The costs and benefits of cross-level quality control rules.
Quality is often monitored by multi-rule schemes that are applied at each level of QC material. Cross Level (CL) quality control rules have been proposed but have not been investigated. We used computer simulation to study the impact of CL rules on time to detection and the false positive rate in a system using multirules (3-1s, 2-2s, 4-1s, and 10x) with 2 levels of QC material We also studied the effect of correlation between shifts at each level. The performance of QC policies was compared using simulation analysis. We also compared the detection rates of QC policies (with and without QC rules) using laboratory QC data. Implementing the CL rule increased the false positive rate and increased the detection rate for small shifts (around 1 standard deviation). CL rules had a greater impact when the correlation of shifts between levels was high. CL rules have the potential to increase detection rates, but also increase false positive rates. It is difficult to identify the circumstances where the benefits of increased detection outweigh the costs of false positives. Alternative approaches to QC should be explored.


A new C-terminal located mutation (V272ter) in the PIT-1 gene manifesting with severe congenital hypothyroidism. Possible functionality of the PIT-1 C-terminus.
We describe a newborn with clinical signs of severe hypothyroidism and combined pituitary hormone deficiency due to a new mutation in the PIT-1 gene. Endocrine stimulation test revealed a deficiency for PRL, TSH and GH, suggesting a defect in the pituitary transcription factor PIT-1. Genetic analysis of the PIT-1 gene was performed by exon-specific PCR, followed by SSCP mutation screening and DNA sequencing of the abnormal migrating fragments. DNA sequencing revealed a new mutation (V272ter) in direct neighborhood to a known mutational hot spot (R271W) in the C-terminal part of the PIT-1 molecule. Whereas the R271W mutation has a dominant negative effect on the mutant protein, the newly described mutation is inherited in an autosomal-recessive way. The biological consequences of these two different mutations are discussed.


The semi-annual residency rotation summary: a means to assess the quality of neurosurgical training.
The periodic evaluation of the progress made by the trainees is an adequate means for quality control of a training programme. The combination of the Neurosurgical Log-book and the new Evaluation Sheet allows a comprehensive assessment of the knowledge, progress, as well as the personal and professional development of the individual resident. Upcoming problems can be recognised at an early time point and be corrected immediately. With such periodic supervision the quality of training will improve with time and with experience.


Synthesis and anti-HIV activities of urea-PETT analogs belonging to a new class of potent non-nucleoside HIV-1 reverse transcriptase inhibitors.
A series of potent specific HIV-1 RT inhibitory compounds is described. The compounds are urea analogs of PETT (PhenylEthylThiazoleThiourea) derivatives and the series includes derivatives with an ethyl linker (1-6) and conformationally restricted analogs (7-13). The antiviral activity is determined both at the RT level and in cell culture on both native and mutant forms of HIV-1. Many compounds display activity in the nM range against wt-RT.


Breast cancer early detection by using Fourier-transform infrared spectroscopy combined with different classification algorithms.
Early detection of breast cancer is of great value in improving the prognosis. The current detection methods of breast cancer have their own limitations. In this study, we investigated the feasibility of Fourier Transform Infrared (FT-IR) spectroscopy combined with different classification algorithms for the early detection of breast cancer in a large sample of 526 patients, including 308 invasive breast cancer, 101 ductal carcinoma in situ, and 117 healthy controls. The serum was measured with FT-IR spectroscopy. Kennard-Stone (KS) algorithm was used to divide the data into the training set and testing set. Support vector machine (SVM) model and back propagation neural network (BPNN) model were used to distinguish ductal carcinoma in situ, invasive breast cancer from healthy controls. The accuracies of the SVM model and BPNN model were 92.9% and 94.2%. To determine the effect of different material absorption bands on early detection, the band was divided into four parts including 900-1425 cm-1, 1475-1710 cm-1, 2800-3000 cm-1, and 3090-3700 cm-1, to be modeled and detected respectively. The final results showed that the ranges 900-1425 cm-1 and 1475-1710 cm-1 had superior classification accuracies. The region 900-1425 cm-1 corresponded to the lipids, proteins, sugar, and nucleic acids, and the region 1475-1710 cm-1 corresponded to the proteins. The biochemical substances in other bands also contributed some unique potential to the classification, so the classification accuracy was the best in the full band. The study indicates that serum FT-IR spectroscopy combined with SVM and BPNN models is an effective tool for the early detection of breast cancer.


Severe prolonged hypocalcaemia following pamidronate for malignant hypercalcaemia.
Hypercalcaemia of malignancy is a frequent occurrence. First line treatment of this condition involves the use of bisphosphonates. This report sets out the clinical findings in a patient presenting with metastatic breast cancer and hypercalcaemia (corrected serum calcium 3.72 mmol/l) who had received previous surgery for a parathyroid adenoma. After treatment with pamidronate, profound, prolonged (more than 60 days) symptomatic hypocalcaemia was observed. We discuss the possible explanations for these observations and conclude that a normal parathyroid reserve is probably necessary for the smooth normalization of blood calcium when bisphosphonates are used to treat malignant hypercalcaemia.


(15S)-15-methyl prostaglandin E1-induced neutrophilia in Brown-Norway rats.
A stable analogue of prostaglandin E1, (15S)-15-methyl prostaglandin E1 (M-PGE1), induces a marked relative and absolute neutrophilia after subcutaneous injection at a pharmacologic dose of 1 mg/kg in Brown-Norway rats. The neutrophils reached a peak of 6 hours after injection at which time the absolute neutrophil count was 13,457 +/- 6,038/mm3 versus 2,451 +/- 1,298/mm3 before injection (p less than 0.001). The absolute white blood cell count/mm3 did not change significantly at 6 hours after injection, but a significant eosinopenia was noted, as has been described by previous investigators, after the administration of prostaglandins. A possible physiologic in vivo role for prostaglandin in the causation of neutrophilia remains to be elucidated.


Test for carcinogenicity of organic contaminants of United States drinking waters by pulmonary tumor response in strain A mice.
The production of lung adenomas in strain A following multiple i.p. injections of selected organic water contaminants was investigated. Of the 16 contaminants tested, only bromoform produced a pulmonary adenoma response that was significantly greater than the pulmonary adenoma response of vehicle-treated control mice.


Determination of theophylline bioavailability using saliva theophylline concentrations.
Substantial error occurs when individual saliva theophylline concentrations are used to predict serum theophylline concentrations. However, the use of saliva theophylline concentrations to determine product bioavailability has never been evaluated. Subjects in this study were 18 stable patients (20-51 yr) with a history of chronic obstructive pulmonary disease. Three preparations--a capsule (Elixophyllin 400 mg), elixir (Elixophyllin 373 mg), and tablet (Theolair 375 mg)--were administered in a randomized crossover design. Serum and saliva samples were obtained pre-dose and 0.25, 0.5, 1, 2, 4, 6, and 8 hours after theophylline administration. The saliva AUC0-infinity and serum AUC0-infinity were highly associated for the elixir (r = 0.84) tablet (r = 0.89), and capsule (r = 0.89). The bioavailability of the tablet and capsule calculated from elixir saliva and elixir serum AUC0-infinity were not significantly different (p = 0.2). The bioavailability of the tablet calculated from saliva and serum was 93% and 102%, respectively. The bioavailability of the capsule calculated from saliva and serum was 113% and 102% respectively. Our data suggests that theophylline bioavailability can be reliably estimated from saliva theophylline concentrations. However, study designs that include larger sample sizes and more frequent sampling may be necessary when determining bioavailability from saliva.


Influence of attention focus on neural activity in the human spinal cord during thermal sensory stimulation.
Perceptions of sensation and pain in healthy people are believed to be the net result of sensory input and descending modulation from brainstem and cortical regions depending on emotional and cognitive factors. Here, the influence of attention on neural activity in the spinal cord during thermal sensory stimulation of the hand was investigated with functional magnetic resonance imaging by systematically varying the participants' attention focus across and within repeated studies. Attention states included (1) attention to the stimulus by rating the sensation and (2) attention away from the stimulus by performing various mental tasks of watching a movie and identifying characters, detecting the direction of coherently moving dots within a randomly moving visual field and answering mentally-challenging questions. Functional MRI results spanning the cervical spinal cord and brainstem consistently demonstrated that the attention state had a significant influence on the activity detected in the cervical spinal cord, as well as in brainstem regions involved with the descending analgesia system. These findings have important implications for the detection and study of pain, and improved characterization of the effects of injury or disease.


Factors of non-compliance with the therapeutic regimen among hypertensive men and women: a case-control study to investigate risk factors of stroke.
To identify potential risk factors among the therapeutic regimen and life style which may increase the risk for stroke, a pair matched case-control study was conducted in Gaza Strip among 112 patients, who had been hospitalized for acute stroke and history of hypertension, and 224 controls with history of hypertension. Conditional logistic regression models show significant associations between stroke and medication not taking as prescribed (OR = 6.07; 95% CI: 1.53, 24.07), using excessive salt at meals (OR = 4.51; 95% CI: 2.05, 9.90), eating diet high in fat (OR = 4.67; 95% CI: 2.09, 10.40), and high level of stress (OR = 2.77; 95% CI: 1.43, 5.38). No significant association between smoking and the development of stroke (OR = 2.12; 95% CI: 0.82, 5.51) was found. Regular physical exercise was a protective factor (OR=0.26; 95% CI: 0.12, 0.57). Using excessive salt at meals was a significant risk factor (OR = 16.61; 95% CI: 4.40, 62.80) in people having low level of stress, whereas it was not significant in people having high level of stress. (OR = 1.76; 95% CI: 0.58, 5.33). Smoking in combination with low level of stress was a significant risk factor for stroke (OR = 9.88; 95% CI: 2.52, 38.78), but a non-significant protective factor in combination with high level of stress (OR=0.52; 95% CI: 0.14, 1.99). An increase in compliance with the pharmacological and non-pharmacological therapeutic regimen might be a key to a reduction of stroke incidence and prevalence among hypertensive patients.


