Somatic referral of visceral sensations and rectal sensory threshold for pain in children with functional gastrointestinal disorders.
To test the hypothesis that abdominal pain related to functional gastrointestinal disorders is associated with visceral hypersensitivity and abnormal perception of visceral sensations. We examined 35 children (10-17.6 years old) fulfilling the Rome II criteria with irritable bowel syndrome (IBS; n = 21), functional abdominal pain (FAP; n = 8) or functional dyspepsia (FD; n = 6) compared with 10 control subjects (10.2-16.1 years). All underwent a rectal barostat examination. Painful sensations were reported on a human body diagram. The projections of sensations induced by rectal distension, the rectal sensory threshold for pain (RSTP) and the diagnostic value of RSTP measurements were measured. Rectal distension induced sensations that projected to the S3 dermatome in the control subjects and FD and to aberrant sites in children with IBS and FAP. The RSTP was decreased in children with IBS and FAP compared with control subjects (P <.002) and was not different in children with FD compared with control subjects. At 30.8 mm Hg, the 5th percentile for the control subjects, the RSTP had a sensitivity rate of 89% and a specificity rate of 83% for IBS and FAP diagnosis. Children with IBS and FAP are characterized by the association of rectal hypersensitivity and abnormal pain referral after rectal distension.


Cigarette smoking and breast cancer: case-control studies of prevalent and incident cancer in the Canadian National Breast Screening Study.
Two case-control studies of Canadian women aged 40-59 years are reported investigating the relation of cigarette smoking with initial visit (prevalent) and subsequent visit (incident) breast cancer detection, respectively, within the Canadian National Breast Screening Study. The analysis of prevalent breast cancer (1982-1985), which involved 254 cases and 762 controls, showed no evidence of an elevated risk for women with a history of cigarette smoking, with odds ratios of 0.9 (95% confidence interval (Cl) 0.6-1.5) and 1.2 (95% Cl 0.8-1.8) in premenopausal and postmenopausal subjects, respectively. Similarly, in the incident breast cancer analysis (1981-1987) based on 317 cases and 951 controls, women with a history of cigarette smoking had odds ratios of 1.2 (95% Cl 0.8-2.0) and 1.2 (95% Cl 0.9-1.7) in the premenopausal and postmenopausal categories, respectively. No evidence of dose response or of elevated risk in ex-smokers or current smokers was found in either study. These results persisted despite adjustment for several important variables. The present data demonstrate no association between smoking and prevalent or incident breast cancer in either menopausal category, contradicting the authors' previous finding of a positive association with premenopausal prevalent disease earlier in this screening study. The relation of smoking and breast cancer remains controversial. Further study is required to determine whether an association truly does not exist or whether smoking might have both protective and harmful effects that are mediated through different pathways, thus accounting for the paradoxical findings in the literature to date.


Can cortisol levels predict the severity of acute whiplash-associated disorders?
The exact underlying mechanism of whiplash-associated disorders still remains obscure. Central sensitization of the brain to painful stimulus and disturbances in the hypothalamic-pituitary-adrenal axis has been suggested to contribute to the development of whiplash-associated disorders. Although cortisol is a well-known factor in the acute stress response and its effects on chronic pain sensation were studied, information is lacking regarding the relation between acute phase cortisol concentrations and the intensity of whiplash-associated disorders. The aim of this prospective observational study was to investigate the relationship between acute serum cortisol concentrations and the severity of whiplash-associated disorders. 55 patients enrolled in the study and they answered a pertinent questionnaire. A blood sample was drawn to determine serum cortisol concentration. The mean cortisol concentration of the whiplash-associated disorder score 2-3 patients was significantly lower compared to the whiplash-associated disorder score 1 patients, 9.5 ± 6.9 vs. 13.22 ± 8.3 µg% (p = 0.02). The mean cortisol concentrations increased significantly from mild through moderate to serious grade of severity of accident as perceived by the patient, 9.64 ± 4.82, 11.59 ± 6.85, 17.39 ± 12.1 µg% (p = 0.02). The study supports the possibility that cortisol plays a role in the development of whiplash-associated disorders. Low or relatively low cortisol concentrations might be associated with more severe forms of the disorder.


FOXO3-Engineered Human ESC-Derived Vascular Cells Promote Vascular Protection and Regeneration.
FOXO3 is an evolutionarily conserved transcription factor that has been linked to longevity. Here we wanted to find out whether human vascular cells could be functionally enhanced by engineering them to express an activated form of FOXO3. This was accomplished via genome editing at two nucleotides in human embryonic stem cells, followed by differentiation into a range of vascular cell types. FOXO3-activated vascular cells exhibited delayed aging and increased resistance to oxidative injury compared with wild-type cells. When tested in a therapeutic context, FOXO3-enhanced vascular cells promoted vascular regeneration in a mouse model of ischemic injury and were resistant to tumorigenic transformation both in vitro and in vivo. Mechanistically, constitutively active FOXO3 conferred cytoprotection by transcriptionally downregulating CSRP1. Taken together, our findings provide mechanistic insights into FOXO3-mediated vascular protection and indicate that FOXO3 activation may provide a means for generating more effective and safe biomaterials for cell replacement therapies.


Mid-term outcomes of minimally invasive infrapubic approach for inflatable penile prosthesis implantation: A single-center study and literature review.
The minimally invasive infrapubic approach (MIIA) for inflatable penile prosthesis (IPP) placement has shown favorable peri-operative safety and efficacy profile, but scarce data exist on long-term follow-up. We investigated the safety and efficacy of IPP implantation via the MIIA after a minimum 5-year follow-up. We identified data of implanted patients prospectively included in our institutional database. Complications and functional outcomes were assessed by using validated tools. Specifically, quality of life and patient satisfaction were evaluated by the Quality of Life and Sexuality with Penile Prosthesis (QoLSPP) questionnaire. Kaplan-Meier method was used to analyze IPP survival (defined as a working IPP). Overall, 67 patients implanted by MIIA with a median (IQR) age of 64 years (61-70) were included. The median (IQR) follow-up duration was 71 months (63-80). Fifteen (22%) patients experienced complications: minor (Clavien ≤2) events included changes in penile sensitivity (n = 1; 1.5%), orgasmic dysfunction (n = 1; 1.5%), pain (n = 5; 7%), urinary tract infection (n = 2; 3%), and chronic discomfort (n = 1; 1.5%); major (Clavien 3) complications were represented by mechanical failure (n = 3; 4.5%), IPP infection (n = 1; 1.5%), and cylinder protrusion (n = 1; 1.5%). The estimated IPP survival was 94% (95% CI, 91.4-96.6), 92.5% (95% CI, 89.7-95.3), and 92.5% (95% CI, 89.7-95.3) at 3, 5, and 7 years after implantation, respectively. In patients using the device at follow-up (n = 61; 91%), median (IQR) scores for QoLSPP domains demonstrated favorable functional outcomes and patient satisfaction: functional 21 (19-23), personal 16 (15-18), relational 14 (12-15), and social 12 (11-14). This study represents the longest follow-up using validated tools to assess the outcomes of IPP implantation via MIIA so far. IPP placement via MIIA confirms to be safe and to offer high satisfaction to both patients and partners at mid-term evaluation.


The influence of partial food deprivation on the quantity and source of triiodothyronine in several tissues of athyreotic thyroxine-maintained rats.
In the present study the influence of partial food deprivation (PFD) on the quantity and source of T3 [i.e. T3 derived from local T4 to T3 conversion (Lc T3 (T4] vs. plasma-derived T3] in several rat tissues was investigated. Two groups of athyroid rats on a synthetic diet received a continuous iv infusion consisting of T4 (1.0 microgram/100 g BW X day), [125I]T4, and [131I]T3 over a prolonged period. For one group of rats the daily food intake was restricted by one third to maintain constant BW during the infusion period. At isotopic equilibrium the mean plasma T3, T4, and TSH levels for control-fed rats were: 38 ng/dl, 5.1 micrograms/dl, and 470 ng/ml, respectively. The values for rats on PFD were T3: 22 ng/dl, T4: 4.8 micrograms/dl, TSH: less than 70 ng/ml. The [125I]T3 and [131I]T3 contents of whole homogenates from liver, kidney, thigh muscle, cerebral cortex, cerebellum, and anterior pituitary gland as well as the subcellular fractions from liver, kidney (nuclei, mitochondria, microsomes, and cytosol), and anterior pituitary gland (nuclei) were determined (after extraction in ethanol) by thin layer chromatography. The contribution of Lc T3(T4) and the total T3 levels in these tissue preparations could then be calculated. In the cerebral cortex, cerebellum, and anterior pituitary gland of PFD rats plasma-derived T3 as well as Lc T3(T4) was decreased. The total T3 level in the liver did not change under PFD, owing to an increase in Lc T3(T4). It is possible that the release of hepatic Lc T3(T4) into the blood stream was reduced. In neither group was there appreciable Lc T3(T4) in muscle. In contrast to the other tissues investigated, the [131I]T3 tissue-plasma ratio for muscle had increased under PFD, suggesting a higher uptake of T3. As a consequence, the T3 levels in the muscles of PFD rats did not differ from those in normally fed animals. For both groups of rats the contribution of Lc T3(T4) in hepatic nuclei was far lower than that found for the other hepatic cellular fractions. This would suggest that the hepatic nucleus preferentially takes up plasma-derived T3. In both control-fed and PFD rats the bulk of renal T3 appeared to be exchangeable with plasma T3. Hence the T3 levels in renal nuclei were reduced under PFD. The nuclear T3 levels in the anterior pituitaries from PFD rats were markedly decreased. Therefore it is likely that other factors determine TSH secretion under PFD.


