Short- and Long-term Outcomes of Ileal Pouch Anal Anastomosis Construction in Obese Patients With Ulcerative Colitis.
Obese patients are traditionally considered difficult pouch candidates because of the potential for intraoperative technical difficulty and increased postoperative complications. The purpose of this study was to compare the outcomes of obese versus nonobese patients with ulcerative colitis undergoing an IPAA. This is a retrospectively, propensity score-matched, prospectively collected cohort study. This study was conducted at an IBD quaternary referral center. Patients with ulcerative colitis undergoing IPAA (1990-2018) were included. Obesity was defined as a BMI ≥30 kg/m 2 . The primary measures included 30-day complications, long-term anastomotic leak, and pouch failure rate (excision, permanent diversion, revision). Of 3300 patients, 631 (19.1%) were obese (median BMI = 32.4 kg/m 2 ). On univariate analysis, obese patients were more likely to be >50 years old (32.5% versus 22.7%, p < 0.001), ASA class 3 (41.7% versus 27.7%, p < 0.001), have diabetes (8.1% versus 3.3%, p < 0.001), and have had surgery in the biologic era (72.4% versus 66.2%, p = 0.003); they were less likely to have received preoperative steroids (31.2% versus 37.4%, p = 0.004). After a median follow-up of 7 years, 66.7% had completed at least 1 quality-of-life survey. Pouch survival in the matched sample was 99.2% (99.8% nonobese versus 95.4% obese, p = 0.002). After matching and controlling for confounding variables, worse clinical outcomes associated with obesity included global quality of life (relative risk, -0.71; p = 0.002) and long-term pouch failure (HR, 4.24; p = 0.007). Obesity was also independently associated with an additional 27 minutes of operating time ( p < 0.001). There was no association of obesity with the likelihood of developing a postoperative complication, length of stay, or pouch leak. Restorative ileoanal pouch surgery in obese patients with ulcerative colitis is associated with a relatively decreased quality of life and increased risk of long-term pouch failure compared with nonobese patients. Obese patients may benefit from focused counseling about these risks before undergoing restorative pouch surgery. See Video Abstract at http://links.lww.com/DCR/B873 . ANTECEDENTES:Habitualmente se considera a los obesos como pacientes difíciles para la realización de un reservorio ileal, debido a su alta probabilidad de presentar dificultades técnicas intraoperatoria y aumento de las complicaciones posoperatorias.OBJETIVO:El propósito de este estudio fue comparar los resultados de pacientes con colitis ulcerosa obesos versus no obesos sometidos a un reservorio ileal y anastomosis anal (IPAA).DISEÑO:Este es un estudio de cohorte recopilado prospectivamente, retrospectivo, emparejado por puntajes de propensión.AJUSTE:Este estudio se llevó a cabo en un centro de referencia de cuarto nivel para enfermedades inflamatorias del intestino.PACIENTES:Se incluyeron pacientes con colitis ulcerosa sometidos a un reservorio ileal y anastomosis anal (1990-2018). Obesidad definida como un IMC ≥ 30 kg/m2.PRINCIPALES RESULTADO MEDIDOS:Los principales resultados medidos incluyeron complicaciones a los 30 días, fuga anastomótica a largo plazo y tasa de falla del reservorio ileal (escisión, derivación permanente, revisión).RESULTADOS:De 3.300 pacientes, 631 (19,1%) eran obesos (mediana de IMC = 32,4 kg/m2). En el análisis univariado, los pacientes obesos tenían más probabilidades de ser > 50 años (32,5% frente a 22,7%, p < 0,001), clase ASA 3 (41,7% frente a 27,7%, p < 0,001), tener diabetes (8,1% frente a 3,3%, p < 0,001), haberse sometido a cirugía en la era biológica (72,4% frente a 66,2%, p = 0,003), y tenían menos probabilidades de haber recibido esteroides preoperatorios (31,2% frente a 37,4%, p = 0,004). Después de una mediana de seguimiento de 7 años, el 66,7% había completado al menos una encuesta de calidad de vida. La supervivencia de la bolsa en la muestra emparejada fue del 99,2% (99,8% no obesos versus 95,4% obesos, p = 0,002). Después de emparejar y controlar las variables de confusión, los peores resultados clínicos asociados con la obesidad incluyeron la calidad de vida global (RR = -0,71, p = 0,002) y el fracaso de la bolsa a largo plazo (HR = 4,24, p = 0,007). La obesidad también se asoció de forma independiente con 27 minutos adicionales de tiempo quirúrgico ( p < 0,001). No hubo asociación de la obesidad con la probabilidad de desarrollar una complicación posoperatoria, la duración de la estadía o la fuga de la bolsa.CONCLUSIÓNES:La cirugía restauradora del reservorio ileoanal en pacientes obesos con colitis ulcerosa se asocia a una disminución relativa de la calidad de vida y un mayor riesgo de falla del reservorio a largo plazo en comparación con los pacientes no obesos. Los pacientes obesos pueden beneficiarse de un asesoramiento centrado en estos riesgos antes de someterse a una cirugía restauradoracon reservorio ileal y anastomosis anal. Consulte Video Resumen en http://links.lww.com/DCR/B873 . (Traducción-Dr. Rodrigo Azolas ).


Genetic diversity among genotypes of Uncaria guianensis (Aubl.) J.F. Gmel. maintained in an in vitro germplasm bank.
Phytotherapeutic preparations from Uncaria guianensis (Aubl.) J.F. Gmel. (Rubiaceae) are marketed worldwide and are mainly used for their anti-inflammatory activity. The species has not yet been domesticated and is threatened by deforestation and overexploitation. It is, therefore, important to preserve and manage this genetic resource in germplasm banks, so that the extractive provision of plant material can be replaced by cultivated production. The aim of this study was to evaluate the genetic diversity among 20 genotypes maintained under in vitro conditions using 9 primers start codon targeted (SCoT) polymorphism, and to determine the concentrations of the pentacyclic oxindole alkaloids (POAs); mitraphylline and isomitraphylline in methanolic extracts by high-performance liquid chromatography (HPLC). Plantlets were cultivated on woody plant medium supplemented with 20 g.L-1 sucrose and 4.4 μM benzylaminopurine and incubated under a 16 h photoperiod for 45 days. SCoT analysis separated the genotypes into four divergent clusters and confirmed significant genetic diversity with up to 70% dissimilarity. Moreover, HPLC revealed considerable chemical variability and allowed the separation of the tested genotypes into high, medium and low producers of mitraphylline/isomitraphylline. Genotypes with the highest concentrations of POAs originated from the state of Acre and Amapá, while those with the lowest levels were from the state of Pará. The results demonstrate that the genetic diversity within the in vitro germplasm bank is sufficient to support breeding studies, selection of elite genotypes and the large-scale multiplication of plants that could serve as feedstock for the industrial-scale production of phytomedicines. The online version contains supplementary material available at 10.1007/s13205-021-03016-y.


The nature of cognitive complaints in healthy older adults with and without objective memory decline.
Cognitive and memory complaints were assessed in 100 healthy older adults on two occasions over 2.5 years as part of a 6-year study assessing cognition, mood, and general health factors. Diminished memory for names and actions and lapses in concentration were common complaints, regardless of the individuals' actual cognitive status. No change in cognitive complaints occurred over time, even for individuals whose memory had declined over 6 years. Cognitive complaints correlated with anxiety, depression, and general mental health but not with objectively measured memory or cognition, education or age. Complaints did not differ with gender, apolipoprotein E epsilon4 genotype, cardiovascular risk factors, or intake of sedating medications. Thus, cognitive complaints could not differentiate memory-declining older adults from cognitively normal older adults and were more closely associated with mood and general mental health than actual cognitive status, age, or potential risk factors for Alzheimer's disease. Thus, the evaluation of cognitive complaints must be broad and must consider the correspondence of complaints not only to relevant measurable cognitive abilities but also to the affect of the individual.


Tardive dyskinesia in Tourette syndrome.
Three patients are reported who developed oral-buccal-lingual movements typical of tardive dyskinesia while being treated with stable doses of haloperidol for Tourette syndrome. In each case signs resolved within a number of weeks after medication was discontinued. One of the patients experienced recurrence of the dyskinesia during a challenge with phenothiazine tranquilizers. In each case the dose of haloperidol was well within the usual therapeutic range. A strong family history of movement disorders, including Tourette syndrome, was present in each family.


The effects of resistance training to near failure on strength, hypertrophy, and motor unit adaptations in previously trained adults.
Limited research exists examining how resistance training to failure affects applied outcomes and single motor unit characteristics in previously trained individuals. Herein, resistance-trained adults (24 ± 3 years old, self-reported resistance training experience was 6 ± 4 years, 11 men and 8 women) were randomly assigned to either a low-repetitions-in-reserve (RIR; i.e., training near failure, n = 10) or high-RIR (i.e., not training near failure, n = 9) group. All participants implemented progressive overload during 5 weeks where low-RIR performed squat, bench press, and deadlift twice weekly and were instructed to end each training set with 0-1 RIR. high-RIR performed identical training except for being instructed to maintain 4-6 RIR after each set. During week 6, participants performed a reduced volume-load. The following were assessed prior to and following the intervention: (i) vastus lateralis (VL) muscle cross-sectional area (mCSA) at multiple sites; (ii) squat, bench press, and deadlift one-repetition maximums (1RMs); and (iii) maximal isometric knee extensor torque and VL motor unit firing rates during an 80% maximal voluntary contraction. Although RIR was lower in the low- versus high-RIR group during the intervention (p < 0.001), total training volume did not significantly differ between groups (p = 0.222). There were main effects of time for squat, bench press, and deadlift 1RMs (all p-values < 0.05), but no significant condition × time interactions existed for these or proximal/middle/distal VL mCSA data. There were significant interactions for the slope and y-intercept of the motor unit mean firing rate versus recruitment threshold relationship. Post hoc analyses indicated low-RIR group slope values decreased and y-intercept values increased after training suggesting low-RIR training increased lower-threshold motor unit firing rates. This study provides insight into how resistance training in proximity to failure affects strength, hypertrophy, and single motor unit characteristics, and may inform those who aim to program for resistance-trained individuals.


The geriatric patient: one- or two-visit complete denture construction technique. Part 1.
The next two articles will discuss the construction of quality complete dentures in one- or two-patient appointments. Material and techniques are presented for controlling costs by reducing laboratory expenses and dentist chair time. A block unit of 12 to 14 attached flat plane acrylic teeth, light cured denture base materials and modified techniques which incorporate multiple procedures are introduced. The procedure will be divided into two segments and described in two articles. The initial article will carry the technique through the completion of the maxillo-mandibular relations and articulation for the casts. The second section, described in the second article, will encompass the set-up of the teeth, try-in of the set-up, processing of the dentures and insertion of the case.