Interstitial radiation therapy for early-stage nasal vestibule cancer: a continuing quest for optimal tumor control and cosmesis.
This article reports on the effectiveness, cosmetic outcome, and costs of interstitial high-dose-rate (HDR) brachytherapy for early-stage cancer of the nasal vestibule (NV) proper and/or columella high-dose-rate (HDR). Tumor control, survival, cosmetic outcome, functional results, and costs were established in 64 T1/T2N0 nasal vestibule cancers treated from 1991-2005 by fractionated interstitial radiation therapy (IRT) only. Total dose is 44 Gy: 2 fractions of 3 Gy per day, 6-hour interval, first and last fraction 4 Gy. Cosmesis is noted in the chart by the medical doctor during follow-up, by the patient (visual analog scale), and by a panel. Finally, full hospital costs are computed. A local relapse-free survival rate of 92% at 5 years was obtained. Four local failures were observed; all four patients were salvaged. The neck was not treated electively; no neck recurrence in follow-up was seen. Excellent cosmetic and functional results were observed. With 10 days admission for full treatment, hospital costs amounted to euro5772 (7044 US dollars). Excellent tumor control, cosmesis, and function of nasal airway passage can be achieved when HDR-IRT for T1/T2N0 NV cancers is used. For the more advanced cancers (Wang classification: T3 tumor stage), we elect to treat by local excision followed by a reconstructive procedure. The costs, admission to hospital inclusive, for treatment by HDR-IRT amounts to euro5772 (7044 US dollars). This contrasts substantially with the full hospital costs when NV cancers are treated by plastic reconstructive surgery, being on average threefold as expensive.


Biofilm inhibiting properties of compounds from the leaves of Warburgia ugandensis Sprague subsp ugandensis against Candida and staphylococcal biofilms.
Warburgia ugandensis Sprague subspecies ugandensis is a plant widely distributed in Eastern, Central and Southern Africa. In humans, it is used to treat respiratory infections, tooth aches, malaria, skin infections, venereal diseases, diarrhea, fevers and aches. This study aims to identify the bioactive compounds against clinically important biofilm-forming strains of Candida and staphylococci that are responsible for tissue and implanted device-related infections. Using a bioassay-guided fractionation approach, hexane -, ethanol -, acetone - and water extracts from the leaves of W. ugandensis, their subsequent fractions and isolated compounds were tested against both developing and preformed 24 h-biofilms of Candida albicans SC5314, Candida glabrata BG2, Candida glabrata ATCC 2001, Staphylococcus epidermidis 1457 and Staphylococcus aureus USA 300 using microtiter susceptibility tests. Planktonic cells were also tested in parallel for comparison purposes. Confocal scanning laser microscopy was also used to visualize effects of isolated compounds on biofilm formation. Warburganal, polygodial and alpha-linolenic acid (ALA) were the major bioactive compounds isolated from the acetone extract of W. ugandensis. For both warburganal and polygodial, the biofilm inhibitory concentration that inhibits 50% of C. albicans developing biofilms (BIC50) was 4.5 ± 1 and 10.8 ± 5 μg/mL respectively. Against S. aureus developing biofilms, this value was 37.9 ± 8 μg/mL and 25 μg/mL with warburganal and ALA respectively. Eradication of preformed 24 h biofilms was also observed. Interestingly, synergy between the sesquiterpenoids and azoles against developing C. albicans biofilms resulted in an approximately ten-fold decrease of the effective concentration required to completely inhibit growth of the biofilms by individual compounds. The hydroxyl group in position C-9 in warburganal was identified as essential for activity against staphylococcal biofilms. We also identified additional promising bioactive sesquiterpenoids; drimenol and drimendiol from the structure-activity relationship (SAR) studies. ALA and four sesquiterpenoids: polygodial, warburganal, drimenol and drimendiol, have shown biofilm-inhibitory activity that has not been reported before and is worth following up. These compounds are potential drug candidates to manage biofilm-based infections, possibly in combination with azoles.


A multiwire microelectrode for single unit recording in deep brain structures.
A method is described by which a single shaft multiwire microelectrode can be fabricated efficiently. The resulting electrode can be attached to a commercial microdrive and used for single neuronal unit recording from one or more tracks in deep brain structures of anesthetized or awake animals. The electrode consists of a 30 gauge stainless steel cannula through which multiple strands of 13 micron insulated tungsten microwires are threaded. At the electrode tip the wires protrude 3-4 mm from the cannula and are cut individually at suitable offsets. The tip is stabilized and fixed to the cannula with cyanoacrylate. At the base of the electrode the wires are threaded through flexible plastic tubing that provides strain relief and are glued to individual pins of a miniature connector that plugs into a field effect transistor (FET) voltage follower. Good single unit recordings have been obtained routinely from the basal ganglia of awake, behaving monkeys with this electrode.


[Parkes-Weber syndrome and pregnancy: anaesthetic implications].
We report two deliveries in a patient with a Parkes-Weber syndrome. This parturient had a complex angiodysplasia including a soft tissue hypertrophy of a lower limb, a cutaneous angioma and arteriovenous malformations. The risk of perimedullar arteriovenous malformations was ruled out by angiographic magnetic resonance imaging of the spinal cord. We also describe other aspects of the management, including prepartum cardiovascular assessment, mode of delivery, the use of epidural analgesia and the prevention of haemorrhagia and thromboembolism.


Folic acid deficiency in intensive care patients: comparison between two regimens of supplementation.
Serum folic acid (SFA) and red blood cell folic acid (RbcFA) levels were determined in 40 patients on the day of admission to our intensive care unit (ICU, D0). 65% of the patients had low SFA (< 3,4 ng/ml) and 27.5% had low RbcFA (< 275 ng/ml)L. Twenty-four hours later (Day 1:D1), both SFA and RbcFA had decreased significantly (respectively 0.49 ng/ml and 21 ng/ml, p < 0.01) in the 40 patients; the magnitude of RbcFA decrease was greater in patients with sepsis than in those without sepsis (p < 0.02). SFA and RbcFA levels were significantly lower in patients with sepsis on D0 and D1. Forty-two other patients with documented hypofolatemia were then randomly allocated to two regimens of FA supplementation. Patients on regimen A had an intravenous injection of 0.5 mg folinic acid daily for ten days whereas patients on regimen B received a single 5 mg intravenous injection of FA on day 1. Both regimens increased significantly SFA and RbcFA levels. But regimen A should be recommended because 1) RbcFA levels were significantly higher than with regimen B (p < 0.05) and 2) the mean increase was higher, particularly in patients with initial sepsis (p < 0.01).


Energy-Adjusted Dietary Inflammatory Index and Diabetes Risk in Postmenopausal Hispanic Women.
Type 2 diabetes is a major public health concern in the United States and worldwide. The dietary inflammatory index (DII) and the energy-adjusted DII (E-DII) are tools that assess dietary inflammation. Previous evidence suggests that obesity can modify the association between inflammation and disease. The aim of this study was to evaluate the association between the DII/E-DII and incident diabetes in self-identified Hispanic women from the Women's Health Initiative (WHI). The secondary aim was to evaluate whether obesity modifies the association between the DII/E-DII scores and incident diabetes. Participants were from the WHI Observational Study and the Clinical Trial Components (except women from the treatment arm in the Dietary Modification Trial) conducted among postmenopausal women in the United States. DII/E-DII scores were calculated from a self-administered food frequency questionnaire at baseline that included 122 food items, of which 12 are representative of Hispanic eating patterns. Participants included 3,849 postmenopausal women who self-identified as Hispanic that were recruited for the WHI from 1993 to 1998 at 40 US clinical centers. The outcome was incident diabetes. Cox regression models were used to assess the association between DII/E-DII and incident diabetes. Models were adjusted for age at baseline, lifestyle-related risk factors, known type 2 diabetes mellitus (T2DM) risk factors, and neighborhood socioeconomic status. Interaction was tested between the DII/E-DII scores and obesity. The incidence of diabetes was 13.1% after a median follow-up of 13 years. Higher E-DII scores were associated with a higher risk of incident diabetes (hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.04-1.14). There was no interaction between E-DII scores and obesity (P = 0.73). Pro-inflammatory diets, as measured by higher E-DII scores, were associated with a higher risk of incident diabetes. Future research is needed for understanding how the inflammatory potential of diets can be decreased.


Post-annealing effect on the electronic structure of Mn atoms in Ga(₁-x)Mn(x)As probed by resonant inelastic x-ray scattering.
The electronic structure of as-grown and post-annealed Ga(₁-x)Mn(x)As epilayers (x≈0.055) has been investigated using resonant inelastic x-ray scattering. Mn L₂,₃ x-ray emission spectra show that the integral intensity ratio of Mn L₂ to L₃ emission lines increases with annealing temperature and comes close to that of manganese oxide. The oxygen K-emission/absorption spectra of post-annealed Ga₀.₉₄₅Mn₀.₀₅₅As show 1.5-3.0 times higher degree of oxidation on the film surface than that of the as-grown sample. These experimental findings are attributed to the diffusion of Mn impurity atoms from interstitial positions in the GaAs host lattice to the surface where they are passivated by oxygen.


Characterizing the biomechanical differences between novice and expert point-of-care ultrasound practitioners using a low-cost gyroscope and accelerometer integrated sensor: A pilot study.
Point-of-care ultrasound (POCUS) has become an important diagnostic tool in acute care medicine; however, little is known about the biomechanical differences between novice and expert practitioners. A low-cost ($50 CAD) gyroscope and accelerometer integrated sensor was assembled and affixed to an ultrasound probe. Seventeen participants, nine novices and eight experts, were recruited to perform three abdominal and four cardiac scans on a standardized patient. Participant demographics, time per scan, average acceleration, average angular velocity, decay in acceleration and angular velocity over time, and frequency of probe movements were analyzed. Video capture with blinded video review was scored. On video review, experts had higher image optimization and acquisition scores for both abdominal and cardiac scans. Experts had shorter scan times for abdominal (7 s vs. 26 s, p = 0.003) and cardiac (11 s vs. 26 s, p < 0.001) scans. There was no difference in average acceleration (g) between novices and experts performing abdominal (1.02 vs. 1.01, p = 0.50) and cardiac (1.01 vs. 1.01, p = 0.45) scans. Experts had lower angular velocity (°/s) for abdominal scans (10.00 vs. 18.73, p < 0.001) and cardiac scans (15.61 vs. 20.33, p = 0.02) There was a greater decay in acceleration over time for experts performing cardiac scans compared to novices (-0.194 vs. -0.050, p = 0.03) but not for abdominal scans or when measuring angular velocity. The frequency of movements (Hz) was higher for novices compared to experts for abdominal (16.68 vs. 13.79, p < 0.001) and cardiac (17.60 vs. 13.63, p = 0.002) scans. This study supports the feasibility of a low-cost gyroscope and accelerometer integrated sensor to quantify the biomechanics of POCUS. It may also support the concept of "window shopping" as a method by which experts obtain abdominal and cardiac views, where sliding is used to find an acoustic window, then smaller rocking and tilting probe movements are used to refine the image.


