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Treatment of hyperglycemia in patients with diabetes mellitus and renal insufficiency is complicated by altered pharmacokinetics of hypoglycemic agents. This study evaluated the pharmacokinetic profile and safety of nateglinide, an amino acid derivative that improves early phase insulin secretion and reduces mealtime glucose excursions. This open‐label, single‐dose, two‐center study included patients (mean age = 57 ± 10 years) with type 1 or 2 diabetes with impaired renal function (IRF) (n = 10) or with renal failure undergoing hemodialysis (n = 10). Both groups were compared with age‐, sex‐, height‐, and weight‐matched healthy controls (n = 20). All participants received a single 120‐mg dose of nateglinide immediately before breakfast. Pharmacokinetic and safety evaluations were undertaken up to 48 hours postdose. All 40 subjects completed the study. Plasma nateglinide concentrations increased rapidly in patients undergoing dialysis and matched healthy subjects (tmax= 0.95 vs. 0.78 h, respectively) and was comparable with patients with IRF and matched healthy subjects (tmax= 0.80 vs. 0.65 h, respectively). There were no statistically significant differences for Cmaxor AUC0‐tbetween the groups. Nateglinide was eliminated rapidly in all groups (t1/2= 1.9–2.8 h). There was no correlation between the level of renal function and systemic exposure. There was a low extent of renal excretion of nateglinide in healthy subjects (11%) and diabetic patients with IRF (3%). Nateglinide was well tolerated. These data suggest that nateglinide is suitable for use in diabetic patients with IRF or with renal failure undergoing dialysis. Given the comparable absorption and elimination profiles of nateglinide in renally impaired and healthy subjects, no dose adjustment appears necessary in the renally impaired.

Periodic fluctuations in natural streamflow are a major driver of river ecosystem dynamics and water resource management. However, most U.S. rivers are impacted both by long‐term hydroclimatic trends and dams that alter flow variability. Despite these impacts, it remains largely unexplored how dams affect the dominant frequencies of natural streamflow over a highly regulated river network. We investigated the entire Colorado River Basin (CRB) to understand how the annual (10–14 months) and multi‐annual (24–60 months) frequencies in natural flow regimes have been progressively altered by dams. Given the significant alteration over the CRB, we captured changes in streamflow frequencies between naturalized and observed monthly flows via wavelet analysis. Based on the similarity of changes in streamflow frequencies (annual and multi‐annual) over the last 30 years, sections of the riverine network were classified into four groups. The annual frequency was relatively well preserved downstream of Hoover Dam, while showing a systematic trend of alteration downstream of Glen Canyon Dam until Hoover Dam. Meanwhile, the multi‐annual frequency component was highly altered for the entire Lower Colorado main stem (i.e., downstream of Glen Canyon). We also identified dams with significant impacts on streamflow frequency by comparing wavelet coherence estimates. This study advances the notion that dams fundamentally alter river flow regimes across multiple frequencies and with varying amplitudes over time and space, with alteration propagating – or being dampened – by both hydroclimatic fluctuations and water resource management. Temporal changes in streamflow frequency are explored in the Colorado River BasinMagnitude of frequency alteration changes with annual frequencies recovering and multi‐annual remaining altered across the river networkDams that significantly alter streamflow frequencies exist across the entire network, and more so in the Lower Colorado Basin Temporal changes in streamflow frequency are explored in the Colorado River Basin Magnitude of frequency alteration changes with annual frequencies recovering and multi‐annual remaining altered across the river network Dams that significantly alter streamflow frequencies exist across the entire network, and more so in the Lower Colorado Basin

Twenty-four patients with malignant tumors of the external auditory canal and middle ear, originally seen between 1960 and 1980, were reviewed retrospectively. Seventeen patients had epidermoid carcinoma, one had adenocarcinoma, three had rhabdomyosarcoma, and one had osteosarcoma. At presentation, four had disease confined to the external auditory canal, three had superficial invasion of the bony canal, four had deeply invasive disease, and thirteen had disease that extended beyond the temporal bone. Treatment consisted of radiation, surgery, and combination therapy. Four patients with osteosarcoma or rhabdomyosarcoma received adjuvant chemotherapy. Five years after therapy, one of four patients with external auditory canal tumor died of disease, and two died of intercurrent disorders. One of three patients with superficial temporal bone invasion and two of four patients with deeply invasive tumor died of their disease; another died of intercurrent disorder. Twelve of 13 patients with tumor beyond the temporal bone died.