Angiotensin receptor blockade in acute stroke. The Scandinavian Candesartan Acute Stroke Trial: rationale, methods and design of a multicentre, randomised- and placebo-controlled clinical trial (NCT00120003).
Elevated blood pressure following acute stroke is common, and yet early antihypertensive treatment is controversial. ACCESS suggested a beneficial effect of the angiotensin receptor blocker candesartan in the acute phase of stroke, but these findings need to be confirmed in new, large trials. The Scandinavian Candesartan Acute Stroke Trial is an international randomised, placebo-controlled, double-blind trial of candesartan in acute stroke. We plan to recruit 2500 patients presenting within 30 h of stroke (ischaemic or haemorrhagic) and with systolic blood pressure ≥140 mmHg. The recruited patients are randomly assigned to candesartan or placebo for 7-days (doses increasing from 4 to 16 mg once daily). Randomisation is performed centrally via a secure web interface. The follow-up period is 6-months. Patients are included from the following nine North-European countries: Norway, Sweden, Denmark, Belgium, Germany, Poland, Lithuania, Estonia and Finland. There are two co-primary effect variables: • Functional status at 6-months, measured by the modified Rankin Scale, and • vascular death, myocardial infarction or stroke during the first 6-months. Secondary outcome variables: Secondary effect variables include • the Barthel index (functional status) • EuroQol (quality of life) and • Mini-mental state examination (cognition) at 6-months • Health economic costs during the first 6-months The Scandinavian Candesartan Acute Stroke Trial receives basic funding from Norwegian health authorities. AstraZeneca supplies the trial drugs, and AstraZeneca and Takeda support the trial with limited, unrestricted grants. The Scandinavian Candesartan Acute Stroke Trial is the first large trial of angiotensin receptor blockers in patients with elevated blood pressure and acute stroke, and aims to answer whether treatment with angiotensin receptor blockers is beneficial for this indication.


Advantage of laparoscopic peritoneal toileting in acute peritonitis with unclear etiology: A case report with inspiring outcome (with video).
Acute peritonitis is a surgical emergency and is conventionally managed with exploratory laparotomy in many centers, but laparoscopy is not contraindicated in such conditions. Operative management remains a cornerstone treatment in peritonitis irrespective of the primary pathology. A 32-years-old man was admitted with acute diffuse peritonitis. As he was clinically stable, we proceeded with conservative treatment and diagnostic workup. He did not respond by 24 h and CT imaging showed ascites, but no definite diagnosis could be made. Diagnostic laparoscopy was performed, thorough peritoneal toileting was done but surprisingly the etiology was unclear. Following laparoscopy, he responded well with an uneventful recovery. Timely proper evaluation and correct intervention are a paramount concern for the positive outcome. Regarding the most effective operative approach (laparotomy or laparoscopy) in acute peritonitis remains controversial in the literature and laparoscopy has been considered as a relative contraindication. However, the laparoscopy is gaining wider acceptance as the limitations of laparoscopy are declining rapidly. We experienced a case of extensive peritonitis with unclear etiology which we managed successfully by laparoscopy. Laparoscopic approach in peritonitis is effective and helpful for accurate diagnosis and to minimize the hazards of an unnecessary laparotomy. This case report might encourage many surgeons to consider laparoscopic approach in peritonitis with confidence and to perform further studies.


The mechanism of action of the cytotoxic lectin from Phoradendron californicum: the RNA N-glycosidase activity of the protein.
A toxic lectin from Phoradendron californicum (PCL) was found to inactivate catalytically 60 S ribosomal subunits of rabbit reticulocytes, resulting in the inhibition of protein synthesis. To study the mechanism of action of PCL, rat liver ribosomes were treated with the toxin and the extracted rRNA was treated with aniline. A fragment containing about 450 nucleotides was released from the 28 S rRNA. Analysis of the nucleotide sequence of the fragment revealed that the aniline-sensitive phosphodiester bond was between A4324 and G4325 of the 28 S rRNA. These results indicate that PCL inactivates the ribosomes by cleaving an N-glycosidic bond at A4324 of 28 S rRNA in the ribosomes as does ricin A-chain.


Glucose-lowering effects of orally administered superoxide dismutase in type 2 diabetic model rats.
Superoxide dismutase (SOD) is an enzyme found in most food sources, might be a candidate to reduce oxidative damage to intestinal barrier, thereby ameliorating the vicious circle between hyperglycemia and the oxidative damage. Here we report the oral administration of SOD, liposome-embedded SOD (L-SOD), and SOD hydrolysate to type 2 diabetic model rats to confirm this hypothesis. Oxidative damage severity in model rat intestine was indicated by malondialdehyde level, GSSG/GSH ratio, and antioxidant enzyme activity. The damage was significantly repaired by L-SOD. Furthermore, blood glucose and related indexes correlated well not only with oxidative damage results but also with indexes indicating physical intestinal damage such as colon density, H&E staining, immunohistochemical analysis of the tight junction proteins occludin and ZO-1 in the colon, as well as lipopolysaccharide and related inflammatory cytokine levels. The order of the magnitude of the effects of these SOD preparations was L-SOD > SOD > SOD hydrolysate. These data indicate that orally administered SOD can exhibit glucose-lowering effect via targeting the intestine of diabetic rats and systemic lipopolysaccharide influx.


Upcycling polyethylene terephthalate wastes for enhancing the performance of polyester from rice straw polyol in HDPE-composites.
Upscaling the utilization of polymer wastes together with the valorization of undesirable waste rice straw (RS) will minimize the environmental impact of waste disposal by traditional tools. This present work assesses the utilization of polyethylene terephthalate wastes in enhancing the production of polyester-(high density polyethylene) HDPE from Rice straw polyol composites. In this respect, the polyester from rice straw polyol in hybrid with glycolysis polyethylene terephthalate wastes (Gly-WPET) was assessed in comparison with that resulted from RS-polyol, using FTIR, non-isothermal analysis, and mechanical tests. The data showed the positive role of Gly-WPET in hybrid with RS-polyol in production polyester with high thermal stability and mechanical properties. It provided an increase in activation energy of degradation, elongation, Young's Modulus, and modulus of toughness from 184.5 to 1201 kJ/mole, from 4.7 to 9.8%, from 47.5 to 66.5 MPa, and from ~ 4.0 to 23 J/m3, respectively. This behavior was reflected in the properties of HDPE-polyester polyol (PEPO) composites, especially in improving elongation (from 55.4 to 72%). These promising data persuade us to recommend the influential role of Gly-WPET in using PEPO from liquefied RS as a plasticizer.


No benefit of a structured treatment interruption based on genotypic resistance in heavily pretreated HIV-infected patients.
To evaluate the potential benefits of a tailored antiretroviral treatment interruption with duration based on the observed reversion of resistance mutations. In this open single-arm pilot study, 23 patients with multiple treatment failure interrupted therapy and underwent longitudinal genotypic resistance testing. Salvage gigatherapy was started when resistance mutations to at least two antiretroviral drug classes reverted. The primary endpoint was a fall in viral load by > 1 log10 copies/ml after 12 weeks of salvage therapy. Baseline median viral load was 5.14 log copies/ml and CD4 cell count 43 x 10 cells/l. Genotypic resistance testing showed a median of six, two and nine resistance mutations to nucleoside analogue reverse transcriptase inhibitors, non-nucleoside analogue reverse transcriptase inhibitors and protease inhibitors, respectively; viral strains were susceptible to no more than one drug in 17/23 patients. The median duration of treatment interruption was 24 weeks (range, 12-37), leading to median changes from baseline of + 0.54 log10 copies/ml and -30 x 10(6) cells/l. At the end of treatment interruption, plasma HIV was susceptible to at least three drugs in 16/23 patients. After 12 weeks of salvage multitherapy, only one patient had a decrease in viral load > 1 log copies/ml. All baseline resistance mutations recurred after treatment resumption. AIDS-defining events occurred in two-thirds of patients during the study period. In HIV-infected patients with multiple failures and no therapeutic options at baseline, significant reversion of resistance mutations after prolonged treatment interruption failed to restore antiviral efficacy of a salvage regimen and was clinically deleterious.


Decoding Neurodegeneration: A Comprehensive Review of Molecular Mechanisms, Genetic Influences, and Therapeutic Innovations.
Neurodegenerative disorders often acquire due to genetic predispositions and genomic alterations after exposure to multiple risk factors. The most commonly found pathologies are variations of dementia, such as frontotemporal dementia and Lewy body dementia, as well as rare subtypes of cerebral and cerebellar atrophy-based syndromes. In an emerging era of biomedical advances, molecular-cellular studies offer an essential avenue for a thorough recognition of the underlying mechanisms and their possible implications in the patient's symptomatology. This comprehensive review is focused on deciphering molecular mechanisms and the implications regarding those pathologies' clinical advancement and provides an analytical overview of genetic mutations in the case of neurodegenerative disorders. With the help of well-developed modern genetic investigations, these clinically complex disturbances are highly understood nowadays, being an important step in establishing molecularly targeted therapies and implementing those approaches in the physician's practice.


Summary from the Kidney Cancer Association's Inaugural Think Thank: Coalition for a Cure.
Close to 74,000 cases of renal cell carcinoma (RCC) are diagnosed each year in the United States. The past 2 decades have shown great developments in surgical techniques, targeted therapy and immunotherapy agents, and longer complete response rates. However, without a global cure, there is still room for further advancement in improving patient care in this space. To address some of the gaps restricting this progress, the Kidney Cancer Association brought together a group of 27 specialists across the areas of clinical care, research, industry, and advocacy at the inaugural "Think Tank: Coalition for a Cure" session. Topics addressed included screening, imaging, rarer RCC subtypes, combination drug therapy options, and patient response. This commentary summarizes the discussion of these topics and their respective clinical challenges, along with a proposal of projects for collaboration in overcoming those needs and making a greater impact on care for patients with RCC moving forward.


Improvement of growth and food utilization by human recombinant growth hormone in uremia.
We compared growth rate, food conversion ratio and morphology of the growth zone in female Sprague-Dawley rats with subtotal nephrectomy or sham operation. Both groups were either given vehicle or 1.4 IU/day recombinant human growth hormone (GH) by s.c. osmotic minipump, or 2.5 IU twice daily intraperitoneally for 14 or 20 days, respectively. Compared to uremic rats infused with vehicle, infusion of GH significantly (P less than 0.01) improved growth; that is, it increased gain of weight (delta 27.0 +/- 7.7 g vs. 11.6 +/- 4.9 g) and length (delta 1.8 +/- 0.3 cm vs. 1.12 +/- 0.44 cm) in ad libitum fed uremic rats. This was accompanied by increased food utilization ratio (0.146 vs. 0.065 g weight gain per g food intake). A similar increment of growth and food utilization ratio was also observed in GH versus solvent infused controls, either pairfed as for the uremic animals or fed ad libitum. Despite administration of GH, growth was not completely restored to normal in uremic animals. Circulating immunoreactive IGF I was not significantly increased by GH infusion in either uremic animals or controls. Histological analyses of the proximal tibia showed increased rate of longitudinal growth, as evaluated by tetracyclin-labeling, and increased volumetric density of primary spongiosa with unchanged width of primary spongiosa trabecules when GH was infused in uremic animals. The data suggest that growth impairment in the uremic rat is partially responsive to GH, and this is not accompanied by an increase of circulating IGF I. Therapeutic trials with recombinant GH in uremic children appear justified.