Mutualistic interaction of native Serratia marcescens UENF-22GI with Trichoderma longibrachiatum UENF-F476 boosting seedling growth of tomato and papaya.
A plethora of bacteria-fungal interactions occur on the extended fungal hyphae network in soil. The mycosphere of saprophytic fungi can serve as a bacterial niche boosting their survival, dispersion, and activity. Such ecological concepts can be converted to bioproducts for sustainable agriculture. Accordingly, we tested the hypothesis that the well-characterised beneficial bacterium Serratia marcescens UENF-22GI can enhance plant growth-promoting properties when combined with Trichoderma longibrachiatum UENF-F476. The cultural and cell interactions demonstrated S. marcescens and T. longibrachiatum mutual compatibility. Bacteria cells were able to attach, forming aggregates to biofilms and migrating through the fungal hyphae network. Long-distance bacterial migration through growing hyphae was confirmed using a two-compartment Petri dishes assay. Fungal inoculation increased the bacteria survival rates into the vermicompost substrate over the experimental time. Also, in vitro indolic compound, phosphorus, and zinc solubilisation bacteria activities increased in the presence of the fungus. In line with the ecophysiological bacteria fitness, the bacterium-fungal combination boosted tomato and papaya plantlet growth when applied into the plant substrate under nursery conditions. Mutualistic interaction between mycosphere-colonizing bacterium S. marcescens UENF-22GI and the saprotrophic fungi T. longibrachiatum UENF-F467 increased the ecological fitness of the bacteria alongside with beneficial potential for plant growth. A proper combination and delivery of mutual compatible beneficial bacteria-fungal represent an open avenue for microbial-based products for the biological enrichment of plant substrates in agricultural systems.


Modification of diet in renal disease and Cockraft-Gaultformula accuracy in glomerular filtration rate estimation in Iranian adults.
The aim of this study was to evaluate the accuracy of modification of diet in renal disease (MDRD) and Cockraft-Gault (C-G) formulas for estimating GFR in a sample of Iranian adult. This study was an analytic cross-sectional study on 54 patients with chronic kidney disease. Glomerular filtration rate was measured by kidney scan via TC99m-labeled diethylenetriaminepentaacetic acid, and it was estimated by MDRD and Cockraft-Gault formulas. The mean of measured GFR and estimated GFR by MDRD and C-G formulas was 61.64 ± 34.26 ml/min, 51.80 ± 25.47, and 54.29 ± 24 ml/min respectively (P-value < 0.001, r = 0.818 and P-value < 0.001, r = 0.847, respectively). Pearson correlation test showed direct linear relationship between sGFR and GFR as estimated by the Cockraft-Gault and MDRD formulas. Based on our results, modification of diet in renal disease (MDRD) and Cockraf-Gault (C-G) formulas are accurate formulas in Iranian adults but they need a correction factor.


Proteolipid and bovine aorta calcification, in vitro.
Proteolipid was examined for nucleation of bovine aorta calcification. Tissue homogenates were tested for in vitro calcifiability before and after lipid extraction followed by similar tests of the extract and its fractions. The tissue calcified before but not after lipid extraction. Of the lipid fractions, only proteolipid calcified. Within the constraints imposed, proteolipid is required for initiation of bovine aorta calcification, in vitro.


Complex Ebstein's malformation: defining preoperative cardiac anatomy and function.
Ebstein's malformation is a congenital malformation of the tricuspid valve and right ventricle, with a highly variable morphology, and clinical presentation, accounting for less than 1% of all congenital heart diseases, and about 40% of congenital malformations of the tricuspid valve. Systematic review of English language literature regarding the morphogenesis and progress of imaging techniques, especially echocardiography and cardiac magnetic resonance imaging, in the preoperative planning of Ebstein's malformation, using the MEDLINE database with the PubMed Entre interface. Technological developments of the recent years, with 3D echocardiographic and cardiac magnetic resonance imaging evolution, have resulted in better understanding of the malformed tricuspid valve and right ventricle in vivo anatomy. Through a better understanding of Ebstein's malformation, there is a continuous trend of surgical techniques favoring tricuspid valve sparing procedures, with a constant decrease in early and late postoperative mortality. Although imaging methods to investigate Ebstein's malformation have continuously evolved, standardization of assessment protocols by 3D echocardiographic imaging, speckle tracking imaging, and cardiac magnetic resonance imaging is required.


Fiber-optic sensor for iodine based on a covalently immobilized aminobenzanthrone Schiff base.
An aminobenzanthrone Schiff base has been synthesized as a new fluorescence carrier for the preparation of an optical chemical sensor for iodine. The response of the sensor is based on fluorescence quenching of the aminobenzanthrone Schiff base by iodine. The sensor shows a linear response toward iodine in the range of 1.0 x 10(-5) to 1.0 x 10(-3) mol l(-1), with a detection limit of 6.0 x 10(-6) mol l(-1) at pH 8.0. Leaching of the fluorophore from the membrane is effectively hindered by covalent immobilization, resulting in an enhanced sensor lifetime. In addition to satisfactory reproducibility and reversibility, the prepared sensor exhibits sufficient selectivity toward iodine with respect to other coexisting ions. The sensor has been applied to the determination of iodine in common salt samples.


Synthesis and evaluation of potent and selective human V1a receptor antagonists as potential ligands for PET or SPECT imaging.
SRX246 is a potent, highly selective human vasopressin V1a antagonist that crosses the blood-brain barrier in rats. CNS penetration makes SRX246 an ideal candidate for potential radiolabeling and use in visualization and characterization of the role of the V1a receptor in multiple stress-related disorders. Before radiolabeling studies, cold reference analogs of SRX246 were prepared. This study describes the synthesis and in vitro screening for human V1a receptor binding and permeability of fluoro, iodo, and methyl reference compounds for SRX246 and the preparation of a tin precursor. For each compound, the potential utility of corresponding radiolabeled analogs for PET and SPECT imaging is discussed.


A sequential treatment of intermediate tropical landfill leachate using a sequencing batch reactor (SBR) and coagulation.
The increase in landfill leachate generation is due to the increase of municipal solid waste (MSW) as global development continues. Landfill leachate has constantly been the most challenging issue in MSW management as it contains high amount of organic and inorganic compounds that might cause pollution to water resources. Biologically treated landfill leachate often fails to fulfill the regulatory discharge standards. Thus, to prevent environmental pollution, many landfill leachate treatment plants involve multiple stages treatment process. The Papan Landfill in Perak, Malaysia currently has no proper leachate treatment system. In the current study, sequential treatment via sequencing batch reactor (SBR) followed by coagulation was used to treat chemical oxygen demand (COD), ammoniacal nitrogen (NH3-N), total suspended solids (TSS), and colour from raw landfill leachate. SBR optimum aeration rate, L/min, optimal pH and dosage (g/L) of Alum for coagulation as a post-treatment were determined. The two-step sequential treatment by SBR followed by coagulation (Alum) achieved a removal efficiency of 84.89%, 94.25%, 91.82% and 85.81% for COD, NH3-N, TSS and colour, respectively. Moreover, the two-stage treatment process achieved 95.0% 95.0%, 95.3%, 100.0%, 87.2%, 62.9%, 50.0%, 41.3%, 41.2, 34.8, and 22.9 removals of Cadmium, Lead, Copper, Selenium, Barium, Iron, Silver, Nickel, Zinc, Arsenic, and Manganese, respectively.


Recovery rate of NTM from AFB smear-positive sputum specimens at a medical centre in South Korea.
To investigate the recovery rate of non-tuberculous mycobacteria (NTM) from acid-fast bacilli (AFB) smear-positive sputum specimens at a tertiary care medical centre in South Korea with a high pulmonary tuberculosis (PTB) burden. Retrospective analysis of data from AFB smear- and culture-positive sputum specimens collected between January 1998 and December 2001. Over 4 years, 1328 sputum specimens collected from 616 patients were AFB smear- and culture-positive. NTM were recovered from 9.1% (121/1328) of the smear-positive sputum specimens, and from 8.1% (50/616) of patients with smear-positive sputum. NTM were isolated at least twice in 94% (47/50) of the patients from whom NTM was recovered. The most common organism found was Mycobacterium avium complex, followed by M. abscessus. These results suggest that a substantial proportion of patients at a tertiary care medical centre in South Korea with AFB smear-positive sputum specimens may have NTM lung disease rather than PTB.


Cognitive Frailty in Older People with Type 2 Diabetes Mellitus: the Central Role of Hypoglycaemia and the Need for Prevention.
To highlight the central role of hypoglycaemia in the causation of cognitive frailty and explore ways of recognition and prevention of hypoglycaemia. Cognitive frailty is an emerging new concept defined as the concomitant presence of physical frailty and cognitive impairment. In older people with diabetes, cognitive frailty is associated with an increased risk of mortality greater than from either physical frailty or cognitive impairment alone. Hypoglycaemia is directly associated with increased risk of cognitive impairment and physical frailty which are the two components of cognitive frailty. The incidence of hypoglycaemia in older people with diabetes is rising and hypoglycaemia-related hospitalisation has overtaken that of hyperglycaemia. Recognition of hypoglycaemic episodes in old age remains challenging which leads to misdiagnoses and under-reporting. Therefore, hypoglycaemia prevention strategies are needed. Research is still required to investigate whether prevention of hypoglycaemia would lead to a reduction in the incidence of cognitive frailty.


Practical limitations of the Deltatrac indirect calorimeter.
Indirect calorimetry is used to assess energy requirements. The Deltatrac Metabolic Monitor is a relatively inexpensive indirect calorimeter which uses a 'fixed' flow of ambient air to collect expired air. Only oxygen and carbon dioxide concentrations are measured and the 'fixed flow' is assumed in the calculation of oxygen consumption ((.)VO(2)) and carbon dioxide production ((.)VCO(2)). Using inert gas dilution we have studied the effect on (.)VO(2), and on the variability in (.)VO(2), of changing and lengthening the 1.77 m length of 35 mm tubing supplied with the instrument to collect expired air, and of using a mask to collect expired air instead of the manufacturer's hood. One would anticipate that changing the tubing could cause a change in resistance to gas flow and thus affect the true flow rate. This would alter the gas concentrations seen by the analysers, but the 'fixed flow' would still be assumed so the results would be in error. Adding extra lengths of manufacturers tubing caused an apparent rise in (.)VO(2) of 0.36%/m of tubing added, and using 22 mm tubing instead of the manufacturer's 35 mm tubing increased (.)VO(2) by 0.42% for each 10 cm of tubing added. Using the mask to collect expired air instead of the canopy (.)VO(2) was higher, possibly due to the energy cost of holding the mask, and was more variable, probably because of poorer mixing of the expired air. To measure (.)VO(2) using a mask with the same precision as a 10 min measurement made with the hood would entail measuring (.)VO(2) for 14.5 min. The methods used to collect expired air (mask or canopy, length and type of tubing) when measuring metabolic rate with the Deltatrac do affect the results obtained but these effects are small and predictable.


