Mesenchymal stem cell-derived exosomes: a new therapeutic approach to osteoarthritis?
Degenerative disorders of joints, especially osteoarthritis (OA), result in persistent pain and disability and high costs to society. Nevertheless, the molecular mechanisms of OA have not yet been fully explained. OA is characterized by destruction of cartilage and loss of extracellular matrix (ECM). It is generally agreed that there is an association between pro-inflammatory cytokines and the development of OA. There is increased expression of matrix metalloproteinase (MMP) and "a disintegrin and metalloproteinase with thrombospondin motifs" (ADAMTS). Mesenchymal stem cells (MSCs) have been explored as a new treatment for OA during the last decade. It has been suggested that paracrine secretion of trophic factors, in which exosomes have a crucial role, contributes to the mechanism of MSC-based treatment of OA. The paracrine secretion of exosomes may play a role in the repair of joint tissue as well as MSC-based treatments for other disorders. Exosomes isolated from various stem cells may contribute to tissue regeneration in the heart, limbs, skin, and other tissues. Recent studies have indicated that exosomes (or similar particles) derived from MSCs may suppress OA development. Herein, for first time, we summarize the recent findings of studies on various exosomes derived from MSCs and their effectiveness in the treatment of OA. Moreover, we highlight the likely mechanisms of actions of exosomes in OA.


Theoretical simulation of the electronic circular dichroism spectrum of calicheamicin.
The aglycon, or so-called 'warhead' portion, of several potent 10-membered ring enediyne antitumor antibiotics contain dienonecarbamate and enediyne chromophores in an unusual bicyclic ring structure in which these two subunits are essentially orthogonal to each other. The circular dichroism (CD) spectra of the calicheamicin, esperamicin, and shisijimicin A families, all of which contain this bicyclic ring system, exhibit a characteristic negative exciton coupled CD at about 310 and 270 nm. This signature CD feature suggested the absolute stereochemical relationship between these chromophores as originally assigned and which was later confirmed by stereospecific total synthesis. Because of the unique nature of this chromophoric interaction and the importance of using this CD spectral feature in the assignment of the absolute stereochemistry of other related enediynes, we report here simulations of the CD spectra of the calicheamicin aglycon A, and of two other truncated models, B and C, by using density functional theory (DFT) and the DeVoe coupled oscillator approach. The DFT calculations provide a strong theoretical basis that the planar enediyne chromophore alone gives a negligible CD contribution, while that coming from the twisted dienonecarbamate is much more substantial. However, the shape and the largest part of the intensity of experimental CD spectrum can only be reproduced when the two unsaturated moieties are simultaneously present. Thus, the exciton coupling between the two chromophores provides the most important contribution to the experimental CD spectrum of calicheamicin. This conclusion is in full agreement with the results from the DeVoe calculation.


Fentanyl effects on breath generation in C57BL/6J and A/J mouse strains.
We examined the effect of fentanyl on chemoresponsiveness in mouse strains divergent in the expression of spontaneous and post-hypoxic pauses. Frequency and tidal volume were recorded with plethysmography in A/J and C57BL/6J (B6) male mice. Mice selected at random received an intraperitoneal (IP) injection of either saline, low dose fentanyl (LDF = 0.04 mg/kg), or high dose fentanyl (HDF = 0.4 mg/kg) under hypoxia (8% O2) or hyperoxia (100%O2). LDF produced a decrease in frequency during hypoxia in B6, but not A/J, mice. HDF significantly decreased frequency and tidal volume in both strains under hypoxia and hyperoxia (p<0.01); naloxone, an opioid antagonist, reversed this response. The acute administration of fentanyl at any dose did not promote apneas in strains of mice exhibiting regular or irregular respiratory patterns. However, higher doses depressed respiratory frequency in both strains. The B6 mice responded with a depressive response to hypoxia that did not recover with reoxygenation, but did recover with time or naloxone.


The use of medroxyprogesterone acetate to study progestin receptors in immature, pregnant, and adult rabbit uterus.
Medroxyprogesterone acetate (MPA)3, a potent synthetic progestin, was employed as the 3H-ligand to investigate the status of the rabbit uterine progestin receptor under various hormonal conditions. MPA dissociated slowly from the cytosol and nuclear progestin receptor obtained from ovariectomized, estrogen-primed rabbits. This slow rate of dissociation permitted a partial characterization of the receptors in pregnant and immature, unprimed rabbit uteri. High affinity progestin binding to 6--7 S and 4 S macromolecular species was detected in cytosol and nuclear extracts, respectively, from these animals. In contrast to the 3 peaks of cytosol receptor activity from estrogen-primed animals which were eluted stepwise from DEAE-cellulose columns, predominantly 2 peaks were obtained with cytosols from pregnant and immature, unprimed uteri. Further studies are required to determine to what extent progestin action is modified through interaction of these binding components with themselves and other cellular proteins.


Dietary Milk Fat Globule Membrane Restores Decreased Intestinal Mucosal Barrier Development and Alterations of Intestinal Flora in Infant-Formula-Fed Rat Pups.
Milk fat globule membrane (MFGM), which contains abundant polar lipids and glycoproteins, can narrow the gap in growth and development between breast-fed and infant-formula-fed babies. The objective of this study is to evaluate the effect of MFGM supplementation in infant formula on intestinal epithelium maturation, tight junctions, and gut colonization in rat pups. Sprague Dawley rat pups consume one of the five diets from postnatal day 8, including rat breastfeeding (BF), infant formula (IF), and infant formula containing MFGM at 260 mg kg-1 body weight (BW), 520 mg kg-1 BW, or 1040 mg kg-1 BW. Results show that MFGM supplementation in infant formula can facilitate intestinal mucosal barrier maturation via promoting intestinal proliferation and differentiation, and increasing tight junction proteins. In addition, compared with that of the IF pups, the intestinal flora composition of MFGM-supplemented pups is more similar to that of BF pups. MFGM supplementation in infant formula can restore the intestinal development in infant-formula-fed pups, which suggests that the supplementation of MFGM in infant formula can better mimic breast milk.


Removal of conjunctival cyst with high-frequency radio-wave electrosurgery.
To introduce a new simple surgical approach for removal of conjunctival cysts with high-frequency radio-wave electrosurgery. Retrospective, noncomparative, interventional case series analysis. Twenty-one eyes of 21 patients. Symptomatic conjunctival cysts, which did not show improvement despite conventional medical management or other surgical procedures were included. The conjunctival cysts were treated using a high-frequency radio-wave electrosurgical unit (Ellman Surgitron; Ellman International Inc, Oceanside, N.Y.). The conjunctiva surrounding the conjunctival cyst was grasped and lifted up using a smooth forcep and a fine-needle electrode (Ellman Insulated Needle Electrodes D6A; Ellman International Inc) was inserted into the cyst. A power setting of 0.5 to 1 was used for coagulation of cysts, without charring the tissue. After surgery, none of the patients had recurrence of conjunctival cysts during the follow-up period of 6 months, and symptoms also disappeared. The surgery did not exceed 5 minutes in all cases, and subconjunctival hemorrhage was observed in 1 case. Subconjunctival hemorrhage had completely resolved within 2 weeks and no other complications were observed. A surgical approach with high-frequency radio-wave electrosurgery successfully removed conjunctival cysts and produced improvement in symptoms. High-frequency radio-wave surgical techniques might be a favourable alternative to surgical treatment of conjunctival cysts.


Perls/DAB Staining to Examine Iron Distribution in Arabidopsis Embryos.
Iron is accumulated in Arabidopsis embryos during seed maturation. Where iron localizes in seed and embryo is important information for seed research. Iron detection can be performed in an inexpensive manner using Perls staining, based on the Prussian blue complex formation. After this first step, DAB intensification can be performed in order to visualize easily where iron pools are located in isolated embryos.


Socio-economic gradients in diagnosed and undiagnosed Type 2 diabetes and its related health complications.
Diagnosed and undiagnosed Type 2 Diabetes (T2D) remains a challenge in high-income countries. In addition, the presence of T2D can cause further disease burden because of its high susceptibility to complications. Nevertheless, there is limited evidence of socio-economic gradients in undiagnosed T2D and its complications in a large population cohort. We investigated this using the Dutch Lifelines Cohort Study (Lifelines). Within Lifelines, baseline data of 102 163 adults aged 30 and above were collected from 2007 to 2013. The associations of Socio-Economic Status (SES), indicated by monthly household income, with the prevalence of T2D status and the number of T2D complications were assessed using multinomial Poisson and linear regressions with adjustments for age and sex. The prevalence of diagnosed and undiagnosed T2D was, respectively, 3.0% and 3.0% in the low SES group compared to 1.1% and 1.8% in the high SES group. Individuals with lower SES were at higher risk of having undiagnosed T2D (relative risk ratio (rrr) [95% CI]: 1.63 [1.47-1.81] for low SES and 1.16 [1.05-1.29] for middle SES) and diagnosed T2D, compared with those with high SES. Lower SES was positively associated with the number of T2D complications (low SES vs. high SES (ref); B [95% CI]: 0.15 [0.13-0.16]). Complementing the known socio-economic gradients in diagnosed T2D, we document socio-economic gradients in undiagnosed T2D and T2D complications in a single, large general representative population. Furthermore, individuals with low SES with diagnosed or undiagnosed T2D were more susceptible to T2D complications.


Role of radiotherapy in the treatment of primary vaginal cancer: Recommendations of the French society for radiation oncology.
Primary vaginal cancers are rare tumours, for which external beam radiotherapy and brachytherapy are major treatment tools. Given the complexity of brachytherapy techniques, the treatment should be performed in specialised centres. We present the recommendations of the French society for radiation oncology on the indications and techniques for external beam radiotherapy and brachytherapy for primary vaginal cancer.


The coordinated mapping of visual space and response features in visual cortex.
Whether general principles can explain the layouts of cortical maps remains unresolved. In primary visual cortex of ferret, the relationships between the maps of visual space and response features are predicted by a "dimension-reduction" model. The representation of visual space is anisotropic, with the elevation and azimuth axes having different magnification. This anisotropy is reflected in the orientation, ocular dominance, and spatial frequency domains, which are elongated such that their directions of rapid change, or high-gradient axes, are orthogonal to the high-gradient axis of the visual map. The feature maps are also strongly interdependent-their high-gradient regions avoid one another and intersect orthogonally where essential, so that overlap is minimized. Our results demonstrate a clear influence of the visual map on each feature map. In turn, the local representation of visual space is smooth, as predicted when many features are mapped within a cortical area.