Synthesis and SAR study of 4-arylpiperidines and 4-aryl-1,2,3,6-tetrahydropyridines as 5-HT₂C agonists.
A series of substituted 4-arylpiperidines and a smaller family of 4-aryl-1,2,3,6-tetrahydropyridines were synthesized and their biological activity at the 5-HT(2C) receptor studied to determine whether either series showed noteworthy agonist activity. Structure-activity relationships were developed from the performed receptor binding assays and functional studies, and the results of the analysis are presented herein.


Clinical profile and outcomes of rhegmatogenous retinal detachment related to trauma in pediatric population.
To analyze the outcomes of trauma-related rhegmatogenous retinal detachment (RD) in pediatric population. Retrospective observational series. All patients under 18 years of age who underwent surgery for RD following trauma from 2010 to 2018. Data were recorded from medical records regarding type of trauma, ocular status at presentation, details of RD (extent, number of breaks, proliferative vitreoretinopathy, choroidal detachment). The surgical intervention (scleral buckling or vitrectomy; tamponade used) and postoperative outcomes, including anatomical success, resurgeries, and visual acuity, were noted. We included 32 eyes of 32 patients, where closed globe injury was seen in 13 eyes (41%) and open globe injury (OGI) in 19 eyes (59%). At presentation, 50% of the eyes had RD, with total RD in 20 eyes (63%). Scleral buckling was performed in 9 eyes (28%), whereas the remainder (n = 23) underwent pars plana vitrectomy with silicon oil tamponade for RD repair. Silicone oil removal was done in 16 eyes (70%) and recurrent or persistent RD was seen 17 eyes (53%). Final reattachment rate was 75% (n = 24). The final best-corrected visual acuity was better in the closed globe injury group (mean = 5/60 Snellen's vs 1/60 Snellen's in OGI group), though this was only marginally significant statistically. Late complications were seen in 26 eyes (81%), of which 18 (69%) had previous OGI. Pediatric traumatic RDs have very poor anatomical and visual outcomes. OGI fares worse than closed globe. Loss of vision in children can be prevented by better safety measures so as to avoid trauma.


Surgical treatment of occlusion of the infrarenal abdominal aorta. Experience with 55 patients.
A series of 55 patients with occlusion of the infrarenal abdominal aorta operated on in the 15-year period 1966-1980 is presented. The type of operation was an extra-anatomic reconstruction in four cases and some type of anatomic repair in 51 cases. The operative mortality was 5.4%. The cause of death was myocardial infarction in two out of three cases. After a follow-up period of 90.4 months on average 25 patients were alive and were reached to a follow-up examination. Nineteen out of these 25 patients (76%) were symptom-free and six patients (24%) complained of mild to moderate symptoms related to obstructive arteriosclerotic lesions of the lower extremities. During the follow-up 27 patients expired. The most common causes of late deaths were myocardial infarction (13 out of 27 patients) and CVA (5 out of 27 patients).


In vitro studies on some parameters of the binding of the rat hemopexin--heme complex with the hepatic membrane receptor.
The binding of [125I]Hpx--heme with the rat hepatic plasma membrane receptor was studied at 37 degrees C as well as different parameters such as plasma membrane concentration, calcium dependence, optimal pH and specific binding. A Scatchard plot revealed the existence of one binding for [125I]Hpx--heme on the isolated liver plasma membrane with a Kd = 3.2 X 10(-8) M.


In vivo labeling of resident peritoneal macrophages.
A novel method for labeling resident peritoneal macrophages (M phi) by injection of a dye into the peritoneal cavity is described. The dye, which fluoresces green, is selectively taken up by the resident M phi. Dye labeled cells can be further characterized by labeling of cell surface antigens with monoclonal antibodies (Mabs) and phycoerythrin conjugated second antibody. After such labeling with the Mabs F4/80 or Mac 1 the resident M phi were labeled by both the green dye and the red Mab markers, while recruited M phi or neutrophils were labeled with just the red Mab; the two populations of cells were readily distinguished by two-color flow cytometry. This technique enabled identification of resident and recruited M phi in each animal without the use of radioisotopes, irradiation, or bone marrow ablation. Sufficient numbers of cells can be analyzed from each animal so that individual animals could be evaluated. We found no adverse effects of this labeling technique on expression of cell surface antigens or M phi mediated cytotoxicity. We did find evidence that the i.p. injection induced a mild inflammation in the peritoneal cavities of animals injected with either the dye or the balanced salt solution vehicle. Examination of the intracellular staining pattern indicated that the label rapidly sequestered in the cytoplasm of the M phi, possibly in the lysosomes. Dye solubility studies showed that the dye was partially soluble at the concentration used for in vivo labeling. We hypothesize that the M phi labeling occurred by a combination of phagocytosis of dye aggregates and endocytosis of labeled plasma membrane.


A new treatment of ischemic bowel disease: steroid delivery via retrograde venous route.
The present therapeutic approach to occlusive mesenteric disease is unable to alter its high mortality and morbidity. We attempted to stabilize the intestinal lysosomal population with steroid prior to revascularization and thus reduce the lysosomal effluent. Steroid delivery during the occlusive period was accomplished via retrograde venous flow in the portal system. During revascularization steroid was further infused via the superior mesenteric artery. Our experimental model compared systemic venous delivery with retrograde portal venous delivery of steroid. Analysis of tissue acid phosphatase levels suggested steroid delivery via retrograde portal venous flow is the most efficient method of lysosomal stabilization.


Surgical pathology of bullae with and without pneumothorax.
Experience with 2030 patients admitted for an actual episode of spontaneous pneumothorax, and with 370 patients hospitalized for bullous emphysema is thoroughly analyzed. Out of these groups, 400 patients (318 and 82 respectively) underwent an open thoracotomy. Macroscopic operative findings were divided into 8 groups. Descriptions of the aspect, size and site of bullae, respiratory function, mortality and follow-up data, are presented. Pathogenesis of the localised apical disease in comparison to the extended and diffuse types is outlined. Attention is drawn to the high operative risk in generalized emphysema and airway obstruction when associated with tension bullae and/or pneumothorax. More than 30% of the patients could not be included in either the juvenile type, isolated apical disease, or in the category of bullae associated with generalized emphysema. Reasons for an early rupture of apical subpleural blebs and the high resistance to check valve pressure of bullae following alveolar disruption are discussed. The observations lead to the conclusion that surgical pathology and treatment problems in bullous emphysema and in spontaneous pneumothorax have a lot in common and their arbitrary separation is not justified.


Comparison of the microbiological milieu of patients randomized to either hydrophilic or conventional PVC catheters for clean intermittent catheterization.
Control of bacteriuria is problematic in patients who perform clean intermittent catheterization for management of neurogenic bladder. This population is often burdened with multiple urinary tract infections (UTIs), placing them at increased risk of end-stage renal disease. Hydrophilic catheters are a potential way to improve smooth and clean insertion, reduce disruption of the urothelium, and reduce bacterial colonization. The goal of the study was to compare the type and virulence of microorganisms recovered from the urine of patients that use either a hydrophilic or conventional polyvinyl chloride (PVC) catheter. Fifty patients with an underlying diagnosis of myelomeningocele were recruited for a 12-month prospective, randomized, investigator-blinded study. Twenty-five patients were allocated to the hydrophilic catheter intervention, and 25 continued use of a PVC catheter. Cultures were performed on urine obtained by catheterization at enrollment, and 3, 6, and 12 months. Bacterial species were assigned a designation as either potentially pathogenic or non-pathogenic. Escherichia coli isolates were the most predominant and were serotyped to further stratify the pathogenicity of the strains. Lastly, patients were surveyed at enrollment, and at the two later time points evaluating their current catheter for satisfaction. A total of 232 different bacterial isolates were obtained from the 182 collected urine cultures. In addition, seven species were recovered from the two UTI reported during the study period. Bacterial growth was not detected in 29 of the samples (16%). Although not statistically significant, collectively there was a 40% decrease in the average number of potentially pathogenic species recovered from those patients using hydrophilic catheters (0.81 per urine sample) compared with PVC catheter use (1.24 per urine sample). Since E. coli species can be either pathogenic or non-pathogenic, we examined 14 of the most commonly implicated serotypes associated with uropathogenic E. coli (UPEC). We identified the serotype of 57% of E. coli strains recovered. There was a trend for the recovery of fewer UPEC serotypes from the hydrophilic group (54% hydrophilic verses 64% PVC), further suggesting that the catheter type may influence the microbiological milieu. Although no significant differences were reported in patient satisfaction, almost half of the patients from the hydrophilic catheter cohort continue use of this type of catheter. There was a trend for reduced recovery of potentially pathogenic bacteria with the use of hydrophilic catheters. The reduction in potentially pathogenic species will reduce antibiotic exposures and some patients may prefer the comfort hydrophilic catheters provide.


Moderate caloric restriction delays cataract formation in the Emory mouse.
Eye lens senile cataract is a major cause of blindness, affecting the elderly in particular. The etiology of the disorder has been elusive, and attempts to delay the onset of senile cataracts have been unsuccessful. The need for more information is underscored by epidemiologists who estimate that the ability to delay cataract formation in humans by only 10 years would eliminate the need for 50% of the cataract extractions performed annually in the United States. The Emory mouse provides the best model for human senile cataracts. Feeding Emory mice a diet that was restricted in calories by approximately 21% delayed the onset of cataracts. This is the first study that demonstrates in vivo the delay of senile-type cataracts. In these animals, aging and cataracts are associated with diverse changes in the proportion of various proteins (particularly 21, 22, 31-34 kDa) and with transformation of proteins from a soluble to an insoluble state. In advanced cataracts, there is a loss of total protein. Within a cataract grade, there is no difference between restricted and nonrestricted animals in relative proportion of specific lens proteins or in amounts of total or soluble proteins. The transition from a clear to cataractous lens appears when the soluble-to-total protein ratio falls below about 0.58. The exclusive use of gamma-crystallin as an indicator of lens viability is questioned. To the extent that cataract formation is due to lens protein oxidation and/or an inability to proteolytically remove damaged protein, it would appear that caloric restriction results in enhanced protection against lens oxidative stress or in prolonged proteolytic function.


