Search

Background: The V2 receptor antagonist tolvaptan is prescribed to patients with autosomal dominant polycystic kidney disease to slow disease progression. Tolvaptan may alter BP via various acute and chronic effects. Methods: To investigate the magnitude and time course of the effect of tolvaptan use on BP, we conducted a post hoc study of the TEMPO 3:4 trial, which included 1445 patients with autosomal dominant polycystic kidney disease randomized 2:1 to tolvaptan or placebo for 3 years. We evaluated systolic and diastolic BP, mean arterial pressure, hypertension status, and use and dosing of antihypertensive drugs over the course of the trial. Results: At baseline, BP did not differ between study arms. After 3 weeks of tolvaptan use, mean body weight had decreased from 79.7 to 78.8 kg, and mean plasma sodium increased from 140.4 to 142.6 mmol/L (both P

Treatment outcomes associated with the use of novel COVID-19 therapeutics in solid organ transplant recipients (SOTR) are not well described in the literature. The objective of this analysis was to characterize 30-day hospitalization and other key secondary endpoints experienced by outpatient SOTR with mild-moderate COVID-19 treated with nirmatrelvir/ritonavir (NR), sotrovimab, or no SARS-CoV-2 specific treatment. This IRB-approved, retrospective study included 154 SOTR with a documented positive SARS-CoV-2 infection between December 16, 2021 and January 19, 2022 (a predominant Omicron BA.1 period in New York City). Patients who received NR (N = 28) or sotrovimab (N = 51) experienced a lower rate of 30-day hospitalization or death as compared to those who received no specific treatment (N = 75) (p = .009). A total of three deaths occurred, all among patients who initially received no specific treatment prior to hospitalization. These results suggest a role for SARS-CoV-2 specific agents in the treatment of SOTR with COVID-19, and that there does not appear to be any difference in effectiveness when comparing NR versus sotrovimab.

Introduction In pivotal trials of patients with autosomal dominant polycystic kidney disease at risk of rapid progression, tolvaptan slowed estimated glomerular filtration rate (eGFR) decline in early-to-moderate (TEMPO 3:4 [NCT00428948]) and moderate- to late-stage (REPRISE [NCT02160145]) chronic kidney disease (CKD). Discontinuation was less frequent in REPRISE (15.0%) than TEMPO 3:4 (23.0%), given that in REPRISE, only subjects who tolerated tolvaptan 60/30 mg daily initiated the double-blind phase. We evaluated whether the greater treatment effect in REPRISE was attributable to different completion rates. Methods We conducted post hoc analyses of TEMPO 3:4 and REPRISE completers, defined as subjects who took trial drug to the end of the treatment period in TEMPO 3:4 (3 years) or REPRISE (1 year). Efficacy (rate of change in eGFR for tolvaptan vs. placebo) was analyzed as in each trial. Subjects from TEMPO 3:4 and REPRISE were also matched by propensity score for age, gender, and baseline eGFR to explore potential additional determinants of treatment effect. Results The annualized tolvaptan treatment effect in TEMPO 3:4 completers (difference vs. placebo of 0.98 ml/min per 1.73 m2/y) and REPRISE completers (difference of 1.23) was similar to that of the respective total trial populations (TEMPO 3:4: 0.94; REPRISE: 1.27). The treatment effect of tolvaptan was also similar between matched subjects. Conclusion Greater treatment completion rate did not drive greater treatment effect in REPRISE. The more advanced CKD of REPRISE subjects may be more relevant. More rapid decline in kidney function in later-stage CKD enabled the effects of tolvaptan to be more easily discerned., Graphical abstract

Introduction In the Mayo Imaging Classification (MIC) for autosomal dominant polycystic kidney disease (ADPKD), the height-adjusted total kidney volume (HtTKV) growth rate is estimated for classification. Estimated HtTKV slope, termed as eHTKV-α, is calculated by the equation [HtTKV at age t] = K(1+α/100)(t-A), where K = 150 and A = 0 are used in MIC. If eHTKV-α is nearly stable during a standard-of-care period, the change in eHTKV-α from baseline can be used for estimation of the treatment effect on the HtTKV slope. Methods The constancy of eHTKV-α (A = 0 and K = 150) was evaluated using 453 placebo-assigned subjects in the Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes (TEMPO) 3:4 trial. A and K were sought out respectively by a converged pattern of regression lines of log10(HtTKV) plotted against age for subgroups divided according to MIC, and by change in eHTKV-α from baseline. A total of 239 standard-of-care patients from the Kyorin University Cohort (KUC) served as validation. Changes in eHTKV-α from baseline were evaluated in 809 tolvaptan-treated subjects in TEMPO 3:4. Results In placebo-assigned subjects, eHTKV-α (A = 0 and K = 150) changed significantly from baseline at the third year. As regression lines of placebo-assigned subgroups converged around age 0, A was set as 0, which was confirmed by KUC. K = 130 was selected because of minimal change in eHTKV-α from baseline. The KUC validated the constancy of eHTKV-α (A = 0 and K = 130) but not that of eHTKV-α (A=0 and K=150). In tolvaptan-treated subjects, eHTKV-α remained significantly lower than baseline for 3 years. Conclusions eHTKV-α (A = 0 and K = 130) was nearly stable from baseline through follow-up in standard-of-care adults. Treatment effects on the HtTKV slope can be estimated by changes in eHTKV-α from baseline.