Basal cell carcinoma: response to systemic chemotherapy for lung carcinoma.
Two patients had regression of basal cell carcinoma while receiving systemic chemotherapy for carcinoma of the lung. The chemotherapeutic agents with some efficacy in basal cell carcinoma are reviewed. Based on our patients and data from the literature, cisplatin appears to be a drug of potential usefulness in some patients with this neoplasm.


Depressive Symptom Trajectories Among People Living with HIV in a Collaborative Care Program.
Depressive symptoms may differ in severity and change over time in people living with HIV (PLWH). Describing depression trajectories and associated clinical characteristics of PLWH in an interventional study may help in developing a more personalized medicine approach. Using latent class growth analysis four, 15-month self-reported depression trajectories were identified in 416 PLWH participating in a collaborative care program. The four subgroups were characterized by improving (58.4% [of participants]), worsening (9.4%), highly responsive (19.5%) and persistently severe (12.7%) depressive symptoms. A high proportion of individuals were in trajectories marked by improvement. Further, the highly responsive group had on average, over 50% reduction of self-reported depressive symptoms. Self-reported trauma, posttraumatic stress disorder, lower neighborhood-level education and fewer HIV and psychiatry clinic visits were associated with worsening or persistently severe depressive symptom trajectories. Members of the persistently severe group were less likely to be virally suppressed after 12-months. Identifying subgroups of PLWH based on changes in self-reported depressive symptoms may further inform intervention approaches that can advance care.


The prevalence and real-world therapeutic analysis of Chinese patients with KRAS-Mutant Non-Small Cell lung cancer.
Kirsten rat sarcoma viral oncogene homolog (KRAS) is an important driver gene of non-small cell lung cancer (NSCLC). Despite a rapid progress achieved in the targeted therapy, chemotherapy remains the standard treatment option for patients with KRAS-mutant NSCLC. This study aimed to assess real-world data of Chinese patients with KRAS-mutant NSCLC undergoing chemotherapy and/or immunotherapy. KRAS mutational status was analyzed using next-generation sequencing of 150,327 NSCLC patients from the Lung Cancer Big Data Precise Treatment Collaboration Group (LANDSCAPE) project (Cohort I). Treatment data were collected and analyzed retrospectively from 4348 NSCLC patients who were admitted to the Peking University Cancer Hospital and Institute between January 2009 and October 2020 (Cohort II). In Cohort I, 18,224 patients were detected with KRAS mutations (12.1%) of whom G12C (29.6%) was the most frequent subtype, followed by G12D (18.1%) and G12V (17.5%). In case of concomitant mutations, TP53 had the highest incidence of 33.6%, followed by EGFR (11.6%), STK11 (10.4%), KEAP1(6.2%), and CDKN2A (6.0%). Cohort II included 497 patients (11.4%) with KRAS mutations. In the first-line chemotherapeutic analysis of Cohort II, patients benefited more from the pemetrexed/platinum (PP) regimen than the gemcitabine/platinum (GP) or taxanes/platinum (TP) regimen (median progression-free survival [PFS], 6.4 vs. 4.9 vs. 5.6 months, hazard ratio [HR] = 0.65, 95% confidence interval [CI] 0.48-0.88, p = 0.033 and HR = 0.69, 95% CI 0.47-1.00, p = 0.05, respectively), with no significant difference when combined with bevacizumab. Regarding patients who received immune checkpoint inhibitors (ICIs), the objective response rate was 26% for a median PFS of 9.6 months (95% CI 6.16-13.03). Patients who received ICIs combined with chemotherapy had a significantly longer survival than monotherapy (median PFS, 13.9 vs. 5.2 months, HR = 0.59, 95% CI 0.35-0.99, p = 0.049). KRAS is an important driver gene in NSCLC, compromising 12.1% in this study, and G12C was noted as the most common subtype. Patients with KRAS-mutant NSCLC could benefit from pemetrexed-based chemotherapy and ICIs.


The rheology of silicone rubber impression materials.
A selection of silicone rubber impression materials were studied for their rheological properties prior to and following mixing. The techniques used were a cone and plate viscometer and a capillary viscometer. All the impression materials were found to show pseudoplastic behaviour which is readily described by a power law function. For the mixed materials the onset of molecular entanglement, whilst theoretically establishing the absolute end of the working time, gave a gross overestimate of the clinical working time. The capillary viscometer is more useful than the cone and plate viscometer in providing information on the clinical working time.


TLR4 mutations (Asp299Gly and Thr399Ile) are not associated with ankylosing spondylitis.
Immunoregulatory genes and Gram negative gut bacteria are thought to be important in disease expression in ankylosing spondylitis (AS). To compare the frequency of two common and functional TLR4 mutations (Asp299Gly, and Thr399Ile) between patients with AS and HLA-B27 healthy controls. The TLR4 genotypes of patients and healthy HLA-B27 controls were determined using allele-specific PCR and restriction fragment length polymorphism analysis. Asp299Gly genotype was determined in 193 patients and 125 HLA-B27 positive controls and Thr399Ile genotype in 184 patients and 113 HLA-B27 controls. Allele frequencies were compared using a chi(2) test of association. 29/193 (15%) patients with AS had a polymorphism in the Asp299 site compared with 18/125 (14.4%) healthy HLA-B27 controls. Of the patients genotyped for the Thr399Ile allele, 29/184 (15.8%) carried the polymorphism compared with 19/113 (16.8%) HLA-B27 controls. No significant difference between the frequencies of the Asp299Gly genotype or the Thr399Ile genotype between patients with AS and healthy HLA-B27 controls was found. No significant difference in allele frequency was found at either site. Two common TLR4 polymorphisms, which cause a functional deficiency in host immune response to Gram negative bacteria, are not overrepresented in patients with AS.


Enhanced circulating soluble LR11 in patients with diabetic retinopathy.
To investigate the relationship of circulating levels of soluble form of LR11 (sLR11; also called SorLA or SORL1), with the progression of proliferative diabetic retinopathy (PDR) in patients with type 2 diabetes mellitus. Cross-sectional study. Fifty-four patients with type 2 diabetes mellitus were divided into 2 sex- and age-matched groups: one with PDR (n = 29) and the other with nonproliferative diabetic retinopathy (n = 25). The serum sLR11 levels were measured with an immunodetection system followed by chemifluorescence quantification. The serum sLR11 levels were higher in the PDR group than in the nonproliferative diabetic retinopathy group (5.8 ± 1.2 U vs 3.7 ± 1.3 U; P < .01). A multivariate regression analysis showed that circulating sLR11 is a factor contributing to the prediction of PDR independent of other classical risk factors, and an area under the receiver operating characteristic curve analysis revealed that the sensitivity and the specificity were equivalent to or more than those of other factors. Among the classical risk factors for PDR, glycosylated hemoglobin levels showed the highest correlation coefficient (P < .01) for the sLR11 concentrations. Serum sLR11 concentration may reflect the progression of PDR in patients with type 2 diabetes mellitus. sLR11, released from immature vascular cells and indicating the development of atherosclerosis, is expected to be a novel candidate biomarker indicating diabetic retinopathy in patients with type 2 diabetes mellitus.


Analytical approaches to the study of monoclonal antibody stability.
The stability of two purified monoclonal antibodies, MN12 and WT31, was investigated. The monoclonal antibodies were incubated for 32 days at different pH values (ranging from 3.0 to 10.0) at 4 and 37 degrees C. Various analytical methods were used to assess changes in physicochemical properties of the proteins. The monoclonal antibodies were more susceptible to degradation at 37 degrees C than at 4 degrees C. At low pH irreversible precipitation occurred. Decomposition of the proteins was enhanced at increasing pH values in the alkaline range. This was concluded from mouse IgG-specific and antigen-specific enzyme-linked immunosorbent assays, flow cytometry, analytical gel permeation chromatography, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, isoelectric focusing, and immunoblotting. No substantial change in the apparent affinity constant of MN12 was observed, as determined by an affinity enzyme-linked immunosorbent assay. Fluorescence spectra, fluorescence polarization values, and fluorescence quenching parameters of MN12 and WT31 were not substantially affected, indicating that no major irreversible conformational changes had occurred. It was concluded that each of the techniques used has only limited value for stability assessment of monoclonal antibodies and, hence, that the application of several analytical techniques is essential to gain insight into monoclonal antibody stability.


Cariogenic effect of caffeine intake during lactation on first molars of newborn rats.
Lactating dams with eight suckling pups were fed either a 20% protein diet as a control or experimentally a 20% protein diet supplemented with caffeine (2 mg/100g body weight) from the birth of the pups to day 22. At day 22, the pups from both groups were weaned and fed a cariogenic diet until day 50, when they were killed. Dental caries of the molars were scored from randomized mandibles. The enamel of the first molars in the caffeine group showed significantly higher caries scores than that of the controls. This appears to be the first unequivocal evidence that caffeine is a cariogenic agent when newborns are exposed to it during critical periods of tooth development. Therefore, the widespread human consumption of caffeine could be a threat to the healthy development of teeth.


Prolonged action of drugs in rats with flavonoid-deficiency.
In flavonoid-deficient Wistar-rats, the action of caffeine, harmine, hexobarbital, morphine and pentobarbital is enhanced. In contrast, the thiopental sleeping time is shortened. These observations may indicate impaired drug metabolism as a consequence of the flavonoid-deficiency state.


Left ventricular apical aneurysm due to unrecognized sarcoidosis.
A 47-year-old woman was hospitalized for syncope. An electrocardiogram showed complete right bundle branch block and T-wave inversion in leads III, aVF, and V2-4. Cardiac catheterization was performed since the echocardiogram demonstrated the existence of a left ventricular apical aneurysm and apical thrombus. Coronary angiography revealed normal coronary arteries. An endomyocardial biopsied specimen from the right ventricular apical wall demonstrated typical noncaseating granulomas with giant cells. There was no evidence suggesting the involvement of other systemic organs. The patient was diagnosed as having cardiac sarcoidosis. Cardiac sarcoidosis should be considered within a spectrum of diseases that cause left ventricular apical aneurysm.


An assumption-free quantitative polymerase chain reaction method with internal standard.
In real-time quantitative polymerase chain reaction (PCR), the standard curve between threshold cycle and logarithm of template concentration is currently the gold standard for template quantification. The efficacy of this approach is limited by the necessary assumption that all samples are amplified with the same efficiency. To overcome this limitation, a new method has been proposed in this contribution for quantitative PCR with internal standard. Unlike existing methods based upon analysis of amplification profile position, the new method tries to determine the initial quantity of the target template in a sample from the fluorescence spectrum measured at a certain point during its PCR reaction. There is no unrealistic prerequisite (e.g., constant amplification efficiency) for the successful application of the new method. The performance of the new method was evaluated by the quantification of KRAS gene in HepG2 samples. Quantitative results with recovery rates in the range of 91.2-118% were achieved by the new method. It is reasonable to expect that the new method would have a place in real-time quantitative PCR, thanks to its features of no unrealistic prerequisite, sound theoretical basis, good performance, and implementation simplicity.