Genomic and metabolic prediction of complex heterotic traits in hybrid maize.
Maize is both an exciting model organism in plant genetics and also the most important crop worldwide for food, animal feed and bioenergy production. Recent genome-wide association and metabolic profiling studies aimed to resolve quantitative traits to their causal genetic loci and key metabolic regulators. Here we present a complementary approach that exploits large-scale genomic and metabolic information to predict complex, highly polygenic traits in hybrid testcrosses. We crossed 285 diverse Dent inbred lines from worldwide sources with two testers and predicted their combining abilities for seven biomass- and bioenergy-related traits using 56,110 SNPs and 130 metabolites. Whole-genome and metabolic prediction models were built by fitting effects for all SNPs or metabolites. Prediction accuracies ranged from 0.72 to 0.81 for SNPs and from 0.60 to 0.80 for metabolites, allowing a reliable screening of large collections of diverse inbred lines for their potential to create superior hybrids.


Increased adherence of oxidant-treated human and bovine erythrocytes to cultured endothelial cells.
Bovine erythrocytes, which normally lack phosphatidyl choline in their membranes, when treated with either H2O2 or diamide (1-3 mM), showed a partial appearance of phosphatidyl ethanolamine (PE 40%) and phosphatidyl serine (PS, 30-33%) in the external leaflet of the bilayer and a concomitant increased (four- to five-fold) propensity to adhere to cultured bovine aortic endothelial cells. Similar treatment of normal human erythrocytes caused an alteration in the organization of the phospholipid bilayer and also resulted in their increased adherence to endothelial cells derived either from human umbilical vein or bovine aorta. Treatment of RBCs with H2O2 at low concentration (0.5 mM) resulted in cross-linking of spectrin without significant changes in the orientation of aminophospholipids but the RBCs exhibited 15-20% increase in adherence to endothelial cells. Pretreatment of either human or bovine erythrocytes with antioxidants such as vitamin E (2 mM) prevented both oxidant-induced reorganization of phospholipids in the bilayer and enhancement of adherence to endothelial cells. Introduction of either phosphatidyl serine or phosphatidyl ethanolamine but not phosphatidyl choline into erythrocyte membranes increased their adherence to endothelial cells threefold. Oxidant-treated RBCs exhibited enhanced binding and fluorescence of Merocyanine 540 dye (MC-540), which is sensitive to the packing of lipids in the lipid bilayer. On flow cytometric analysis, 78% of H2O2 (0.5 mM)-treated erythrocytes compared to 30% of untreated RBCs exhibited MC-540 binding and fluorescence, indicating differences in the lipid packing in the outer leaflet of the bilayer. Oxidant-treated erythrocytes adhere preferentially to endothelial cells rather than to bovine aortic smooth muscle cells and skin fibroblasts. It is suggested that the alterations in the erythrocyte membrane surface due to spectrin cross-linking and the organization of the phospholipids concomitant with less ordered packing in the external leaflet of the bilayer, either induced by oxidative manipulation in normal RBC or in pathological erythrocytes, play a role in erythrocyte-endothelial cell interaction.


Ester derivatives of the mammary-tumor-inhibiting antiestrogen 2,3-bis(2-fluoro-4-hydroxyphenyl)-2,3-dimethylbutane.
The synthesis of the bisacetate (8), the bisdichloroacetate (9), the biscarbamate (10) and the bisphosphate (11) of the "partial" antiestrogen 2,3-bis(2-fluoro-4-hydroxyphenyl)-2,3-dimethylbutane (7) is described. In the case of 8-10 the introduction of ester functions slightly reduces the estrogen receptor affinity of 7. However, it was strongly diminished in 11. Compared with 7 the estrogenic potency of 8-11 is moderately increased. Compounds 8-11 cause a strong inhibition of the hormone-dependent MXT M3.2 mouse mammary tumor. Only 9 containing cytotoxic dichloroacetate groups shows a significantly better antitumor effect than 7.


Cystic parathyroid adenoma with coexistent sarcoid granulomas.
A 55-year-old woman with sarcoidosis developed hyperparathyroidism that was associated with fluctuating serum calcium levels. Ultrasonography and a computed tomography (CT) scan of the neck demonstrated a cystic lesion in the lower posterior area of the left thyroid lobe. Histological examination after subsequent surgery revealed sarcoid granulomas within a parathyroid adenoma. The pathogenesis of this rare association is discussed.


Proximal Biceps Tendon and Rotator Cuff Tears.
The long head of biceps tendon (LHBT) is frequently involved in rotator cuff tears and can cause anterior shoulder pain. Tendon hypertrophy, hourglass contracture, delamination, tears, and tendon instability in the bicipital groove are common macroscopic pathologic findings affecting the LHBT in the presence of rotator cuff tears. Failure to address LHBT disorders in the setting of rotator cuff tear can result in persistent shoulder pain and poor satisfaction after rotator cuff repair. Tenotomy or tenodesis of the LHBT are effective options for relieving pain arising from the LHBT in the setting of reparable and selected irreparable rotator cuff tears.


Is hyperkinetic gallbladder an indication for cholecystectomy?
The (99m) technetium-labelled hepato imino diacetic acid (HIDA) scan is widely used to evaluate patients with biliary colic with a normal trans-abdominal ultrasound scan. Most studies recommend cholecystectomy for patients with biliary dyskinesia, defined by gallbladder ejection fraction (GBEF) of less than 35-40% on HIDA scan. There are no recommendations regarding management of hyperkinetic gallbladder defined by GBEF of greater than 80% on HIDA scan. The aim of our study was to evaluate the outcomes following cholecystectomy on patients with biliary colic associated with hyperkinetic gallbladder. We performed a retrospective chart review of all patients with biliary colic associated with hyperkinetic gallbladder that underwent cholecystectomy in our practice from July 2014 to February 2018. Data collection included age, gender, body mass index, preoperative symptoms, comorbidities, additional tests, ejection fraction, surgery, and histopathology of the gallbladder. Symptomatic improvement was assessed during routine 2-week postoperative visit and a follow-up phone interview. Thirty-two patients had undergone laparoscopic cholecystectomy during the study period for symptomatic hyperkinetic gallbladder. All the patients had abdominal pain related to food intake and 17 (53%) patients had worsening of symptoms with CCK infusion. The average GBEF was 92%. Chronic cholecystitis was seen in 29 (90%) patients on pathology. 23 (74%) patients had complete resolution of biliary symptoms, 5 (16%) had improved symptoms, and 3 (10%) had no change in symptoms. Patients with biliary colic and hyperkinetic gallbladder respond favorably to laparoscopic cholecystectomy. Our results suggest that patients with biliary colic in the setting of hyperkinetic gallbladder have symptomatic improvement following cholecystectomy.


Enterocutaneous fistula associated with ePTFE mesh: case report and review of the literature.
A case of enterocutaneous fistula secondary to the erosion of an expanded polytetrafluoroethylene (ePTFE) prosthesis into the jejunum is described. This case is unusual secondary to the long experience with ePTFE and the lack of published cases similar to this one. The technical details of this case reveal extenuating circumstances associated with the fistula formation, and it is concluded that this particular case does not provide sufficient evidence to implicate ePTFE, by itself, as an etiologic agent for gastrointestinal fistulization. In addition, the published safety record of ePTFE in abdominal wall surgery is reviewed.


Effect of 1,1-dimethylhydrazine (UDMH) on Corynebacterium parvum-associated immunosuppression in mice.
These studies further investigate the immunoenhancement properties of UDMH by utilizing Corynebacterium parvum-induced immunosuppressed mice as well as evaluating activated macrophage production of reactive oxygen intermediates or their effects. Forty-eight hour Con A-induced lymphoblastogenic responses from splenocytes isolated from C. parvum and UDMH-treated Balb/C mice were significantly increased compared with C. parvum alone, although less than normal control mice (no treatment). In vitro bioassay of IL-2 production in cell culture supernatant isolated from these same treatment groups exhibited a pattern of stimulation similar to that of lymphocyte blastogenesis. In addition, UDMH did not interfere with H2O2-mediated suppression of either Con A- or LPS-induced lymphocyte blastogenesis and actually enhanced suppression of Con A-induced lymphocyte cultures at 25 micrograms/ml. We also report that production of superoxide anion from TPA-activated peritoneal macrophages exposed to various concentrations of UDMH in vitro was not affected. Although in vivo exposure to UDMH partially reversed C. parvum-induced immunosuppression in mice, the exact mechanism by which UDMH acts to reverse this immune suppression is not clear. UDMH does not appear to interfere with either activated peritoneal macrophage production of superoxide anion or H2O2-induced suppression of lymphocyte blastogenesis to elicit immune enhancement.


Daytime sleepiness and sleep quality in Charcot-Marie-Tooth disease.
Sleep abnormalities have been reported in Charcot-Marie-Tooth disease (CMT), but data are scanty. We investigated their presence and correlation in a large CMT patients' series. Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI) were administered to CMT patients of the Italian registry and controls. ESS score > 10 indicated abnormal daytime somnolence, PSQI score > 5 bad sleep quality. We analyzed correlation with disease severity and characteristics, Hospital Anxiety and Depression Scale (HADS), Modified Fatigue Impact Scale (MFIS), Body Mass Index, drug use. ESS and PSQI questionnaires were filled by 257 and 253 CMT patients, respectively, and 58 controls. Median PSQI score was higher in CMT patients than controls (6 vs 4, p = 0.006), with no difference for ESS score. Abnormal somnolence and poor sleep quality occurred in 23% and 56% of patients; such patients had more frequently anxiety/depression, abnormal fatigue, and positive sensory symptoms than those with normal ESS/PSQI. Moreover, patients with PSQI score > 5 had more severe disease (median CMT Examination Score, CMTES, 8 vs 6, p = 0.006) and more frequent use of anxiolytic/antidepressant drugs (29% vs 7%, p < 0.001). Bad sleep quality and daytime sleepiness are frequent in CMT and correlated with anxiety, depression and fatigue, confirming that different components affect sleep. Sleep disorders, such as sleep apnea and restless leg syndrome, not specifically investigated here, are other factors known to impact on sleep quality and somnolence. CMT patients' management must include sleep behavior assessment and evaluation of its correlated factors, including general distress and fatigue.


Receptor-mediated particle uptake by liver macrophages. The galactose-particle receptor mediates uptake via coated and also non-coated structures.
The endocytosis pathways of particles with terminal beta-D-galactosyl groups were studied in isolated rat Kupffer cells by electron microscopy. Colloidal gold particles of sizes 5, 17 and 50 nm were coated with asialofetuin (ASF) and isolated liver macrophages were allowed to bind (at 4 degrees C) or take up (at 37 degrees C) these ligands. Particles of all three sizes were bound via the galactose-particle receptor as shown by carbohydrate inhibition experiments and were ingested effectively. But, whereas ASF-gold particles of sizes 5 and 17 nm are taken up via the coated pit/coated vesicle pathway, the 50 nm particles are not. These enter the cell via non-coated endocytic vacuoles. All three particle sizes are transported to the same lysosomal compartment. These observations demonstrate that at least in macrophages one receptor is capable to mediate endocytosis via two different pathways depending on ligand size and/or valency.