[Daptomycin in diabetic patients].
In diabetic patients, there is a high prevalence of skin or nasal carriage of Staphylococcus aureus, which is associated with an increased risk of local or systemic infections and consequently with greater morbidity and mortality. The microorganisms causing most infections in diabetic ulcers and diabetic foot are S. aureus and Streptococcus pyogenes, although chronic diabetic foot infections are generally polymicrobial, including Pseudomonas aeruginosa and enterobacteria. The present article describes experience with daptomycin in the treatment of the most frequent infectious complications in diabetic patients. The Cubicin Outcomes Registry and Experience (CORE) registry contains information on 60 patients with skin and soft tissue infections treated with daptomycin, with a success rate of 83%. Other recent studies comparing daptomycin with vancomycin or semi-synthetic penicillins have also shown the efficacy and safety of daptomycin with cure rates of between 70% and 80%. In the European version of the CORE registry, the EUROCORE, diabetic patients who developed bacteremia or endocarditis due to Gram-positive pathogens and who received daptomycin showed success rates of 76.8% and 72%, respectively. No significant differences were found in a study comparing daptomycin or standard therapy with vancomycin in methicillin-resistant S. aureus (MRSA) or antistaphylococcal penicillin in methicillin-susceptible S. aureus (MSSA) in diabetic patients with bacteremia or endocarditis. Because of its rapid bactericidal action and scarce adverse effects, daptomycin is an attractive antimicrobial agent in the treatment of Gram-positive infections in diabetic patients, whether in monotherapy or in association with other agents.


Asystole during treatment with amiodarone in a patient with persistent atrial tachycardia.
During treatment with amiodarone, digoxin and nadolol, asystole occurred repeatedly in a patient with chronic persistent automatic atrial tachycardia. Asystole did not occur after discontinuation of drug therapy, and rechallenge with amiodarone alone produced marked overdrive suppression of all pacemakers resulting in asystole. Amiodarone serum level was within therapeutic range. The possible electrophysiologic mechanisms by which amiodarone might suppress both normal and abnormal pacemakers are discussed. The occurrence of asystole at therapeutic serum concentration of amiodarone suggests that this drug should be used with caution.


RPE Adenocarcinoma as the Presenting Sign of Bronchogenic Carcinoma: Diagnostic Dilemma in the Management of a Case.
Neoplasms of retinal pigment epithelium are rare and must be differentiated from choroidal melanoma. The possibility of a metastatic disease with possible primary sites as lung, breast, or kidney should be ruled out. Herein we report a case of adenocarcinoma arising from the RPE with a lung lesion suspicious of bronchogenic carcinoma. In this paper, ocular symptoms were the first sign of a systemic malignancy.


An immunologic comparison between bone marrow and spleen-derived pluripotent hemopoietic stem cells (CFU-S) of mouse : effect of rabbit anti-mouse brain serum.
We used rabbit anti-mouse brain serum (RAMBS), with known activity against pluripotent hemopoietic stem cells (CFU-S) of mice, to compare the proportions of CFU-S from bone marrow and spleen which express the brain-associated CFU-S antigen(s). Eighty percent of marrow and 77% of spleen-derived CFU-S were inactivated by RAMBS. This suggests that these two populations of CFU-S are antigenically similar with respect to the brain-associated CFU-S antigen(s); this is in contrast to functional differences which are known to exist between the two populations of CFU-S.


Maturation of odor representation in the honeybee antennal lobe.
The antennal lobe (AL) is the first center for processing odors in the insect brain, as is the olfactory bulb (OB) in vertebrates. Both the AL and the OB have a characteristic glomerular structure; odors sensed by olfactory receptor neurons are represented by patterns of glomerular activity. Little is known about when and how an odor begins to be perceived in a developing brain. We address this question by using calcium imaging to monitor odor-evoked neural activity in the ALs of bees of different ages. We find that odor-evoked neural activity already occurs in the ALs of bees as young as 1 or 2 days. In young bees, the responses to odors are relatively weak and restricted to a small number of glomeruli. However, different odors already evoke responses in different combinations of glomeruli. In mature bees, the responses are stronger and are evident in more glomeruli, but continue to have distinct odor-dependent signatures. Our findings indicate that the specific glomerular patterns for odors are conserved during the development, and that odor representations are fully developed in the AL during the first 2 weeks following emergence.


Are we enrolling the right patients? A scoping review of external validity and generalizability of clinical trials in bloodstream infections.
Having a representative population in randomized clinical trials (RCTs) improves external validity and generalizability of trial results. There are limited data examining differences between RCT-enrolled and real-world populations in bloodstream infections (BSI). We conducted a scoping review aiming to review studies assessing generalizability of BSI RCT populations, to identify sub-groups that have been systematically under-represented and to explore approaches to improve external validity of future RCTs. MEDLINE, Embase, and Cochrane Library databases were searched for terms related to external validity or generalizability, BSI, and clinical trials in papers published up to 1 August 2023. Studies comparing enrolled versus nonenrolled patients, or papers discussing external validity or generalizability in the context of BSI RCTs were included. Sixteen papers were included in the final review. Five compared RCT-enrolled and nonenrolled participants from the same source population. There were significant differences between the two groups in all studies, with nonenrolled patients having a greater comorbidity burden and consistently worse outcomes including mortality. We identified several barriers to improving generalizability of RCT populations and outlined potential approaches to reduce these barriers, such as alternative/simplified consent processes, streamlining eligibility criteria and follow-up procedures, quota-based sampling techniques, and ensuring diversity in site and study team selection. Study cohorts in BSI RCTs are not representative of the general BSI patient population. As we increasingly adopt large pragmatic trials in infectious diseases, it is important to recognize the importance of maximizing generalizability to ensure that our research findings are of direct relevance to our patients.


Anti-diabetic activity of embelin: involvement of cellular inflammatory mediators, oxidative stress and other biomarkers.
Embelin (benzoquinone), an active constituent of methanolic extracts of the fruit of Embelia basal (Myrsinaceae), was studied in high fat diet (HFD)+streptozotocin (STZ) diabetic rats. Treatment of embelin (25 and 50 mg/kg/day, p.o.) for 3 weeks to HFD+STZ diabetic rats elicited insignificant increase in body weight, reduced the elevated plasma glucose, glycosylated haemoglobin and pro-inflammatory mediators (interleukin 6 and tumour necrosis factor α) significantly. Furthermore, embelin treatment at both the doses significantly decreased the elevated malondialdehyde, restored depleted glutathione, antioxidant enzymes, superoxide dismutase and catalase in liver. The increased lipid profiles in HFD+STZ diabetic rats were also reduced by embelin treatment significantly. Embelin treatment to HFD+STZ diabetic rats also improved the altered histoarchitecture of β-islets of pancreas and hepatocytes. The embelin effect on progression of type 2 diabetes mellitus in rats appears to be through the inhibition of intracellular pro-inflammatory mediators, lowering of lipid profile and amelioration of oxidative stress. Considering the pharmacological activity profile of embelin, it is suggested that embelin be a useful diabetic modulator or adjuvant along with clinically effective anti-diabetic drugs in the treatment of type 2 diabetes mellitus and needs to be clinically evaluated on human subjects.


Evaluation of a tubeless pancreatic function test in patients with steatorrhoea in a district general hospital.
The Pancreolauryl Test (PLT), a tubeless pancreatic function test, has been evaluated in an unselected series of outpatients with steatorrhoea presenting to a district general hospital (DGH). This is the first study of the PLT in a DGH, involving an unselected series of patients and not those from secondary or tertiary referral hospitals. Health controls (n = 15) and patients with self-limiting diarrhoea (n = 8) had normal urinary excretion indices (greater than or equal to 30). Coeliac disease (n = 13) and small bowel bacterial overgrowth (n = 12) were the commonest causes of steatorrhoea and there were no false-positive results in these patients. The mean urinary excretion index in patients with untreated coeliac disease (mean index = 38%) was lower than in healthy controls (n = 15, mean index = 53%; P less than 0.05 greater than 0.02). No patient with proven pancreatic steatorrhoea had a normal PLT result, confirming the high negative predictive value found by others. Low results in patients with steatorrhoea following gastric surgery indicate poor mixing of food with pancreatic juices. The PLT proved to be a simple, inexpensive and noninvasive outpatient screening test suitable for use in a DGH to exclude a pancreatic origin of steatorrhoea.


Maxillary arch changes during leveling and aligning with fixed appliances and low-friction ligatures.
The aim of this study was to evaluate the changes in the transverse dimension and the perimeter of the maxillary arch produced by a low-friction system during the leveling and aligning phases of fixed appliance therapy. The low-friction protocol consisted of a combination of preadjusted brackets, superelastic nickel-titanium archwires, and nonconventional elastomeric ligatures; it was used in 20 consecutively treated patients with mild crowding. Statistically significant increases were recorded for all dentoalveolar widths (with the exception of intermolar width measured lingually) and arch perimeter (3.5 mm on average). The increase in arch perimeter showed a significant negative relationship with the individual perimeter of the maxillary arch before treatment. No significant change was found for arch depth. The low-friction system produced statistically significant increases in the transverse dentoalveolar width and the perimeter of the maxillary arch during the leveling and aligning phases of treatment with an average duration of 6 months.


FasL is a catabolic factor in alveolar bone homeostasis.
Fas ligand (FasL) belongs to the tumour necrosis factor superfamily regulating bone turnover, inflammation, and apoptosis. The appendicular and axial skeleton phenotype of mature Faslgld mice has been reported. The impact of FasL on the alveolar bone providing support for the teeth at mature stages under healthy and induced inflammatory conditions remains unknown. We performed a phenotypical analysis of mice carrying the homozygous Faslgld mutation and wild-type (WT) mice (C57BL/6) under healthy conditions and upon ligature-induced periodontitis. After 12 days, micro-computed tomography analysis revealed the distance between the cement enamel junction and the alveolar bone crest. Additional structural parameters, such as the bone volume fraction (BV/TV) and the periodontal ligament space volume, were measured. Histological analyses were performed to visualize the catabolic changes at the defect site. Healthy Faslgld mice were found to have more periodontal bone than their WT littermates. Faslgld had no significant effect on inflammatory osteolysis compared to WT controls with ligatures. Histology revealed eroded surfaces at the root and in the inter-proximal bone in both strains. Our findings suggest that FasL is a catabolic factor in alveolar bone homeostasis but it does not affect the inflammatory osteolysis.