Rupture of the left ventricle in the atrioventricular (AV) groove is a rare and usually fatal complication of mitral valve replacement (MVR). The successful repair of a delayed type I left ventricular rupture is described. The technique of repair is described, the literature reviewed, and three further cases from the authors' experience are reported.

This paper reviews a technique for patients with head and neck cancer that achieves adequate inferior margins on the lateral ports by rotating the treatment couch. This technique has the advantage of avoiding multiple ports in an area of high risk or over a tumor mass.

Objective: The aims were to determine: (1) if angiotensin converting enzyme (ACE) inhibition and angiotensin II receptor blockade can prevent angiotensin II induced coronary vascular damage; (2) if the cardioprotective properties of ACE inhibition are dose dependent; and (3) if the cardioprotective properties of ACE inhibition are independent of its ability to prevent the conversion of angiotensin I to angiotensin II. Methods: Control rats and rats with either renovascular hypertension or continuous angiotensin II infusion (150 ng · min−1) for 14 d were subdivided into nine groups as follows: unoperated and untreated controls (n = 5); untreated renovascular hypertension (n = 8); untreated angiotensin II (n = 9); a renovascular hypertension group receiving one of the following doses of lisinopril 20 (n = 8), 2.5 (n = 4), and 0.6 (n = 6) mg · kg−1 · d−1; a renovascular hypertension group receiving losartan (7.5 mg · d−1, n = 4); and an angiotensin II group receiving either the high dose of lisinopril (n = 6) or losartan (n = 4). Treatment was started one day before initiation of renovascular hypertension and angiotensin II infusion and continued throughout the study period. The number and size of necrotic areas and numbers of damaged coronary vessels were determined in sections of right and left ventricular tissue. Results: Both coronary vascular injury and myocyte injury induced by angiotensin II were prevented by losartan. In renovascular hypertension, the lowest dose of lisinopril prevented vascular and attenuated myocyte damage but to a lesser degree than the higher doses. The cardioprotective ability of ACE inhibition is primarily the result of its ability to prevent the conversion of angiotensin I to angiotensin II. Conclusions: Angiotensin II related cardiomyocyte necrosis and coronary vascular damage are angiotensin type 1 receptor mediated and completely preventable with the receptor antagonist losartan. The ability of ACE inhibition to prevent this damage is dose dependent and primarily related to the degree to which the inhibitor can prevent the conversion of angiotensin I to angiotensin II.

The study of DNA damage repair response (DDR) in prostate cancer is restricted by the limited number of prostate cancer cell lines and lack of surrogates for heterogeneity in clinical samples. Here, we sought to leverage our experience with patient derived explants (PDEs) cultured ex vivoto study dynamics of DDR in primary tumors following application of clinically relevant doses of ionizing radiation (IR) to tumor cells in their native 3-dimensional microenvironment. We compared DDR dynamics between prostate cancer cell lines, PDEs and xenograft derived explants (XDEs) following treatment with IR (2Gy) either alone or in combination with pharmacological modulators of DDR. We have shown that following treatment with 2Gy, DDR can be consistently detected in PDEs from multiple solid tumors, including prostate, kidney, testes, lung and breast, as evidenced by γ-H2AX, 53BP1, phospho-ATM and phospho-DNA-PKcs foci. By examining kinetics of resolution of IR-induced foci, we have shown that DDR in prostate PDEs (complete resolution in 8 h) is much faster than in prostate cancer cell lines (<50% resolution in 8 h). The transcriptional profile of DDR genes following 2Gy IR appears to be distinct between PDEs and cell lines. Pre-treatment with drugs targeting DDR pathways differentially alter the kinetics of DDR in the PDEs and cell lines, as evidenced by altered kinetics of foci resolution. This study highlights the utility of PDEs as a robust model system for short-term evaluation of DDR in primary solid tumors in clinically relevant microenvironment.