Informed consent and patient videotaping.
To determine whether videotaping consent forms used in family medicine residencies meet the criteria for informed consent, adhere to published guidelines for videotaping patients, and are written at a suitable reading level. Three reviewers independently evaluated videotaping consent forms obtained from 20 family practice residencies to determine whether they included the elements of informed consent and conformed to published guidelines for ethical videotaping. The reading level of each consent form was also determined using a standardized assessment. Depending on the reviewer, only one to three of the 20 consent forms were judged adequate in providing a patient with enough information to make an informed choice. Specific aspects of voluntariness were absent from most of the forms. In addition, the reading level was, on average, well above recommended levels for patient comprehension. Most of the videotaping consent forms analyzed in this study did not provide adequate information to assist patients in making a voluntary, informed choice to be videotaped. The absence of this information raises the potential for violations of patient privacy and confidentiality.


The development of the sweat and sebaceous glands in the skin of the one-humped camel (Camelus dromedarius).
The sweat gland primordium appeared as a solid bud from the ental side of the epithelial cords of the growing hair follicles in the CRL 36 cm-fetus from the primary hair follicles and in the CRL 64 cm-fetus from the secondary ones. In the CRL 68 cm-fetus the glands were tubular with a slight curving of their lower third, which became convoluted at the CRL 83 cm-stage. At the latter age, clear myoepithelial cells were observed in the secretory portion as also in the duct. The buds of the sebaceous glands could be observed in the CRL 45 cm-fetus from the primary hair follicles and in the CRL 68 cm-fetus from the secondary ones. At the CRL 83 cm-fetal stage, the branched glands were elongated in shape and opened into the follicles by two separated ducts, united at the hair canal. The glands were in function nearly from its early development.


[Symptoms of asbestos-related diseases and correction of hemodynamic and ventilation changes in asbestosis patients].
The authors present results of thorough examination of asbestosis and dust bronchitis patients, features of dust load and X-ray functional changes, efficiency of physical therapy complexes in correcting cardio-pulmonary syndrome.


Transfer dynamics of macroplastics in estuaries - New insights from the Seine estuary: Part 2. Short-term dynamics based on GPS-trackers.
The dynamics of plastic debris were assessed in the Seine River, especially in the estuary, using plastic bottles equipped with GPS-trackers. In one year, 50 trajectories were recorded, covering a wide range of hydrometeorological conditions. Results show a succession of stranding/remobilization episodes in combination with alternating upstream and downstream transport in the estuary. In the end, 100% of the tracked bottles stranded somewhere, for hours or weeks, from one to several times at different sites. The overall picture shows that different physical phenomena interact with various time scales ranging from hours/days (high/low tides) to weeks/months (spring/neap tides and highest tides) and years (seasonal river flow). Thus, the fate of plastic debris is highly unpredictable, but the consequence of those interactions is that the transfer of debris is chaotic and not straightforward, and its residence time is much longer than the transit time of water.


[Receptor virus-cell interactions as an initial stage of infection].
The overview analyzes an update on and current concepts of the initial stage of viral infection of sensitive cells. It considers the nature of virus receptors, the mechanisms of virus-receptor interaction, methodical approaches to identifying the receptor role of cell molecules for various viruses, and the association of the initial stage of viral infection with its subsequent ones.


Modulation of Brain Transcriptome by Combined Histone Deacetylase Inhibition and Plasma Treatment Following Traumatic Brain Injury and Hemorrhagic Shock.
We previously showed that the addition of valproic acid (VPA), a histone deacetylase inhibitor, to fresh frozen plasma (FFP) resuscitation attenuates brain lesion size and swelling following traumatic brain injury (TBI) and hemorrhagic shock (HS). The goal of this study was to use computational biology tools to investigate the effects of FFP+VPA on the brain transcriptome following TBI+HS. Swine underwent TBI+HS, kept in shock for 2 h, and resuscitated with FFP or FFP + VPA (n = 5/group). After 6 h of observation, brain RNA was isolated and gene expression was analyzed using a microarray. iPathwayGuide, Gene Ontology (GO), Gene-Set Enrichment Analysis, and Enrichment Mapping were used to identify significantly impacted genes and transcriptomic networks. Eight hundred differentially expressed (DE) genes were identified out of a total of 9,118 genes. Upregulated genes were involved in promotion of cell division, proliferation, and survival, while downregulated genes were involved in autophagy, cell motility, neurodegenerative diseases, tumor suppression, and cell cycle arrest. Seven hundred ninety-one GO terms were significantly enriched. A few major transcription factors, such as TP53, NFKB3, and NEUROD1, were responsible for modulating hundreds of other DE genes. Network analysis revealed attenuation of interconnected genes involved in inflammation and tumor suppression, and an upregulation of those involved in cell proliferation and differentiation. Overall, these results suggest that VPA treatment creates an environment that favors production of new neurons, removal of damaged cells, and attenuation of inflammation, which could explain its previously observed neuroprotective effects.


Treatment of systemic sclerosis.
Systemic sclerosis (SSc) is a rare connective tissue disease characterized by skin and visceral fibrosis, vascular hyperreactivity and obliterative vasculopathy. Some of its complications such as interstitial lung disease (ILD), pulmonary arterial hypertension (PAH) and heart involvement can be life-threatening and are associated with a high mortality and a poor prognosis. Many clinical trials were carried out in order to improve the survival and prognosis of SSc patients. The management of SSc is based on the frequent and regular assessment of the potential organ damage, and if present, the establishment of graduated pharmacological therapeutic strategies, associated with non-pharmacological procedures. Several randomized clinical trials have showed significant positive outcomes regarding some specific involvements. Many advances have been made, especially in the field of targeted therapies and personalized medicine, based on specific characteristics of the patient and the SSc.


[Transfusion and sickle cell disease].
Sickle cell disease is a hereditary pathology of the haemoglobin which affects only individuals from African ancestry. The frequency of the disease increases in France. Transfusion remains a major treatment of this disease. Depending of the indication, transfusion can be a simple transfusion or an exchange transfusion. In this last case, exchange can be performed manually or automatically. The transfusion protocols have to be adapted to the polytransfused status of these patients, but also to the high incidence of alloimmunisation against red blood cells. Alloimmunisation is a consequence of the polymorphism of blood groups between sickle cell disease patients and donors of European ancestry. Axes to optimize transfusion safety in these patients have to be developed. But the first step relies on the promotion of blood donation within individuals of African ancestry.


Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes.
Novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) tirzepatide demonstrated substantially greater glucose control and weight loss (WL) compared with selective GLP-1RA dulaglutide. Explore mechanisms of glucose control by tirzepatide. Post hoc analyses of fasting biomarkers and multiple linear regression analysis. Forty-seven sites in 4 countries. Three hundred and sixteen subjects with type 2 diabetes. Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), placebo. Analyze biomarkers of beta-cell function and insulin resistance (IR) and evaluate WL contributions to IR improvements at 26 weeks. Homeostatic model assessment (HOMA) 2-B significantly increased with dulaglutide and tirzepatide 5, 10, and 15 mg compared with placebo (P ≤ .02). Proinsulin/insulin and proinsulin/C-peptide ratios significantly decreased with tirzepatide 10 and 15 mg compared with placebo and dulaglutide (P ≤ .007). Tirzepatide 10 and 15 mg significantly decreased fasting insulin (P ≤ .033) and tirzepatide 10 mg significantly decreased HOMA2-IR (P = .004) compared with placebo and dulaglutide. Markers of improved insulin sensitivity (IS) adiponectin, IGFBP-1, and IGFBP-2 significantly increased by 1 or more doses of tirzepatide (P < .05). To determine whether improvements in IR were directly attributable to WL, multiple linear regression analysis with potential confounding variables age, sex, metformin, triglycerides, and glycated hemoglobin A1c was conducted. WL significantly (P ≤ .028) explained only 13% and 21% of improvement in HOMA2-IR with tirzepatide 10 and 15 mg, respectively. Tirzepatide improved markers of IS and beta-cell function to a greater extent than dulaglutide. IS effects of tirzepatide were only partly attributable to WL, suggesting dual receptor agonism confers distinct mechanisms of glycemic control.


Pancreatic lithostathine as a calcite habit modifier.
Most biological fluids are supersaturated with calcium salts. A mechanism controlling crystal growth is therefore necessary to prevent excessive precipitation and development of a lithiasis. In pancreatic juice, calcite precipitation is prevented by lithostathine, a glycoprotein that inhibits calcite crystal growth. We describe here the interaction of lithostathine with calcite crystals. Without lithostathine, calcite crystals grew as rhombohedra showing six (104) faces. At low concentration (1 microM), lithostathine already altered crystal growth by generating new (110) faces. At physiological concentrations (3-10 microM), adsorption resulted in a transition from rhombohedral to sub-cubic habits. Immunochemical localization demonstrated that, although all (104) faces are equivalent, lithostathine binding was restricted to the face edges distal to the c axis. Scanning electron microscopy showed that, at the site of lithostathine binding, spreading of new CaCO3 layers during crystal growth was arrested before reaching the crystal diad axis-bearing edges. The successive kinks generated during crystal growth formed the new, striated (110)faces. Similar modifications were observed with the N-terminal undecapeptide of lithostathine that bears the inhibitory activity. With 100 microM lithostathine, (110) faces could reach the c axis outcrop of the former rhombohedron, resulting in an olive-shaped crystal. Finally, the number of crystals increased and their average size decreased when lithostathine concentration increased from 0.1 to 100 microM. Decreased Ca2+ concentration during crystal growth was delayed in the presence of lithostathine. It was concluded that lithostathine controls lithogenesis 1) by triggering germination of numerous calcite crystals and 2) by inhibiting the rate of Ca2+ ion apposition on the nuclei and therefore interfering with the apposition of new layers on calcite. Formation of smaller crystals, whose elimination is easier, is thereby favored.


Predictors of psychosis severity in individuals with primary stimulant addictions.
The goal of this study is to define the factors that could contribute to the development, severity, and persistence of psychotic symptoms in individuals with stimulant addiction. We hypothesize that particular drug use variables may contribute to the severity of psychiatric symptoms. Thirty-seven stimulant users, abstinent for >30 days were recruited from the community. Previous drug use and current and past psychiatric symptoms were assessed using validated objective rating scales and several self-report questionnaires. Age at first use of the stimulant drug was inversely related to the Beck Anxiety Inventory score, and the subjects with more than 5 years duration of chronic use exhibited greater severity of symptoms on the PANSS Positive and General Scales and total score. The method of drug administration, duration of abstinence, latency from first use to regular use, and prior solicitation of treatment were not related to PANSS total and subscale scores or other clinical variables. Severity of psychosis appears to be related to earlier and longer exposure to stimulants, consistent with a "threshold" effect of stimulant use on the development of psychotic symptoms. The association may also suggest a critical developmental period that is most susceptible to the deleterious effects of stimulant exposure.