In Support of a Simple Urethrocutaneous Fistula Closure Technique Following Hypospadias Repair.
To evaluate the success rates of a simple posthypospadias urethrocutaneous fistula repair. We evaluated children who underwent urethrocutaneous fistula closure by means of a simple standard technique in which the fistula tract was dissected to its base and resected and the urethral defect closed with a single layer of continuous sutures and covered with local subcutaneous tissue. No urethral stents or catheters were used, and the patients were discharged on the same day. Excluded were children who underwent fistula repair by a different technique, revision hypospadias repair for fistula, or concomitant meatoplasty for meatal stenosis. Study endpoints were fistula recurrence and the need for further penile surgery other than fistula repair. Seventy-two children underwent 81 repairs. The mean follow-up was 7.9 years. Recurrence occurred in 17 cases (21%). Seven children (9%) underwent penile surgery other than fistula repair, including meatoplasty (n = 5) and re-do hypospadias repair for a diagnosis other than fistula recurrence (n = 2). There was no significant difference in recurrence rate between large and small fistulas, coronal or more proximal fistulas, or children w/wo prior fistula repairs. Standard fistula closure solely by adjacent tissues yielded success rates of 79% after long-term follow-up. This repair can be safely offered with the expectation of similar results for a variety of urethrocutaneous fistulas in children.


[Radiologically-guided hysterosalpingography and tubal catheterization].
Radiological exploration of hypofertility by means of hysterosalpingography is a method still valid but no longer sufficient. Tubal catheterization has thus become a necessary complementary exam in order to eliminate the pseudo-obturations of hysterosalpingography and, in case of proximal tubal obstructions, to obtain pregnancies. The conditions for the realization of hysteroalpingography and tubal catheterization are hereby described, with emphasis on the rigorous technique that is required together with careful listening to the patients.


Mechanisms of glomerular albumin filtration and tubular reabsorption.
Albumin is filtered through the glomerulus with a sieving coefficient of 0.00062, which results in approximately 3.3 g of albumin filtered daily in human kidneys. The proximal convoluted tubule reabsorbs 71%, the loop of Henle and distal tubule 23%, and collecting duct 3% of the glomerular filtered albumin, thus indicating that the kidney plays an important role in protein metabolism. Dysfunction of albumin reabsorption in the proximal tubules, due to reduced megalin expression, may explain the microalbuminuria in early-stage diabetes. Meanwhile, massive nonselective proteinuria is ascribed to various disorders of the glomerular filtration barrier, including podocyte detachment, glomerular basement membrane rupture, and slit diaphragm dysfunction in focal segmental glomerulosclerosis, membranous nephropathy, and other glomerulonephritis. Selective albuminuria associated with foot process effacement and tight junction-like slit alteration is observed in the patients with minimal-change nephrotic syndrome, and the albumin uptake is enhanced in the podocyte cell body, possibly mediated by albumin receptors in the low-dose puromycin model. The role of enhanced podocyte albumin transport needs to be investigated to elucidate the mechanism of the selective albuminuria in minimal-change disease.


Association between hyperuricaemia and clinical pathological characteristics of patients with IgA nephropathy.
To study the association of hyperuricaemia with clinical and pathological characteristics of patients with IgA nephropathy, and to clarify adverse effects of hyperuricaemia on the onset and progression of IgA nephropathy. A total of 244 patients with IgA nephropathy enrolled in Jiangjin Center Hospital were divided into a group with normal serum uric acid level and a group with elevated level. Age, gender, course of disease, blood pressure, liver function, renal function, blood lipid levels, blood glucose level, 24-hour urine protein level and pathological grades were recorded. The correlations of serum uric acid level with clinical indices and pathological grades were analyzed. The incidence rate of IgA nephropathy complicated with hyperuricaemia was 25.4%. The two groups had significantly different course of disease, body mass index (BMI), and levels of urea nitrogen, creatinine, triglyceride and urine protein (p<0.05). The group with elevated serum uric acid level had higher Lee's grade, tubulointerstitial lesion grade and renal arteriolar lesion grade. Patients with IgA nephropathy were prone to hyperuricaemia, being closely correlated with BMI, course of disease, blood pressure, triglyceride level and renal function. High pathological grades were important indices for poor prognosis. The serum uric acid levels of patients with IgA nephropathy should be monitored to effectively control hyperuricaemia and to avoid its complications.


Where are the Sunday babies? II. Declining weekend birth rates in Switzerland.
Birth dates from almost 3 million babies born between 1969 and 2005 in Switzerland were analyzed for the weekday of birth. As in other countries but with unprecedented amplitude, a very marked non-random distribution was discovered with decreasing numbers of births on weekends, reaching -17.9% in 2005. While most of this weekend births avoidance rate is due to fewer births on Sundays (up to -21.7%), the downward trend is primarily a consequence of decreasing births on Saturdays (up to -14.5%). For 2005, these percentages mean that 3,728 fewer babies are born during weekends than could be expected from equal distribution. Most interestingly and surprisingly, weekend birth-avoiding rates are significantly correlated with birth numbers (r = 0.86), i.e. the lower the birth number per year, the lower the number of weekend births. The increasing avoidance of births during weekends is discussed as being a consequence of increasing numbers of caesarean sections and elective labor induction, which in Switzerland reach 29.2 and 20.5%, respectively, in 2004. This hypothesis is supported by the observation that both primary and secondary caesarean sections are significantly correlated with weekend birth avoidance rates. It is therefore likely that financial aspects of hospitals are a factor determining the avoidance of weekend births by increasing the numbers of caesarean sections.


Duhamel operation 40 years after: a multicentric study.
The authors present the results of an international retrospective study evaluating the present situation in using Duhamel's technique or its modifications in the treatment of Hirschsprung's disease on the basis a series of 2430 patients. After evaluation of all important criteria and discussion with data from the literature it is concluded that the techniques is simple, fast, less shocking, logical, reliable, respecting the rectal anatomy and physiology, ingenious in its principle, without serious complications. The rectum is preserved in place with all its vascular drainage and innervation. This technique can be performed by every sufficiently experienced surgeon.


Sociocognitive determinants of self-reported compliance with standard precautions: Development and preliminary testing of a questionnaire with French health care workers.
Inconsistent compliance of health care workers with standard precautions has already been documented. The objective of this study was to develop a questionnaire to investigate the sociocognitive determinants of compliance with standard precautions based on the theory of planned behavior. To construct the Standard Precautions Questionnaire (SPQ), items were selected using a systematic review of literature and semistructured interviews with 54 health care workers. Thirty-five items were selected for a draft questionnaire. These questionnaires were sent to 649 health care workers in 3 medical specialties (pediatrics, geriatrics, and intensive care) in a French University hospital. A total of 331 valid questionnaires were analyzed. Factor analysis yielded a final 7-factor solution with an explained variance of 66.51%, with 24 items. The 7 dimensions were the following: attitude toward standard precautions, social influence facilitating organization, exemplary behavior of colleagues, organizational constraints, individual constraints, and intention to perform standard precautions. Some differences were observed between medical specialties on attitude toward standard precautions, social influence, and individual constraints. The SPQ met the conditions of reliability and validity in accordance with psychometric demands and could be used to evaluate attitudes and intention to perform standard precautions among medical and nursing staff.


A comparison of quality of life between patients with small and large gastric remnant volumes after gastrectomy for gastric cancer.
The impact of gastric remnant volumes (GRVs) after gastrectomy on patients' quality of life (QOL) has not yet been clarified. The aim of the present study was to compare QOL after gastrectomy between small and large gastric remnant volume patients.We prospectively collected clinical data from 78 consecutive patients who underwent distal gastrectomy with Billroth II gastrojejunostomy for gastric cancer. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Stomach questionnaire and gastric computed tomography scans were performed. The patients were subdivided into 2 groups by remnant stomach volume (the S group ≤110 mL vs L group >110 mL).The worst scores for most items were observed at postoperative month 1 and usually improved thereafter. There was no difference in the STO22 score except for dysphagia between the S and L groups after gastrectomy (P > .05). The QOL score of dysphagia was different at postoperative 6 months (S vs L, 12.4 vs 22.8, P < .03), but there was no difference at postoperative months 1, 3, 12, 24, or 36 (P > .05).The remnant gastric volume after partial gastrectomy affects neither functional differences nor QOL after 6 months following appropriate radical surgery.


Thermodynamics and Kinetics Parameters of Eichhornia crassipes Biomass for Bioenergy.
Eichhornia crassipes is an aquatic plant well known for its role in soil reclamation due to the containment of valuable nutrients. Moreover, its biomass is an abundant and low-cost biological resource. Pyrolysis of a biomass offers one of the cleanest methods to harness the bioenergy stored in the biomass. The present study was focused on evaluating the bioenergy potential of Eichhornia crassipes via pyrolysis. Biomass of E. crassipes was collected from a municipal wastewater pond. Oven dried powdered biomass of E. crassipes was subjected to pyrolysis at three heating rates including 10, 30 and 50 °C min-1 in a simultaneous Thermogravimetry-Differential Scanning Calorimetry analyzer under an inert environment containing nitrogen. Data obtained were subjected to isoconversional models of Kissenger-Akahira-Sunose (KSA) and Flynn-Wall-Ozawa (FWO) to understand the reaction chemistry. Kinetic parameters have shown that the pyrolysis followed first-order reaction kinetics. The average values of activation energies (129.71-133.03 kJ mol-1) and thermodynamic parameters including high heating values (18.12 MJ kg-1), Gibb's free energies (171-180 kJ mol-1) and enthalpy of reaction (124-127 kJ mol-1) have shown the remarkable bioenergy potential of this biomass. This low-cost biomass may be used to produce liquids, gases, and biochar in a costefficient and environmentally friendly way via pyrolysis or co-pyrolysis in the future.