Introduction Tolvaptan slowed estimated glomerular filtration rate (eGFR) decline in subjects with autosomal dominant polycystic kidney disease (ADPKD) in TEMPO 3:4 and REPRISE trials. Tolvaptan effects in subjects with eGFR 15 to 24 ml/min per 1.73 m2 were not investigated. This post hoc analysis retrospectively investigated eGFR decline in REPRISE versus an open-label, phase 3b extension trial (open-label extension [OLE] NCT02251275) in subjects who received placebo in REPRISE and tolvaptan in OLE with eGFR 15 to 24 and 25 to 29 ml/min per 1.73 m2, respectively. Methods One data subset comprised subjects with OLE baseline eGFR 15 to 29 ml/min per 1.73 m2 who had received placebo in REPRISE and began tolvaptan in OLE. The second comprised subjects who had received tolvaptan in REPRISE and were matched to REPRISE placebo-treated subjects for REPRISE baseline characteristics. Annualized eGFR slopes in REPRISE versus OLE were compared within the REPRISE placebo (i.e., placebo vs. tolvaptan treatment) and tolvaptan (i.e., 2 periods of tolvaptan treatment) subsets. Results Mean annualized eGFR slopes (ml/min per 1.73 m2) during tolvaptan treatment in OLE versus placebo treatment in REPRISE were −3.4 versus −5.2 for subjects with OLE baseline eGFR 15 to 29 (difference, 1.7; P < 0.001), −3.6 versus −5.4 with baseline eGFR 15 to 24 (difference, 1.8; P < 0.001), and −3.3 versus −4.9 with baseline eGFR 25 to 29 (difference, 1.6; P < 0.001). In REPRISE tolvaptan subjects who continued tolvaptan in OLE, treatment effect was maintained (no difference between mean annualized eGFR slopes). Conclusion Initiating or maintaining tolvaptan therapy significantly delayed eGFR decline in subjects with baseline eGFR 15 to 24 and 25 to 29 ml/min per 1.73 m2., Graphical abstract

Background and Aims ADPKD is a progressive inherited disease that causes end-stage renal disease (ESRD) in ∼50% of the affected individuals by 60 years of age. TOL, a selective vasopressin V2-receptor antagonist, has been shown in randomized, placebo-controlled trials to slow the progression of renal function decline in ADPKD subjects with an eGFR of 25 mL/min/1.73m2 or higher. The efficacy and safety of TOL in subjects with lower eGFR remain understudied. This post-hoc analysis evaluated the efficacy and safety of TOL in subjects with stage 4 ADPKD (eGFR of Method This is a retrospective analysis of a subgroup of ADPKD subjects who enrolled in the TOL long-term open-label extension (OLE) trial (NCT02251275). Included subjects had a baseline eGFR of Results Of the 1,803 subjects enrolled, 159 (8.8%) subjects (76 in Subgroup 1 and 83 in Subgroup 2) met the selection criteria for analysis. Annualized eGFR change slopes for all subjects (n=148) were -5.28 (SE 0.27) in the control period and -3.16 (SE 0.30) in the treatment period with a treatment effect of 2.11 mL/min/1.73m2/year (95% CI 1.56, 2.66), p Conclusion This post-hoc analysis demonstrated that TOL significantly decreases the rate of eGFR decline in ADPKD subjects with stage 4 CKD, including those with an eGFR of

A clinical trial often has primary and secondary endpoints and comparisons of high and low doses of a study drug to a control. Multiplicity is not only caused by the multiple comparisons of study drugs versus the control, but also from the hierarchical structure of the hypotheses. Closed test procedures were proposed as general methods to address multiplicity. Two commonly used tests for intersection hypotheses in closed test procedures are the Simes test and the average method. When the treatment effect of a less efficacious dose is not much smaller than the treatment effect of a more efficacious dose for a specific endpoint, the average method has better power than the Simes test for the comparison of two doses versus control. Accordingly, for inferences for primary and secondary endpoints, the matched parallel gatekeeping procedure based on the Simes test for testing intersection hypotheses is extended here to allow the average method for such testing. This procedure is further extended to clinical trials with more than two endpoints as well as to clinical trials with more than two active doses and a control.

There are no guidelines for antibiotic prophylaxis for ureteral stent removal after kidney transplantation. We reviewed the charts of 277 adult kidney transplant recipients with ureteral stents transplanted at our center between September 2014 and December 2015 and investigated whether antibiotic prophylaxis for stent removal was associated with reduced incidence of urinary tract infections (UTI). We defined UTI as a urine culture ≥104 CFU/mL of bacterial isolates irrespective of symptoms. Primary outcome was the incidence of UTI within four weeks of stent removal. Among the 277 recipients, 199 (72%) were on sulfamethoxazole/trimethoprim (SMZ/TMP) as Pneumocystis jirovecii prophylaxis. At the time of ureteral stent removal, 56 recipients (20%) received additional antibiotic prophylaxis (ABX+) and 221 (80%) did not (ABX-). The difference in the incidence of UTI in the ABX(+) group (16%) and ABX(-) group (19%) was not statistically significant (P = 0.85). Variables independently associated with the development of UTI were recipient age (odds ratio [OR] 1.04, [95% confidence interval 1.01-1.07]) and UTI while stents were in situ (OR 3.9 [2.00-7.62]). Use of SMZ/TMP was protective (OR 0.35 [0.18-0.7]). Our study does not show a statistically significant benefit for additional antibiotic prophylaxis for ureteral stent removal. Antibiotic prophylaxis may be beneficial for recipients not on SMZ/TMP at the time of stent removal.