Age at acquisition of Helicobacter pylori in a pediatric Canadian First Nations population.
Few data exist regarding the epidemiology of Helicobacter pylori infections in aboriginal, including the First Nations (Indian) or Inuit (Eskimo) populations of North America. We have previously found 95% of the adults in Wasagamack, a First Nations community in Northeastern Manitoba, Canada, are seropositive for H. pylori. We aimed to determine the age at acquisition of H. pylori among the children of this community, and if any association existed with stool occult blood or demographic factors. We prospectively enrolled children resident in the Wasagamack First Nation in August 1999. A demographic questionnaire was administered. Stool was collected, frozen and batch analyzed by enzyme-linked immunosorbent assay (ELISA) for H. pylori antigen and for the presence of occult blood. Questionnaire data were analyzed and correlated with the presence or absence of H. pylori. 163 (47%) of the estimated 350 children aged 6 weeks to 12 years, resident in the community were enrolled. Stool was positive for H. pylori in 92 (56%). By the second year of life 67% were positive for H. pylori. The youngest to test positive was 6 weeks old. There was no correlation of a positive H. pylori status with gender, presence of pets, serum Hgb, or stool occult blood. Forty-three percent of H. pylori positive and 24% of H. pylori negative children were < 50th percentile for height (p = 0.024). Positive H. pylori status was associated with the use of indoor pail toileting (86/143) compared with outhouse toileting (6/20) (p = 0.01). In a community with widespread H. pylori infection, overcrowded housing and primitive toileting, H. pylori is acquired as early as 6 weeks of age, and by the second year of life 67% of children test positive for H. pylori.


[Value of suspicious and doubtful cytological findings in gynecologic serial examinations].
Cytological follow-up and histological results of 2336 patients with Pap III and 10584 with Pap II control of 1973 and 1974 were checked up to May 1976 and compared with new literature. 50% of Pap III became to negatives, 10% of Pap III and 0,82% of Pap II control became positive (Pap IV and Pap V). Up to now histological findings has been resulted in 10% invasive cancers; in 53% carcinomata in situ and severe dysplasia, in 16% moderate and mild dysplasias, and in 5% normal epithelium from repeated Pap III. To avoid to many conizations we have introduced Pap IIID for moderate and mild dysplasia into screening cytology.


Direct observation of endoglucanase fibrillation and rapid thickness identification of cellulose nanoplatelets using constructive interference.
Better understanding through direct observation of the mechanisms involved in chemical and enzymatic hydrolysis of biomass is of great importance, to implement a substitute for the common cellulose standards. We report the hydrolysis of biomass, using exclusively the parenchyma, to isolate cellulose nanoplatelets using a less harsh pretreatment. Then, we show direct evidence of the effect of endoglucanase on the structure of cellulose nanoplatelets, finding that amorphous cellulose is exclusively digested, loosening the cellulose nanofibrils in the process. The analysis of micrographs demonstrates that when cellulose nanoplatelets are deposited on a silicon wafer, its thickness can be qualitatively measured by the interference color detected using an optical microscope. This finding facilitates further studies of mechanisms involved in lignin removal and cellulose nanofibrils production by specific enzymatic digestion.


The erythromycin breath test as a predictor of cyclosporine blood levels.
The daily dose of cyclosporine required to attain a desired blood level can vary greatly among patients. Because elimination of cyclosporine depends on its metabolism in the liver by an enzyme (cytochrome P-450IIIA) that also demethylates erythromycin, we reasoned that the ability of patients to demethylate a test dose of erythromycin might be useful in estimating their appropriate daily doses of cyclosporine. Accordingly, the [14C-N-methyl] erythromycin breath test was administered to 32 patients before they received 3.0, 5.0, or 7.5 mg/kg/day cyclosporine to treat psoriasis. We found that a simple mathematical equation incorporating just the 14CO2 production, the age of the patient, and the daily dose of cyclosporine accounted for almost 80% (R2 = 0.78) of the interpatient variability in cyclosporine blood levels we observed. Our data indicate that P-450IIIA activity largely accounts for the relationship between dose of cyclosporine and blood levels for an individual patient. We conclude that the erythromycin breath test may be a convenient guide for cyclosporine dosing.


Epidemiology of out-of-Hospital Cardiac Arrests, knowledge of cardiovascular disease and risk factors in a regional setting in India: The Warangal Area out-of-hospital Cardiac Arrest Registry (WACAR).
Out-of-Hospital Cardiac Arrest (OHCA) is a global public health problem. There is inadequate data on OHCA in India. The Warangal Area out-of-hospital Cardiac Arrest Registry (WACAR) was planned to understand OHCA in a regional setting in India. WACAR is a prospective one-year observational cohort study of OHCA in the Warangal area, Telangana, India. The study included 814 subjects of OHCA of presumed cardiac etiology brought to the Mahatma Gandhi Memorial Hospital during January 1, 2018, and December 31, 2018. The data collected included; standard Utstein variables with additional data on clinical characteristics (modified Utstein template). The majority of OHCA subjects were male with a median age of 60 years, and mostly occurring in residential locations within 1 h of onset of symptoms. Individuals with knowledge of CVD risk factors were more likely to report symptoms before OHCA. Data on resuscitation characteristics were inadequate. The WACAR study provides baseline data regarding OHCA in a regional setting in India. The study demonstrated barriers involving data collection, patient knowledge of CVD risk factors and disease, and access to healthcare, which; impacted the data registry.


Interactions of Chitosan-coated Green Synthesized Silver Nanoparticles using Mentha spicata and Standard Antibiotics against Bacterial Pathogens.
Infectious diseases are caused by various multidrug-resistant pathogenic bacteria and in recent scenarios, nanoparticles have been used as innovative antimicrobial agents. This current research aimed to evaluate the bactericidal effect of chitosan-coated green synthesized silver nanoparticles using aqueous extract of Mentha spicata (MSaqu) against bacterial pathogens, i.e., Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Serratia marcescens, Staphylococcus aureus, and Streptococcus pyogenes. Synthesis and characterization of silver nanoparticles (MSAgNPs) were carried out via atomic absorption spectrometer and Fourier-transform infrared spectroscopy. Agar well and agar disc diffusion methods were used to assess the antibacterial and synergistic effect of chitosanmediated biogenic silver nanoparticles and standard antibiotics. Three types of interactions, i.e., antagonistic (↓), synergistic (↑), and additive (¥) were observed. Synergistic effect was recorded against Pseudomonas aeruginosa (8.5±0.25 mm↑), Serratia marcescens (19.0±1.0 mm↑), and Klebsiela pneumonia (8.5±0.25 mm↑), an additive effect was exhibited by Escherichia coli (9.0±0.0 mm¥), Streptococcus pyogenes (10.0±0.0 mm¥), and Staphylococcus aureus (7.5±0.25 mm↓) and they showed antagonistic effects when chitosan-coated silver nanoparticles (CLMSAgNPs) were applied compared to chitosan, MSaqu, and MSAgNPs. Interesting antibacterial results were recorded when chitosan-coated Mentha spicata extract and silver nanoparticles were applied along with antibiotics. The synergistic effects of chitosan-coated silver nanoparticles (CLMSAgNPs) + K were recorded against E. coli (14.5±0.25 mm). The synergistic effects of chitosan-coated silver nanoparticles (CLMSAgNPs) + AML were recorded against E. coli (5.5±0.0 mm), S. pyogenes (10.0±0.0 mm), K. pneumonia (5.5±0.0 mm), and S. aureus (4.0±0.0 mm). The synergistic effects of chitosan-coated silver nanoparticles (CLMSAgNPs) + NOR were recorded against E. coli (16.0±0.0 mm), P. aeruginosa (19.0±0.0 mm), S. marcescens (19.5±0.25 mm), S. pyogenes (11.5.0±0.25 mm), K. pneumonia (23.0±0.0 mm), and S. aureus (8.5±0.25 mm). Current findings concluded that chitosan-coated biogenic silver nanoparticles have potential bactericidal effects against infectious pathogens and could be used as forthcoming antibacterial agents.


Factors affecting duration of inability to work after intramedullary stabilization of displaced midshaft clavicular fractures.
Duration of inability to work (DIW) after displaced midshaft clavicular fractures (DMCF) is an important clinical and socioeconomic treatment outcome. However, evidence on DIW after DMCF intramedullary stabilization (IMS) is still limited. We aimed to examine DIW and identify medical and socioeconomic predictors with direct or indirect impact on DIW after IMS of DMCF. Socioeconomic predictors can explain the unique proportion of the DIW variance after IMS of DMCF above the variance explained by medical predictors. Using a retrospective cohort unicentric design, we included patients surgically treated with IMS after DMCF from 2009-2022 with employment status subject to compulsory social security contributions, and without major postoperative complications, in one level II trauma center in Germany. In total, we tested the impact of 17 different medical (i.e., smoking, body mass index [BMI], operative duration, etc.) and socioeconomic predictors (i.e., health insurance type, physical workload, etc.) on DIW. Statistics included multiple regression and path analyses. A total of 166 patients met the eligibility criteria, with DIW 35.1±31.1days. Operative duration, physical workload, and physical therapy prolonged the DIW (p<0.001). In contrast, enrollment in private health insurance reduced the DIW (p<0.05). Furthermore, the effect of BMI and fracture complexity on DIW was fully mediated by operative duration. The model explained 43% of the DIW variance. Socioeconomic factors were found to directly predict the DIW, even after controlling for medical predictors, which confirmed our research question. This is in line with previous findings and highlights the relevance of socioeconomic predictors in this context. We believe that the proposed model can serve surgeons and patients as an orientation guide to estimate the DIW after IMS of DMCF. IV - retrospective observational cohort study with no control group.


Impella ventricular support in clinical practice: Collaborative viewpoint from a European expert user group.
Mechanical circulatory support represents an evolving field of clinical research and practice. Currently, several cardiac assist devices have been developed but, among different institutions and countries, a large variation in indications for use and device selection exists. The Impella platform is an easy to use percutaneous circulatory support device which is increasingly used worldwide. During 2014, we established a working group of European physicians who have collected considerable experience with the Impella device in recent years. By critically comparing the individual experiences and the operative protocols, this working group attempted to establish the best clinical practice with the technology. The present paper reviews the main theoretical principles of Impella and provides an up-to-date summary of the best practical aspects of device use which may help others gain the maximal advantage with Impella technology in a variety of clinical settings.