Coordinate expansion of murine hematopoietic and mesenchymal stem cell compartments by SHIPi.
Promoting the expansion of adult stem cell populations offers the potential to ameliorate radiation or chemotherapy-induced bone marrow failure and allows for expedited recovery for patients undergoing these therapies. Previous genetic studies suggested a pivotal role for SH2 domain-containing inositol-5-phosphatase 1 (SHIP1) in limiting the size of the hematopoietic stem cell (HSC) compartment. The aim of this study was to determine whether our recent development of small molecule SHIP1 inhibitors offers the potential for pharmacological expansion of the HSC compartment in vivo. We show here that treatment of mice with aminosteroid inhibitors of SHIP1 (SHIPi) more than doubles the size of the adult mesenchymal stem cell (MSC) compartment while simultaneously expanding the HSC pool sixfold. Consistent with its ability to target SHIP1 function in vivo, SHIPi also significantly increases plasma granulocyte colony-stimulating factor (G-CSF) levels, a growth factor that supports proliferation of HSC. Here, we show that SHIPi-induced G-CSF production mediates HSC and MSC expansion, as in vivo neutralization of G-CSF abrogates the SHIPi-induced expansion of both the HSC and MSC compartments. Due to its expansionary effect on adult stem cell compartments, SHIPi represents a potential novel strategy to improve declining stem cell function in both therapy induced and genetically derived bone marrow failure syndromes.


Increased histamine-output from the isolated gastric mucosa of the rat in response to pentagastrin and methacholine.
1 A rat isolated gastric mucosal preparation was used to monitor histamine output and acid secretion during stimulation by different secretagogues. 2 In non-stimulated preparations, spontaneous histamine output decreased over 450 min. 3 Stimulation of secretion with 4 (5)-methylhistamine or dibutyryl cyclic adenosine 3'5'-monophosphate (db cyclic AMP) and theophylline did not influence histamine output. 4 Pentagastrin, gastrin and methacholine increased both acid secretion and histamine output. Pentagastrin and gastrin mobilized six times more histamine and relation to acid secretion than did methacholine. 5 Spontaneous histamine output and secretagogue-induced increases were unaffected by changes in external Ca2+ (0.0 to 7.2 mM) or Mg2+ (1.2 to 4.8 mM). 6 These results support the hypothesis that mucosal histamine plays a more important role in the action of gastrin than of cholinomimetics on the parietal cell.


Isotopic fingerprints of the Lake Żabińskie (NE Poland) hydrological system on contemporary carbonates precipitated in the lake.
An isotopic monitoring was undertaken in 2012-2014 at Lake Żabińskie (Mazurian Lakeland, NE Poland). The aim was to identify the factors and processes controlling an isotopic composition of the lake water and to explore the mechanism responsible for recording the climatic signal in stable isotope composition of deposited carbonates. δ18O and δ2H in the precipitation, lake water column, inflows and outflow, δ18O and δ13C in the carbonate fraction of sediments trapped in the water column were recorded with monthly resolution. A relationship between δ18O and δ2H in local precipitation was used to estimate the local meteoric water line. The dataset obtained for the water enabled to identify the modification of the water's isotopic composition due to evaporation, connected with seasonal lake water stratification and mixing patterns. Statistically significant correlation coefficients suggest that the δ18O of the carbonate fraction in the sediment traps depends on the δ18O of rainfall water and on air temperature. The fractionation coefficient α shows that in summer months the carbonate precipitation process is closest to equilibrium. As expected for an exorheic lake, no significant correlation was observed between δ18O and δ13C in precipitated carbonate.


Heterotopic pancreas presenting as dysphagia.
Heterotopic pancreatic tissue, also known as a pancreatic rest, is an uncommon congenital anomaly defined as extrapancreatic tissue located far from the pancreas and without connection via vascular or anatomical means to it. Such tissue may occur throughout the GI tract but has a propensity to affect the stomach and the proximal small intestine. The majority of patients with pancreatic heterotopia are asymptomatic, but when symptoms occur, they can present in a variety of ways. We report a case of a patient whose pancreatic rest presented primarily as dysphagia for solid food and in whom endoscopic ultrasound was used to further define the lesion. There have been only two cases reported of a pancreatic rest causing symptoms of dysphagia. A review of the literature on pancreatic heterotopia as well as the use of endoscopic ultrasound as an aid in evaluation is included.


Psychosocial issues for patients with ventricular assist devices: a qualitative pilot study.
Surgical implantation of a ventricular assist device is being used increasingly in patients in the United Kingdom, yet few studies have focused on patients' experiences from a phenomenological (psychological) perspective. To explore, through a pilot study, the impact of implantation of a ventricular assist device on patients' bodies and lives. This qualitative retrospective study included 6 patients (4 men and 2 women) and 3 of these patients' relatives. Patients were from 17 to 50 years old and had used Thoratec, Heartmate, or VentrAssist devices. The participants' accounts clustered around a number of themes, 2 of which are reported here: (1) body and self and (2) trust. Each theme comprised several subthemes: body and self had sub-themes of shock, restrictions, scarring, and infection; trust had subthemes of keeping me alive, device failure, and confidence. The ventricular assist device has a considerable effect on a patient's body and sense of self. This effect is often accommodated without much difficulty, but some patients and their families need additional psychological support during and after use of a ventricular assist device. Assessment before implantation of such a device can sometimes reveal this need, but such assessment may not be possible in emergency procedures. Trusting the new heart or the native recovered heart may be difficult for some patients. Further research is needed to understand this phenomenon.


Prevalence and clinical significance of pancreatic cystic lesions in immunosuppressed patients following solid organ transplantation.
Pancreatic cystic lesions (PCLs) are occasionally found in solid organ transplant (SOT) recipients. In such recipients, the risk of cancer is increased due to immunosuppressive therapy. This study investigated the prevalence of PCLs and described their clinical course in immunosuppressed patients following SOT. The presence of PCLs in a retrospective cohort of 805 consecutive SOT recipients from 2009 to 2019 was examined. The characteristics of PCLs were compared using initial and follow-up imaging, where available. These results were compared to an age- and sex-matched immunocompetent control group monitored for at least 12 months. PCLs were present in 15 of 805 SOT patients (seven liver and eight kidney transplantations). The median diameter of the largest lesion was 20 mm (range, 0.2-60 mm) and 60% of lesions were benign. During follow-up imaging, the cyst size remained stable in 46.7%, increased in 13.3%, and decreased in 40.0% of the SOT group. Significantly more of the SOT patients showed PCL size reductions (P=0.007). Among SOT patients diagnosed with intraductal papillary mucinous neoplasms (6/15), worrisome features were noted in one patient at the time of cyst diagnosis. Differences in the development of worrisome features between the study and control groups were not statistically significant. The malignant transformation of PCLs in SOT recipients is rare and most such PCLs can be managed conservatively. The presence of a PCL should therefore not affect transplant eligibility.


Fucanomics and galactanomics: marine distribution, medicinal impact, conceptions, and challenges.
Glycomics turned out to be a very extensive project where its subdivision is consequently emerging. This is seen by the growing number of terminologies used to define subprojects concerning particular classes of bioactive carbohydrates. Sulfated fucans (SFs) and sulfated galactans (SGs) are relatively new classes of sulfated polysaccharides (SPs) that occur mostly in marine organisms, and exhibit a broad range of medicinal effects. Their structures are taxonomically dependent, and their therapeutic actions include benefits in inflammation, coagulation, thrombosis, angiogenesis, cancer, oxidation, and infections. Some red algae, marine angiosperm and invertebrates express SPs of unique structures composed of regular repeating oligomeric units of well-defined sulfation patterns. This fine pattern of structural regularity is quite rare among any naturally occurring long SPs, and enables accurate structure-biofunction correlations. Seeing that, fucanomics and galactanomics may comprise distinguished glycomics subprojects. We hereby discuss the relevance that justifies the international recognition of these subprojects in the current glycomics age associated with the beneficial outcomes that these glycans may offer in drug development.


Post-operative aspirin use and colorectal cancer-specific survival in patients with stage I-III colorectal cancer.
Recent observational studies suggest that postoperative aspirin use may improve Colorectal cancer (CRC)-specific survival and overall survival (OS). In this study, we aimed to assess the effects of aspirin use on outcomes in a predominantly Asian cohort of patients with CRC. Case records of patients undergoing curative resection for stage I-III CRC were retrieved for clinical data and patterns of aspirin use and vital data were determined from hospital electronic prescription records, hospital pharmacy dispensing records, national clinical and prescription databases. CRC-specific and recurrence-free survival (RFS) amongst aspirin users and non-users were analyzed and compared using the Cox proportional hazards model. Out of 726 patients with CRC, 103 were regular aspirin users and 623 were non-users. The median age of the cohort was 65 years (range=22-94 years) and the majority of patients were Chinese (90%). Nineteen percent, 31% and 47% had stage I, II and III CRC respectively; tumor staging was unknown for 3%. After adjusting for prognostic factors (age, stage, lymph node stage, grade, lesion site, perineural invasion, lymphvascular invasion), the risk of CRC relapse or death from CRC was approximately 60% lower compared to patients who were not postoperative aspirin users (Hazard Ratio=0.38, 95% Confidence Interval=0.17-0.84, p=0.017). No benefit was observed for preoperative use of aspirin. In this single-Institution study, with long-term follow-up of patients with stage I-III-resected CRC, postoperative aspirin use was associated with reduced risk of relapse of and death from CRC.