Effect of legislation and changing trends of Diwali ocular firecracker injuries in Northern India.
The objective of this study is to study the impact of temporary legislation implemented during Diwali on ocular firecracker injuries in Delhi-National Capital Region (NCR) region. In this retrospective study, records of the patients presenting with ocular firecracker injury during 10 days of Diwali (prediwali, Diwali and 8 days postdiwali) from 2014 to 2019 were retreived from the medical record section. Clinico-demographic profile, relevant history pertaining to the use of firecracker, and details of eye examination, namely presenting visual acuity (VA), laterality and classification of injury based on Birmingham Eye Trauma Terminology System were noted. Six hundred and sixty-seven eyes of 646 patients were recruited. The median age of patients was 14 years (R = 3-65 years) and male: Female ratio was 4.9:1. Majority of patients (57.7%; n = 373) were from outside Delhi. Most of them were open globe injuries (66.8%). In 55.4% (n = 356) eyes, presenting VA was perception of light to finger counting close to face and 28% (n = 180) eyes could not perceive any light. A significant reduction was noted in the number of ocular firecrcaker injuries after regulation (preregulation [2014-2016] n = 456; postregulation [2017-2019] n = 211; [P = 0.01, t-test]). During preregulation period, presenting VA was worse than 1/60 in significantly higher number of eyes (85.5%; n = 376) than post regulation (78.8%, n = 160) (P = 0.03, Chi-square test). Although temporary legislation seems to be effective in reducing ocular firecracker injuries (52.7% reduction) in NCR, uniform implementation of stricter laws nationwide is essential to further minimize the problem.


Long-term apparent diffusion coefficient value changes in patients undergoing radiosurgical treatment of meningiomas.
A noninvasive method to predict the progress or treatment response of meningiomas is desirable to improve the tumor management. Studies showed that apparent diffusion coefficient (ADC) pretreatment values can predict treatment response in brain tumors. The aim of this study was to analyze changes of intratumoral ADC values in patients with meningiomas undergoing conservative or radiosurgery. MR images of 51 patients with diagnose of meningiomas were retrospectively reviewed. Twenty-five patients undergoing conservative or radiosurgery treatment, respectively, were included in the study. The follow-up data ranged between 1 and 10 years. Based on ROI analysis, the mean ADC values, ADC10%min, and ADC90%max were evaluated at different time points during follow-up. Baseline ADC values in between both groups were similar. The ADCmean values, ADC10%min, and ADC90%max within the different groups did not show any significant changes during the follow-up times in the untreated (ADCmean over 10 years period: 0.87 ± 0.05 × 10-3 mm2/s) and radiosurgically treated (ADCmean over 4 years period: 1.02 ± 0.12 × 10-3 mm2/s) group. However, statistically significant difference was observed when comparing the ADCmean and ADC90%max values of untreated with radiosurgically treated (p < 0.0001) meningiomas. Also, ADC10%min revealed statistically significant difference between the untreated and the radiosurgery group (p < 0.05). ADC values in conservatively managed meningiomas remain stable during the follow-up. However, meningiomas undergoing radiosurgery reveal significant change of the mean ADC values over time, suggesting that ADC may reflect a change in the biological behavior of the tumor. These observations might suggest the value of ADC changes as an indicator of treatment response.


Laser acupuncture combined with auricular acupressure improves low-back pain and quality of life in nurses: A randomized controlled trial.
Low-back pain (LBP) in nurses is a major health concern that affects their quality of life and ability to work, with consequences for their economic status. This study evaluates the effect of low-level laser acupuncture combined with auricular acupressure (LAA) on pain intensity, pain interference and quality of life in nurses with LBP. This randomized controlled trial recruited a convenience sample of hospital-based nurses from one teaching hospital in Taiwan, China. Participants were randomly assigned to the LAA group (n = 38) receiving low-level laser acupuncture and auricular acupressure for 4 weeks, and the control group (n = 38) receiving only sham laser acupuncture treatment without laser energy output. Data were collected for the primary pain outcome using the Short Form of the Brief Pain Inventory, while the secondary outcome, quality of life, was evaluated using the Roland-Morris Disability Questionnaire. Both primary and secondary outcomes were scored before the intervention, and after 2-week and 4-week intervention. The rate of LBP recurrence was evaluated at the 4th week and 8th week after the end of intervention. After controlling for prior pain, the result of linear mixed model analysis showed trends in significant between-group differences in the level of current pain occurring in week 4 (P < 0.001), worst pain in week 2 (P < 0.001) and week 4 (P < 0.001), least pain in week 2 (P = 0.032) and week 4 (P < 0.001), pain interference in week 2 (P = 0.009) and week 4 (P < 0.001), and in the life dysfunction in week 2 (P < 0.001) and week 4 (P < 0.001). Recurrence rates of LBP at the 4th and 8th weeks after the end of intervention were 0% and 36.89% in the LAA group, and 69.44% and 36.11% in the control group. This study shows that 4-week LAA intervention reduced pain intensity and pain interference, and improved quality of life for hospital-based nurses with LBP. These effects were maintained continuously for at least 4 weeks after the intervention. The nonpharmacological intervention, LAA, may be another efficacious, feasible, noninvasive, analgesic intervention for LBP. This study is registered at Clinicaltrials.gov (registration number NCT04423445).


Flow cytometry used to distinguish between complete and partial hydatidiform moles.
Cells prepared from fresh tissue from a normal conception, and three complete hydatidiform moles (CHMs), were shown to be diploid by flow cytometry, while triploid populations were identified in tissue from two partial hydatidiform moles (PHMs). Similar results were found in cells from formalin-fixed, paraffin-embedded material. In nine cases where cytogenetic analysis was carried out this correlated with the results from flow cytometry. Using flow cytometry we were able to show that two cases which were pathologically complete were in fact diploid, despite the finding of trisomy at one locus in the molar tissue using biochemical markers. The most likely explanation of apparent trisomy of the enzymes in the molar tissue was contamination by maternal tissue.


Haemodynamics in the horse: 3. Duration of the phases of the cardiac cycle.
The paper reports observations on the duration of various phases of the cardiac cycle using a bipole ECG record as a time base from which to measure the timing of pressure changes in the chambers of the heart and great vessels. From the findings the likely sequence of mechanical events during the cardiac cycle in the atria and ventricles is described.


Alcohol related falls: an interesting pattern of injuries.
To discover if there is a significant difference in the pattern and severity of injury sustained during falls in patients who have consumed alcohol and those who have not. To determine how pattern and severity of injury correlates with blood alcohol concentration. A prospective quasi-randomised controlled study between November 2001 and July 2002. All healthy adults between 16 and 60 years who had fallen from standing height were included. A systematic history and examination permitted calculation of injury severity scores as per abbreviated injury scale update 1998. Blood alcohol concentrations were obtained from intoxicated patients with consent. 351 healthy adult patients were included in the study, there were 238 in the no alcohol group, 113 had consumed alcohol and blood alcohol intake were obtained for 47. The alcohol group had a higher incidence of head injuries (46 (48%) versus 22 (9%)) with a lower incidence of limb injuries (39 (39%) versus 183 (76%)) than the no alcohol group. There was a significant difference in the pattern of injury between the alcohol and no alcohol groups (chi(2), p<0.001) and there was a significant difference in the injury severity scores (p<0.001, Z = -2.5). In the alcohol group severity and pattern correlated with alcohol concentration at the time of injury. Patients with an alcohol concentration<2 g/l had mostly soft tissue limb injuries (58%), 2-2.5 mostly significant limb fractures (55%), and >2.5 mostly significant head injuries (90%). Alcohol related falls are more often associated with severe craniofacial injury. The severity of both limb and head injury is greater and correlates directly with blood alcohol concentration.


Elevation of neuron-specific enolase and S-100beta protein level in experimental acute spinal cord injury.
We evaluated the protein levels of neuron-specific enolase (NSE) and S-100beta in serum and cerebrospinal fluid (CSF) in an animal model of acute spinal cord injury and ascertained their relevance. Spinal cord injury was induced at the T8 level in rats. Enzyme-linked immunosorbent assay was used to measure the protein levels of NSE and S-100beta in both serum and CSF at different time points (30 min, 2 h, 6 h, 12 h and 24 h after induction of spinal cord injury). There existed a significant correlation between neurological deficits and the severity of spinal cord injury (p<0.05). Compared with the control group, the protein levels of NSE and S-100beta in serum and CSF significantly increased from 2 h after injury (p<0.05) and reached a maximum at 6 h. Within a certain time window, the protein levels of NSE and S-100beta in serum and CSF were closely related to the severity of injury level (p<0.05). The protein levels of NSE and S-100beta in serum and CSF significantly increased after experimental spinal cord injury in a time-dependent manner and thus may be considered specific biomarkers for acute spinal cord injury.


Monoclonal antibody-based optical molecular imaging probes; considerations and caveats in chemistry, biology and pharmacology.
The monoclonal antibody (mAb) has proven to be a good platform for designing specific molecular imaging probes due to its superior binding specificity. Several optical imaging probes have been developed for surgical navigation in patients and are in early phase clinical trials. However, an inherent limitation of using the mAb is its pharmacokinetics which result in a prolonged circulating half-life and slow clearance from the body. This results in undesirable target to background ratios during imaging. In this review, we first describe the mAb as a platform material for optical probe design and then discuss optimizing the design of monoclonal antibody-based optical molecular imaging probes by focusing on chemistry, biology and pharmacology.


Optimal surgical methods to treat intertrochanteric fracture: a Bayesian network meta-analysis based on 36 randomized controlled trials.
There are several surgical methods to treat intertrochanteric fracture: dynamic hip screw (DHS), compression hip screw (CHS), percutaneous compression plate (PCCP), Medoff sliding plate, less invasive stabilization system (LISS), Gamma nail, proximal femoral nail (PFN), and proximal femoral nail anti-rotating (PFNA). We therefore conducted a network meta-analysis to compare eight surgical interventions, including DHS, CHS, PCCP, Medoff sliding plate, LISS, Gamma nail, PFN, and PFNA, to provide the optimal surgical intervention for intertrochanteric fracture. An electronic search of 4 databases (PubMed, Embase, Cochrane library, and Web of Science) from inception to July 2020. Two or more of the eight surgical interventions, including the DHS, CHS, PCCP, Medoff sliding plate, LISS, Gamma nail, PFN, and PFNA, for intertrochanteric fracture were included. The methodological quality of the included studies was assessed using the Cochrane Collaboration risk of bias (ROB) tool. Network meta-analysis was conducted by using R-3.5.1 software with the help of package "gemtc". The odd ratios (ORs) with 95% credibility interval (CrI) were used to assess complications and standard mean difference (SMD) with 95% CrI to calculate the continuous outcomes (operative time, intraoperative blood loss, and Harris hip score). Surfaces under the cumulative ranking curves (SUCRA) were used to rank the intervention. A total of 36 RCTs were included in this study. The results of this network meta-analysis showed that, compared with the CHS and DHS group, PFNA exhibited a beneficial role in reducing the blood loss (SMD, 152.50; 95% CrI, 72.93 to 232.45; and SMD, 184.40; 95% CrI, 132.99 to 235.90, respectively). PFNA achieved the lowest value for the surface under the cumulative ranking curve (SUCRA) for the blood loss (SURCA = 0.072) and highest of Harris hip score (SURCA = 0.912). PCCP may have the lowest probability of the operative time (SURCA = 0.095). There were no significant differences among the eight surgical procedures in complications. PFNA technique is the optimal treatment method for intertrochanteric fracture. Larger, longitudinal RCTs addressing current limitations, including sources of bias, inconsistency, and imprecision, are needed to provide more robust and consistent evidence.