Space-based microwave radiometers (MRs) have a long history of providing critical inputs for retrieval algorithms that generate accurate estimates of geophysical properties of the Earth’s surface and atmosphere. Mission cost reduction pressure has led to increased use of small spacecraft (e.g. CubeSats and SmallSats) for scientific and operational Earth observation applications. The need for miniaturized MR electronics that fit into SmallSats and maintain performance poses a challenge for conventional MR technologies. Channel filters are one driver of MR size and weight. Microwave photonics (MWP) fabricated on silicon photonic integrated circuits (PICs) is one means to dramatically reduce the size of these filters enabling SmallSat platform integration and enhanced measurement capability. In this paper, we address the performance requirements for PICs to provide a viable path for low cost, size, weight and power (c-SWaP) MRs. We present experimental results of a silicon PIC filter development and a new electro-optic modulator (EOM) design that will integrate monolithically with these filters. The performance of an integrated MWP-based MR is modeled and compared to an operational MR. It is shown that the MWP design using the new EOM can provide radiometric performance comparable to conventional MRs but within a dramatically smaller sensor volume and in a purely silicon platform enabling low cost.

Magnetic resonance imaging (MRI) was used to investigate muscle rehabilitation following cast immobilization. The aim was to explore MRI as an imaging biomarker of muscle function. Sixteen patients completed an eight-week rehabilitation programme following six weeks of cast immobilization for an ankle fracture. MRI of the lower leg was performed at two-week intervals for 14 weeks. Total volume and anatomical cross-sectional areas at 70% of the distance from lateral malleolus to tibial tuberosity (ACSA) were measured for tibialis anterior (TA), medial and lateral gastrocnemius (GM and GL) and soleus (SOL). Pennation angle of muscle fascicules was measured at the same position in GM. Fractional fat/water contents and T2 relaxation times before and after exercise were calculated. Strength was measured as maximum isometric torque developed in plantar- and dorsi-flexion. Torque increased by (mean [SD]) 1.10 (0.32) N m day−1 in males, 0.74 (0.43) N m day−1 in females in plantar-flexion (0.9% of final strength p...

Excitation-inhibition (E-I) imbalance is considered a hallmark of various neurodevelopmental disorders, including schizophrenia and autism. How genetic risk factors disrupt coordinated glutamatergic and GABAergic synapse formation to cause an E-I imbalance is not well understood. Here, we show that knockdown of Disrupted-in-schizophrenia 1 (DISC1), a risk gene for major mental disorders, leads to E-I imbalance in mature dentate granule neurons. We found that excessive GABAergic inputs from parvalbumin-, but not somatostatin-, expressing interneurons enhance the formation of both glutamatergic and GABAergic synapses in immature mutant neurons. Following the switch in GABAergic signaling polarity from depolarizing to hyperpolarizing during neuronal maturation, heightened inhibition from excessive parvalbumin(+) GABAergic inputs causes loss of excitatory glutamatergic synapses in mature mutant neurons, resulting in an E-I imbalance. Our findings provide insights into the developmental role of depolarizing GABA in establishing E-I balance and how it can be influenced by genetic risk factors for mental disorders.

Surgical stress, corticosteroids, and mycophenolate may contribute to gastrointestinal ulcers/bleeding after kidney transplantation. Prophylactic acid suppression with H2RAs or PPIs is often utilized after transplantation, although unclear if truly indicated after early corticosteroid withdrawal (CSWD). PPIs have been associated with increased risks of Clostridium difficile infection (CDI), pneumonia, and acute rejection. This retrospective cohort study investigated benefits and risks of prolonged PPI use following kidney transplantation and included 286 kidney recipients undergoing CSWD within five d of transplant who were maintained on tacrolimus and mycophenolate mofetil/sodium. Patients on PPI before transplant, H2RA before/after transplant, and/or those with pre-transplant GI complications were excluded. A total of 171 patients received PPI>30 d, mean duration 287 ± 120 d (PPI group); 115 patients were not maintained on acid suppression (No-PPI group). GI ulceration and bleeding events were rare in PPI group (1.2% and 2.3%, respectively) and not observed in No-PPI group (p = NS). The incidence of infectious or hematological complications was not significantly different between groups. The PPI group experienced more biopsy-proven acute rejection (9.4% vs. 2.6%, p = 0.03). No direct benefit was observed with PPI in reducing the incidence of GI ulcers and bleeding events in kidney transplant recipients undergoing early CSWD. Further studies are needed to investigate the association of PPI and acute rejection.