Short stature and functional impairment: a systematic review.
To review the available evidence on the association between primary short stature and intellectual and physical dysfunction among children. Systematic searches were performed through October 2001 of English-language studies of children with short stature and functional limitations. Included studies evaluated children with isolated short stature, constitutional growth delay, growth hormone deficiency, or multiple hormone deficiency. Evaluated outcomes included intelligence, academic achievement, visual-motor skills, psychomotor development, and behavior problems. Eleven studies evaluated academic achievement, and 22 evaluated intelligence. No substantial deviation from normal was seen among short children, but many studies found that children with short stature had significantly lower intelligence and academic achievement scores than controls. Three studies found significant visual-motor skill reduction among short children. One study of psychomotor development found a delay in meeting early developmental landmarks among children with Russell-Silver syndrome. Five studies evaluating teacher-rated behavior found that short children had no more behavior problems than controls. While, on average, children with short stature score lower than their peers on functional tests, few short children scored outside the normal range. Furthermore, there is no evidence to explain the cause of any deficits, and limited data suggest that treatment of short stature does not improve children's functional status. Nevertheless, treatment may be warranted in children with severe short stature to alleviate restrictions on activities of daily living. Further research focusing on physical limitations due to short stature is needed to address these issues.


Germline mitochondrial DNA mutations aggravate ageing and can impair brain development.
Ageing is due to an accumulation of various types of damage, and mitochondrial dysfunction has long been considered to be important in this process. There is substantial sequence variation in mammalian mitochondrial DNA (mtDNA), and the high mutation rate is counteracted by different mechanisms that decrease maternal transmission of mutated mtDNA. Despite these protective mechanisms, it is becoming increasingly clear that low-level mtDNA heteroplasmy is quite common and often inherited in humans. We designed a series of mouse mutants to investigate the extent to which inherited mtDNA mutations can contribute to ageing. Here we report that maternally transmitted mtDNA mutations can induce mild ageing phenotypes in mice with a wild-type nuclear genome. Furthermore, maternally transmitted mtDNA mutations lead to anticipation of reduced fertility in mice that are heterozygous for the mtDNA mutator allele (PolgA(wt/mut)) and aggravate premature ageing phenotypes in mtDNA mutator mice (PolgA(mut/mut)). Unexpectedly, a combination of maternally transmitted and somatic mtDNA mutations also leads to stochastic brain malformations. Our findings show that a pre-existing mutation load will not only allow somatic mutagenesis to create a critically high total mtDNA mutation load sooner but will also increase clonal expansion of mtDNA mutations to enhance the normally occurring mosaic respiratory chain deficiency in ageing tissues. Our findings suggest that maternally transmitted mtDNA mutations may have a similar role in aggravating aspects of normal human ageing.


Effects of Anti-Diabetic Drugs on Fracture Risk: A Systematic Review and Network Meta-Analysis.
Available data on the effects of anti-diabetic drugs on fracture risk are contradictory. Therefore, our study aimed to analyze all available data on the effects of anti-diabetic drugs on fracture risk in type 2 diabetes mellitus (T2DM) patients. Embase, Medline, ClinicalTrials.gov, and Cochrane CENTRAL were searched for relevant trials. All data analyses were performed with STATA (12.0) and R language (3.6.0). Risk ratio (RR) with its 95% confidence interval (CI) was calculated by combining data for the fracture effects of anti-diabetic drugs, including sodium-glucose co-transporter 2 (SGLT2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, meglitinides, α-glucosidase inhibitors, thiazolidinediones, biguanides, insulin, and sulfonylureas. One hundred seventeen eligible randomized controlled trials (RCTs) with 221,364 participants were included in this study. Compared with placebo, trelagliptin (RR 3.51; 1.58-13.70) increased the risk of fracture, whereas albiglutide (RR 0.29; 0.04-0.93) and voglibose (RR 0.03; 0-0.11) decreased the risk of fracture. Other medications were comparable in terms of their effects on fracture risk, and no statistical significance was observed. In terms of fractures, voglibose (0.01%) may be the safest option, and trelagliptin (13.64%) may be the worst. Sensitivity analysis results were consistent with those of the main analysis. No statistically significant differences were observed in the regression coefficients of age (1.03; 0.32-2.1), follow-up duration (0.79; 0.27-1.64), and sex distribution (0.63; 0.15-1.56). We found varied results on the association between the use of anti-diabetic drugs and fracture risk. Specifically, trelagliptin raised the risk of fracture, whereas voglibose and albiglutide showed benefit with statistical difference. Other drugs were comparable in terms of their effects on fracture risk. Some drugs (omarigliptin, sitagliptin, vildagliptin, saxagliptin, empagliflozin, ertugliflozin, rosiglitazone, pioglitazone, and nateglinide) may increase the risk of fracture, while others (such as dulaglutide, exenatide, liraglutide, semaglutide, lixisenatide, linagliptin, alogliptin, canagliflozin, dapagliflozin, glipizide, gliclazide, glibenclamide, glimepiride, metformin, and insulin) may show benefits. The risk of fracture was independent of age, sex distribution, and the duration of exposure to anti-diabetic drugs. When developing individualized treatment strategies, the clinical efficacy of anti-diabetic drugs must be weighed against their benefits and risks brought about by individual differences of patients. This Systematic Review was prospectively registered on the PROSPERO (https://www.crd.york.ac.uk/PROSPERO/, registration number CRD42020189464).


Simultaneous myocardial revascularization and ascending aorta to femoral-artery bypass grafting.
In this report a case is described where simultaneous myocardial revascularization and ascending to femoral bypass grafting was performed for severe coronary artery disease and impending gangrene of the foot.


The case for wider use of recombinant factor VIII concentrates.
The introduction of clotting factor concentrates led to major advances in hemophilia care. Rather than simply providing an alternative to plasma-derived concentrates, the introduction in the 1990s of recombinant concentrates added value to replacement therapy particularly with respect to prophylaxis and immune-tolerance induction. While the safety of plasma-derived concentrates has improved considerably, these concentrates may still pose an infectious risk through as-yet unknown pathogens and poor impurity constituent characterization. Recombinant concentrates are increasingly used because of their benefits in pathogen safety, convenience and the potential for unfettered supply. Yet worldwide they remain accessible only to a limited number of patients due to fear of the potential for inhibitor development, overestimation of their costs and underestimation of their benefits. This article reviews the characteristics and properties of recombinant FVIII concentrates to help physicians and patient representatives promote the right of access of patients to the safest products.


Optimal flow sensor placement on wastewater treatment plants.
Obtaining high quality data collected on wastewater treatment plants is gaining increasing attention in the wastewater engineering literature. Typical studies focus on recognition of faulty data with a given set of installed sensors on a wastewater treatment plant. Little attention is however given to how one can install sensors in such a way that fault detection and identification can be improved. In this work, we develop a method to obtain Pareto optimal sensor layouts in terms of cost, observability, and redundancy. Most importantly, the resulting method allows reducing the large set of possibilities to a minimal set of sensor layouts efficiently for any wastewater treatment plant on the basis of structural criteria only, with limited sensor information, and without prior data collection. In addition, the developed optimization scheme is fast. Practically important is that the number of sensors needed for both observability of all flows and redundancy of all flow sensors is only one more compared to the number of sensors needed for observability of all flows in the studied wastewater treatment plant configurations.


Metal-insulator transition in films of doped semiconductor nanocrystals.
To fully deploy the potential of semiconductor nanocrystal films as low-cost electronic materials, a better understanding of the amount of dopants required to make their conductivity metallic is needed. In bulk semiconductors, the critical concentration of electrons at the metal-insulator transition is described by the Mott criterion. Here, we theoretically derive the critical concentration nc for films of heavily doped nanocrystals devoid of ligands at their surface and in direct contact with each other. In the accompanying experiments, we investigate the conduction mechanism in films of phosphorus-doped, ligand-free silicon nanocrystals. At the largest electron concentration achieved in our samples, which is half the predicted nc, we find that the localization length of hopping electrons is close to three times the nanocrystals diameter, indicating that the film approaches the metal-insulator transition.


[Practical approach to recurrent benign paroxysmal positional vertigo].
Benign paroxysmal positional vertigo is the most common vestibular disorder and it has a significant impact on health-related quality of life. The disease is probably caused by the accumulation of lithiasis material from the otolithic membrane of the utricle. Patients experience multiple short vertigo crises lasting seconds when they go to bed or turn over. There are several clinical variants affecting posterior, horizontal or anterior canals and in some cases vestibular lithiasis can occur in two canals simultaneously. Diagnosis is by video-oculographic recording of positional nystagmus during positional tests to identify the canal affected. There are specific treatment manoeuvres for each clinical variant, which a high degree of short-term effectiveness.


Liver regeneration following partial hepatectomy is improved by enhancing the HGF/Met axis and Akt and Erk pathways after low-power laser irradiation in rats.
A simple, easy, and safe procedure aiming to improve liver regeneration could be of great clinical benefit in critical situations such as major hepatectomy, trauma, or hemorrhage. Low-power laser irradiation (LPLI) has come into a wide range of use in clinical practice by inducing regeneration in healthy and injured tissues. However, the effect of LPLI on the process of liver regeneration, especially those related to the molecular mechanisms, is not fully understood. Thus, the aim of the present study was to investigate the main molecular mechanisms involved in liver regeneration of partially hepatectomized rats exposed to LPLI. We used Wistar male rats, which had their remaining liver irradiated or not with LPLI (wavelength of 632.8 nm and fluence of 65 mW/cm(2)) for 15 min after a 70% hepatectomy. We subsequently investigated hepatocyte growth factor (HGF), Met, Akt, and Erk 1/2 signaling pathways through protein expression and phosphorylation analyses along with cell proliferation (proliferating cell nuclear antigen (PCNA) and Ki-67) using immunoblotting and histological studies. Our results show that LPLI can improve liver regeneration as shown by increased HGF protein expression and the phosphorylation levels of Met, Akt, and Erk 1/2 accompanied by higher levels of the PCNA and Ki-67 protein in the remnant livers. In summary, our results suggest that LPLI may play a clinical role as a simple, fast, and easy-to-perform strategy in order to enhance the liver regenerative capacity of a small liver remnant after hepatectomy.


