of the NS4A region that binds to NS3. Inhibition of NS2/3 by NS4A peptides can be rationalized from the organizing effect of NS4A on the N terminus of NS3 (the NS2/3 cleavage point) as suggested by the known three-dimensional structure of the NS3 protease domain (Yan, Y., Li, Y., Munshi, S., Sardana, V., Cole, J. L., Sardana, M., Steinkuhler, C., Tomei, L., De Francesco, R., Kuo, L. C., and Chen, Z. (1998) Protein Sci. 7, 837-847). These findings may imply a sequential order to proteolytic maturation events in hepatitis C virus.

Purification, solution properties and crystallization of SIV integrase containing a continuous core and C-terminal domain.

The C-terminal two-thirds segment of integrase derived from the simian immunodeficiency virus has been cloned, expressed in Escherichia coli, and purified to greater than 95% homogeneity. The protein encompasses amino-acid residues 50-293 and contains a F185H substitution to enhance solubility. In dilute solutions at concentrations below 1 mg ml(-1), the enzyme is predominantly dimeric. At the higher concentrations (>10 mg ml(-1)) required to enable crystallization, the enzyme self-associates to form species with molecular weights greater than 200 kDa. Despite the apparent high aggregation in solution, the enzyme crystallizes from a 8%(v/v) polyethylene glycol (molecular weight 6000) solution in a form suitable for X-ray diffraction studies. The resulting single crystals belong to the space group P2(1)2(1)2(1), with unit-cell parameters a = 79.76, b = 99.98, c = 150.2 A, alpha = beta = gamma = 90 degrees and Z = 4. Under X-ray irradiation generated with a rotating-anode generator, the crystals diffract to 2.8 A resolution and allow collection of a native 3 A resolution diffraction data set.