Purpose: To investigate MRI biomarkers of muscle atrophy during cast immobilization of the lower leg. Materials and Methods: Eighteen patients (8 male, 10 female), who had one lower leg immobilized in a cast, underwent 3.0 Tesla (T) MR imaging 5, 8, 15, 29, and 43 days after casting. Measurements were made on both lower legs of total muscle volume. Cross-sectional area (CSA), fractional water content, and T2 were measured in tibialis anterior (TA), gastrocnemius medialis (GM) and lateralis (GL) and soleus (SOL). Fiber pennation angle was measured in GM. Results: Total muscle volume decreased by 17% (P < 0.001) over the 6 weeks of immobilization. The greatest loss in CSA (mean[SD]) was seen in GM (−23.3(8.7)%), followed by SOL (−19.0(9.8)%), GL (−17.1(6.5)%), and TA (−10.7(5.9)%). Significant reductions of CSA were also detectable in the contra-lateral leg. T2 increased in all muscles: TA 27.0(2.5) ms to 29.6(2.8) ms (P < 0.001), GM 34.6(2.9) ms to 39.8(5.4) ms (P < 0.001) and SOL 34.4 (2.9) ms to 44.9(5.9) ms (P < 0.001). Small reductions were found in fractional water content. Pennation angle decreased in the cast leg (P < 0.001). Conclusion: Quantitative MR imaging can detect and monitor progressive biochemical and biophysical changes in muscle during immobilization. J. Magn. Reson. Imaging 2012;35:686-695. © 2011 Wiley Periodicals, Inc.

Summary Objective The sensitivity to change of quantitative analysis of cartilage in knee osteoarthritis using magnetic resonance imaging (MRI) is compromised by the spatial heterogeneity of cartilage loss. We explore whether extended (medial–lateral) "ordered values" (OVs) are superior to conventional approaches of analyzing subregional cartilage thickness loss and to radiography, in differentiating rates of progression in knees with and without joint space narrowing (JSN). Methods 607 Osteoarthritis Initiative (OAI) participants (308 without and 299 with baseline JSN at baseline) were studied over 12 months. Subregional femorotibial cartilage loss was determined in all knees, and changes in minimum joint space width (mJSW) in a subset of 290 knees. Subregional thickness changes in medial and lateral tibial and femoral cartilages were sorted in ascending order (OV1-16). A Wilcoxon rank-sum test was used to compare rates of change in knees with and without JSN. Results JSN-knees displayed greater cartilage loss than those without JSN, with minimal P -values of 0.008 for femorotibial subregions, 3.3×10 −4 for medial OV1, and 5.4×10 −7 for extended (medial and lateral) OV1. mJSW measurements ( n =290) did not discriminate between longitudinal rates of change in JSN vs no-JSN knees ( P =0.386), whereas medial OV1 ( P =5.1×10 −4 ) and extended OV1 did ( P =2.1×10 −5 ). Conclusion Extended OVs showed higher sensitivity to detecting differences in longitudinal rates of cartilage loss in knees with and without baseline JSN than anatomical (sub)regions and radiography. The OV technique also circumvents challenges of selecting particular regions "a priori" in clinical trials and may thus provide a powerful tool in studying risk factors or treatment efficacy in osteoarthritis.

Summary Objective To compare femorotibial cartilage thickness changes over a 2- vs a 1-year observation period in knees with radiographic knee osteoarthritis (OA). Methods One knee of 346 Osteoarthritis Initiative (OAI) participants was studied at three time points [baseline (BL), year-1 (Y1), year-2 (Y2) follow-up]: 239 using coronal fast low angle shot (FLASH) and 107 using sagittal double echo at steady state (DESS) MR imaging. Changes in cartilage thickness were assessed in femorotibial cartilage plates and subregions, after manual segmentation with blinding to time-point. Results The standardized response mean (SRM) of total joint cartilage thickness over 2 years was modestly higher than over 1 year (FLASH: −0.44 vs −0.32/−0.28 [first/second year]; DESS: −0.42 vs −0.39/−0.18). For the subregion showing the largest change per knee (OV1), the 2-year SRM was similar or lower (FLASH: −1.20 vs −1.22/−1.61; DESS: −1.38 vs −1.64/−1.51) than the 1-year SRM. The changes in total joint cartilage thickness were not significantly different in the first and second year (FLASH: −0.8% vs −0.7%; DESS: −1.3% vs −0.8%) and were negatively correlated. Analysis of smallest detectable changes (SDCs) revealed that only few participants displayed significant progression in both consecutive periods. The location of the subregion contributing to OV1 in each knee was highly inconsistent between the first and second year observation period. Conclusions The SRM of region-based cartilage thickness change in OA is modestly larger following a 2-year vs a 1-year observation period, while it is relatively similar when an OV-approach is chosen. Structural progression displays strong temporal and spatial heterogeneity at an individual knee level that should be considered when planning clinical trials.