Pathology of the vagina.
This review summarizes key articles published in 1990 relevant to abnormalities of the vagina. The subjects covered include vaginal squamous neoplasia, including epidemiologic characteristics, vaginal intraepithelial neoplasia, superficially invasive carcinoma of the vagina, and the expression of epidermal growth factor and HER-2neu in normal and neoplastic epithelium. Clear cell adenocarcinoma is discussed, and recent epidemiologic factors distinguishing vaginal from cervical clear cell adenocarcinoma, as they are related to in utero diethylstilbestrol exposure, are presented. Small cell neuroendocrine carcinoma of the Bartholin's gland, presenting as a vaginal mass, is documented in a reviewed case report. A series of primary malignant melanomas of the vagina are presented and clinical and pathologic features, as well as survival data and factors influencing survival are presented. Three studies on vaginal fibroepithelial polyps, clinical and pathologic evaluations, as well as differential diagnosis and concepts of origin, are reviewed. These findings provide new insights into the understanding of the properties of the subepithelial stroma of the lower female genital tract and its capacity to change in pregnancy and the postpartum state.


The influence of chain dynamics on the far-infrared spectrum of liquid methanol.
Far-infrared-absorption spectroscopy is used to investigate the low-frequency (<or=100 cm-1) intermolecular interactions in liquid methanol. Using an intense source of far-infrared radiation, modes are elucidated at approximately 30 and 70 cm-1 in the absorption spectrum. These modes are believed to arise from intermolecular bending and librational motions, respectively, and are successfully reproduced in an ab initio molecular-dynamics simulation of methanol.


In silico and in vitro human metabolism of IOX2, a performance-enhancing doping agent.
IOX2 is a potent inhibitor of prolyl hydroxylase 2, a key enzyme in the regulation of hypoxia-inducible factor (HIF) and oxygen homeostasis. As such, it can be used to enhance athletic performance and is currently banned by the World Anti-Doping Agency (WADA). Detection of metabolites is critical to demonstrate drug use in doping. However, there is currently little data on IOX2 human metabolism. Our aim was to identify relevant biomarkers of IOX2 use in humans. For this purpose, IOX2 was incubated with 10-donor-pooled human hepatocytes for 3 h, incubates were analyzed by liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS), and LC-HRMS/MS data were screened with Compound Discoverer (Thermo Scientific) for a comprehensive identification of IOX2 metabolites. Additionally, IOX2 human metabolites were predicted with GLORYx open-access software (University of Hamburg, Germany) to assist in the LC-HRMS/MS analysis and data mining. Thirteen metabolites were identified, oxidation at the quinolinyl group, O-glucuronidation, and combinations being predominant biotransformations. The results were consistent with previous animal studies and a single case of oral microdose administration. We suggest hydroxyquinolinyl-IOX2 as major biomarker of IOX2 use in biological samples, glucuronide hydrolysis being critical to increase IOX2 and hydroxyquinolinyl-IOX2 detectability in urine.


Independent effects of interleukin-1 on proteoglycan breakdown, proteoglycan synthesis, and prostaglandin E2 release from cartilage in organ culture.
Exposure of bovine nasal cartilage in culture to interleukin-1 (IL-1) leads to a time- and concentration-dependent stimulation of proteoglycan breakdown and prostaglandin E2 (PGE2) release, and to inhibition of proteoglycan synthesis. The threshold levels of IL-1 required for initiating these effects were different, and IL-1 was 10 times more potent in inhibiting synthesis than in stimulating breakdown of proteoglycan. Kinetic studies indicated that the effects on proteoglycan metabolism occurred earlier (16-24 hours) than those for PGE2 release (48 hours). Selective effects were observed with inhibitors. Nonsteroidal antiinflammatory drugs blocked PGE2 production in response to IL-1, but had no effect on proteoglycan metabolism, and the antiarthritic drugs that blocked IL-1-stimulated breakdown augmented the inhibition of proteoglycan synthesis. We suggest that the effects of IL-1 on proteoglycan breakdown, proteoglycan synthesis, and PGE2 release are mediated by independent post-receptor mechanisms.


Metabolomics reveals the role of acetyl-l-carnitine metabolism in γ-Fe2O3 NP-induced embryonic development toxicity via mitochondria damage.
Iron oxides nanoparticles (FeOX NPs), including α-Fe2O3, γ-Fe2O3, and Fe3O4, are employed in many technological applications. However, very few studies have investigated the embryonic developmental toxicity of FeOX NPs. In this study, metabolomics analysis were used to uncover the potential mechanisms of FeOX NPs developmental toxicity on embryo-larval zebrafish and mice. Our results indicated that γ-Fe2O3 NP treatment could cause increased mortality, dropped hatching rate, etc., while α-Fe2O3 and Fe3O4 NPs showed no obvious effect. Through metabolomics analysis, a total of 42 metabolites were found to be significantly changed between the γ-Fe2O3 NP-treated group and the control group (p < 0.05). Pathway enrichment analysis indicated the impairment of mitochondria function. γ-Fe2O3 NP treatment caused abnormal mitochondrion structure and a decrease in mitochondrial membrane potential in zebrafish embryos. Meanwhile, ATP synthesis was decreased while oxidative stress levels were affected. It is noteworthy that acetyl-l-carnitine (ALCAR) (p = 6.79E - 04) and l-carnitine (p = 1.43E - 03) were identified with minimal p values, the relationship between the two counter-balance was regulated by acetyltransferase (crata). Subsequently, we performed rescue experiments with ALCAR on zebrafish embryos, and found that the mortality rates reduced and hatching rates raised significantly in the γ-Fe2O3 NP-treated group. Additionally, γ-Fe2O3 exposure could lead to increased absorbed fetus rate, decreased placental weight, lower expression of acetyltransferase (Crat), reduced ATP synthesis as well as increased oxidative stress (p < 0.05). Our findings demonstrated that γ-Fe2O3 NP might affect the mitochondrial membrane potential and ATP synthesis by affecting the metabolism of ALCAR, thereby stimulating oxidative stress, cell apoptosis, and causing embryonic development toxicity.


Treatment Efficacy and Resistance Mechanisms Using the Second-Generation ALK Inhibitor AP26113 in Human NPM-ALK-Positive Anaplastic Large Cell Lymphoma.
ALK is a tyrosine kinase receptor involved in a broad range of solid and hematologic tumors. Among 70% to 80% of ALK(+) anaplastic large cell lymphomas (ALCL) are caused by the aberrant oncogenic fusion protein NPM-ALK. Crizotinib was the first clinically relevant ALK inhibitor, now approved for the treatment of late-stage and metastatic cases of lung cancer. However, patients frequently develop drug resistance to Crizotinib, mainly due to the appearance of point mutations located in the ALK kinase domain. Fortunately, other inhibitors are available and in clinical trial, suggesting the potential for second-line therapies to overcome Crizotinib resistance. This study focuses on the ongoing phase I/II trial small-molecule tyrosine kinase inhibitor (TKI) AP26113, by Ariad Pharmaceuticals, which targets both ALK and EGFR. Two NPM-ALK(+) human cell lines, KARPAS-299 and SUP-M2, were grown in the presence of increasing concentrations of AP26113, and eight lines were selected that demonstrated resistance. All lines show IC50 values higher (130 to 1,000-fold) than the parental line. Mechanistically, KARPAS-299 populations resistant to AP26113 show NPM-ALK overexpression, whereas SUP-M2-resistant cells harbor several point mutations spanning the entire ALK kinase domain. In particular, amino acid substitutions: L1196M, S1206C, the double F1174V+L1198F and L1122V+L1196M mutations were identified. The knowledge of the possible appearance of new clinically relevant mechanisms of drug resistance is a useful tool for the management of new TKI-resistant cases. This work defines reliable ALCL model systems of AP26113 resistance and provides a valuable tool in the management of all cases of relapse upon NPM-ALK-targeted therapy.


Identification of small molecular inhibitors for efflux protein Rv2688c of Mycobacterium tuberculosis.
Mycobacterium tuberculosis (Mtb) is the pathogen, which causes tuberculosis. The development of multidrug-resistant and extensively drug-resistant strains in Mtb is due to an efflux mechanism of antibiotics in the bacteria. The efflux pump proteins in the bacteria are implicated in the active efflux of antibiotics. The efflux pump protein, "fluoroquinolones export ATP-binding protein Rv2688c" (FEAB), is considered as a potential therapeutic target to prevent tuberculosis. In the present work, in silico protocols are applied to identify inhibitors for the FEAB protein to arrest the efflux mechanism. Comparative modeling techniques are used to build the protein structure. The generated structure consists of 9 helices, 13 beta strands, and 3 β sheets. The active site is predicted using active site prediction server tools. The virtual screening protocols are carried out to generate small ligand inhibitor structures. The identified ligand molecules show selective binding with Ser97, Glu99, Lys149, Asp171, Glu172, and Ser175 amino acid residues of the protein. The ligand molecules are subjected to in silico prediction of pharmaco kinetic properties, and the predicted IC50 (HERG) of all the molecules are less than -5.0, which is indicative of the identified ligand molecules is being potentially good FEAB inhibitors.


Prognostic value and clinical relevance of the 6th Edition 2002 American Joint Committee on Cancer staging system in patients with resectable hepatocellular carcinoma.
A simplified American Joint Committee on Cancer (AJCC) TNM staging system for hepatocellular carcinoma (HCC) (the 6th edition) was proposed in 2002. In this study, we validated the prognostic value of the staging system in a patient cohort undergoing hepatic resection with longterm followup. From a prospective database, the study cohort consisted of 440 patients who underwent curative hepatic resection for HCC between July 1991 and January 1999. Median followup time was 66 months. Multivariate analysis was performed to identify the independent prognostic factors related to postoperative survival. Patients were staged according to both the 5th edition (TNM-5) and 6th edition (TNM-6) AJCC TNM staging criteria. The independent prognostic factors included major vascular invasion, microvascular invasion, surgical margin < 1 cm, indocyanine green retention rate at 15 minutes > 10%, multiple tumors, tumor rupture, male, and serum aspartate aminotransferase > 90 U/L. The breakdown by TNM-5 staging: I, 27 (6.1%); II, 108 (24.5%); III, 218 (49.5%); and IVA, 87 (19.8%) and by TNM-6 staging: I, 120 (27.3%); II, 170 (38.6%); and III, 150 (34.1%). When stratified according to the TNM-5 system, difference in survival was notable between stages II and IIIA (p < 0.001), between stages IIIA and IVA (p < 0.001), but not between stages I and II (p > 0.05). When stratified according to the TNM-6 system, difference in survival was considerable between stages I and II (p < 0.01), stages II and III (p < 0.001), and stages I and III (p < 0.001). Overall, the TNM-6 staging system appears to provide a reliable prognostic classification of HCC patients and is simpler to use than the TNM-5 staging system.