Chronic venous leg ulcers: effect of a community nursing intervention on pain and healing.
To investigate the effectiveness of a new community nursing model of care for clients with chronic leg ulcers in terms of levels of pain and ulcer healing. A randomised controlled trial comparing the new model of care with standard community nursing care was conducted with a sample of 56 clients with chronic venous leg ulcers, 28 clients in the intervention group and 28 in the control group. Data were collected on admission to the study and at 12 weeks from admission. Significant improvements in levels of pain and ulcer healing were found in the intervention group receiving the new model of care. Results from this study have implications for health professionals providing care for clients with chronic leg ulcers.


Effect of octreotide on mouth-to-caecum transit time in healthy subjects and in the irritable bowel syndrome.
The effect of a single subcutaneous injection of octreotide (50 micrograms) on mouth-to-caecum transit time was determined in patients with the irritable bowel syndrome who complained of bowel frequency, and in healthy volunteers. The assessment of mouth-to-caecum transit time was performed by monitoring breath hydrogen concentration and noting a sustained 10 p.p.m. rise after ingestion of lactulose 40 ml. Measurements were performed fasting, and on a separate day, after a standard breakfast which included 40 ml lactulose. The studies were performed double-blind in a pre-determined random order. Octreotide prolonged mouth-to-caecum transit time in irritable bowel syndrome patients and healthy subjects by factors of 2.4 and 2.6 after lactulose when fasting, respectively, and by factors of 2.8 and 2.6 after the breakfast which contained lactulose. The upper gastrointestinal transit rate was similar in irritable bowel syndrome patients and healthy controls.


Immortalized mouse brain endothelial cells are ultrastructurally similar to endothelial cells and respond to astrocyte-conditioned medium.
Studies of brain microvessel endothelial cell physiology and blood-brain barrier properties are often hampered by the requirement of repeatedly producing and characterizing primary endothelial cell cultures. The use of viral oncogenes to produce several immortalized brain microvessel cell lines has been reported. The resulting cell lines express many properties of the blood-brain barrier phenotype but do not completely mimic primary endothelial cells in culture. As immortalized brain microvessel endothelial cell lines have not yet been produced from mice, we transformed mouse brain endothelial cells with the adenovirus E1A gene using a retroviral vector (DOL). Eight of 11 clones produced exhibited an endothelial-like cobblestone morphology and were characterized as endothelial with a panel of antibodies, lectins, and ultrastructural criteria. These cells are endothelial in origin and share ultrastructural features with primary cultures of endothelial cells. Examination of freeze fracture and transmission electron micrographs show adherens junctions exist between the transformed cells, and culture in astrocyte-conditioned medium induces the formation of gap junctions. This is one indication that responses to astrocyte-derived factors are retained by the transformed cell lines.


Enhancer dependence of cell-type-specific gene expression increases with developmental age.
How overall principles of cell-type-specific gene regulation (the "logic") may change during ontogeny is largely unexplored. We compared transcriptomic, epigenomic, and three-dimensional (3D) genomic profiles in embryonic (EryP) and adult (EryD) erythroblasts. Despite reduced chromatin accessibility compared to EryP, distal chromatin of EryD is enriched in H3K27ac, Gata1, and Myb occupancy. EryP-/EryD-shared enhancers are highly correlated with red blood cell identity genes, whereas cell-type-specific regulation employs different cis elements in EryP and EryD cells. In contrast to EryP-specific genes, which exhibit promoter-centric regulation through Gata1, EryD-specific genes rely more on distal enhancers for regulation involving Myb-mediated enhancer activation. Gata1 HiChIP demonstrated an overall increased enhancer-promoter interactions at EryD-specific genes, whereas genome editing in selected loci confirmed distal enhancers are required for gene expression in EryD but not in EryP. Applying a metric for enhancer dependence of transcription, we observed a progressive reliance on cell-specific enhancers with increasing ontogenetic age among diverse tissues of mouse and human origin. Our findings highlight fundamental and conserved differences at distinct developmental stages, characterized by simpler promoter-centric regulation of cell-type-specific genes in embryonic cells and increased combinatorial enhancer-driven control in adult cells.


Differential expression of microRNA-210 in gliomas of variable cell origin and correlation between increased expression levels and disease progression in astrocytic tumours.
The microRNA, miR-210, is frequently associated with hypoxia induction, and an increase in its levels is often correlated with poor prognosis in many solid tumours. The present study examines the levels of miR-210 in glioma tumours of multiple origins to determine if an association can be established with disease progression. Tissue samples were acquired from normal brain tissue, oligodendroglial tumours and astrocytic tumours. The astrocytic tumours were further divided by grade: diffuse astrocytomas (WHO grade II), anaplastic astrocytomas (WHO grade III), and glioblastoma (WHO grade IV). The expression of miR-210 was examined by real-time quantitative RT-PCR. The correlation of the expression of miR-210 and astrocytic tumour grade was analyzed by the Spearman correlation test. MiR-210 presents a differential expression depending on the origin of the glioma. Oligodendroglial tumours exhibit a significantly reduced level of miR-210 as compared with normal brain tissue. In contrast, astrocytic tumours demonstrate significantly increased levels of miR-210. Furthermore, the expression of miR-210 is positively correlated with the grade of astrocytic tumour, in the following order: grade IV > grade III > grade II > normal brain tissue (p < 0.05). MiR-210 levels can be potentially established as a biomarker for pathological diagnosis of malignant astrocytic tumour progression. In addition, the expression of miR-210 can be utilized as an additional identification measure of glioma tumour origin.


Zebrafish collagen XIV is transiently expressed in epithelia and is required for proper function of certain basement membranes.
We found that zebrafish has two differentially expressed col14a1 paralogs. col14a1a expression peaked between 18-somite stage and 24 hours postfertilization (hpf), whereas col14a1b was first expressed at 32 hpf. To uncover functions of collagen XIV (COLXIV) during early embryogenesis, we focused our study on col14a1a. We characterized the α1 (XIV-A) chain as a collagenase-sensitive 200-kDa protein that formed dimer that could be reduced at high pH. As observed for the transcript, COLXIV-A protein expression peaked between 24 and 48 hpf. Using antisense probes and polyclonal antibodies, we show that col14a1a and its protein product COLXIV-A are transiently expressed in several epithelia, including epithelia undergoing shape changes, such as the fin folds. In contrast, anti-COLXII antibodies stained only connective tissues. COLXIV-A was also detected in the basement membrane (BM), where it co-localized with COLXII. At later developmental stages, COLXIV-A was not expressed in epithelia anymore but persisted in the BM. Morpholino knockdown of COLXIV-A provoked a skin detachment phenotype. Electron microscopy analysis revealed that morpholino-injected embryos lacked a lamina densa and lamina lucida at 24 hpf, and BM defects, such as gaps in the adepidermal granules, were still detected at 48 hpf. These BM defects were accompanied by a rupture of the dermis and detachment of the epidermis. Taken together, these data suggest an unexpected role of COLXIV-A in undifferentiated epithelia and in the formation of embryonic basement membranes.


A novel method for histological examination of hair follicles.
Intact and healthy hair follicles are important for hair growth after hair follicle transplantation. However, effective and practical evaluation methods for the quality of hair follicles are currently lacking. In the present study, we developed a novel fast staining method for histological examination of hair follicles. The whisker follicles from mice were used to explore the staining protocols, and the final protocol for the evaluation of human hair follicles was derived from animal experiments. After extraction, human hair follicles or mouse whisker follicles were permeabilized with 0.3% Triton X-100. Subsequently, hair follicles were processed by either hematoxylin or alkaline phosphatase staining. The integrity and growth state, including the status of hair follicle stem cells and blood vessels of the extracted hair follicles, were clearly identified under a light microscope. Unhealthy hair follicles from donors or hair follicles broken during extraction were easily revealed by this method. Importantly, it took less than half an hour to obtain images of an individual hair follicle. This method is simple and practical for evaluating the quality and status of hair follicles, providing a fast-screening procedure for hair follicle transplantation.


Reducing delirium and cognitive dysfunction after off-pump coronary bypass: A randomized trial.
Neuropsychiatric complications of surgical coronary revascularization are inconspicuous but frequent and clinically relevant. So far, attempts to reduce their occurrence, such as the introduction of off-pump coronary artery bypass (OPCAB) grafting method, have not brought the desired results. The aim of this trial was to determine whether using any of the 2 selected modifications of OPCAB could decrease the incidence of these undesired sequelae. In this single-center, assessor- and patient-blinded, superiority, randomized controlled trial, 192 patients scheduled for elective isolated OPCAB were randomized to 3 parallel arms. The control arm underwent "conventional" OPCAB with vein grafts. The first study arm underwent anaortic OPCAB (ANA) with total arterial revascularization. The second study arm underwent OPCAB with vein grafts using carbon dioxide surgical field flooding (CO2FF). Outcomes included the incidence of postoperative delirium (PD) and early postoperative cognitive dysfunction (ePOCD). The incidence of PD was 35.9% in the control (OPCAB) arm, 32.8% in the CO2FF arm, and 12.5% in the ANA arm (χ2 [2, N = 191] = 10.17; P = .006). Post hoc tests revealed that the incidence of PD in the ANA arm differed from that in the OPCAB arm (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.09-0.68; P = .002). The incidence of ePOCD was 34.4% in the OPCAB arm, 28.1% in the CO2FF arm, and 9.5% in the ANA arm (χ2 [2, N = 191] = 11.58; P = .003). Post hoc tests revealed that the incidence of ePOCD differed between the ANA and OPCAB arms (OR, 0.20; 95% CI, 0.06-0.58; P < .001). Performing ANA significantly decreases the incidence of PD and ePOCD compared with "conventional" OPCAB with vein grafts, whereas CO2FF is inconsequential in this regard. These results, which probably reflect decreased delivery of embolic load to the brain in ANA, may have practical applicability in daily practice to improve clinical outcomes.


Depression of spontaneous and ionophore-induced neurotransmitter release by Salmonella.
Exposure of frog neuromuscular junctions to heat-killed, lyophilized Salmonella typhimurium (SR 11) produces an early increase in spontaneous transmitter release followed by depression of release and blockade of the obligatory release usually induced by ionophore X537A.


Subchronic toxicity study in rats fed gum karaya.
Gum karaya was given to groups of 15 rats of each sex at levels of 0 (control), 0.2, 1 or 5% (w/w) in the diet for 13 wk. An increase in faecal bulk was seen in all treated groups throughout the study. There was a decrease in weight-gain at the highest dietary level (significant only in the females), which was associated with a marginal reduction in food-conversion efficiency. Males given 1 or 5% drank more than the controls and a transient increase in water intake was seen in females given the highest level. The no-untoward-effect level from this study was 5% (w/w) of the diet, providing a mean intake of about 4 g karaya gum/kg body weight/day.


Expanding the phenotype of oculoectodermal syndrome: possible relationship to encephalocraniocutaneous lipomatosis.
Oculoectodermal syndrome (OES) is characterized by epibulbar dermoids, aplasia cutis congenita, and other abnormalities. Here, we report 2 new cases, review 13 previous cases, and propose that OES may be a mild variant of encephalocraniocutaneous lipomatosis (ECCL), differing primarily in its lack of intracranial pathology.