Objective Traumatic joint injury can damage cartilage and release inflammatory cytokines from adjacent joint tissue. The present study was undertaken to study the combined effects of compression injury, tumor necrosis factor α (TNFα), and interleukin-6 (IL-6) and its soluble receptor (sIL-6R) on immature bovine and adult human knee and ankle cartilage, using an in vitro model, and to test the hypothesis that endogenous IL-6 plays a role in proteoglycan loss caused by a combination of injury and TNFα. Methods Injured or uninjured cartilage disks were incubated with or without TNFα and/or IL-6/sIL-6R. Additional samples were preincubated with an IL-6–blocking antibody Fab fragment and subjected to injury and TNFα treatment. Treatment effects were assessed by histologic analysis, measurement of glycosaminoglycan (GAG) loss, Western blot to determine proteoglycan degradation, zymography, radiolabeling to determine chondrocyte biosynthesis, and Western blot and enzyme-linked immunosorbent assay to determine chondrocyte production of IL-6. Results In bovine cartilage samples, injury combined with TNFα and IL-6/sIL-6R exposure caused the most severe GAG loss. Findings in human knee and ankle cartilage were strikingly similar to those in bovine samples, although in human ankle tissue, the GAG loss was less severe than that observed in human knee tissue. Without exogenous IL-6/sIL-6R, injury plus TNFα exposure up-regulated chondrocyte production of IL-6, but incubation with the IL-6–blocking Fab significantly reduced proteoglycan degradation. Conclusion Our findings indicate that mechanical injury potentiates the catabolic effects of TNFα and IL-6/sIL-6R in causing proteoglycan degradation in human and bovine cartilage. The temporal and spatial evolution of degradation suggests the importance of transport of biomolecules, which may be altered by overload injury. The catabolic effects of injury plus TNFα appeared partly due to endogenous IL-6, since GAG loss was partially abrogated by an IL-6–blocking Fab.

Hyponatremia (serum sodium [Na+] concentration136 mmol/L) is a prevalent and potentially life-threatening medical comorbidity for schizophrenic patients. No definitive pharmacological treatments have been established. Tolvaptan (OPC-41061), an oral non-peptide V2-receptor antagonist, was recently shown to correct hyponatremia in a diverse population of 448 hyponatremic patients. Efficacy in a sub-set of 19 schizophrenic patients with idiopathic hyponatremia included in that sample is specifically examined.Nineteen subjects were randomly assigned to receive placebo (n = 12) or tolvaptan (n = 7) once daily for 30 days. Dosage adjustment was based on serum Na+ changes, initially 15 mg, titratable to 30 or 60 mg. The average daily area under the curve (AUC) changes in serum Na+ from baseline to Day 4 and Day 30 were co-primary end points.Increases in serum Na+ concentrations were significantly greater with tolvaptan than placebo at Day 4 (p = .0055) and at Day 30 (p.0001). Two subjects receiving tolvaptan (28.6%) became dehydrated and experienced hypotension, and five subjects receiving placebo (41.7%) experienced symptoms associated with dilutional hyponatremia.These results suggest that tolvaptan effectively normalizes idiopathic hyponatremia in schizophrenic patients. Clinicians are advised to carefully monitor fluid status especially at the beginning of treatment to prevent dehydration.

Researchers have found that immigrants in the United States gradually relinquish cultural practices and adopt health behaviors similar to native born individuals as they acculturate. Few studies have looked at acculturation and Complementary and Alternative Medicine (CAM) use, particularly ethnic forms of CAM. This study uses data from the 2001 California Health Interview Survey-Complementary and Alternative Medicine (CHIS-CAM) supplement to estimate the prevalence of CAM provider use among Mexican- and Asian- Americans and examine the relationship of acculturation on use. Multinomial logistic regression models were used to predict the probability of provider use based on socio-demographic variables, health status and acculturation. Mexican- and Asian- Americans who have spent more time in the US were more likely to use chiropractors or massage therapists compared to no CAM provider. Both groups were less likely to use ethnic-specific CAM providers with more time in the US compared to chiropractors or massage therapists.

Soliton self-frequency shift (SSFS), a consequence of Raman self-pumping that continuously red-shifts a soliton pulse, has been widely studied recently for applications to fiber-based sources and signal processing. In this paper, the fundamentals of SSFS are reviewed. Various fiber platforms for SSFS (single-mode fiber, microstructured fiber, and higher order mode fiber) are presented and experimental SSFS demonstrations in these fibers are discussed. Observation of Cerenkov radiation in fibers exhibiting SSFS is also presented. A number of interesting applications of SSFS, such as wavelength-agile lasers, analog-to-digital conversion, and slow light, are briefly discussed.

Background Population-based data about utilization of complementary and alternative medicine (CAM) among those with chronic conditions is lacking. Objective To describe whether CAM use by California adults with cancer and other chronic conditions reflects condition-specific patterns or a general tendency to use CAM modalities. Methods Interviews of 9,187 respondents including all participants with cancer from a prior representative survey of California households, and a stratified sample of all other respondents. Almost 74% of the respondents reported at least one chronic health problem. Results Use of all forms of CAM among those with chronic health problems is high. Those with a diagnosis of cancer are more likely to use prayer, dietary supplements, and support groups, and less likely to use CAM providers and special diets. Overall, individuals diagnosed with most chronic problems use a similar set of CAM modalities. Demographic correlates of CAM use differ in their impact and vary according to what type of CAM is being used. Conclusions Clinicians should be aware that while a diagnosis of cancer is associated with a greater use of some forms of CAM, overall patterns of CAM use are similar to those with most other chronic problems.