Mimicking lichens: incorporation of yeast strains together with sucrose-secreting cyanobacteria improves survival, growth, ROS removal, and lipid production in a stable mutualistic co-culture production platform.
The feasibility of heterotrophic-phototrophic symbioses was tested via pairing of yeast strains Cryptococcus curvatus, Rhodotorula glutinis, or Saccharomyces cerevisiae with a sucrose-secreting cyanobacterium Synechococcus elongatus. The phototroph S. elongatus showed no growth in standard BG-11 medium with yeast extract, but grew well in BG-11 medium alone or supplemented with yeast nitrogen base without amino acids (YNB w/o aa). Among three yeast species, C. curvatus and R. glutinis adapted well to the BG-11 medium supplemented with YNB w/o aa, sucrose, and various concentrations of NaCl needed to maintain sucrose secretion from S. elongatus, while growth of S. cerevisiae was highly dependent on sucrose levels. R. glutinis and C. curvatus grew efficiently and utilized sucrose produced by the partner in co-culture. Co-cultures of S. elongatus and R. glutinis were sustained over 1 month in both batch and in semi-continuous culture, with the final biomass and overall lipid yields in the batch co-culture 40 to 60% higher compared to batch mono-cultures of S. elongatus. The co-cultures showed enhanced levels of palmitoleic and linoleic acids. Furthermore, cyanobacterial growth in co-culture with R. glutinis was significantly superior to axenic growth, as S. elongatus was unable to grow in the absence of the yeast partner when cultivated at lower densities in liquid medium. Accumulated reactive oxygen species was observed to severely inhibit axenic growth of cyanobacteria, which was efficiently alleviated through catalase supply and even more effectively with co-cultures of R. glutinis. The pairing of a cyanobacterium and eukaryotic heterotroph in the artificial lichen of this study demonstrates the importance of mutual interactions between phototrophs and heterotrophs, e.g., phototrophs provide a carbon source to heterotrophs, and heterotrophs assist phototrophic growth and survival by removing/eliminating oxidative stress. Our results establish a potential stable production platform that combines the metabolic capability of photoautotrophs to capture inorganic carbon with the channeling of the resulting organic carbon directly to a robust heterotroph partner for producing biofuel and other chemical precursors.


Molecular studies neglect apparently gram-negative populations in the human gut microbiota.
Studying the relationships between gut microbiota, human health, and diseases is a major challenge that generates contradictory results. Most studies draw conclusions about the gut repertoire using a single biased metagenomics approach. We analyzed 16 different stool samples collected from healthy subjects who were from different areas, had metabolic disorders, were immunocompromised, or were treated with antibiotics at the time of the stool collection. The analyses performed included Gram staining, flow cytometry, transmission electron microscopy (TEM), quantitative real-time PCR (qPCR) of the Bacteroidetes and Firmicutes phyla, and pyrosequencing of the 16S rRNA gene amplicons targeting the V6 region. We quantified 10(10) prokaryotes per gram of feces, which is less than was previously described. The Mann-Whitney test revealed that Gram-negative proportions of the prokaryotes obtained by Gram staining, TEM, and pyrosequencing differed according to the analysis used, with Gram-negative prokaryotes yielding median percentages of 70.6%, 31.0%, and 16.4%, respectively. A comparison of TEM and pyrosequencing analyses highlighted a difference of 14.6% in the identification of Gram-negative prokaryotes, and a Spearman test showed a tendency toward correlation, albeit not significant, in the Gram-negative/Gram-positive prokaryote ratio (ρ = 0.3282, P = 0.2146). In contrast, when comparing the qPCR and pyrosequencing results, a significant correlation was found for the Bacteroidetes/Firmicutes ratio (ρ = 0.6057, P = 0.0130). Our study showed that the entire diversity of the human gut microbiota remains unknown because different techniques generate extremely different results. We found that to assess the overall composition of bacterial communities, multiple techniques must be combined. The biases that exist for each technique may be useful in exploring the major discrepancies in molecular studies.


[Prostate specific monoclonal antibody gained by glycolipid immunization].
Extraction of glycolipid component from hypertrophic and cancerous prostatic tissue were performed using chloroform-methanol solution and isopropanol-hexan-solution. The extract was separated into the "upper phase" and "lower phase" by Folchs fractionation technic. Each fraction was conjugated with acid treated salmonella minesota and than it was injected subcutaneously, intra-peritoneally and finally intravenously to BALB/c mice. Spleen cells from immunized mice were fused with P3X63, and antibody APG1 was obtained. APG1 shows a preferential reactivity towards prostatic tissue by the immunohistochemical analysis. Furthermore, the immunohistochemical analysis using enzyme and acid treated tissue and TLC immunostaining indicate that this monoclonal antibody specifically recognizes the sialylglycochain expressed in the prostatic tissue.


Should the surgeon or the general practitioner (GP) follow up patients after surgery for colon cancer? A randomized controlled trial protocol focusing on quality of life, cost-effectiveness and serious clinical events.
All patients who undergo surgery for colon cancer are followed up according to the guidelines of the Norwegian Gastrointestinal Cancer Group (NGICG). These guidelines state that the aims of follow-up after surgery are to perform quality assessment, provide support and improve survival. In Norway, most of these patients are followed up in a hospital setting. We describe a multi-centre randomized controlled trial to test whether these patients can be followed up by their general practitioner (GP) without altering quality of life, cost effectiveness and/or the incidence of serious clinical events. Patients undergoing surgery for colon cancer with histological grade Dukes's Stage A, B or C and below 75 years of age are eligible for inclusion. They will be randomized after surgery to follow-up at the surgical outpatient clinic (control group) or follow-up by the district GP (intervention group). Both study arms comply with the national NGICG guidelines. The primary endpoints will be quality of life (QoL) (measured by the EORTC QLQ C-30 and the EQ-5D instruments), serious clinical events (SCEs), and costs. The follow-up period will be two years after surgery, and quality of life will be measured every three months. SCEs and costs will be estimated prospectively. The sample size was 170 patients. There is an ongoing debate on the best method of follow-up for patients with CRC. Due to a wide range of follow-up programmes and paucity of randomized trials, it is impossible to draw conclusions about the best combination and frequency of clinic (or family practice) visits, blood tests, endoscopic procedures and radiological examinations that maximize the clinical outcome, quality of life and costs. Most studies on follow-up of CRC patients have been performed in a hospital outpatient setting. We hypothesize that postoperative follow-up of colon cancer patients (according to national guidelines) by GPs will not have any impact on patients' quality of life. Furthermore, we hypothesize that there will be no increase in SCEs and that the incremental cost-effectiveness ratio will improve. This trial has been registered at ClinicalTrials.gov. The trial registration number is: NCT00572143.


Preoperative skin tumours thickness determination by high-frequency ultrasound on head and neck region.
High-frequency ultrasound is non-invasive imaging method for examination of skin tumours. The aim of our study was to examine validity of 20-MHz ultrasound in preoperative determination of skin tumour thickness localized on head and neck region as a potentially useful tool for planning of the surgical intervention. Seventy-three different skin tumours were preoperatively examined using Dermascan C (Cortex Technology, Denmark) 20-MHz ultrasound equipment. Maximal vertical thickness of tumours was preoperatively determined by ultrasound, and after surgical excision of tumours, on pathohistological preparations using Nippon-Kogaku ocular micrometre. All patohistological specimens were controlled for presence of tumour cells on specimens' margins. Obtained correlation was very high, r = 0.82, without significant statistical difference (P < 0.01) between dimensions determined by 20-MHz ultrasound and histometry. There were no pathohistological specimens with tumours cells found on margins. Examination of skin tumours by 20-MHz ultrasound gives reliable additional information about tumour dimensions, sometimes important for therapeutic strategy.


Design, synthesis, and biological evaluation of 2,4-dihydropyrano[2,3-c]pyrazole derivatives as autotaxin inhibitors.
Inhibition of Autotaxin (ATX) is a potential treatment strategy for several diseases, including tumors with elevated ATX-lysophosphatidic acid (LPA) signaling. Combining structure-based virtual screening together with hen egg-white Autotaxin (ewATX) activity assays enabled the discovery of novel small-molecule ATX inhibitors with a 2,4-dihydropyrano[2,3-c]pyrazole scaffold. These compounds are suggested to bind to the lipophilic pocket, leaving the active site unrestrained. Our most potent compound, (S)-6-amino-4-(3,4-dichlorophenyl)-3-(4-[(4-fluorobenzyl)oxy]phenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile [(S)-25], inhibited human ATX (hATX) with an IC50-value of 134nM. It also blocked ATX-evoked but not LPA-mediated A2058 melanoma cell migration. Noteworthy, molecular modeling correctly predicted the biologically active enantiomer of 2,4-dihydropyrano[2,3-c]pyrazoles, as verified by compound crystallization and activity assays. Our study established the ewATX activity assay as a valid and affordable tool in ATX inhibitor discovery. Overall, our study offers novel insights and approaches into design of novel ATX inhibitors targeting the hydrophobic pocket instead of the active site.