We introduce the idea of simultaneous heavy precipitation events (SHPEs) to understand whether extreme precipitation has a spatial organization manifested as specified tracks or contiguous fields with inherent scaling relationships. For this purpose, we created a database of SHPEs using ground‐based precipitation observations recorded by the daily Global Historical Climatology Network across the conterminous United States during 1900–2014. SHPEs are examined for their seasonality, spatial manifestation, orientation, and areal extent. We quantified the spatial distribution of the centroids and principal axes of SHPEs and their quasi‐elliptical manifestations, azimuthal orientations, and areal extents on the ground. Four seasons, December‐January‐February (DJF), March‐April‐May (MAM), June‐July‐August (JJA), and September‐October‐November (SON) are considered to examine the spatial patterns and associated large‐scale atmospheric circulations. Results indicate that there are 54, 58, 103, and 204 SHPEs in DJF, MAM, JJA, and SON seasons, and their longest stretches range on average between 650 and 1,600, between 850 and 1,500, between 950 and 1,550, and between 750 and 1,450 km, respectively. SHPEs in the DJF, MAM, and JJA seasons occur mostly over the Pacific coast and central and midwestern United States, respectively. The atmospheric circulation patterns and mechanisms of precipitable water vapor and moisture transport in the atmosphere are also discussed in relation to these SHPEs. Power laws explain SHPEs' underlying area scaling behavior in all the four seasons, with stronger evidence in DJF and MAM. A seasonal spatial risk model is developed to predict the likelihood of SHPEs. Quantifying the characteristics of SHPEs and modeling their footprints can improve the projections of flood risk and understanding of damages to interconnected infrastructure systems. We present a new approach to quantify extreme regional precipitation considering the spatial structure of extreme events. Defined as simultaneous heavy precipitation events (SHPEs), they measure the central location, spatial extent, and the orientation of widespread heavy rains on the land. These characteristics are derived for four seasons over the entire 20th and early 21st centuries (115 years). We interpret the features of SHPEs over the Pacific Coast, Midwest, and the Northeastern United States using a combination of atmospheric circulation and moisture transport features. A seasonal spatial risk model is also developed to identify the probability of any region experiencing SHPEs. The framework and findings presented in this study can help in developing improved flood risk management methods by public/private planners and agencies. The database can be used by the Earth system scientists working on extreme events to explore new avenues of research. The location, area, and orientation of widespread precipitation extremes (SHPEs) vary seasonally and spatially across the United StatesThe longest stretch of SHPEs range on average between 650 and 1,600 km, and the frequency distribution of their areal extents follows a power lawA combination of a strong upper‐level wave and moisture convergence are the most common elements of the atmosphere required for the SHPEs

A patient was referred for coronary artery bypass reoperation. After a left internal mammary artery was grafted to the left anterior descending coronary artery, the diseased but patent old saphenous vein graft was ligated. This resulted in severe myocardial failure, which was corrected only after restoration of flow through the old vein graft. We suggest the decision to ligate or replace an old vein graft should be individualized to avoid the risk of myocardial ischemia.

• The in vitro efficacy of 20 Gy (2000 rad) of external beam irradiation delivered to patients with choroidal melanomas prior to enucleation was investigated in 11 patients whose tumors were grown in cell culture. Phase-contrast microscopy was used to compare growth patterns between irradiated and nonirradiated tumors. Cell types were determined by histologic stains, and electron microscopy identified intracytoplasmic melanin. Irradiated melanomas did not grow and did not attach to culture flasks, thus demonstrating that preenucleation irradiation alters the in vitro growth of melanoma cells.

Blunt chest trauma resulted in a unique cardiac injury, namely, isolated rupture of a mitral papillary muscle causing acute mitral insufficiency. The valve was successfully replaced.