Oceanographic lidar profiles measured in an aerial survey were compared with in situ measurements of water optical properties made from a surface vessel. Experimental data were collected over a two-week period in May 2010 in East Sound, Washington. Measured absorption and backscatter coefficients were used with the volume-scattering function in a quasi-single-scattering model to simulate an idealized lidar return, and this was convolved with the measured instrument response to accurately reproduce the measured temporal behavior. Linear depth-dependent depolarization from the water column and localized depolarization from scattering layers are varied to fine tune the simulated lidar return. Sixty in situ measurements of optical properties were correlated with nearly collocated and coincident lidar profiles; our model yielded good matches (±3 dB to a depth of 12 m) between simulated and measured lidar profiles for both uniform and stratified waters. Measured attenuation was slightly higher (5%) than diffuse attenuation for the copolarized channel and slightly lower (8%) for the cross-polarized channel.

The role of latent membrane protein 2 (LMP2) in Epstein-Barr virus (EBV) infection was evaluated by using latently infected primary B lymphocytes that had been growth transformed by wild-type or specifically mutated EBV recombinants. LMP2 null mutant recombinant EBV-infected cells were similar to normal B lymphocytes in their rapid increase in intracellular free calcium after surface immunoglobulin crosslinking. These cells also became more permissive for lytic EBV replication. In sharp contrast, wild-type control infected cells had little or no increase in intracellular free calcium or in permissivity for EBV replication. The block to surface immunoglobulin crosslinking-induced permissivity in cells expressing wild-type LMP2 could be bypassed by raising intracellular free calcium levels with an ionophore and by activating protein kinase C with phorbol 12-myristate 13-acetate. LMP2A, not LMP2B, mediates this effect on calcium mobilization. Genetic and biochemical data are consistent with these effects being due to the interaction of the LMP2A N-terminal cytoplasmic domain with B lymphocyte src family tyrosine kinases.

OBJECTIVE: To assess international shortfall inequality in life expectancy at birth among women and men and the influence of geography and country income group. METHODS: The authors used estimates of life expectancy at birth, by sex, for 12 five-year periods between 1950-1955 and 2005-2010 and estimates of population for the midpoints of each period from the World population prospects, 2008 revision. Shortfall inequality was defined as the weighted average of the deviations of each country's average life expectancy by sex from the highest attained life expectancy by sex for each period. FINDINGS: International shortfall inequalities in life expectancy among men and among women decreased between 1950 and 1975 but stagnated thereafter. International shortfall inequality in life expectancy has been higher in women than in men, ranging from 1.9 to 2.9 years. Women in low-income countries have the biggest shortfall, currently at around 26.7 years. CONCLUSION: International shortfall inequality is higher among women than men primarily because women in low-income and lower-middle-income country groups show larger differences in life expectancy than men. Further investigation is needed to determine the pathways causing these inequalities.

We design and implement a novel class of highly precise network instrumentation, capable of the first-ever capture of exact packet timings of network traffic. Our instrumentation — combining real-time physics test equipment with off-line postprocessing software — prevents interference with the system under test, provides reproducible measurements by eliminating non-deterministic error, and uses transparent and ubiquitous lab equipment and open-source software for ease of replication. We use our technique to perform in-situ observations of 10 Gigabit Ethernet packets in flight on optical fiber, showing improvements in timing precision of two to six orders of magnitude over existing methods of measurement, which generally employ software on commodity computer endpoints of network paths.

We use the time-lens concept to demonstrate a new scheme for synchronization of two pulsed light sources for biological imaging. An all fiber, 1064 nm time-lens source is synchronized to a picosecond solid-state Ti: Sapphire mode-locked laser by using the mode-locked laser pulses as the clock. We demonstrate the application of this synchronized source for CARS and SRS imaging by imaging mouse tissues. Synchronized two wavelength pulsed source is a major technical difficulty for CARS and SRS imaging. The time-lens source demonstrated here may provide an all-fiber, user friendly alternative for future SRS imaging.

We characterize the focusing properties of the LP02 mode in a typical multiphoton microscope. Under varying back-aperture filling conditions, we measure vastly different point spread functions, including a null at the focus.

Objective To identify structural differences in total subchondral bone area (tAB) and cartilage thickness between healthy reference knees and knees with radiographic osteoarthritis (OA). Methods Baseline magnetic resonance images from 1 knee of 1,003 Osteoarthritis Initiative participants were studied: 112 healthy reference knees without radiographic OA, symptoms, or risk factors; 70 preradiographic OA knees (calculated Kellgren/Lawrence [K/L] grade 0/1); and 821 radiographic OA knees (calculated K/L grade ≥2). Means and standard (Z) scores (SD unit differences compared with normal subjects) of the tAB and regional cartilage thickness were assessed in the weight-bearing femorotibial joint and compared between groups. Results In men, tAB was 8.2% larger in preradiographic OA knees and 6.6%, 8.1%, and 8.5% larger in calculated K/L grade 2, 3, and 4 radiographic OA knees, respectively, than in reference knees. In women, the differences were +6.8%, +7.3%, +9.9%, and +8.1%, respectively. The external medial tibia showed the greatest reduction in cartilage thickness (Z scores −5.1/−5.6 in men/women) with Osteoarthritis Research Society International medial joint space narrowing (JSN) grade 3, and the external lateral tibia (Z scores −6.0 for both sexes) showed the greatest reduction with lateral JSN grade 3. In all subregions of end-stage radiographic OA knees, ≥25% of the average normal cartilage thickness was maintained. An overall trend toward thicker cartilage was found in preradiographic OA and calculated K/L grade 2 knees, especially in the external central medial femur. Conclusion tABs were larger in preradiographic OA and radiographic OA knees than in healthy reference knees, and the difference did not become larger with higher calculated K/L grades. Specific subregions with substantial cartilage thickening or thinning were identified in pre-, early, and late radiographic OA.