Kerr-lens mode-locked Cr:ZnS oscillator reaches the spectral span of an optical octave.
We report, to the best of our knowledge, the first super-octave femtosecond polycrystalline Cr:ZnS laser at the central wavelength 2.4 µm. The laser is based on a non-polarizing astigmatic X-folded resonator with normal incidence mounting of the gain element. The chromatic dispersion of the resonator is controlled with a set of dispersive mirrors within one third of an optical octave over 2.05-2.6 µm range. The resonator's optics is highly reflective in the range 1.8-2.9 µm. The components of the oscillator's output spectrum at the wavelengths 1.6 µm and 3.2 µm are detected at -60 dB with respect to the main peak. Average power of few-cycle Kerr-lens mode-locked laser is 1.4 W at the pulse repetition frequency 79 MHz. That corresponds to 22% conversion of cw radiation of Er-doped fiber laser, which we used for optical pumping of the Cr:ZnS oscillator.


Effects of hesperidin, a flavanone glycoside interaction on the conformation, stability, and aggregation of lysozyme: multispectroscopic and molecular dynamic simulation studies?
Hesperidin (HESP), a flavanone glycoside, shows high antioxidant properties and possess ability to go through the blood-brain barrier. Therefore, it could be a potential drug molecule against aggregation based diseases such as Alzheimer's, Parkinson's, and systemic amyloidoses. In this work, we investigated the potential of HESP to interact with hen egg-white lysozyme (HEWL) monomer and prevent its aggregation. The HESP-HEWL binding studies were performed using a fluorescence quenching technique, molecular docking and molecular dynamics simulations. We found a strong interaction of HESP with the lysozyme monomer (Ka, ~ 5 × 10(4) M(-1)) mainly through hydrogen bonding, water bridges, and hydrophobic interactions. We showed that HESP molecule spanned the highly aggregation prone region (amino acid residues 48-101) of HEWL and prevented its fibrillar aggregation. Further, we found that HESP binding completely inhibited amorphous aggregation of the protein induced by disulfide-reducing agent tries-(2-carboxyethyl) phosphine. Conformational and stability studies as followed by various tertiary and secondary structure probes revealed that HESP binding only marginally affected the lysozyme monomer conformation and increased both stability and reversibility of the protein against thermal denaturation. Future studies should investigate detail effects of HESP on solvent dynamics, structure, and toxicity of various aggregates. The answers to these questions will not only target the basic sciences, but also have application in biomedical and biotechnological sciences.


Protein-lipid interplay in fusion and fission of biological membranes.
Disparate biological processes involve fusion of two membranes into one and fission of one membrane into two. To formulate the possible job description for the proteins that mediate remodeling of biological membranes, we analyze the energy price of disruption and bending of membrane lipid bilayers at the different stages of bilayer fusion. The phenomenology and the pathways of the well-characterized reactions of biological remodeling, such as fusion mediated by influenza hemagglutinin, are compared with those studied for protein-free bilayers. We briefly consider some proteins involved in fusion and fission, and the dependence of remodeling on the lipid composition of the membranes. The specific hypothetical mechanisms by which the proteins can lower the energy price of the bilayer rearrangement are discussed in light of the experimental data and the requirements imposed by the elastic properties of the bilayer.


The effects of monoplanar and biplanar medial open wedge high tibial osteotomy on pain and functional capacity.
This prospective cross-sectional study aimed to compare the effects of operation types on pain and functional capacity in patients who underwent monoplanar and biplanar medial open wedge high tibial osteotomy. The study included a total of 117 patients who presented at our clinic between January 2012 - January 2016 and underwent monoplanar (n=63) and biplanar (n=54) medial open wedge high tibial osteotomy. The groups were evaluated in age, gender, Body Mass Index (BMI), operation side, operation time, follow-up period, Modified Insall Salvati ratio, Blackburn Peel Index (BPI), Slope, Knee Society Function Score (KSSF), Knee Society Score (KSSK), Visual Analog Scale (VAS), Kellgren Lawrence score, tibiofemoral angle varus, and Tegner score. Most of the patients in the monoplanar group were operated on the right side, while most patients in the biplanar group on the left side, and the difference between the groups was significant (p<0.05). The operation time was significantly longer in the biplanar group, while the duration of follow-up was statistically significantly longer in the monoplanar group (p<0.05). The preoperative BPI and Kellgren Lawrence scores were significantly higher in the monoplar group, while BMI, KSSK, and tibiofemoral angle varus scores were statistically significantly higher in the biplanar group (p<0.05). Postoperative VAS and Kellgren Lawrence scores were higher in the monoplanar group, and the Modified Insall Salvati ratio, BPI, BMI, KSS function score, KSSK score, tibiofemoral angle varus, and Tegner scores were statistically significantly higher in the biplanar group (p<0.05). Postoperatively, the mean VAS score was lower in the biplanar group, and the range of change was greater. In the monoplanar group, the postoperative VAS values were closer to each other and were higher than in the biplanar group. The mean postoperative KSS function score was higher in the biplanar group, and the range of change was higher in the monoplanar group. The study results showed that biplanar medial open wedge high tibial osteotomy was more successful in terms of both pain and functional capacity. However, the operation time was longer than the monoplanar method.


[Combination chemotherapy with carboplatin and etoposide for elderly patients aged 76 years or older with small cell lung cancer].
Eighteen elderly patients aged 76 years or older with small cell lung cancer were treated with carboplatin (AUC = 4 mg/ml.min, i.v. day 1) and etoposide (70 mg/m2 i.v. day 1-3) and 17 patients were evaluable. The median age of the study population was 77 years (range: 76-81). Eight patients had limited disease (LD) and nine did extensive disease (ED). The overall response rate was 88% for LD patients and 67% for ED patients. Median survival time was 219 days for LD patients and 158 days for ED patients. Grade 3 and 4 leukopenia, neutropenia, thrombocytopenia and anemia occurred in 41%, 76%, 24% and 6% of patients, respectively. There was one treatment-related death due to pneumonitis.


Serum MicroRNA-21 Negatively Relates to Expression of Programmed Cell Death-4 in Patients with Epithelial Ovarian Cancer
Background: Ovarian cancer is the third most common cancer of the female genital tract and the leading cause of cancer death associated with gynecologic tumors. MicroRNAs regulate at least 60% of human genes, including tumor suppressor genes and oncogenes and, thereby, can affect cancer risk. Aim of the work: We aimed to assess any diagnostic role for serum miR-21 as a biomarker in human ovarian cancer and to study relations with programmed cell death-4 (PDCD4), one of its target proteins, hoping to help explain heterogeneity of this cancer type and facilitate stratification of regimens for therapy. Subjects and Methods: A total of 60 newly diagnosed ovarian cancer cases and 30 apparently healthy females were recruited. Serum microRNA-21 levels were measured by TaqMan- Real time PCR assay and PDCD4 by ELISA. Results: Significant over-expression of serum miR-21 and lower serum PDCD4 levels were observed in ovarian cancer patients as compared to the control group. A statistically significant inverse correlation was also evident between miR-21 and PDCD4. However, no significant links were noted observed between miR-21 and tumor grade, stage or histopathological type. Conclusion: The present work showed significantly up-regulation of serum miR21 in the recruited group of patients and a significant inverse relation association between miR-21and PDCD4. These findings suggest that miR-21 may be used as a diagnostic biomarker for human ovarian cancer.


[Non-specific immune defenses present in pregnancy].
The state of pregnancy changes the immune system by allowing the trophoblast to go on developing without letting the mother's body be invaded by it, and by keeping intact immune defences against the usual assaults. The non specific immune system is the first bulwark against invaders. The elements of this system, which do not depend on immunological memory, are: the macrophage-monocyte system, Natural Killer cells (NK), the complement component and other bactericidal substances such as lysozyme, fibronectin and interferon. Pregnancy improves the working of the monocyte-macrophage system. In fact, the macrophages of th reticulo-endothelial system, which can be found in different strategic places in the body, phagocytose abnormal particles more intensely. The monocytes in the circulation are more aggressive in pregnancy. They are drawn to the feto-placental interface where they are activated by different lymphokines and cytokines which can be found in quantity at this site. The role of these local active monocytes is not limited only to phagocytosis because among the hundred substances that they can elaborate are some that will regulate trophoblastic proliferation. The activity of the Natural Killer cells that are circulating and which can control tumour cell growth and cells infected by viruses is lowered in pregnancy. The serum taken from pregnant women seems to have a substance that counters the maturation of the Natural Killer cell lines. The complement system of protein synthesis, which normally acts to lyse bacteria in the chemotaxis during opsonisation, is raised in pregnancy. At the feto-placental interface it does seem to activate this system but not elsewhere in the general circulation. Interferon, which is a molecule that normally activates NK cells, has been found at the feto-placental site, without seeming to have a particular role. Pregnancy changes the quantity and the distribution of other elements in the non specific immune system such as transferrin , fibronectin and beta-lysin.


Characterization of three commercial ELISA kits for detection of BOHV-1 gE specific antibodies in serum and milk samples and applicability of bulk milk for determination of herd status.
Vaccination of animals with gE-deleted vaccine strains (gE- marker vaccines) and differential detection of vaccinated vs infected animals with antibody ELISA targeting the gE or the gB proteins have been proved to be useful tools in programs for control and eradication of the bovine herpesvirus 1 (BoHV-1) responsible for infectious bovine rhinotracheitis (IBR), a major pathogen of cattle. The diagnostic sensitivity (DSe) and specificity (DSp) of three commercial gE ELISA kits from IDEXX, IDVet and CIV-HIPRA were compared for serum and milk matrices. Limiting the analysis to 198 individual with concordant ELISA results in serum (91 naïve, 37 vaccinated and 70 infected) the DSe of gE kits was estimated to 0,97 for IDEXX, 0,93 for CIV-HIPRA and 0,53 for IDVet using milk samples and the DSp to 0,95 for IDEXX, 1,00 for IDVet and CIV-HIPRA. The applicability of gE ELISA for individual or bulk milk testing as an additional tool in control programs dedicated to the certification and control of vaccinated herds was evaluated. Two of the three evaluated gE ELISA kits presented substantial to good agreement individual milk and serum samples. The bulk-tank milk also proved to be suitable for the detection of BoHV-1 in vaccinated herds provided that gE prevalence is superior to 10% as false negative results are often observed at lower gE herd prevalence. This limitation could be reduced to 8% of prevalence when a prior concentration step was applied to bulk milk samples.