Design considerations for a pilot trial using a novel approach for evaluating smoking-cessation medication in methadone-maintained smokers.
The prevalence of smoking in methadone-maintained (MM) patients is over 80% and smoking-abstinence rates are strikingly low, even with the use of first-line smoking-cessation medications. Research has found that cigarettes increase the reinforcing properties of methadone; this interaction may be an additional, daily, challenge to smoking cessation in MM-smokers. This paper describes a novel approach in which patients who experience a particular barrier to achieving smoking abstinence are selected, and the impact of smoking-cessation medications on the identified barrier is evaluated. This is a 7-week, outpatient, randomized, within-subject, placebo-controlled, crossover trial with a follow-up visit at week 8. MM-smokers, who smoke ≥40% of their total daily cigarettes in the 4-h post-methadone-dosing period, as assessed with a Quitbit electronic cigarette lighter, will be recruited from a methadone program in Cincinnati, Ohio. Eligible participants will be randomized to receive four interventions (nicotine nasal spray (1mg per dose, up to 40 times per day), placebo nicotine nasal spray, varenicline (2mg/day), and varenicline placebo) in one of four orders to mitigate potential order effects. The primary outcome analysis will consist of two sets of statistical analyses, one comparing the effect of nicotine nasal spray to its placebo, and one comparing the effect of varenicline to its placebo, on the proportion of daily cigarettes smoked during the 4-h post-methadone-dosing period. This trial is of interest both as an efficient, precision-medicine-based approach to testing smoking-cessation interventions and as a specific strategy for identifying effective smoking-cessation treatment for MM-smokers.


Explore of the reasons of irrational prescribing in Iran: A qualitative study.
Irrational prescribing is highly prevalent in Iran, and it is under the impact of different factors. This research aims to recognize the reasons for Irrational prescribing in Iran. A qualitative approach and a conventional content analysis were employed to perform this research. The research community includes some experts and key specialists in medication prescribing. Semi-structured interviews were used for data collection. The intentional sampling method was applied, and theoretical saturation was reached by conducting 40 interviews with experts. The data analysis process was done following the steps suggested by Graneheim and Lundman. Four main categories and 12 subcategories appeared after analyzing the data. The main categories are organizational and management factors, legal factors, cultural factors, and economic factors. Irrational prescribing can be prevented by reforming the referral system, overseeing pharmacies and physicians, raising public awareness and correcting their misconceptions about the medications, and creating an appropriate mechanism for pricing and selling medicines.


Serum Prolactin Level to Tumor Size Ratio as a Potential Parameter for Preoperative Differentiation of Prolactinomas from Hyperprolactinemia-Causing Non-functional Pituitary Adenomas.
Preoperative diagnosis of prolactinomas is critical because dopamine agonists have been regarded as a primary treatment. However, serum prolactin level alone is suboptimal for differentiating prolactinomas from hyperprolactinemia-causing non-functioning pituitary adenomas (NFPAs). By using the tumor size, the authors tried to investigate an effective parameter for the discrimination. We performed a retrospective review of patients who underwent trans-sphenoidal surgery for pituitary lesions in a single institute between January 2015 and May 2021. Using receiver operating curve (ROC) analyses, we compared performances of serum prolactin levels (PRL), a ratio of serum PRL levels to maximal tumor diameter (MD) (PRL/MD; PDR1), and MD squared (PRL/[MD]2; PDR2) in preoperative diagnosis of prolactinomas. A total of 223 patients with NFPAs (n = 175) and prolactinomas (n = 48) were included in the analysis. A moderate correlation was found between serum prolactin levels and MDs in prolactinomas (Pearson's rprl = 0.43, P = 0.002), whereas a weak correlation was observed in NFPAs (Pearson's rnfpa = 0.17, P = 0.028). Among diagnostic parameters, PDR2 exhibited the optimal diagnostic performance with the cutoff value of 0.83 [㎍/L]/mm2 (area under the curve [AUC] = 0.945), compared with the PDR1 (8.93 [㎍/L]/mm with AUC 0.938) and PRL (99.4 ㎍/L with AUC 0.910). In the external validation study, PDR2 maintained superior performance over PDR1 and PRL (accuracy of 94.8%, 91.8%, and 75.8%, respectively). PDR2 was a more effective indicator than prolactin alone in the preoperative differential diagnosis of prolactinomas and NFPAs, which may help select patients who need medical treatment first.


Paradoxical Radiographic Changes of Coflex Interspinous Device with Minimum 2-Year Follow-Up in Lumbar Spinal Stenosis.
Studies have yet to investigate long-term radiologic changes in lumbar spinal stenosis patients treated with interspinous device (Coflex). This study aimed to evaluate which radiologic parameters change significantly after surgery with Coflex and identify which parameter most affects the radiologic outcome. Of 101 patients with lumbar spinal stenosis treated by Coflex insertion on L4-5, the radiologic parameters of 30 patients were measured before and at least 2 years after surgery. On the basis of the development of bony erosion around Coflex, patients were divided into the erosion group (n = 14) or the nonerosion group (n = 16). The mean anterior disc height (ADH) and range of motion (ROM) were significantly decreased after surgery (15.161 mm vs. 13.788 mm and 9.63° vs. 7.13°). The erosion group showed substantially higher values in preoperative ADH, postoperative posterior disc height (PDH), and intervertebral foramen height (6.52 mm vs. 8.05 mm; 5.80 mm vs. 8.03 mm; 19.20 mm vs. 21.06 mm). Postoperative ROM and ROM ratio were higher in the erosion group (5.95° vs. 8.47° and 0.659 vs. 0.938). However, only ADH showed a significant change in the erosion group after surgery (15.86 mm vs. 14.29 mm). On the contrary, ADH and PDH, as well as ROM, were significantly decreased in the nonerosion group (14.55 mm vs. 13.34 mm; 6.52 mm vs. 5.82 mm; 9.46° vs. 5.95°). The preoperative state including relatively higher ADH, PDH, and larger ROM could induce erosion. The long-term preservation of disc height and ROM may also induce erosion. That reduction of most radiologic parameters seems to be natural after surgery, and insufficient reduction of disc height and ROM may induce adverse effects, which can increase the possibility of spinous process fracture or device malposition.


Increased myometrial blood flow evoked by substance P.
Substance P (SP), a vasoactive neuropeptide, has recently been demonstrated in the female genital tract. In the present paper we have investigated the relationship between substance P (0, 0.065, 6.5, 650 pmol X min-1 X kg-1) administered by close intraarterial infusions, and myometrial blood flow (MBF). The MBF was measured by the 133Xe washout technique in ten non-pregnant, estrogen pretreated, female rabbits anaesthetized with sodium pentobarbitone. SP increased MBF in a dose-dependent fashion. This effect was not influenced by cholinergic, adrenergic or enkephalinergic blocking agents, indicating a direct effect of substance P on vascular smooth muscle. Substance P may therefore play a physiological role in the local nervous control of myometrial blood flow.


Hematocrit, urea and gender: the Hematocrit, Urea and GEnder formula for prognosing progressive renal failure in diabetic nephropathy.
Diabetic nephropathy is a common cause of end stage renal disease. Notwithstanding, wide inter-individual variations in the speed of progression of diabetic nephropathy are frequent. We have used the score of the HUGE formula to predict progression of kidney disease in a group of diabetic nephropathy patients. The sample consisted of 84 type 2 diabetic patients. At treatment entry, the mean age was 62.1 ± 12.5 years and 59.5% were male. Blood pressure was measured at office at each visit. Serum creatinine, urea, hematocrit and 24h proteinuria were analyzed every 6 months. HUGE score was calculated from gender, urea and hematocrit. Mean HUGE score was 0.99 ± 3.88. Using as cut off point 1.5, those patients who had a score equal or higher (n=31) showed a bigger increase in serum creatinine after one year (41.8 ± 62.1%) than those subjects with score<1.5 (n=53) (18.7 ± 38.6%, p=0.041). 5 patients with low HUGE score reached end stage renal failure (9.4%) and 10 patients in the high HUGE score group (32.3, p=0.008). When logistic regression analysis was performed only a HUGE score higher than 1.5 (p=0.003) and proteinuria higher than 2g/day (p=0.041) were independently associated to CRF progression (creatinine increment>25%). In diabetic nephropathy patients the HUGE equation may be useful to detect the subjects prone to progressive renal failure. Wider samples will be needed to confirm this finding and, most important, its applicability to other kinds of nephropathy.


Targets and moving goal posts: changes in waiting times in a UK emergency department.
To describe changes in the case mix, demographics, waiting times (WTs; time from arrival in the emergency department (ED) until seen by a clinician) and treatment times (TTs; time from seeing a clinician until leaving the ED) of adult patients presenting to the EDs in Sheffield, UK, between 1993 and 2003. A retrospective analysis of routinely collected data. Of a total of 252,156 patients included in the study, the proportion of attendees aged 16-29 years decreased from 38.7% in 1993 to 28.8% in 2003 (rate of change (b) = -1.10% per year, 95% CI -1.20% to -0.82%, p < 0.001) whereas the proportion aged 80-99 years increased from 6.2% to 10.4% (b = 0.37% per year, 95% CI 0.29% to 0.45%, p < 0.001). The proportion of "minors" (patients not arriving by ambulance and subsequently discharged) fell from 71.1% in 1993 to 60.8% in 2003 (b = -1.04% per year, 95% CI -1.36% to -0.73%, p < 0.001). WTs increased from a median of 21 minutes in 1993 to 48 minutes in 2003 (b = 3.5 min per year, 95% CI 2.23 min to 4.77 min, p < 0.001). The median TT for minors was unchanged but that for majors (patients arriving by ambulance and admitted to hospital from the ED) increased from 55 to 205 minutes (b = 11.55 min per year, 95% CI 6.54 min to 16.55 mins, p = 0.01). The demographics, case mix, and waiting times of patients presenting to EDs in Sheffield changed considerably over an 11 year period. There is evidence that the service for minor case patients improved slightly at the end of the period studied, but this is possibly at the expense of a deteriorating experience for major case patients.