We demonstrate an all-fiber, 2-ps, 1063-nm source using time-lens compression of a continuous-wave laser, with variable repetition rates, pulse sequence, and alternating pulse amplitude. We demonstrate Cerenkov radiation in a higher-order-mode fiber using the source.

Objective To study the longitudinal rate of (and sensitivity to) change of knee cartilage thickness across defined stages of radiographic osteoarthritis (OA), specifically healthy knees and knees with end-stage radiographic OA. Methods One knee of 831 Osteoarthritis Initiative participants was examined: 112 healthy knees, without radiographic OA or risk factors for knee OA, and 719 radiographic OA knees (310 calculated Kellgren/Lawrence [K/L] grade 2, 300 calculated K/L grade 3, and 109 calculated K/L grade 4). Subregional change in thickness was assessed after segmentation of weight-bearing femorotibial cartilage at baseline and 1 year from coronal magnetic resonance imaging (MRI). Regional and ordered values (OVs) of change were compared by baseline radiographic OA status. Results Healthy knees displayed small changes in plates and subregions (±0.7%; standardized response mean [SRM] ±0.15), with OVs being symmetrically distributed close to zero. In calculated K/L grade 2 knees, changes in cartilage thickness were small (

Pro-inflammatory cytokines induce meniscal matrix degradation and inhibition of endogenous repair mechanisms, but the pathogenic mechanisms behind this are mostly unknown. Therefore, we investigated details of interleukin-1 (IL-1alpha)-induced aggrecan turnover in mature meniscal tissue explants. Fibro-cartilagenous disks (3 mm diameter x 1 mm thickness) were isolated from the central, weight-bearing region of menisci from 2-year-old cattle. After 3 or 6 days of IL-1alpha-treatment, GAG loss (DMMB assay), biosynthetic activity ([(35)SO(4)]-sulfate and [(3)H]-proline incorporation), gene expression (quantitative RT-PCR) and the abundance (zymography, Western blot) of matrix-degrading enzymes and specific aggrecan products were determined. Meniscal fibrocartilage had a 4-fold lower GAG content (per wet weight) than adjacent articular cartilage, and expressed MMPs-1, -2, -3 and ADAMTS4 constitutively, whereas ADAMTS5 m-RNA was essentially undetectable. Significant IL-1 effects were a decrease in biosynthetic activity, an increase in GAG release and in the expression/abundance of MMP-2, MMP-3 and ADAMTS4. Fresh tissue contained aggrecan core protein products similar to those previously described for bovine articular cartilage of this age. IL-1 induced the release of aggrecanase-generated CS-substituted products including both high (250 kDa) and low molecular weight (about 75 kDa) species. TIMP-3 (but not TIMP-1 and -2 or a broad spectrum MMP inhibitor) inhibited IL-1-dependent GAG loss. In addition, IL-1 induced the release of preformed pools of three known G1-bearing products. We conclude that aggrecanases are responsible for IL-1-stimulated GAG release from meniscal explants, and that IL-1 also stimulates release of G1-bearing products, by a process possibly involving hyaluronan fragmentation.

We studied changes in chondrocyte gene expression, aggrecan degradation, and aggrecanase production and activity in normal and mechanically injured cartilage co-cultured with joint capsule tissue. Chondrocyte expression of 21 genes was measured at 1, 2, 4, 6, 12, and 24h after treatment; clustering analysis enabled identification of co-expression profiles. Aggrecan fragments retained in cartilage and released to medium and loss of cartilage sGAG were quantified. Increased expression of MMP-13 and ADAMTS4 clustered with effects of co-culture, while increased expression of ADAMTS5, MMP-3, TGF-beta, c-fos, c-jun clustered with cartilage injury. ADAMTS5 protein within cartilage (immunohistochemistry) increased following injury and with co-culture. Cartilage sGAG decreased over 16-days, most severely following injury plus co-culture. Cartilage aggrecan was cleaved at aggrecanase sites in the interglobular and C-terminal domains, resulting in loss of the G3 domain, especially after injury plus co-culture. Together, these results support the hypothesis that interactions between injured cartilage and other joint tissues are important in matrix catabolism after joint injury.

This study investigated the role of matrix metalloproteases and aggrecanases during dynamic compression-induced aggrecan catabolism in chondrocyte-seeded self-assembling peptide hydrogel. One- to two-week-old bovine chondrocytes were encapsulated into peptide hydrogel and cultured for 14 days prior to the application of an alternate day loading protocol. Dynamic compression-induced aggrecan catabolism was explored by evaluating GAG loss to the culture medium, zymography for matrix metalloproteases (MMPs), gene expression of MMPs and ADAMTS proteases, and Western blot analysis for aggrecan fragments. The application of loading over 4 days increased GAG loss to the medium three- to four-fold relative to free-swelling controls. Zymogram analysis detected increased concentrations of latent MMP-9 and MMP-3 in the culture medium relative to free-swelling culture. Real-time PCR showed expression levels of MMPs and ADAMTS proteases in loaded samples that ranged from 2.5- to 95-fold higher than free-swelling culture. Aggrecan fragment analysis did not detect small (50-80 kDa) molecular weight fragments in free-swelling culture; however, dynamic compression samples contained 60-80 kDa fragments that were detected by both anti-G1 and NITEGE probes, demonstrating ADAMTS but not MMP degradation. These data suggest that partially mature cartilage tissue engineering constructs may be susceptible to catabolic degradation.