Surgical treatment of hydatidothorax. Series of 79 cases.
A retrospective review of 79 cases of ruptured intrapleural pulmonary hydatid cysts. We analyse and evaluate our experience in the surgical treatment of this complication. In a ten-year period, from 1990 to 1999, 79 patients were operated on in our service for intrapleural rupture of a pulmonary hydatid cyst. There were 51 males and 28 females with a mean age of 35.4 years. The diagnosis was established on the basis of different clinical signs and imaging studies. Surgical approach consisted of a posterolateral thoracotomy in all cases. After decortication, different procedures were performed on the pulmonary lesions according to the importance of lung destruction. Radical resections were done in 48 cases, including lobectomies (15), segmentectomies (33) and conservative treatment: simple capitonnage and bronchial fistula closure (31). Postoperative complications occurred in 8 cases (10.1%), including one pyothorax, one haemothorax, one prolonged air leak, two pneumonias and two wound infections. There was one postoperative death, by respiratory failure. Ninety-five percent (95%) of patients were free of recurrence of thoracic hydatid disease in a follow-up ranging from 1 to 10 years (mean: 5.4 years). Hydatid cysts of the lung should be treated before complications occur, particularly intrapleural rupture because it considerably increases morbidity.


The study of dental occlusion in ancient skeletal remains from Mallorca (Spain): A new approach based on dental clinical practice.
Occlusal characteristics, fundamental to assess the presence of malocclusion, have been often unexplored in bioarchaeological analyses. This is largely due to the fragmented condition of the skeletal remains. By applying a method that considers dental and maxillary features useful to evaluate occlusion in ancient fragmentary material, the purpose of this work is to define the occlusal features and explore the causes of malocclusion in a mediaeval population from Mallorca. The findings of this study suggest that normocclusion was present in ca. 60% of the individuals (N=31), and that some characteristics, such as molar relationship, were slightly different from those of modern populations. The analysis of the occlusal features revealed for example that open-bite was absent in 85% of the sample, posterior open-bite was completely absent and overbite and overjet were normal in around 90% of the individuals. Statistically significant correlations between canine and molar relationships and between molar relationship and dental wear of the superior and inferior canines and incisors were observed. In addition, wear could affect the curve of Spee. All these findings strengthen the hypothesis that in ancient times malocclusion was not as generalized as in modern times. Although the factors that lead to malocclusion throughout centuries could have several causes, we suggest that in this population dental wear, which is strongly associated with the diet, was the fundamental causing factor.


Cross sensitivity in colour developers.
Colour developers are widely used and contact dermatitis and lichen planus-like eruptions from them are well-known. As a result of automation, there have been few recent reports of contact dermatitis from colour developers. We describe here 4 cases of dermatoses from Kodak CD4 colour developer and study their cross sensitivity to other colour developers and PPD. Attempts were made to determine the purity of the patch test allergens to ensure that cross sensitivity was not the result of contamination and decomposition of the allergens.


The potential role of mannan-binding lectin in the clearance of self-components including immune complexes.
Mannan-binding lectin (MBL) is a pattern recognition receptor in the innate immune system. It recognizes certain sugar residues arranged in a pattern that enables MBL to bind with sufficient strength. Such sugar patterns are common on the surface of many microorganisms, and MBL has therefore been considered to be an agent that can discriminate between self and nonself. There is, however, increasing evidence supporting that MBL, like many membrane-bound C-type lectin-like receptors, also helps to dispose of various outworn or abnormal body components. Most self-components are protected with sialic acid or galactose that disrupt the pattern of the sugars that MBL can bind, but MBL may be significantly involved in the elimination of self-components that have lost these protective terminal residues. The role of MBL in the clearance of invading pathogens has previously been thoroughly reviewed. Here, we review some findings that support the notion that MBL may contribute to noninflammatory removal of immune complexes and abnormal cells by the reticuloendothelial system. Defects in this clearance mechanism may cause an accumulation of potentially dangerous self-components, thereby increasing the likelihood of chronic inflammation and autoimmunity.


Megaloblastic hematopoiesis in vitro. Interaction of anti-folate receptor antibodies with hematopoietic progenitor cells leads to a proliferative response independent of megaloblastic changes.
We tested the hypothesis that anti-placental folate receptor (PFR) antiserum-mediated effects on hematopoietic progenitor cells in vitro of increased cell proliferation and megaloblastic morphology were independent responses. We determined that (a) purified IgG from anti-PFR antiserum reacted with purified apo- and holo-PFR and specifically immunoprecipitated a single (44-kD) iodinated moiety on cell surfaces of low density mononuclear cells (LDMNC); (b) when retained in culture during in vitro hematopoiesis, anti-PFR IgG (in contrast to PFR-neutralized anti-PFR IgG and nonimmune IgG) consistently led to increased cloning efficiency of colony forming unit-erythroid (CFU-E), burst forming unit-E (BFU-E), CFU-granulocyte macrophage (CFU-GM), and CFU-GEM megakaryocyte (CFU-GEMM), and objectively defined megaloblastic changes in orthochromatic normoblasts from CFU-E- and BFU-E-derived colonies; (c) when anti-PFR antiserum was removed after initial (less than 1 h) incubation with LDMNC, a cell proliferation response was induced, but megaloblastic changes were not evident. (d) Conversely, delay at 4 degrees C for 24 h before long-term plating with antiserum resulted in megaloblastosis without increased cell proliferation; (e) however, 500-fold molar excess extracellular folate concentrations completely abrogated the expected anti-PFR antiserum-induced megaloblastic changes, without altering cell proliferative responses. Thus, although cell proliferative and megaloblastic changes are induced after short-term and prolonged interaction of antibody with folate receptors on hematopoietic progenitors, respectively, they are independent effects.


Recombinant human thyrotropin reduces serum vascular endothelial growth factor levels in patients monitored for thyroid carcinoma even in the absence of thyroid tissue.
In this study, we have investigated in vivo the time-dependent effects of TSH on vascular endothelial growth factor (VEGF) production in patients monitored for thyroid carcinoma. Serum VEGF, thyroglobulin (Tg), and TSH levels were assayed at baseline and 6, 24, 30, 48, 72, and 96 h and 1 wk after administration of recombinant human TSH (rhTSH) in 45 thyroidectomized patients affected by differentiated thyroid carcinoma. At baseline, the patients with metastasis (18 cases) showed serum Tg and VEGF values significantly higher than those seen in the cured patients (27 cases). During rhTSH stimulation, the mean VEGF levels decreased significantly in both patient groups. In 60% of patients with metastasis, VEGF nadir occurred at the same time as serum TSH reached the highest values, whereas in 85.7% of the cured patients VEGF decreased after the TSH peak (P = 0.003). In conclusion, we demonstrate for the first time that short-term administration of rhTSH in patients monitored for differentiated thyroid carcinoma induces a significant reduction in serum VEGF values even in the absence of thyroid tissue. This result would suggest that TSH may be able in vivo to regulate VEGF production from tissues other than the thyroid gland.


Redox proteomics and physiological responses in Cistus albidus shrubs subjected to long-term summer drought followed by recovery.
The interaction between enzymatic and non-enzymatic antioxidants, endogenous levels of ABA and ABA-GE, the rapid recuperation of photosynthetic proteins under re-watering as well the high level of antioxidant proteins in previously drought-stressed plants under re-watering conditions, will contribute to drought resistance in plants subjected to a long-term drought stress under Mediterranean field conditions. This work provides an overview of the mechanisms of Cistus albidus acclimation to long-term summer drought followed by re-watering in Mediterranean field conditions. To better understand the molecular mechanisms of drought resistance in these plants, a proteomic study using 2-DE and MALDI-TOF/TOF MS/MS was performed on leaves from these shrubs. The analysis identified 57 differentially expressed proteins in water-stressed plants when contrasted to well watered. Water-stressed plants showed an increase, both qualitatively and quantitatively, in HSPs, and downregulation of photosynthesis and carbon metabolism enzymes. Under drought conditions, there was considerable upregulation of enzymes related to redox homeostasis, DHA reductase, Glyoxalase, SOD and isoflavone reductase. However, upregulation of catalase was not observed until after re-watering was carried out. Drought treatment caused an enhancement in antioxidant defense responses that can be modulated by ABA, and its catabolites, ABA-GE, as well as JA. Furthermore, quantification of protein carbonylation was shown to be a useful marker of the relationship between water and oxidative stress, and showed that there was only moderate oxidative stress in C. albidus plants subjected to water stress. After re-watering plants recovered although the levels of ABA-GE and antioxidant enzymes still remain higher than in well-watered plants. We expect that our results will provide new data on summer acclimation to drought stress in Mediterranean shrubs.