Retrograde intrarenal surgery for urinary stone disease in patients with solitary kidney: A retrospective analysis of the efficacy and safety.
To compare outcomes of retrograde intrarenal surgery for urolithiasis between patients with solitary kidneys and patients who have single-side urolithiasis with bilateral kidneys. We retrospectively analyzed outcomes of retrograde intrarenal surgery in solitary kidney patients (group A) carried out during 2007-2014, and in patients with bilateral kidneys with comparable stone burdens (group B). Stone-free status was defined as no residual fragment on computed tomography 1 month later. There were 19 patients in group A (mean age 62.5 ± 18.4 years, range 14-76 years). The mean stone diameter and burden were 6.0 mm (range 3-24 mm) and 10.42 ± 6.92 mm, respectively. The stone-free rate was 94.7%, and no repeat procedure was required. The glomerular filtration rate tended to rise post-surgery (postoperative day 1: 48.67 ± 15.92 mL/min, 100.2%, P = 0.940; postoperative month 1: 51.32 ± 16.90 mL/min, 105.7%, P = 0.101) compared with preoperative rates. The stone-free rate and surgery time were not significantly different between the two groups, although post-surgical hospitalization time was longer for group A (4.05 vs 3.08 days, P = 0.037). The change in glomerular filtration rate was not significantly different between groups A and B (postoperative day 1: +0.101 vs +0.547 mL/min, respectively, P = 0.857; postoperative month 1: +2.749 vs 3.161 mL/min, respectively, P = 0.882). No significant difference was found in terms of complication rate. Retrograde intrarenal surgery in solitary kidney patients is as safe and effective as in bilateral kidney patients.


Implications of chirality and geometric isomerism in some psychoactive drugs and their metabolites.
Many drugs contain a chiral centre, or such a centre is introduced during metabolism of the drug in man and in animals. If a single chiral centre is present, the drug will normally exist as a mixture of two enantiomers, of which one may have quite different pharmacologic and/or toxic effects than the other. Chiral drugs that are used in psychiatry, and some other pharmacologically related drugs are identified, and the implications of the presence of one or two chiral centres in these drugs are discussed. Differences in pharmacologic properties of drug and metabolite enantiomers are identified and discussed. Also reviewed are the properties of some drugs used in psychiatry that both are chiral and display geometric isomerism.


Efficient degradation method of emerging organic pollutants in marine environment using UV/periodate process: Case of chlorazol black.
Sea has historically been subject to high anthropogenic pressures of direct and indirect loads of emerging organic pollutants (EOPs) from intensive industrial and agricultural activities. Photoactivated periodate (UV/IO4-) is an innovative oxidation technique that was never tested in seawater as pollutants matrix. In this work, we attempted to investigate the treatment of seawater contaminated with chlorazol black (CB) dye, as a model of EOPs, using photoactivated periodate process. It was found that periodate (0.5mM) assisted-UV treatment of CB (20mgL-1) in seawater resulted in 13.16-fold increase in the initial degradation rate, compared to UV alone, and 82% of CB was removed after 40min face to 38% under UV alone. The beneficial effect of UV/IO4- treatment is strongly dependent on operational parameters. More interestingly, SDS surfactant, as an organic matter, did not affect the degradation process, making UV/IO4- a promising technique for treating seawater contaminated with EOPs.


Structural basis for the interaction between unfarnesylated progerin and the Ig-like domain of lamin A/C in premature aging disorders.
Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder caused by C-terminally truncated lamin A, termed as the pre-progerin product. Progerin is a C-terminally farnesylated protein derived from pre-progerin, which causes nuclear deformation at the inner-nuclear membrane. As an alternative or additional mechanism, a farnesylation-independent abnormal interaction between the C-terminus of progerin and Ig-like domain has been proposed. However, the molecular mechanism underlying the role of unfarnesylated C-terminus of pre-progerin in HGPS remains largely unknown. In this study, we determined the crystal structures of C-terminal peptide of progerin and Ig-like domain of lamin A/C. Results showed that the C-terminal cysteine residue of progerin forms a disulfide bond with the only cysteine residue of the Ig-like domain. This finding suggested that unfarnesylated progerin can form a disulfide bond with the Ig-like domain in the lamin meshwork. The Alphafold2-assisted docking structure showed that disulfide bond formation was promoted by a weak interaction between the groove of Ig-like domain and the unfarnesylated C-terminal tail region of progerin. Our results provide molecular insights into the normal aging process as well as premature aging of humans.


Psychiatry and ethics: the problematics of respect for religious meanings.
Over the past two decades American psychiatrists have had to address the emergence of an increasingly fervent religious pluralism. Particularly in cases of socially controversial new religious movements (NRMs), distressed families have pressured psychiatrists to assess the mental state of recruits to such sects, often labeled "cults." At this inevitably acrimonious interface between family values and religious liberties, psychiatrists have for the most part resisted pressures to medicalize religious conversions. This article provides an historical review of American psychiatric response to NRMs with respect to nosology and practice. It introduces this response in the more general context of ethics and the problematics of respect for religious meanings.


Chromosomes and causation of human cancer and leukemia. LI. A hairy cell leukemia case with 14q+ and ring chromosomes: significance of ring chromosomes in blood disorders.
What appears to be the first hairy cell leukemia case with a 14q+ anomaly is described. In addition to the 14q+ anomaly, a 6q- and a ring chromosome were seen in a blood sample stimulated with lipopolysaccharide, a B-cell mitogen. The clinical course of the present case was short, stormy, and had a poor response to therapy. The correlation between the clinical course and the presence of a ring chromosome in myelo- and lymphoproliferative blood disorders is discussed in relation to the various blood disorders with this karyotype anomaly described in the literature.


Post-traumatic stress disorder, anxiety, depression and burnout in nursing home staff in South France during the COVID-19 pandemic.
The high mortality rate in nursing homes during the COVID-19 pandemic may be linked to psychological disorders in staff. Hence, we assessed the prevalence and associated factors of probable post-traumatic stress disorder (PTSD), anxiety, depression, and burnout of nursing home staff during the COVID-19 pandemic in a cross-sectional study including 66 randomly selected nursing homes in southern France. 537 of the contacted 3 821 nursing home workers (14.0%) responded between April and October 2021. We collected information on center organization, severity of COVID-19 exposure, and socio-demographic information in an online survey. The prevalence of probable PTSD (PCL-5), anxiety and depressive disorders (Hospital Anxiety Depression Scale) and the sub-scores of burnout syndrome (Maslach Burnout Inventory Human Services Survey for Medical Personnel) were assessed. Probable PTSD was reported in 115/537 responders (21.4% (95% CI [18.0%-24.9%])). After adjustment, low-level exposure to COVID-19 in nursing home residents (AOR, 0.5; 95% CI [0.3-0.9]), fear of managing COVID-19 residents (AOR, 3.5; 95% CI [1.9-6.4]), conflicts with residents (AOR, 2.3; 95% CI, [1.2-4.4]), conflicts with colleagues (AOR, 3.6; 95% CI [1.7-8.6]), cancellation of leave (AOR, 4.8; 95% CI [2.0-11.7]) and temporary worker employment (AOR, 3.4; 95% CI [1.7-6.9]) were associated with higher prevalence of probable PTSD. The prevalence of probable anxiety and depression were 28.8% (95% CI [24.9%-32.7%]) and 10.4% (95% CI [7.8%-13.1%]), respectively. Psychological disorders were observed in nearly one third of nursing home workers during the COVID-19 pandemic. Hence, continuous surveys and preventive measures are needed in this particularly at-risk population.


Intraocular-pressure-lowering effect of low-dosage combination of guanethidine and terbutaline in rabbit.
A low dosage combination of terbutaline plus guanethidine was applied topically to the eyes of rabbits with experimentally induced ocular hypertension, markedly lowering intraocular pressure. The effect of this combination is markedly greater than that produced separately by the two components at corresponding dosages and seems to be due to a true synergistic phenomenon. The low-dosage combination of terbutaline and guanethidine appears to be well tolerated, very potent and effective as a topical ocular hypotensive agent.


Axillary lymph node metastasis from serous ovarian cancer: a case report and review of the literature.
The symptoms and findings of ovarian cancer are parallel with the degree of intra-abdominal expansion of the tumor. Metastases in the early stage occur by peritoneal fluid's tracking via the circulatory system. Renal and cerebral metastases of ovarian cancer have been previously reported, but axillary lymph node metastasis is quite rare. Axillary lymph node metastasis usually occurs in the advanced stage. We present a 47-year-old female who had applied adjuvant chemotherapy following cyto-reductive surgery because of stage 3C ovarian cancer. Axillary lymph node metastasis was detected in the postoperative 32 months. As tumors in axillary lymph nodes are found in patients with an ovarian carcinoma, the treatment is also so important too. Metastasis to the breast be differentiated accurately from primary breast cancer, because prognosis and treatment differ significantly. Accurate diagnosis of these metastases may allow more appropriate therapy, such as chemotherapy, and prevent the patient from an unnecessary major breast surgery.


Patient education in asthmatic adults.
Despite the advances in the understanding of the pathogenic mechanisms, clinical assessment, and medical treatment of asthma, an increase of mortality and morbidity has been observed. It is clear from several studies, however, that this discrepancy may be at least partly due to serious defects, among asthmatic patients, in the ability to judge the severity of their asthma, and in the knowledge of medication and the correct action to take, when deterioration occurred. Therefore, to effectively manage asthma, structured education programs for adult asthmatics appear to be useful including information about the disease and the medication as well as training of self-management of airflow limitation by the patients. The evaluation of the course of the disease before and after the education revealed a reduction of severe attacks, hospitalizations, and days lost from work in trained asthmatics.


Universal long-time properties of Lagrangian statistics in the Batchelor regime and their application to the passive scalar problem.
We consider the transport of dynamically passive quantities in the Batchelor regime of a smooth in space velocity field. For the case of arbitrary temporal correlations of the velocity, we formulate the statistics of relevant characteristics of Lagrangian motion. This allows us to generalize many results obtained previously for strain delta correlated in time, thus answering a question about the universality of these results.