Recent studies demonstrate that chondrocytes in native articular cartilage and in tissue-engineered constructs respond to mechanical stimuli through multiple regulatory pathways. Responses of the cells are manifested by intra- and intercellular signalling, alterations in transcription level, protein translation, post-translational modifications, and synthesis of intracellular and extracellular macromolecules. In addition, mechanical stimuli can alter the balance between anabolic and catabolic processes that are critically important to cell-mediated extracellular assembly and degradation of the tissue matrix and, therefore, to the survival of tissue engineered constructs. Chondrocyte mechanotransduction is therefore a critically important link to the biomechanical properties of native cartilage and to developing constructs. Since implanted cartilage repair tissue will be subjected to mechanical loads throughout its lifetime, it is essential that the resident cells respond appropriately to the range of static and dynamic compressive and shear deformations in vivo in a manner that enables adaptive remodelling and minimizes catabolic degradation. The in vivo environment should thereby signal tissue-specific maturation and integration processes in order to achieve the most appropriate tissue morphology and biomechanical function.

Using time-lens compression in a loop configuration, we generate 516 fs pulses at 3.5 nJ pulse energy from a continuous-wave 1.55 mum source without mode locking. Just as a spatial lens can expand or focus a beam in space, so can a time-lens broaden or compress a pulse in time. By placing a time-lens in a loop, we maximize the efficiency of bandwidth generation by using one time-lens driven at low power to emulate a stack of many lenses. Our system is compact, is all fiber, and allows large tuning of the repetition rate and continuous tuning of the pulse width and center wavelength.

We generate 516 fs pulses at 3.5 nJ energy from a continuous wave 1.55 mum source without mode-locking. Our system is compact, all-fiber, and allows continuous tuning of pulse width and center wavelength.

We demonstrate a method of generating short pulses at 1350 nm by exciting Cerenkov radiation in a higher-order-mode fiber with a 1064 nm femtosecond fiber laser. We measure a 106 fs, 0.66 nJ output pulse. Cerenkov radiation in fibers allows for energy transfer between a soliton and a dispersive wave, providing an effective and engineerable platform to shift the wavelength of a femtosecond source. With appropriate design of the higher-order-mode fiber, this method of generating short pulses at 1350 nm can be extended to other wavelengths and to higher pulse energies.

We demonstrate soliton self-frequency shift of more than 12% of the optical frequency in a higher-order mode solid, silica-based fiber below 1300nm. This new class of fiber shows great promise for supporting Raman-shifted solitons below 1300nm in intermediate energy regimes of 1 to 10nJ that cannot be reached by index-guided photonic crystal fibers or air-core photonic bandgap fibers. By changing the input pulse energy of 200fs pulses from 1.36 to 1.63nJ we observe Raman-shifted solitons between 1064 and 1200nm with up to 57% power conversion efficiency and compressed output pulse widths less than 50fs. Furthermore, due to the dispersion characteristics of the HOM fiber, we observe redshifted Cerenkov radiation in the normal dispersion regime for appropriately energetic input pulses.

Objective Joint injury in young adults leads to an increased risk of developing osteoarthritis (OA) later in life. This study was undertaken to determine if injurious mechanical compression of cartilage explants results in changes at the level of gene transcription that may lead to subsequent degradation of the cartilage. Methods Cartilage was explanted from the femoropatellar groove of newborn calves. Levels of messenger RNA encoding matrix molecules, proteases, their natural inhibitors, transcription factors, and cytokines were assessed in free swelling control cultures as compared with cartilage cultures at 1, 2, 4, 6, 12, and 24 hours after application of a single injurious compression. Results Gene-expression levels measured in noninjured, free swelling cartilage varied over 5 orders of magnitude. Matrix molecules were the most highly expressed of the genes tested, while cytokines, matrix metalloproteinases (MMPs), aggrecanases (ADAMTS-5), and transcription factors showed lower expression levels. Matrix molecules showed little change in expression after injurious compression, whereas MMP-3 increased approximately 250-fold, ADAMTS-5 increased approximately 40-fold, and tissue inhibitor of metalloproteinases 1 increased approximately 12-fold above the levels in free swelling cultures. Genes typically used as internal controls, GAPDH and beta-actin, increased expression levels approximately 4-fold after injury, making them unsuitable for use as normalization genes in this study. The expression levels of tumor necrosis factor alpha and interleukin-1beta, cytokines known to be involved in the progression of OA, did not change in the chondrocytes after injury. Conclusion Changes in the level of gene expression after mechanical injury are gene specific and time dependent. The quantity of specific proteins may be altered as a result of these changes in gene expression, which may eventually lead to degradation at the tissue level and cause a compromise in cartilage structure and function.

The effect of two-photon absorption on DPSK and OOK transmission is analyzed by simulation. DPSK is found to have an advantage over OOK in both Q and eye closure penalty for multi-channel WDM transmissions.