The present investigation was undertaken with an objective of formulating mouth dissolving films (MDFs) of Amlodipine Besylate (AMLO) to enhance convenience and compliance of the elderly and pediatric patients for better therapeutic efficacy. Film formers like hydroxy propyl methyl cellulose (HPMC) and methyl cellulose (MC) along with film modifiers like poly vinyl pyrrolidone K30 (PVP K30), and sodium lauryl sulphate (SLS) as solubilizing agents were evaluated. The prepared MDFs were evaluated for in vitro dissolution characteristics, in vitro disintegration time, and their physicomechanical properties. All the prepared MDFs showed good mechanical properties like tensile strength, folding endurance, and % elongation. MDFs were evaluated by means of FTIR, SEM, and X-RD studies. MDFs with 7.5% (w/w) of HPMC E3 gave better dissolution properties when compared to HPMC E5, HPMC E15, and MC. MDFs with PVP K30 and SLS gave superior dissolution properties when compared to MDFs without PVP K30 and SLS. The dissolution properties of MDFs with PVP K30 were superior when compared to MDFs with SLS. In the case of F3 containing 7.5% of HPMC E3 and 0.04% of PVP K30, complete and faster release was observed within 60?sec when compared to other formulations. Release kinetics data reveals diffusion is the release mechanism.

CMC-544 is an IgG4 CD22-humanized targeted immunoconjugate of calicheamicin. Upon CD22 biding, CMC-544 internalizes inducing cell apoptosis in vitro/in vivo against NHL with minimal modulation of the immune system. In addition to direct cell-death, rituximab, anti-CD20 monoclonal antibody (mAb), can induce complement-dependent cytotoxicity (CDC) and antibody dependent cellular cytotoxicity (ADCC). Combination of mAbs directed against unique tumor-associated targets can potentially enhance anti-tumor activity. Objectives: To study the effects of targeting CD20 and CD22 using rituximab in combination with CMC-544. Material and Methods: For in vitro studies, a panel of NHL cell lines [Raji, SUDHL-4, SU-DHL-10, Ramos, and two rituximab resistant cell lines (RRCL), [2R and 4RH] were exposed to CMC-544 (0.4pg/ml to 0.4μg/ml) +/− Rituximab (10μg/ml) or appropriate controls for 24 or 48 hrs. DNA synthesis was quantified by [H3]Thymidine incorporation and apoptosis was detected by multiparameter flow cytometric analysis and Poly(ADP-ribose) polymerase (PARP) cleavage. For ADCC/CMC studies, 51Cr-labeled NHL cells were exposed to CMC-544 (0.4μg/ml) prior to treatment with rituximab (10mg/ml) and peripheral blood mononuclear cells (Effector: Target ratio 40:1) or human serum, respectively. 51Cr-release was measured and the percentage of lysis was calculated. Statistical analysis of results was performed using the Chi-square test. For in vivo studies, 6–8-week old SCID mice were inoculated via tail vein injection (iv) with Raji cells (1 × 106 on day 0). Animals were assigned to receive 8 doses of either saline, CMC-544 (40μg/kg/dose), rituximab (10mg/kg/dose iv), or rituximab alternating with CMC-544. Antibodies were administered iv every other day starting on day +5. Survival analysis was performed by Kaplan-Meier curves and p values calculated using log rank test. Results: Exposure of various NHL cells to CMC-544 resulted in a dose-dependent significant decrease in cell proliferation and apoptosis. Rituximab-associated CMC or ADCC was not further enhanced by CMC-544 in vitro. In vivo studies demonstrated that the mean survival for animals treated with CMC-544 increased when compared to control mice [64 days (95% C.I. 48–80; 22 days (95% C.I. 21–23), respectively, P=0.001]. To a lesser degree rituximab monotherapy resulted in significant anti-tumor effects and the median survival reached 44 days (95% C.I. 31–56). Notably, animals treated with rituximab in combination with CMC-544 had the longest median survival (not reached at +90 days, log rank P=0.007). Conclusions: Our data suggest targeting CD20 and CD22 by rituximab and CMC-544 resulted in a longer survival in lymphoma-bearing SCID mice. Clinical trials with this combination will be needed to confirm these results for the treatment of lymphoma patients