Early mucosal reactions during and after head-and-neck radiotherapy: dependence of treatment tolerance on radiation dose and schedule duration.
To more precisely localize the dose-time boundary between head-and-neck radiotherapy schedules inducing tolerable and intolerable early mucosal reactions. Total cell-kill biologically effective doses (BED(CK)) have been calculated for 84 schedules, including incomplete repair effects, but making no other corrections for the effect of schedule duration T. [BED(CK),T] scatterplots are graphed, overlying BED(CKboundary)(T) curves on the plots and using discriminant analysis to optimize BED(CKboundary)(T) to best represent the boundary between the tolerable and intolerable schedules. More overlap than expected is seen between the tolerable and intolerable treatments in the 84-schedule [BED(CK),T] scatterplot, but this was largely eliminated by removing gap and tolerated accelerating schedules from the plot. For the remaining 57 predominantly regular schedules, the BED(CKboundary)(T) boundary increases with increasing T (p = 0.0001), curving upwards significantly nonlinearly (p = 0.00007) and continuing to curve beyond 15 days (p = 0.035). The regular schedule BED(CKboundary)(T) boundary does not describe tolerability well for accelerating schedules (p = 0.002), with several tolerated accelerating schedules lying above the boundary where regular schedules would be intolerable. Gap schedule tolerability also is not adequately described by the regular schedule boundary (p = 0.04), although no systematic offset exists between the regular boundary and the overall gap schedule tolerability pattern. All schedules analyzed (regular, gap, and accelerating) with BED(CK) values below BED(CKboundary)(T)=69.5x(T/32.2)/sin((T/32.2)((radians)))-3.5Gy(10)(forT< or =50 days) are tolerable, and many lying above the boundary are intolerable. The accelerating schedules analyzed were tolerated better overall than are the regular schedules with similar [BED(CK),T] values.


Involvement of the oxygen storage protein myoglobin in muscle damage under oxidative stress.
Myoglobin (Mb), the muscular oxygen reservoir, was shown to possess peroxidative reactivity in presence of H2O2 leading to oxidation of isolated cellular proteins like myosin. The objective of this study was to investigate the peroxidative effect of Mb/H2O2 on proteins in intact myofibrils (MF). Incubation of chicken leg MF in isotonic, pH 7.3 buffer at 37 degrees C in the presence of Mb (30 microM) and H2O2 (200 microM), resulted in aggregation of MF material as inspected under light microscope. SDS-PAGE analysis revealed presence of high molecular weight aggregates at the expense of myosin heavy chains, but not actin. This crosslinking was unaffected by S-S reducing agents. Continuous low flow (0.03-3.00 microM/minute), produced by glucose oxidase and glucose, was more active than bolus H2O2 addition in myosin crosslinking in MF material. Hemin which may be released from Mb under oxidative stress, was more active than Mb as a trigger of MF peroxidative aggregation. Calcium-ATPase activity of crosslinked MF was considerably lost. These findings suggest that Mb/H2O2 may lead to oxidation of neighbouring muscular protein thereby jeopardize their functioning thus explaining muscular malfunction under oxidative stress.


Visual abstracting as a decision-making tool in the selection of mediated material.
Visual Abstracts are abbreviated versions of complete instructional packages, designed to serve as decision-making tools for instructors to evaluate whether or not the complete package will meet desired instructional needs. This article describes development of four prototype visual abstracts and a pilot field test. The pilot field testing indicated that all four prototype visual abstracts were effective decision-making tools. Further research is clearly indicated to more fully document the effectiveness of visual abstracts.


A large non-marine turtle from the Upper Cretaceous of Alabama and a review of North American "Macrobaenids".
The abundant record of marine turtles from the Late Cretaceous of Appalachia contrasts with the relatively poor record of contemporaneous terrestrial and freshwater species. A new taxon from the Santonian-Campanian of Alabama, Appalachemys ebersolei gen. et sp. nov., is described here and assigned to a grade of freshwater turtles known as "macrobaenids." Appalachemys can be differentiated from other "macrobaenids" by the presence of a nearly round carapace, deep nuchal emargination, and nine pairs of costals. With a carapace more than 80 cm in length, Appalachemys is among the largest freshwater turtles to ever inhabit North America. The absence of pre-Campanian "macrobaenids" from Laramidia indicates that the North American distribution of this grade may have been restricted to Appalachia prior to the recession of the Western Interior Seaway. Phylogenetic analysis places Appalachemys as the sister taxon to all post-Santonian "macrobaenids." Although the phylogeny lacks statistical support, it demonstrates morphological similarities between the K/Pg boundary species Osteopygis emarginatus and Maastrichtian-Danian species referred to Judithemys. We, therefore, refer all but the Campanian type species of Judithemys to the genus Osteopygis. A review of all North American "macrobaenid" occurrences reveals that despite originating in Asia, the record of the grade (as defined here) is predominantly North American. Future studies can test whether late Paleocene records in Asia and Europe resulted from dispersal from North America.


Empathy, diversity, and telepathy in mother-daughter dyads: an empirical investigation utilizing Rogers' conceptual framework.
The purpose of this study was to examine empathy, diversity, and telepathy in natural mother-daughter dyads. The investigation was conceptualized and conducted according to the concepts and principles of the Rogerian Science of Unitary Human Beings. The sample for this descriptive study consisted of 180 volunteer mother-daughter dyads; the mother served as the receiver and the child as sender of telepathic messages. Empathy and diversity were expected to be related to telepathy levels. Results indicated that one form of empathy (personal distress) and diversity were significantly (p less than .05) related to telepathy. When the components of the diversity score were further examined, only those subjects who were moderately differentiated and mobile demonstrated significant telepathy scores. Multiple regression analysis showed that 6% of the variance in telepathy was accounted for by diversity and empathy. Findings added to what is known about living systems that manifest negentrophy and evolve toward increasing diversity.


The safety and efficacy of bladder cryoablation in a beagle model by using a novel balloon cryoprobe.
The poor quality of initial transurethral resection (TUR) would leave residual tumor and compromise the prognosis. The common therapeutic option is to perform re-TUR, which adds burden to patients. We assumed that cryoablation could be applied as adjuvant therapy combined with TUR, thus lead to maxium tumor control. In our study, we investigated the safety and effects of focal bladder wall cryoablation in beagle model using a novel cryoablation balloon probe. Temperature was recorded throughout the freeze process in different parts of the bladder. The bladder was harvested immediately, 2 weeks or 3 months after surgery for histological evaluation. The results demonstrated cryoablation using our newly designed probe is safe and effective. Two-minute cryoablation could induce necrosis within 2-cm range in diameter to superficial muscle layer. The findings provided us reference before cryoablation could be applied in clinical practice.


Which is a more reliable indicator of survival after gastric cancer surgery: Postoperative complication occurrence or C-reactive protein elevation?
The impact of postoperative complications on long-term outcome has been reported in several types of malignancies. However, it is unclear why postoperative complications affect long-term outcome. The aim of this study is evaluating whether postoperative complication occurrence or C-reactive protein (CRP) elevation better reflects long-term outcome in gastric cancer patients. This study included 305 patients who underwent curative surgery for pT2-T4b gastric cancer. Patients were divided into two groups based on the peak CRP value (CRPmax): low (<12 mg/dl) and high CRPmax (≥ 12 mg/dl). A multivariate analysis was conducted to identify independent prognostic factors for recurrence-free survival (RFS). Postoperative complications (≥ Grade II) occurred in 86 of 305 patients (28.2%). Although CRP elevation (P = 0.001) and postoperative complication occurrence (P = 0.045) was each significantly associated with RFS in the univariate analysis, multivariate analysis identified CRP elevation (P = 0.017) but not complication occurrence (P = 0.682) as an independent prognostic factor. Among patients without complications, those in the high CRPmax group had significantly worse RFS than those in the low CRPmax group (P = 0.004). CRP elevation is a more reliable indicator of survival after gastric cancer surgery than postoperative complication occurrence. Surgeons should minimize the postoperative inflammatory response to improve prognosis.


Molecular epidemiological study of molluscum contagiosum virus in two urban areas of western Japan by the in-gel endonuclease digestion method.
The in-gel endonuclease digestion method was introduced for the molecular epidemiology of molluscum contagiosum virus (MCV). We obtained clear electrophoretic patterns from 90.3% of single lesions. The distribution of MCV types in Western Japan was revealed to be different from that in other countries.


Upper extremity injuries due to medications.
One hundred eleven patients were treated for upper extremity complications due to therapeutic agents. Forty-nine injuries were associated with chemotherapy and 62 with so-called "non-toxic" solutions. Twenty-five required debridement and skin coverage operations, and six required emergency fasciotomies. The most effective regimen included immediately stopping the intravenous line, elevation, avoidance of antidotes, late debridement and coverage, and early rehabilitation.


Pharmacokinetics of buspirone in elderly subjects.
Twenty-four men and 24 women ages 20-77 years received a single 15 mg oral dose of buspirone followed by 4 days of 15 mg tid administration. Plasma concentrations of buspirone and 1-pyrimidinylpiperazine following both single and multiple dosing were determined by RIA and GCMS, respectively. There were no significant differences between the young and elderly of either gender with regard to buspirone AUC, Cmax, Tmax and half-life values. The 1-PP AUC values were higher for young of either gender compared to the corresponding group of elderly subjects and the 1-PP Cmax values were higher for women than men. These differences are unlikely to be of clinical significance. The buspirone and 1-PP AUC values for a dosing interval during multiple dosing are not significantly different than the respective single dose AUC values. Buspirone treatment was well-tolerated by all subjects even though the 45 mg/day dose was 3 times the recommended starting dose in clinical practice. Overall, the lack of marked or consistent differences in buspirone or 1-PP pharmacokinetics in elderly subjects compared to younger subjects of the same gender suggest there is no need to alter the initial dose of buspirone based solely on patient age.


Environmental water extracts differentially activate zebrafish and human nuclear progesterone receptors.
Many reports on anti-progestogenic activities in aquatic environments have been published in the past decade. These are monitored mainly by in vitro reporter gene bioassays based upon the human progesterone receptor (PR). However, results obtained by some human in vitro bioassays may not be relevant for aquatic animals, especially fish. The present work aimed to detect fish (anti-)PR activity in waste- and receiving surface waters. In parallel, human (anti-)PR activity was analysed to determine if there was any connection between human and fish (anti-)PR activities. Finally, (anti-)PR activities were linked to the occurrence of progestins in water samples. Human PR agonistic activity was detected in all wastewater and most receiving surface water samples. Nevertheless, zebrafish PR (zfPR) agonistic activity was found in only two influent wastewater samples (max. 117 ng/L 17α,20β-dihydroxy-4-pregnen-3-one [DHP] equivalents). Analysed synthetic progestins and progesterone accounted for 14 % to 161 % of detected human PR (hPR) agonistic activity in water samples. Progesterone also contributed significantly to zfPR agonistic activity (up to 10 %) in raw wastewater. The anti-hPR activity was detected also in most wastewater and some surface water samples, but synthetic progestins did not trigger anti-zfPR activity in excess of LOQ values. In addition, altrenogest, dienogest, and ulipristal acetate were tested for their potency to zfPR for the first time. The activity analyses of both pure substances and environmental samples showed that human and zebrafish progesterone receptors are differentially activated. Therefore, results based on human PR in vitro bioassays could not predict fish PR activities in the environment.