Trends in HeartMate 3: What we know so far.
The HeartMate 3 left ventricular assist device (LVAD) is a novel, intrapericardial, centrifugal-flow pump with a fully magnetically-levitated rotor designed to provide hemodynamic support in patients with end-stage heart failure. Unique aspects of this LVAD have allowed for improved hemocompatibility and the development of minimally-invasive implantation techniques. The PubMed, EMBASE, and Google Scholar databases were searched for publications relating to the HeartMate 3 device, with a focus on hemocompatibility related outcomes, anticoagulation management, and surgical techniques. Nine articles analyzing hemocompatibility related outcomes from two clinical trials, two clinical studies, and one registry series were identified. HeartMate 3 has reduced the rate of disabling stroke and pump thrombosis. However, despite increased hemocompatibility due to specialized design features, the residual risk of both surgical, and gastrointestinal bleeding remains a major adverse outcome. Different anticoagulation management and surgical techniques have been evaluated to address the remaining complications.


Specific staining of 9h in human somatic interphase cells by D 287/170.
Somatic interphase cells from males and females with normal karyotypes and with variants of the heterochromatic regions on chromosomes 9 and Y were stained with the fluorochrome D 287/170. The results showed that only 9h retained the ability to stain with D 287/170 in the interphase state, whereas 15ph and Yqh lost the specific staining pattern seen in metaphase. The number and size of the specific stained interphase bodies correlated with the ploidy of the cell population and the size of the 9h as seen in metaphase.


Osteoprotegerin inactivation accelerates advanced atherosclerotic lesion progression and calcification in older ApoE-/- mice.
Osteoprotegerin (OPG), a member of the tumor necrosis factor (TNF) superfamily of proteins, plays an important role in bone remodeling and is expressed in both mouse and human atherosclerotic lesions. The current study was designed to assess whether OPG plays a role in the progression and calcification of advanced atherosclerotic lesions in apoE(-/-) mice. Atherosclerotic lesion area and composition and aortic calcium content were examined in mice deficient in both OPG and apolipoprotein E (OPG(-/-).apoE(-/-) mice) at 20, 40, and 60 weeks of age. Littermate OPG(+/+).apoE(-/-) mice were used as controls. The average cross-sectional area of lesions in the innominate arteries was increased in OPG(-/-).apoE(-/-) mice at 40 and 60 weeks of age. The increase in lesion area was coupled with a reduced cellularity and an increase in connective tissue including laminated layers of elastin. Sixty-week-old OPG(-/-).apoE(-/-) mice also had an increase in the area of calcification of the lesions. There were no differences in markers of plaque stability. In vitro, OPG induced matrix metalloproteinase-9 (MMP-9) activity in macrophages and smooth muscle cells and acted as a survival factor for serum-deprived smooth muscle cells. OPG inhibits advanced plaque progression by preventing an increase in lesion size and lesion calcification. OPG may act as a survival factor and may modulate MMP9 production in vascular cells.


Crystal structure of a purine/pyrimidine phosphoribosyltransferase-related protein from Thermus thermophilus HB8.
Adenine phosphoribosyltransferase (APRTase) is a widely distributed enzyme involved in the salvage of adenine to form an adenine nucleotide. We crystallized and determined the X-ray crystallographic structure of a purine/pyrimidine phosphoribosyltransferase-related protein from the thermophilic bacterium, Thermus thermophilus HB8. The crystal space group was C2 with unit cell dimensions of a = 167.42 A, b = 61.41 A, c = 102.39 A, beta = 94.0 degrees . Initial phases were determined to 2.6 A using the multiple wavelength anomalous dispersion method and selenomethionine substituted protein (Se-MAD), and refined using a 1.9 A "native" data set. The asymmetric unit contains two pairs of identical dimers, each related by noncrystallographic two-fold symmetry. The fifth monomer forms a similar dimer across a crystallographic two-fold axis. These dimers appear to be the biological unit with both monomers contributing to an unusual highly charged arginine-rich bridge region separating the two active sites. Comparison with distantly related APRTases reveal similarities and differences of the active site.


CNTF induces Clcf1 in astrocytes to promote the differentiation of oligodendrocyte precursor cells.
NSCs play an essential role in the regeneration process of the central nervous system. However, due to the influence of the harsh pathological microenvironment, the viability of neural stem cells is limited, and the therapeutic effect needs improvement. Previous studies have found that stem cells overexpressing ciliary neurotrophic factor (CNTF) have apparent therapeutic effects on remyelination, but the specific mechanism of action still needs to be further explored. We found that astrocytes, the most numerous groups in the CNS, exhibited a pathological role in the experimental autoimmune encephalomyelitis model, but after stimulation with CNTF-NSCs, a phenotypic switch occurred and induced the neurotrophic factor cardiotrophin-like cytokine 1 (Clcf1) production. Mechanistically, Clcf1 can significantly promote the differentiation of oligodendrocyte precursor cells (OPCs), and the advanced effect can attenuate by the Clcf1 antibody. Therefore, this study was conducted to investigate the pathway by which CNTF-NSCs exert their therapeutic effects by affecting astrocytes. It is expected to identify a potential therapeutic factor, Clcf1, for the treatment of demyelinating diseases.


Behaviors of N-ethyl perfluorooctane sulfonamide ethanol (N-EtFOSE) in a soil-earthworm system: Transformation and bioaccumulation.
N-ethyl perfluorooctane sulfonamido ethanol (N-EtFOSE) is a typical precursor of perfluorooctane sulfonate (PFOS). In this study, the behaviors of N-EtFOSE in a soil-earthworm system, including biodegradation in soil and bioaccumulation and biotransformation in earthworms (Eisenia fetida) were investigated. N-EtFOSE could be biodegraded in soil and biotransformed in earthworms to several metabolites, including n-ethylperfluorooctane sulfonamide acetate (N-EtFOSAA), perfluorooctane sulfonamide acetate (FOSAA), perfluorooctane sulfonamide (FOSA) and PFOS, with N-EtFOSAA as the predominant intermediate and PFOS as the terminal product in both soil and earthworm. The uptake rate coefficients (ku, 0.746 goc gdw(-1)d(-1)), degradation rate constant in soil (k0, 0.138 d(-1)) and the biota-to-soil accumulation factor (BSAF, 0.523 goc gdw(-1)) of N-EtFOSE were estimated. For N-EtFOSE, N-EtFOSAA, FOSAA, FOSA and PFOS, their loss rate constants in earthworms were in the range of 0.467-30.2 (α) and 0.006-0.415 (β) d(-1), respectively. The results provided important information about the behaviors of N-EtFOSE in the soil-earthworm system.


The Effect of Timing on the Treatment and Outcome of Combined Fourth and Fifth Carpometacarpal Fracture Dislocations.
In this study, we designed a prospective project to test the hypothesis that acute fourth and fifth carpometacarpal (CMC) fracture dislocations can be treated conservatively with good restoration of strength, range of motion (ROM), and function, whereas patients with delayed treatment of fourth and fifth CMC fracture dislocations should be treated with open reduction and internal fixation (ORIF). We evaluated the results of 20 patients with acute and 6 patients with subacute fourth and fifth CMC fracture dislocations. All 20 acute CMC fracture dislocations were treated conservatively, whereas 3 of the 6 patients with subacute injuries underwent operative intervention. The sensibility, ROM, and grip strength of the hands were tested during 1-year follow-up. The Michigan Hand Outcomes Questionnaire and control radiographs were also taken. All 20 patients with acute CMC fracture dislocations showed good restoration of grip strength, ROM, and function, with an average Michigan Hand Outcomes Questionnaire score of 98 ± 2 at 1-year follow-up. Patients with delayed diagnosis who underwent conservative treatment had noticeable deformity of their injured hands, pain complaints, limited ROM at the fourth and fifth CMC joints, and decreased grip strength. The 3 patients with delayed diagnosis treated with ORIF showed good restoration of grip strength, ROM, and function. Patients with acute CMC fracture dislocations can be treated by closed reduction with good restoration of grip strength, ROM, and function. In patients with delayed presentation of CMC fracture dislocations, we recommend ORIF. Therapeutic IV.


Expression analysis of circulating miR-22, miR-122, miR-217 and miR-367 as promising biomarkers of acute lymphoblastic leukemia.
The role of serum-based biomarkers such as microRNAs in cancer diagnosis has been extensively established. This study aimed to determine the expression levels of bioinformatically selected miRNAs and whether they can be used as biomarkers or a new therapeutic target in patients with acute lymphoblastic leukemia (ALL). The expression levels of serum miR-22, miR-122, miR-217, and miR-367 in 21 ALL patients and 21 healthy controls were measured using quantitative real-time PCR. The receiver operating characteristic (ROC) curve and the associated area under the curve (AUC) was used to assess candidate miRNAs' diagnostic value as a biomarker. The results showed that miR-217 was markedly decreased in patients with ALL compared to controls. Moreover, miR-22, miR-122, and miR-367 were found to be upregulated. Furthermore, ROC analysis showed that serum miR-217 and miR-367 could differentiate ALL patients from healthy individuals, while miR-22 has approximate discriminatory power that requires further investigation. These results provide promising preliminary evidence that circulating miR-217 and miR-367 could be considered potent diagnostic biomarkers and therapeutic goals in this disease.


Reducing Smoking Cessation Disparities: Capacity for a Primary Care- and Technology-Based Approach Among Medicaid Recipients.
While cigarette use among U.S adults has recently decreased, vulnerable subgroups continue to smoke at high rates, including individuals receiving Medicaid insurance. These individuals have also experienced treatment access disparities, highlighting the need for approaches that leverage their strong desire to quit. We conducted interviews with 100 adult primary care patients receiving Medicaid who were current tobacco users about their use, openness to technology-based interventions, and readiness to change. Most (92%) reported current cigarette use and readiness to change averaged 6.98 out of 10 (SD = 2.82). Nearly all were open to completing an iPad-based tobacco screening (95%) and brief intervention (90%) at their next appointment, while 91% and 88% were willing to talk with their provider or a cessation counselor, respectively, about the subsequent results. Results persisted across age, sex, and race/ethnicity. Openness to technology-based interventions in this population provides support for future work that may ultimately reduce disparities.