Recurrent de novo WFS1 pathogenic variants in Chinese sporadic patients with nonsyndromic sensorineural hearing loss.
Hereditary hearing loss (HL) is heterogeneous in terms of their phenotypic features, modes of inheritance, and causative gene mutations. The contribution of genetic variants to sporadic HL remains largely expanding. Either recessive or de novo dominant variants could result in an apparently sporadic occurrence of HL. In an attempt to find such variants we recruited 128 Chinese patients with sporadic nonsyndromic sensorineural HL (NSHL) and performed targeted deafness multigene sequencing in these unrelated trios-families to elucidate the molecular basis. We analyzed a total of 384 available members (probands and their two parents) from 128 unrelated Chinese families presenting with bilateral sensorineural HL, in which previous screening had found no mutations with the GJB2, SLC26A4, and MT-RNR1 genes. We used a targeted genomic enrichment platform to simultaneously capture exons, splicing sites, and immediate flanking intron sequences of 127 known deafness genes. Sanger sequencing was used to identify probands and their two parents segregating causative variants in the candidate gene. We observed that two heterozygous de novo WFS1 mutations in exon 8: c.2051C>T (p.A684V) and c.2590G>A (p.E864K) in five families. The two de novo WFS1 mutations were found in 3.9% (5/128) of sporadic HL patients. We found that four of the five patients had the same de novo p.A684V mutation, and their audiograms showed symmetrical bilateral and profound sensorineural hearing impairments at all frequencies, but only the proband with de novo p.E864K mutation demonstrated significantly bilateral moderate low-mid frequency sensorineural HL. Our data suggest that this WFS1 p.A684V is likely to be a de novo mutational hot spot. We found 3.9% (5/128) of sporadic NSHL is caused by de novo WFS1 mutations. Our data provide that the de novo p.E864K mutation is first identified and de novo p.A684V mutation is likely to be a mutational hot spot in WFS1. It is the first study to highlight that WFS1 gene with the two de novo mutations has been indicated to classify the distinct hearing impairment phenotypes. Furthermore, de novo p.A684V serves as a WFS1 mutational hot spot that was found in the Chinese population with sporadic childhood NSHL, and our study also provides pointers toward the necessity for sequencing of asymptomatic parents of a sporadic case with an apparent dominant pathogenic variant.


Motion analysis for better understanding of psychomotor skills in laparoscopy: objective assessment-based simulation training using animal organs.
Our aim was to characterize the motions of multiple laparoscopic surgical instruments among participants with different levels of surgical experience in a series of wet-lab training drills, in which participants need to perform a range of surgical procedures including grasping tissue, tissue traction and dissection, applying a Hem-o-lok clip, and suturing/knotting, and digitize the level of surgical competency. Participants performed tissue dissection around the aorta, dividing encountered vessels after applying a Hem-o-lok (Task 1), and renal parenchymal closure (Task 2: suturing, Task 3: suturing and knot-tying), using swine cadaveric organs placed in a box trainer under a motion capture (Mocap) system. Motion-related metrics were compared according to participants' level of surgical experience (experts: 50 ≤ laparoscopic surgeries, intermediates: 10-49, novices: 0-9), using the Kruskal-Wallis test, and significant metrics were subjected to principal component analysis (PCA). A total of 15 experts, 12 intermediates, and 18 novices participated in the training. In Task 1, a shorter path length and faster velocity/acceleration/jerk were observed using both scissors and a Hem-o-lok applier in the experts, and Hem-o-lok-related metrics markedly contributed to the 1st principal component on PCA analysis, followed by scissors-related metrics. Higher-level skills including a shorter path length and faster velocity were observed in both hands of the experts also in tasks 2 and 3. Sub-analysis showed that, in experts with 100 ≤ cases, scissors moved more frequently in the "close zone (0 ≤ to < 2.0 cm from aorta)" than those with 50-99 cases. Our novel Mocap system recognized significant differences in several metrics in multiple instruments according to the level of surgical experience. "Applying a Hem-o-lok clip on a pedicle" strongly reflected the level of surgical experience, and zone-metrics may be a promising tool to assess surgical expertise. Our next challenge is to give completely objective feedback to trainees on-site in the wet-lab.


The flavonoids induce the transcription of mRNA encoding erythropoietin in cultured embryonic stem cells via the accumulation of hypoxia-inducible factor-1α.
Flavonoids are the most common phytochemicals in vegetables and herbal products. The beneficial functions of flavonoids in the brain and erythropoietic system have been proposed. Erythropoietin (EPO) is a potent protective agent in the brain; but which has difficulty to cross the blood brain barrier (BBB). Here, about 60 flavonoids were screened for their potential activation on the transcription of EPO mRNA in the neuronal embryonic stem cell lines, NT2/D1 and PC12. Amongst the screened flavonoids, formononetin, calycosin, ononin, chrysin, baicalein and apigenin showed robust up regulation of EPO production via enhancement of hypoxia response element (HRE) activity in cultured embryonic stem cells. In addition, the flavonoids showed activation of HRE activity by having increased accumulation of HIF-1α, but not on level of HIF-1β, in the cultures. The accumulation of HIF-1α was attributed to up regulation of HIF-1α mRNA and blockade of HIF-1α degradation upon treatment of the flavonoids. These results suggested a promising trend of developing commercial products of flavonoids as food supplements tailored for brain health.


Global trends, local harms: availability of fentanyl-type drugs on the dark web and accidental overdoses in Ohio.
As America's opioid crisis has become an "epidemic of epidemics," Ohio has been identified as one of the high burden states regarding fentanyl-related overdose mortality. This study aims to examine changes in the availability of fentanyl, fentanyl analogs, and other non-pharmaceutical opioids on cryptomarkets and assess relationship with the trends in unintentional overdoses in Ohio to provide timely information for epidemiologic surveillance. Cryptomarket data were collected at two distinct periods of time: (1) Agora data covered June 2014-September 2015 and were obtained from Grams archive; (2) Dream Market data from March-April 2018 were extracted using a dedicated crawler. A Named Entity Recognition algorithm was developed to identify and categorize the type of fentanyl and other synthetic opioids advertised on cryptomarkets. Time-lagged correlations were used to assess the relationship between the fentanyl, fentanyl analog and other synthetic opioid-related ads from cryptomarkets and overdose data from the Cincinnati Fire Department Emergency Responses and Montgomery County Coroner's Office. Analysis from the cryptomarket data reveals increases in fentanyl-like drugs and changes in the types of fentanyl analogues and other synthetic opioids advertised in 2015 and 2018 with potent substances like carfentanil available during the second period. The time-lagged correlation was the largest when comparing Agora data to Cincinnati Emergency Responses 1 month later 0.84 (95% CI 0.45, 0.96). The time-lagged correlation between Agora data and Montgomery County drug overdoses was the largest when comparing synthetic opioid-related Agora ads to Montgomery County overdose deaths 7 months later 0.78 (95% CI 0.47, 0.92). Further investigations are required to establish the relationship between cryptomarket availability and unintentional overdose trends related to specific fentanyl analogs and/or other illicit synthetic opioids.


Ultrastructural changes of smooth and rough titanium implant surfaces induced by metal and plastic periodontal probes.
To determine the ultrastructural changes of titanium surfaces of dental implants induced by the tip of periodontal probes. A total of 40 samples of smooth and rough surfaces of titanium implants were randomly assigned for the treatment with metal or plastic periodontal probes under application angles of 20° and 60°. Titanium surfaces have been evaluated with CLSM prior and following to experimental probing determining various standardized 2D and 3D roughness parameters. The average profile and surface roughness (Ra and Sa) showed no significant difference between treated and untreated samples on smooth and rough surface areas irrespective of the probe material. On smooth surfaces several amplitude roughness parameters were increased with metal probes but reached significance only for Rp (p = 0.007). Rough surface parts showed a slight but not significant reduction of roughness following to the contact with metal probes. The surface roughness remained almost unchanged on smooth and rough implant surfaces using plastic probes. The surface roughness on implant surfaces was not dependent on the application angle irrespective of the probe material. Probing of titanium implants with metal probes and even less with plastic probes causes only minor changes of the surface roughness. The clinical significance of these changes remains to be elucidated. Using plastic probes for the clinical evaluation of the peri-implant sulcus might avoid ultrastructural changes to titanium implant surfaces.


Intraventricular Sialidase Administration Enhances GM1 Ganglioside Expression and Is Partially Neuroprotective in a Mouse Model of Parkinson's Disease.
Preclinical and clinical studies have previously shown that systemic administration of GM1 ganglioside has neuroprotective and neurorestorative properties in Parkinson's disease (PD) models and in PD patients. However, the clinical development of GM1 for PD has been hampered by its animal origin (GM1 used in previous studies was extracted from bovine brains), limited bioavailability, and limited blood brain barrier penetrance following systemic administration. To assess an alternative therapeutic approach to systemic administration of brain-derived GM1 to enhance GM1 levels in the brain via enzymatic conversion of polysialogangliosides into GM1 and to assess the neuroprotective potential of this approach. We used sialidase from Vibrio cholerae (VCS) to convert GD1a, GD1b and GT1b gangliosides to GM1. VCS was infused by osmotic minipump into the dorsal third ventricle in mice over a 4-week period. After the first week of infusion, animals received MPTP injections (20 mg/kg, s.c., twice daily, 4 hours apart, for 5 consecutive days) and were euthanized 2 weeks after the last injection. VCS infusion resulted in the expected change in ganglioside expression with a significant increase in GM1 levels. VCS-treated animals showed significant sparing of striatal dopamine (DA) levels and substantia nigra DA neurons following MPTP administration, with the extent of sparing of DA neurons similar to that achieved with systemic GM1 administration. The results suggest that enzymatic conversion of polysialogangliosides to GM1 may be a viable treatment strategy for increasing GM1 levels in the brain and exerting a neuroprotective effect on the damaged nigrostriatal DA system.