The Fungal Root Endophyte Serendipita indica (Piriformospora indica) Enhances Bread and Durum Wheat Performance under Boron Toxicity at Both Vegetative and Generative Stages of Development through Mechanisms Unrelated to Mineral Homeostasis.
While the importance of beneficial soil microorganisms for soil health and crop performance has been receiving ever-increasing attention, Serendipita indica has been widely studied as a fungal root endophyte with significant potential for increasing the stress tolerance of host plants. Boron (B) toxicity as an adverse soil condition is particularly prevalent in arid and semi-arid regions and threatens crop production. Studies on S. indica-wheat symbiosis are limited, and effects of S. indica on crops have never been reported in the context of B toxicity. Here, two pot experiments were conducted under greenhouse conditions to investigate the effects of S. indica on the growth and yield parameters of bread (Triticum aestivum) and durum wheat (Triticum durum) grown at different levels of B toxicity in native vs. sterilized soil, and parameters related to root colonization, membrane damage, oxidative stress, chlorophyll, and mineral nutrition were measured to elucidate the physiological mechanisms of damage and benefit. Boron toxicity decreased early vegetative growth and grain yield, but it did not affect the straw dry weight of mature plants, whereas S. indica significantly enhanced the vegetative growth, straw dry weight, and the grain number of both wheat species. Membrane damage as demonstrated by increased lipid peroxidation and relative electrolyte leakage was caused by B toxicity and alleviated by S. indica. The benefits provided by S. indica could not be attributed to any significant changes in tissue concentrations of B or other minerals such as phosphorus. Soil sterilization generally improved plant performance but it did not consistently strengthen or weaken the effects of S. indica. The presented results suggest that S. indica may be used as an effective microbial inoculant to enhance wheat growth under adverse soil conditions such as B toxicity through mechanisms that are possibly unrelated to mineral homeostasis.


Heparin induced thrombocytopenia with mechanical circulatory support devices: review of the literature and management considerations.
Whether for temporary or long term use, mechanical circulatory support (MCS) has seen increased utilization and interest over the past several years. Even though these devices innately cause thrombocytopenia, co-administration of heparin anticoagulation carries the risk for heparin-induced thrombocytopenia (HIT). This poses challenges for practitioners as very few studies provide guidance for the management of this condition, particularly in this population. This has led to a wide spectrum of treatment protocols within current practice. This review was developed to bring together available literature on the management of HIT in patients with MCS along with practical experience and clinical opinion in order to help guide the management of these patients.


Deep sequencing-based transcriptome analysis of Plutella xylostella larvae parasitized by Diadegma semiclausum.
Parasitoid insects manipulate their hosts' physiology by injecting various factors into their host upon parasitization. Transcriptomic approaches provide a powerful approach to study insect host-parasitoid interactions at the molecular level. In order to investigate the effects of parasitization by an ichneumonid wasp (Diadegma semiclausum) on the host (Plutella xylostella), the larval transcriptome profile was analyzed using a short-read deep sequencing method (Illumina). Symbiotic polydnaviruses (PDVs) associated with ichneumonid parasitoids, known as ichnoviruses, play significant roles in host immune suppression and developmental regulation. In the current study, D. semiclausum ichnovirus (DsIV) genes expressed in P. xylostella were identified and their sequences compared with other reported PDVs. Five of these genes encode proteins of unknown identity, that have not previously been reported. De novo assembly of cDNA sequence data generated 172,660 contigs between 100 and 10000 bp in length; with 35% of > 200 bp in length. Parasitization had significant impacts on expression levels of 928 identified insect host transcripts. Gene ontology data illustrated that the majority of the differentially expressed genes are involved in binding, catalytic activity, and metabolic and cellular processes. In addition, the results show that transcription levels of antimicrobial peptides, such as gloverin, cecropin E and lysozyme, were up-regulated after parasitism. Expression of ichnovirus genes were detected in parasitized larvae with 19 unique sequences identified from five PDV gene families including vankyrin, viral innexin, repeat elements, a cysteine-rich motif, and polar residue rich protein. Vankyrin 1 and repeat element 1 genes showed the highest transcription levels among the DsIV genes. This study provides detailed information on differential expression of P. xylostella larval genes following parasitization, DsIV genes expressed in the host and also improves our current understanding of this host-parasitoid interaction.


Characterization of cyclophosphamide-induced suppressor cells.
Spleen cells from mice injected with cyclophosphamide (200 mg/kg body weight) suppress the secondary immunoglobulin (IgG antibody response of memory cells to a T-dependent antigen, dinitrolphenylated (DNP) human gamma globulin, in Millipore diffusion chambers. Characterization of the suppressor cell revealed that it was nylon wool nonadherent, insensitive to treatment with anti-Thy 1.2 or anti-Ig serum plus C, found in spleen but not thymus or lymph nodes, generated in thymectomized mice and nude mice, and heat-sensitive. Because of these unique characteristics, it was concluded that the suppressor cell was not a typical B cell, T cell, or macrophage. The suppressor cell was found to be regulated, i.e., inhibited, by a T cell found in the thymus and possibly the lymph nodes of normal mice. The suppressor cells may have biological significance in relation to development of self-tolerance.


Intraepidermal type VII collagen. Evidence for abnormal intracytoplasmic processing of a major basement membrane protein in rare patients with dominant and possibly localized recessive forms of dystrophic epidermolysis bullosa.
Of 84 patients with dystrophic forms of epidermolysis bullosa consecutively enrolled in the National Epidermolysis Bullosa Registry, four were noted by indirect immunofluorescence with the LH 7:2 monoclonal antibody to have granular basilar keratinocyte intracytoplasmic deposits, rather than exclusively linear basement membrane deposits, of type VII collagen. Indirect immunoelectron microscopy demonstrated that these deposits were primarily perinuclear, although lesser amounts were also detectable between tonofibril bundles, within hemidesmosomes, and within and beneath the lamina densa. In two patients the mode of transmission was autosomal dominant; in two others the inheritance pattern was unknown. Whereas widespread lesions were present at birth, in each case blistering ceased within the first year of life, reminiscent of the findings in transient bullous dermolysis of the newborn. We interpret these laboratory findings as indicative of the presence of a defect in the intracytoplasmic packaging or in the transport of type VII collagen within basilar keratinocytes.


Radiofrequency Ablation-Induced Tumor Growth Is Suppressed by MicroRNA-21 Inhibition in Murine Models of Intrahepatic Colorectal Carcinoma.
To investigate the role of microRNA-21 (miR21) in radiofrequency (RF) ablation-induced tumor growth and whether miR21 inhibition suppresses tumorigenesis. Standardized liver RF ablation was applied to 35 C57/BL6 mice. miR21 and target proteins pSTAT3, PDCD4, and PTEN were assayed 3 hours, 24 hours, and 3 days after ablation. Next, 53 Balb/c and 44 C57BL/6 mice received Antago-miR21 or scrambled Antago-nc control, followed by intrasplenic injection of 10,000 CT26 or MC38 colorectal tumor cells, respectively. Hepatic RF ablation or sham ablation was performed 24 hours later. Metastases were quantified and tumor microvascular density (MVD) and cellular proliferation were assessed at 14 or 21 days after the procedures, respectively. RF ablation significantly increased miR21 levels in plasma and hepatic tissue at 3 and 24 hours as well as target proteins at 3 days after ablation (P < .05, all comparisons). RF ablation nearly doubled tumor growth (CT26, 2.0 SD ± 1.0 fold change [fc]; MC38, 1.9 SD ± 0.9 fc) and increased MVD (CT26, 1.9 SD ± 1.0 fc; MC38, 1.5 ± 0.5 fc) and cellular proliferation (CT26, 1.7 SD ± 0.7 fc; MC38, 1.4 SD ± 0.5 fc) compared with sham ablation (P < .05, all comparisons). RF ablation-induced tumor growth was suppressed when Antago-miR21 was administered (CT26, 1.0 SD ± 0.7 fc; MC38, 0.9 SD ± 0.4 fc) (P < .01, both comparisons). Likewise, Antago-miR21 decreased MVD (CT26, 1.0 SD ± 0.3 fc; MC38, 1.0 SD ± 0.2 fc) and cellular proliferation (CT26, 0.9 SD ± 0.3 fc; MC38, 0.8 SD ± 0.3 fc) compared with baseline (P < .05, all comparisons). RF ablation upregulates protumorigenic miR21, which subsequently influences downstream tumor-promoting protein pathways. This effect can potentially be suppressed by specific inhibition of miR21, rendering this microRNA a pivotal and targetable driver of tumorigenesis after hepatic thermal ablation.


Assessment of alcohol consumption by mailed questionnaire in epidemiological studies: evaluation of misclassification using a dietary history interview and biochemical markers.
Self-reported information on alcohol from questionnaires is generally assumed to introduce misclassification of consumption, mainly in the direction of underestimation. The aim of this study was to evaluate self-reported information on alcohol consumption from a mailed questionnaire by comparing to a dietary history interview and biochemical markers of alcohol intake. For 76 male twin pairs of the Finnish Twin Cohort Study aged 40-70 years information on self-reported alcohol consumption was collected through mailed questionnaire and dietary history interview. Carbohydrate-deficient transferrin (CDT), Gamma-glutamyltransferase (Gamma-GT) and mean corpuscular volume (MCV) were determined from blood samples. Mean levels of CDT, gamma-GT and MCV showed a rise with increased self-reported alcohol consumption already at low levels of reported consumption (<20 g alcohol/day). There was a positive correlation between reported amount alcohol intake per day and levels of CDT (r = 0.46), gamma-GT (r = 0.32) and MCV (r = 0.36) but within the high consumption group (> or = 30 g/day) there was no such correlation. The questionnaire had sensitivity of 28-43% and specificity of 89% for identification of high consumers of alcohol using the biochemical markers as reference and sensitivity 41% and specificity 94% using the dietary history interview as reference. Sensitivity was improved when information on binge drinking (82%) or possible drinking problems (73%) was considered. Comparison to dietary history interview as well as to biochemical markers indicate that self-reported information on alcohol consumption from a mailed questionnaire may be used to distinguish between groups with different levels of alcohol consumption. The suggested misclassification of high consumers implies that only strong associations between high alcohol intake and disease are likely to be detected in studies based on questionnaire data.