Genome screen for a combined bone phenotype using principal component analysis: the Framingham study.
Genetic factors substantially contribute to variation in bone mass. There is a controversy as to whether shared genetic factors exist for bone mass at different sites. We hypothesize that using a composite phenotypic score of several correlated bone mass measures may provide complementary results for linkage studies. In the members of 323 pedigrees from the Framingham Osteoporosis Study, bone mineral density (BMD) was measured at the lumbar spine and three femoral sites (Lunar DPX-L), and quantitative ultrasound (QUS) measured at the calcaneus (Hologic Sahara). Data on age, sex, anthropometry, alcohol and caffeine intake, smoking status, physical activity, menopause, and estrogen use (in females) were also obtained. Principal component analyses of BMD and QUS phenotypes were performed in each sex and generation (parents and offspring). The principal component analyses yielded two components, whose loadings were extracted as principal component scores (PC1 and PC2) for each individual, with PC1 explaining up to 66% of the total variation of all bone mass measurements, and PC2 an additional 24%. Principal component analysis of the three femoral BMD measures resulted in one component (PC_hip) that explained 89-91% of the common variation of hip BMD measures. Quantitative genetic analysis (using the variance components method) revealed that both principal component scores were under significant genetic influences (covariate-adjusted heritabilities of PC1, PC2, and PC_hip were 0.66 +/- 0.07, 0.44 +/- 0.07, and 0.61 +/- 0.06, respectively). For PC1, loci of suggestive linkage were identified on chromosomes 1q21.3 and 8q24.3 with the maximum multipoint LOD scores 2.5 and 2.4, respectively. For PC2, multipoint LOD score was 2.1 on 1p36. Suggestive linkage of PC_hip was found on 8q24.3 and 16p13.2 (LODs>1.9). In conclusion, an approach to linkage analysis using the linear combination of several correlated bone phenotypes suggests that there are chromosomal loci regulating bone mass, with seemingly pleiotropic effects at different skeletal sites.


Multiple-locus VNTR Analyses of Methicillin-resistant Staphylococcus aureus from Jamaica.
This study assessed the antimicrobial susceptibilities and the presence of inducible macrolide-lincosamide-streptogramin B (iMLSB) resistance in methicillin-resistant Staphylococcus aureus (MRSA) of Jamaica as well as the relatedness using polymerase chain reaction-based staphylococcal cassette chromosome mec (SCCmec) and multiple-locus variable numbers of tandem repeat analyses (MLVAs). Antimicrobial susceptibility, the presence of MLSB resistance, and SCCmec and MLVA patterns were assessed for 61 nonduplicate isolates of MRSA from hospitalized patients. While no isolate was resistant to vancomycin, 53 (86.9%) isolates were resistant to ciprofloxacin, 52 (85.3%) to erythromycin, 49 (80%) to lincomycin, and 45 (74%) to clindamycin. Of the 52 erythromycin-resistant isolates, 48% exhibited constitutive resistance and 8% showed inducible MLSB (iMLSB) resistance. Most (85%) of typable isolates were SCCmec type IV, and among these, 16 MLVA patterns were identified. Multidrug resistance continues to characterize MRSA. Among the erythromycin-resistant isolates, constitutive resistance and iMLSB resistance are common. These facts will complicate the treatment of MRSA infections and warrant continued surveillance and judicial use of antimicrobial agents.


Oxidation of dicyano-bis(1,10 phenanthroline) iron(II) by compounds I and II of cytochrome c peroxidase.
The apparent bimolecular rate constant for the oxidation of dicyano-bis(1,10 phenanthroline) iron(II) by compound II of cytochrome c peroxidase (ferrocytochrome c; hydrogen-peroxide oxidoreductase EC 188.8.131.52) has been measured over the pH range 2.5-11.0 at 0.1 M ionic strength, 25 degrees C, by the stopped-flow technique. An ionizable group in the enzyme, with a pKa of 4.5, strongly influences the electron transfer rate between the ferrous complex and the oxidized site in the enzyme. The electron transfer is fastest when the group is protonated, with a rate constant of 2.9 - 10-5 M--1 - s-1. The rate constantdecreases over three orders of magnitude when the proton dissociates. The apparent bimolecular rate constant for the oxidation of the ferrous complex by compound I of cytochrome c peroxidase was determined between pH 3.5 and 6. Under all conditions where this rate constant could be measured it was about three times larger than that for the oxidation by compound II.


Partial deletion of the X chromosome in gonadal dysgenesis 46,X,del(X)(p22) identified by BudR treatment.
In this report we describe a deletion of the short arm of the X chromosome in a 16-year-old female with gonadal dysgenesis. The breakpoint was localized by BUdR treatment and acridine orange staining in region 2, band 2. Of the examined cells, 3% showed an early replication of the deleted X chromosome.


Isolation of baculovirus-expressed human vitamin D receptor: DNA responsive element interactions and phosphorylation of the purified receptor.
Two controversial aspects in the mechanism of human vitamin D receptor (hVDR) action are the possible significance of VDR homodimers and the functional role of receptor phosphorylation. To address these issues, milligram quantities of baculovirus-expressed hVDR were purified to 97% homogeneity, and then tested for binding to the rat osteocalcin vitamin D responsive element (VDRE) via electrophoretic mobility shift and half-site competition assays in the presence or absence of a CV-1 nuclear extract containing retinoid X receptor (RXR). Methylation interference analysis revealed that both the hVDR homodimer and the VDR-RXR heterodimer display similar patterns of VDRE G-base protection. However, in competition studies, the relative dissociation of the homodimeric hVDR complex from the VDRE was extremely rapid (t1/2 < 30 s) compared to the dissociation of the heteromeric complex (t1/2 > 5 min), thus illustrating the relative instability and low affinity of homodimeric VDR binding to DNA. These results indicate that VDR-RXR heterodimers are the preferred VDRE binding species. Further, two dimensional gel electrophoresis of hVDR demonstrated several isoelectric forms of the receptor, suggesting that it is subject to multiple phosphorylation events. In vitro kinase assays confirmed that purified hVDR is an efficient substrate for protein kinases A and Cbeta, as well as casein kinase II. In vivo studies of the expressed receptor in intact cells, namely baculovirus vector infected Sf9 insect cells and transfected mammalian COS-7 cells, demonstrated that hVDR was phosphorylated in a hormone-enhanced fashion. Functional consequences of hVDR phosphorylation were suggested by the observations that: (i) potato acid phosphatase (PAP)-treated hVDR no longer interacted with the VDRE as either a homodimer or a heteromeric complex with RXR, and (ii) treatment of transfected COS-7 cells with a phosphatase inhibitor (okadaic acid) along with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) resulted in a synergistic enhancement of both hVDR phosphorylation and transactivation of a VDRE-linked reporter gene, compared to the effect of treatment with either agent alone. These studies point to a significant role for phosphorylation of VDR in regulating high-affinity VDR-RXR interactions with VDREs, and also in modulating 1,25(OH)2D3-elicited transcriptional activation in target cells.


Adenosine antagonists prevent hypoxia-induced depression of excitatory but not inhibitory synaptic currents.
Hypoxia induces depression of excitatory postsynaptic currents (EPSCs) and inhibitory postsynaptic currents (IPSCs) in CA1 neurons of the hippocampus. The effect of antagonists that act at the A1 adenosine receptor on hypoxia-induced depression of EPSCs and IPSCs were examined in hippocampal slices with the patch clamp technique (whole-cell configuration). The A1 receptor antagonists 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (200 nM) and 8-phenyltheophilline (8-PT) (10 microM) significantly prevented depression of EPSCs by hypoxia but failed to protect IPSCs. This result suggests that the hypoxia-induced depression of the EPSC involves the activation of adenosine receptors (possibly of the A1 subtype), whereas depression of the IPSC results from a different mechanism.


Diagnostic accuracy of bimanual palpation in bladder cancer patients undergoing cystectomy: A prospective study.
To prospectively assess the concordance of examination under anesthesia (EUA)-based clinical T stage with pathological T stage and diagnostic accuracy of EUA in patients with bladder cancer undergoing cystectomy. Consecutive patients with bladder cancer undergoing cystectomy between June 2017 and October 2020 in a single academic center were included in a prospective study. Two urologists performed EUA (one blinded to imaging) before patients underwent cystectomy. We assessed the concordance between clinical T stage in bimanual palpation (index test) and pathological T stage in cystectomy specimens (reference test). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated with 95% confidence intervals (CIs) to detect or exclude locally advanced bladder cancer (pT3b-T4b) in EUA. The data of 134 patients were analyzed. Given that stage pT3a cannot be palpated, for the nonblinded examiner, T staging in EUA was concordant with pT in 107 (79.9%) patients, 20 (14.9%) cases being understaged in EUA and 7 (5.2%) overstaged. For the blinded examiner, staging was correct in 106 (79.1%) patients, 20 (14.9%) cases being understaged and 8 (6%) overstaged. For the nonblinded examiner, sensitivity, specificity, PPV, and NPV of EUA were 55.9% (95% CI 39.2%-72.6%), 93% (88%-98%), 73.1% (56%-90.1%), and 86.1% (79.6%-92.6%), respectively; for the blinded examiner, they were 52.9% (36.2%-69.7%), 93% (88%-98%), 72% (54.4%-89.6%) and 85.3% (78.7%-92%), respectively. Awareness of imaging results did not have a major impact on EUA results. Bimanual palpation should still be used for clinical staging, given its specificity, NPV, and that it could correctly determine bladder cancer T stage in 80% of cases.


Trophic availability buffers the detrimental effects of clogging in an alpine stream.
Clogging, the streambed colmation by fine sediments, is an important widespread source of impact affecting freshwaters. Alterations in stream morphology and hydrology, added to the effects of global climate change, are responsible for this phenomenon, that is particularly pernicious in mountainous lotic systems naturally characterized by coarse substrates. Among the studies investigating this issue some were descriptive, while others used artificial substrates to compare ongoing fine sediment accumulation and macroinvertebrate assemblage recruitment. Other studies used from the outset artificial substrates arranged with different levels of clogging. Our study fits into this line, but adding an innovative element simulating different availability of coarse particulate organic matter, i.e. the main trophic input in low-order, mountainous stream. To investigate how clogging and CPOM can influence macroinvertebrate communities, we placed 135 artificial substrates in the upper Po river (NW Italy). We set up a three way factorial design with three different levels of sedimentation and terrestrial leaf material. Artificial substrates were removed on three different dates. Benthic invertebrates were identified and classified according to their bio-ecological traits. We also measured macroinvertebrate dry mass and CPOM degradation in the different trap types. Our findings show that clogging acts as a selective filter influencing taxa richness, density, functional composition and biomass of benthic assemblage. Moreover, fine sediments affect the energetic dynamics in the river ecosystem, decreasing the mass loss rate of terrestrial leaves. Interestingly, our results clearly demonstrate that high availability of CPOM can buffer the negative effect of clogging, suggesting that an adequate input of allochthonous organic matter may lessen the impact of fine sediment deposition. Because land use transformation and removal of wooded riparian areas increase clogging and simultaneously reduces the input of CPOM, our findings stress the importance to include the management of river basins in the conservation strategies of mountainous streams.


Laser ablation of a biliary duct for treatment of a persistent biliary-cutaneous fistula.
A persistent biliary-cutaneous fistula detected after biliary drainage catheter removal could not be resolved with diversionary techniques and Gelfoam and fibrin glue administration in the fistulous tract. As an alternative approach for treatment of the fistula, obliteration of the contributing bile duct with laser ablation was performed.