SHBG and endothelial function in older subjects.
Endothelial dysfunction is predictor of cardiovascular diseases that have different prevalence in men and women before menopause. Sex hormones and sex hormone binding globulin (SHBG), novel risk factors for diabetes and cardiovascular diseases even in older individuals, might explain this difference. However, the relationship between these hormones and endothelial function has never been addressed in the elderly. 430 men and,424 women 70 years older of Prospective Study of the Vasculature in Uppsala Seniors study, with complete data on SHBG, testosterone(T), estradiol(E2), endothelium-independent vasodilation (EIDV), endothelium-dependent vasodilation(EDV), flow-mediated vasodilation (FMD) and the pulse wave analysis (reflection index, RI) were evaluated. Multivariate regression analysis adjusted for confounders was used to assess the relationship between T, E2, SHBG and endothelial function. In men we found a positive relationship between SHBG and EDV (β ± SE 3.60 ± 0.83, p<0.0001), EIDV (2.42 ± 0.58, p<0.0001) but not with FMD. The relationship between SHBG and EDV and EIDV was maintained after adjustment for sex (1.64 ± 0.47, p<0.001 and 1.79 ± 0.35, p<0.0006, respectively). After adjustment for confounders, the relationship between SHBG and EDV and EIDV was still statistically significant (2.63 ± 0.90 and 1.86 ± 0.63, p = 0.004 for both). In women SHBG and EIDV were positively associated (1.58 ± 0.46; p = 0.0007), and this relationship was independent of sex (1.79 ± 0.35; p<0.001). No significant interaction SHBG * SEX was found for EIDV (p = 0.72). In a combined analysis in two sexes, SHBG and EIDV were positively associated (1.13 ± 0.45; p = 0.01). SHBG was not associated with EDV, FMD and RI. No significant relationship was found between T or E2 and EDV, EIDV, FMD or RI in both sexes. In older men SHBG, but not T and E2, is positively and independently associated with EDV in resistance arteries. In both sexes, SHBG was positively and independently associated with EIDV.


Construction of lncRNA-m6A gene-mRNA regulatory network to identify m6A-related lncRNAs associated with the progression of lung adenocarcinoma.
We evaluated the prognostic value of m6A-related long noncoding RNAs (lncRNAs) in lung adenocarcinoma (LUAD). The expression levels of lncRNAs and mRNAs in LUAD and normal adjacent tissues from The Cancer Genome Atlas dataset were analyzed using the limma package. m6A enzyme-related differentially expressed lncRNAs and mRNAs were identified and used to construct a regulatory network. Survival analysis was performed and the correlation between lncRNAs, m6A regulators, and mRNAs was analyzed; followed by functional enrichment analysis. A comparison of LUAD samples and normal tissues identified numerous differentially expressed lncRNAs and mRNAs, demonstrating that a comprehensive network was established. Two lncRNAs and six mRNAs were selected as prognosis related factors including SH3PXD2A-AS1, MAD2L1, CCNA2, and CDC25C. The pathological stage and recurrence status were identified as independent clinical factors (P < 0.05). The expression levels of these RNAs in the different clinical groups were consistent with those in the different risk groups. The interactions of m6A proteins, two lncRNAs, and six mRNAs were predicted, and functional analysis showed that m6A target mRNAs were involved in the cell cycle, progesterone-mediated oocyte maturation, and oocyte meiosis pathways. These m6A target lncRNAs and mRNAs may be promising biomarkers for predicting clinical prognosis, and the lncRNA-m6A regulator-mRNA regulatory network could improve our understanding of m6A modification in LUAD progression.


Structure function analysis of SH2D2A isoforms expressed in T cells reveals a crucial role for the proline rich region encoded by SH2D2A exon 7.
The activation induced T cell specific adapter protein (TSAd), encoded by SH2D2A, interacts with and modulates Lck activity. Several transcript variants of TSAd mRNA exist, but their biological significance remains unknown. Here we examined expression of SH2D2A transcripts in activated CD4+ T cells and used the SH2D2A variants as tools to identify functionally important regions of TSAd. TSAd was found to interact with Lck in human CD4+ T cells ex vivo. Three interaction modes of TSAd with Lck were identified. TSAd aa239-256 conferred binding to the Lck-SH3 domain, whereas one or more of the four tyrosines within aa239-334 encoded by SH2D2A exon 7 was found to confer interaction with the Lck-SH2-domain. Finally the TSAd-SH2 domain was found to interact with Lck. The SH2D2A exon 7 encoding TSAd aa 239-334 was found to harbour information essential not only for TSAd interaction with Lck, but also for TSAd modulation of Lck activity and translocation of TSAd to the nucleus. All five SH2D2A transcripts were found to be expressed in CD3 stimulated CD4+ T cells. These data show that TSAd and Lck may interact through several different domains and that Lck TSAd interaction occurs in CD4+ T cells ex vivo. Alternative splicing of exon 7 encoding aa239-334 results in loss of the majority of protein interaction motives of TSAd and yields truncated TSAd molecules with altered ability to modulate Lck activity. Whether TSAd is regulated through differential alternative splicing of the SH2D2A transcript remains to be determined.


Prediction of unfavourable response to checkpoint blockade in lung cancer patients through an integrated tumour-immune expression score.
Treatment by immune checkpoint blockade (ICB) provides a remarkable survival benefit for multiple cancer types. However, disease aggravation occurs in a proportion of patients after the first couple of treatment cycles. RNA sequencing data was retrospectively collected. 6 tumour-immune related features were extracted and combined to build a lung cancer-specific predictive model to distinguish responses as progression disease (PD) or non-PD. This model was trained by 3 public pan-cancer datasets and a lung cancer cohort from our institute, and generated a lung cancer-specific integrated gene expression score, which we call LITES. It was finally tested in another lung cancer dataset. LITES is a promising predictor for checkpoint blockade (area under the curve [AUC]=0.86), superior to traditional biomarkers. It is independent of PD-L1 expression and tumour mutation burden. The sensitivity and specificity of LITES was 85.7% and 70.6%, respectively. Progression free survival (PFS) was longer in high-score group than in low-score group (median PFS: 6.0 vs. 2.4 months, hazard ratio=0.45, P=0.01). The mean AUC of 6 features was 0.70 (range=0.61-0.75), lower than in LITES, indicating that the combination of features had synergistic effects. Among the genes identified in the features, patients with high expression of NRAS and PDPK1 tended to have a PD response (P=0.001 and 0.01, respectively). Our model also functioned well for patients with advanced melanoma and was specific for ICB therapy. LITES is a promising biomarker for predicting an impaired response in lung cancer patients and for clarifying the biological mechanism underlying ICB therapy.


Investigating friendship quality: an exploration of self-control and social control theories' friendship hypotheses.
While associations with deviant peers are well understood to impact individual development, less is understood about the relationship between friendship quality and delinquency. Two criminological theories--social control theory and self-control theory--are able to offer an explanation for the latter relationship. Social control and self-control theories both premise that delinquents will have largely fractured, weak, and "cold and brittle" friendships. This study investigates how variations in perceptions of friendship quality are related to the delinquency, maternal attachment, school attachment, and self-control levels of both a participant and his/her close friend. To explore these relationships, we use a diverse (14% black; 18% Hispanic; 9% Asian) sample of 2,154 emerging adults within 1,077 friendship pairs (66% female). In each dyad, both members perceived the friendship's quality and reported personal markers of delinquency, social bonds, and self-control. Several series of multilevel models are estimated that regress each participant's friendship quality perception onto the participant's and their friend's delinquency, attachments, self-control, and demographic characteristics. Results show that delinquents have as intense, or more intense, friendships as non-delinquents. However, low levels of both actor and partner attachments and self-control are independently related to low friendship quality, and this is especially true for self-control. Supplemental analyses demonstrate that the effect of self-control on friendship quality may be reduced when individuals in dyads are delinquent. In conclusion, studies that address friendship quality without including characteristics of multiple members of the friendship are only capturing part of one's estimate of friendship quality.


Suberoylanilide hydroxamic acid combined with gemcitabine enhances apoptosis in non-small cell lung cancer.
We have shown that non-small cell lung cancer (NSCLC) is resistant to the histone deacetylase inhibitor (HDI) suberoylanilide hydroxamic acid (SAHA) through upregulation of the antiapoptotic transcription factor nuclear factor-kappaB (NF-kappaB). HDIs also promote chromatin remodeling, potentially making the DNA more accessible to chemotherapy. We hypothesize that combined SAHA and gemcitabine sensitizes NSCLC to apoptosis. Three NSCLC cell lines (A549, H358, H460) were untreated, or treated with SAHA, gemcitabine, or both agents. NF-kappaB-dependent transcription was determined by reporter gene assays, reverse transcriptase-polymerase chain reaction RT-PCR, and Western blot analysis for the NF-kappaB-regulated antiapoptotic gene MnSOD. Survival of NSCLC cells overexpressing Bfl/A1, Bcl-X(L), or MnSOD and treated with SAHA and gemcitabine was determined in the presence or absence of NF-kappaB. Survival of treated cells overexpressing HDAC-1, 2, 3 or p/CAF was determined. Apoptosis was determined by fluorescence-activated cell sorter analysis, DNA fragmentation, and caspase-3 activity. Colony formation assays were performed on cells treated concurrently and sequentially with SAHA and gemcitabine. Assays were performed in triplicate, and the Student t test was applied as appropriate. SAHA-activated NF-kappaB (P <or= .05) and gemcitabine inhibited these effects (P <or= .01). Increased cell survival was observed after overexpression of antiapoptotic genes, as well as in cells overexpressing HDAC-1, -2, and -3. Fluorescence-activated cell sorter analysis, DNA fragmentation, and caspase-3 assays all showed enhanced apoptosis with combined therapy, compared with single-agent therapy (P <or= .01). Sequential treatment offered no improvement over concurrent treatment. Combined SAHA and gemcitabine sensitized NSCLC cells to apoptosis. Potential "proapoptotic" mechanisms for this finding include gemcitabine inhibition of SAHA-induced NF-kappaB activation and chromatin remodeling mediated by the inhibition of histone deacetylases.


Local intramural delivery of 60% ethyl alcohol for treatment of recalcitrant in-stent restenosis.
We report a case of recalcitrant in-stent restenosis after intracoronary brachytherapy failure that was successfully treated with a novel and experimental technique of local intramural delivery of 60% ethyl alcohol.


Indomethacin-induced gastric ulceration in rats: Protective roles of Spondias mombin and Ficus exasperata.
This study investigated the quantitative polyphenolic constituents and gastroprotective effects of aqueous leaf extracts of Spondias mombin and Ficus exasperata against indomethacin-induced gastric ulcer in rats. Ulceration was induced by a single oral administration of indomethacin (30 mg/kg body weight). Wistar rats were pretreated with esomeprazole (reference drug) at a dose of 20 mg/kg body weight, S. mombin or F. exasperata at 100 and 200 mg/kg body weight once daily for 21 days prior to ulcer induction. At the end of the experiment, gastric secretions and antioxidant parameters were evaluated. We observed that the significantly increased (p < 0.05) ulcer index, gastric volume, malondialdehyde level and pepsin activity were effectively reduced following treatment with S. mombin and F. exasperata. The extracts also markedly attenuated the reduced activity of superoxide dismutase as well as pH and mucin content in the ulcerated rats. These findings are indicative of gastroprotective and antioxidative potentials of the extracts which is also evident in the degree of % inhibition against ulceration. The available data in this study suggest that the extracts of S. mombin and F. exasperata proved to be capable of ameliorating indomethacin-induced gastric ulceration and the probable mechanisms are via antioxidative and proton pump inhibition.