Red cabbage yield, heavy metal content, water use and soil chemical characteristics under wastewater irrigation.
The objective of this 2-year field study was to evaluate the effects of drip irrigation with urban wastewaters reclaimed using primary (filtration) and secondary (filtration and aeration) processes on red cabbage growth and fresh yield, heavy metal content, water use and efficiency and soil chemical properties. Filtered wastewater (WW1), filtered and aerated wastewater (WW2), freshwater and filtered wastewater mix (1:1 by volume) (WW3) and freshwater (FW) were investigated as irrigation water treatments. Crop evapotranspiration decreased significantly, while water use efficiency increased under wastewater treatments compared to FW. WW1 treatment had the lowest value (474.2 mm), while FW treatments had the highest value (556.7 mm). The highest water use efficiency was found in the WW1 treatment as 8.41 kg m(-3), and there was a twofold increase with regard to the FW. Wastewater irrigation increased soil fertility and therefore red cabbage yield. WW2 treatment produced the highest total fresh yield (40.02 Mg ha(-1)). However, wastewater irrigation increased the heavy metal content in crops and soil. Cd content in red cabbage heads was above the safe limit, and WW1 treatment had the highest value (0.168 mg kg(-1)). WW3 treatment among wastewater treatments is less risky in terms of soil and crop heavy metal pollution and faecal coliform contamination. Therefore, WW3 wastewater irrigation for red cabbage could be recommended for higher yield and water efficiency with regard to freshwater irrigation.


Development of evidence-based consensus on critical issues in the management of patients with vitiligo: A modified Delphi study.
Vitiligo remains a major challenge in dermatology. However, much of the treatment remains unclear, because little evidence is available. We sought to answer some critical questions pertaining to management of vitiligo patients. A modified Delphi process among 31 vitiligo experts was conducted. A total of 12 clinical vitiligo treatment questions without clear answers were collected via a vote. To address each question, two members performed systematic literature reviews and prepared draft statements along with the levels of evidence and strength of recommendation. After reviewing the draft, all expressed their extent of agreement from 1 (strong disagreement) to 9 (strong agreement) for each item. The drafts were revised to reflect suggested comments. Discussion continued until all members agreed with the ultimate decision. The consensus process was completed after five rounds. We identified the best answers to 12 key questions, including issues on long-term phototherapy, systemic and topical corticosteroids, topical calcineurin inhibitors, immunosuppressants, excimer laser treatment, and surgical interventions. This consensus would complement current guidelines and aid both physician and patient decision-making in the treatment of vitiligo.


Estimating more than two pure component spectra from only two mixture spectra using two-dimensional correlation.
A procedure is described to estimate the pure component spectra of mixtures from only a pair of available spectra even when there are more than two component species present in the system. In contrast, traditional multivariate curve resolution (MCR) technique cannot be used for such a case. The method relies on the use of two-trace two-dimensional (2T2D) correlation spectroscopy. Asynchronous 2T2D spectrum is used to identify the characteristic bands most strongly associated with the individual mixture component species. Correlation coefficients derived from the synchronous 2T2D spectrum are used to obtain a set of correlative filtering functions to distribute the spectral intensity of the average spectrum among the estimates of the pure component spectra. Efficacy of the method was demonstrated using a pair of ATR IR spectra obtained for two solution mixtures containing three main ingredients with very similar compositions. Relatively congested and overlapped spectral region was used first for the demonstration, and reasonable resolution was accomplished yielding a set of the estimates of pure component spectra with most of the expected pertinent features included. The analysis was then extended to a broader spectral region containing well-isolated spectral signatures of individual components for positive validation. While traditional MCR technique seems to perform better with a large number of spectra, this technique can be effectively used in conjunction with MCR to improve its stability and performance, especially under some challenging conditions.


Cost-effectiveness of a 12-month fixed-duration venetoclax treatment in combination with obinutuzumab in first-line, unfit chronic lymphocytic leukemia in the United States.
BACKGROUND: Chronic lymphocytic leukemia (CLL) is a significant health and economic burden in the United States. Treatments include chemoimmunotherapy, such as obinutuzumab (G) plus chlorambucil (Clb) or bendamustine plus rituximab (BR), and chemotherapy-free regimens incorporating oral targeted therapies such as ibrutinib (Ibr), acalabrutinib (Acala), or venetoclax (Ven). Most chemotherapy-free regimens require continuous treatment to progression, while Ven plus G (VenG) is given for a fixed duration of 12 months, based on the CLL14 trial that led to its approval. Fixed-duration VenG has the potential for cost savings compared with treat-to-progression chemotherapy-free regimens. OBJECTIVE: To evaluate the cost-effectiveness of 12 months fixed-duration VenG in first-line treatment of unfit patients with CLL from a US health care payer perspective compared with GClb, BR, Ibr, Ibr + G, Ibr + R, Acala, and Acala + G. METHODS: A partitioned survival model was developed with 3 health states: progression-free survival (PFS), postprogression survival, and dead. The patient population, as based on the CLL14 trial, comprised previously untreated unfit patients with CLL (mean age 71.1 years, 33.1% female). The distribution of patients in each health state over time was estimated using extrapolated PFS and overall survival (OS) curves for VenG and GClb, based on CLL14 data 2 or more years after treatment cessation. PFS and OS for the other comparators were estimated using hazard ratios vs VenG, based on a network metaanalysis. Adverse events, utility values, and costs were obtained from published literature. The model estimated life-years gained, quality-adjusted life-years (QALYs) gained, and costs. The time horizon was 20 years, with a cycle time of 28 days. Outcomes and costs were discounted at 3.0% per year, and costs were estimated from a US health care payer perspective. One-way and probabilistic sensitivity analyses were conducted. RESULTS: In this cross-trial analysis of unfit CLL patients, in the base case, VenG had lower projected total costs than all comparators investigated. VenG also had larger projected health benefits (more QALYs gained) than GClb, BR, Ibr, and Ibr + R. VenG was therefore more effective and less costly than these comparators (dominant). Ibr + G, Acala, and Acala + G showed higher QALYs gained vs VenG (0.022, 0.672, and 0.961, respectively), and substantially higher projected costs vs VenG ($1,488,400, $1,579,737, and $1,656,154, respectively). Thus, Ibr + G, Acala, and Acala + G would cost more than $1,000,000 per QALY gained vs VenG. At the commonly used willingness-to-pay threshold of $150,000 per QALY gained, Ibr + G, Acala, and Acala + G were not cost-effective compared with VenG. CONCLUSIONS: Fixed-duration VenG for 12 months is a cost-effective first-line treatment option for unfit CLL patients compared with other available options and provides value for money to US health care payers at a threshold of $150,000 per QALY gained. Future studies with longer trial follow-up and more mature survival data may help to confirm longer-term cost benefits of VenG. DISCLOSURES: Genentech Inc. and AbbVie provided financial support for this study. Genentech Inc., AbbVie, and Pharmerit - An OPEN Health Company participated in the design, study conduct, analysis, and interpretation of data, as well as the writing, review, and approval of the manuscript. Venetoclax is being developed in a collaboration between Genentech Inc. and AbbVie. Ravelo and Shapouri are employed by Genentech Inc. and have ownership interests. Manzoor and Sail are employed by AbbVie and have ownership interests. Chatterjee, van de Wetering, and Qendri, employees of Pharmerit - An OPEN Health Company, received consultancy fees from AbbVie. Davids has received consultancy fees from AbbVie, AstraZeneca, Eli Lilly, Genentech Inc., Janssen, MEI Pharma, Novartis, Pharmacyclics, and Verastem; research funding from Ascentage Pharma, Genentech Inc., MEI Pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, and Verastem; and has served on board of directors or advisory committees for AbbVie, Adaptive Biotechnologies, AstraZeneca, BeiGene, Eli Lilly, Genentech Inc., Janssen, Pharmacyclics, TG Therapeutics, and Verastem. This study was presented as a poster at ASH 61st Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL.


Synthesis, Characterization and In vitro Antitumour Activity of Novel Organotin Derivatives of 1,2- and 1,7-Dicarba-Closo-dodecaboranes.
Several organotin derivatives of 1,2- and 1,7-dicarba-closo-dodecaboranes were synthesized and characterized by (119)Sn Mössbauer, (1)H, (13)C and (119)Sn NMR spectroscopy. Their antitumour activities in vitro against cancerous cell lines of human origin are reported.


Quantitative studies of neuronal RNA on the subiculum of demented old individuals.
Autopsied human brains from three patients with senile dementia were studied for the effect of neurofibrillary tangles on neuronal RNA content. Nerve cell bodies were dissected out from the subiculum under the phase contrast microscope and were separated into two groups based on the presence or absence of neurofibrillary tangles within the perikaryon. It was found that the mean RNA content of the tangle-bearing cells was 28.61 pg, whereas that measured in nerve cell bodies considered as free from the tangles was 41.21 pg. Thus, a significant decrease in neuronal RNA content could be correlated to an excess accumulation of neurofibrillary tangles.


A phase II trial of chimeric monoclonal antibody G250 for advanced renal cell carcinoma patients.
Chimeric monoclonal antibody G250 (WX-G250) binds to a cell surface antigen found on >90% of renal cell carcinoma (RCC). A multicentre phase II study was performed to evaluate the safety and efficacy of WX-G250 in metastatic RCC (mRCC) patients. In all, 36 patients with mRCC were included. WX-G250 was given weekly by intravenous infusion for 12 weeks. Patients with stable disease (SD) or response were eligible to receive additional treatment for 8 weeks. None of the 36 enrolled patients experienced any drug-related grade III or IV toxicity. Only three patients had grade II toxicity possibly related to the study medication. In all, 10 patients had SD and received extended treatment. One complete response and a significant regression was observed during the follow-up of the treatment. Five patients with progressive disease at study entry were stable for more than 6 months after study entry. The median survival after treatment start was 15 months. The weekly schedule of WX-G250 was well tolerated. With a median survival of 15 months after the start of this treatment and two late clinical responses, WX-G250 seems to be able to modulate mRCC. To improve the activity of WX-G250-specific antibody-dependent cellular cytotoxicity and the clinical response rate, currently combinations of WX-G250 with cytokines are in phase II trials.


[Physiology of the visual retinal signal: From phototransduction to the visual cycle].
The retinal photoreceptors (rods and cones) are responsible for light absorption and transduction of the signal, which is transmitted to the other retinal nerve cells and then to the brain. The chromophore of visual pigments of rods and cones is a particular isomer of a vitamin A derivative. Light absorption by this chromophore leads to its isomerization and to a phototransduction cascade, which results in photoreceptor hyperpolarization and cessation of glutamate secretion at their synaptic terminals. Phototransduction of cones and rods differs in their signal amplification and inactivation, which is consistent with their respective functions. The rods serve for dim light vision, whereas color and detailed vision is provided by cones. The rods are thus much more sensitive than cones, but the time course of cones' photoresponse is ∼10 times faster than that of rods. The orientation of cone visual pigments in the retina is optimized to achieve their function. The isomerized chromophore of visual pigments is regenerated by a mechanism known as the visual cycle. This process takes place mainly in the retinal pigment epithelium for the rods and the glial Müller cells for the cones. Mutations of a large number of proteins involved in visual phototransduction and in the retinoid visual cycle are responsible for hereditary diseases leading to photoreceptor degeneration. However, gene therapy offers quite a bit of hope for treatment.