Mechanisms of giant papillary formation in vernal keratoconjunctivitis.
Tissue remodeling, known to accompany exacerbation of bronchial asthma (BA) and characterized by thickening of reticular basement membrane, increased fibrosis, and angiogenesis, is believed to be an important mechanism in giant papillary formation in vernal keratoconjunctivitis (VKC). This study was conducted to confirm the difference of tissue remodeling between BA and VKC and to determine the most relevant factor for VKC exacerbation. Histopathologic analysis of conjunctival specimens from 6 patients with VKC and 4 normal controls was performed. Immunohistochemistry tests for collagen types 1, 3, and 5, fibronectin, laminin (a marker of the basement membrane of the epithelium or vessels), fibroblast (prolyl 4-hydroxylase), and alpha-smooth muscle actin (alpha-SMA) were performed. Morphometric analysis evaluated immunoreactive areas for collagens and fibronectin and the number of cell nuclei in VKC papillae and normal control specimens. In histopathologic sections of VKC papillae, mononuclear cells were mainly observed in the central region and granulocytes preferentially in the peripheral stroma. Immunohistochemistry showed increased vascularity and existence of fibroblasts and alpha-SMA-positive cells in VKC papillae. Morphometric analysis showed that the number of cell nuclei in VKC papillae was 7.3 times higher versus in normal controls (P < 0.05). Furthermore, the immunoreactive area for fibronectin was 4.5 times larger versus in normal controls (P < 0.05), although collagens were not significantly different between the 2 groups. Giant papillary formation in VKC is thought to occur in relation to tissue remodeling. However, the most relevant factor for the exacerbation of VKC seems to be inflammation rather than fibrosis.


Fermentative production of l-galactonate by using recombinant Saccharomyces cerevisiae containing the endogenous galacturonate reductase gene from Cryptococcus diffluens.
The GAR1 gene, encoding d-galacturonate reductase in Cryptococcus diffluens, was isolated, and the GAR1-expression plasmid was constructed by insertion of GAR1 downstream of the yeast constitutive promoter in the yeast-integrating vector. Recombinant Saccharomyces cerevisiae expressing C. diffluensd-galacturonate reductase from a genome integrated copy of the gene was cultured for use the conversion of d-galacturonic acid to l-galactonic acid. The optimum conditions for l-galactonic acid production were determined in terms of the initial concentration of d-galacturonic acid, fermentation pH, and mixed sugars. The following conditions yielded high efficiency in the conversion of d-galacturonic acid to l-galactonic acid in large-scale cultures: 0.1% initial d-galacturonic acid concentration, pH 3.5, and glucose as additional sugar. The aerobic condition was necessary for the conversion of d-galacturonic acid. Subculture of that recombinant was not showing to decrease of the d-galacturonic acid conversion rate even though it was repeated in ten generations. Culturing in scale-up, the conversion rate of d-galacturonic acid to l-galactonic acid was increased.


Ordered alternating binary polymer nanodroplet array by sequential spin dewetting.
We report a facile technique for fabricating an ordered array of nearly equal-sized mesoscale polymer droplets of two constituent polymers (polystyrene, PS and poly(methyl methacrylate), PMMA) arranged in an alternating manner on a topographically patterned substrate. The self-organized array of binary polymers is realized by sequential spin dewetting. First, a dilute solution of PMMA is spin-dewetted on a patterned substrate, resulting in an array of isolated PMMA droplets arranged along the substrate grooves due to self-organization during spin coating itself. The sample is then silanized with octadecyltrichlorosilane (OTS), and subsequently, a dilute solution of PS is spin-coated on to it, which also undergoes spin dewetting. The spin-dewetted PS drops having a size nearly equal to the pre-existing PMMA droplets position themselves between two adjacent PMMA drops under appropriate conditions, forming an alternating binary polymer droplet array. The alternating array formation takes place for a narrow range of solution concentration for both the polymers and depends on the geometry of the substrate. The size of the droplets depends on the extent of confinement, and droplets as small as 100 nm can be obtained by this method, on a suitable template. The findings open up the possibility of creating novel surfaces having ordered multimaterial domains with a potential multifunctional capability.


Symptomatic Giant Lipoma Under the Latissimus Muscle.
Lipoma is a common benign tumor derived from stroma that can arise in any location where fat is normally present. Giant lipoma is defined as a lesion that is >10 cm in length and weighs >1000 g. Axillary region might have been exposed to microtraumas with each movement of upper extremity, leading to the development of giant lipoma. In this report, a 56-year-old man visited us because of a soft tissue mass on the left axilla that had been noticed 5 years before. We removed the tumor from the patient under general anesthesia. A lipoma measuring 21 cm × 12 cm in size was removed, and the weight of the mass was 455 g. The case of our patient is very interesting because there have been few reported patients with a diagnosis of a giant lipoma in a sublatissimusdorsi muscle.


Expression of transforming K-Ras oncogene affects mitochondrial function and morphology in mouse fibroblasts.
K-ras transformed fibroblasts have been shown to have a stronger dependence from glycolysis, reduced oxidative phosphorylation ability and a fragility towards glucose depletion compared to their immortalized, normal counterparts. In this paper, using RNA profiling assays and metabolic perturbations, we report changes in expression of genes encoding mitochondrial proteins and alterations in mitochondrial morphology that correlate with mitochondrial functionality. In fact, unlike normal cells, transformed cells show reduced ATP content and inability to modify mitochondria morphology upon glucose depletion. Being reverted by GEF-DN expression, such morphological and functional changes are directly connected to Ras activation. Taken together with reported partial mitochondrial uncoupling and more sustained apoptosis of transformed cells, our results indicate that activation of the Ras pathway strikingly impacts on energy and signaling-related aspects of mitochondria functionality, that in turn may affect the terminal phenotype of transformed cells.


Positron emission tomography for target volume definition in the treatment of non-small cell lung cancer.
The additional benefit of positron emission tomography (PET) in the initial staging of non-small cell lung cancer (NSCLC) has generated interest in 18F-fluorodeoxyglucose (FDG) PET as a means of defining the extent of primary lung tumour for radiotherapy treatment planning (RTP). A review of published data suggests that PET results in a reduction in the CT-derived GTV for NSCLC primary target volume in 15% of the patients. This is principally due to the ability of PET to distinguish tumour from atelectasis. However, the difficulty of tumour edge definition, limited spatial resolution and tumour motion during image acquisition currently limits the accuracy of PET in target volume delineation in NSCLC without adjacent lung consolidation. This is compounded by the lack of data correlating PET with spatial pathology at the primary tumour site. With the current technical limitations, it is not established that PET can add accuracy to the CT-defined primary target delineation in RTP of NSCLC. It is hoped that advances in PET and combined PET/CT imaging may overcome some of the technical limitations. Future use of PET for primary tumour delineation in NSCLC will also be critically dependent on the detailed studies of imaging-pathology correlation.


Deep tendon reflex: The background story of a simple technique.
Wilhelm Erb and Carl Otto Westphal from Prussia first described the knee jerk in the same issue of the journal Archiv für Psychiatrie und Nervenkrankheiten in January 1875. This article retraces the history of development of 'deep tendon reflex' as an integral clinical sign during every neurological examination. The history of the evolving shapes of the reflex hammer, the iconic trademark and the ultimate signature of a neuroscientist, is also presented.


Green is clean: the role of ICT in resource management.
It is well documented that carbon emissions can be reduced by replacing conventional energy resources with renewable energy resources; thereby, the role of green technology is essential as it protect natural environment. Given that, the United Nations' agenda of "green is clean" may be achievable by adoption of green technologies. The objective of the study is to examine the link between information and communication technology (ICT), economic growth, energy consumption, and carbon dioxide (CO2) emissions in the context of South Korean economy, by using a novel Morlet wavelet approach. The study applies continuous wavelet power spectrum, the wavelet coherency, and the partial and the multiple wavelet coherency to the year during 1973-2016. The outcomes reveal that the connections among the stated variables progress over frequency and time domain. From the frequency domain point of view, the current study discovers noteworthy wavelet coherence and robust lead and lag linkages. From the time-domain sight, the results display robust but not consistent associations among the considered variables. From an economic point sight, the wavelet method displays that ICT helps to reduce environmental degradation in a medium and long run in the South Korean economy. This emphasizes the significance of having organized strategies by the policymakers to cope up with 2 to 3 years of the occurrence of the huge environmental degradation in South Korea.


Cannabinoid-hypocretin cross-talk in the central nervous system: what we know so far.
Emerging findings suggest the existence of a cross-talk between hypocretinergic and endocannabinoid systems. Although few studies have examined this relationship, the apparent overlap observed in the neuroanatomical distribution of both systems as well as their putative functions strongly point to the existence of such cross-modulation. In agreement, biochemical and functional studies have revealed the existence of heterodimers between CB1 cannabinoid receptor and hypocretin receptor-1, which modulates the cellular localization and downstream signaling of both receptors. Moreover, the activation of hypocretin receptor-1 stimulates the synthesis of 2-arachidonoyl glycerol culminating in the retrograde inhibition of neighboring cells and suggesting that endocannabinoids could contribute to some hypocretin effects. Pharmacological data indicate that endocannabinoids and hypocretins might have common physiological functions in the regulation of appetite, reward and analgesia. In contrast, these neuromodulatory systems seem to play antagonistic roles in the regulation of sleep/wake cycle and anxiety-like responses. The present review attempts to piece together what is known about this interesting interaction and describes its potential therapeutic implications.


Role of duct excision surgery in the treatment of pathological nipple discharge and detection of breast carcinoma: systematic review.
The role of duct excision surgery is not clearly defined in patients with pathological nipple discharge without other clinical and radiological abnormalities. The primary aim of this systematic review was to determine the malignancy rate in patients with pathological nipple discharge after duct excision surgery (microdochectomy/major duct excision). The secondary aims were to determine the recurrence rate of pathological nipple discharge after surgery and to assess breast cancer development after surgery. MEDLINE and Embase were searched from inception to March 2023, using search terms related to 'nipple discharge', 'nipple fluid', 'microdochectomy', 'duct excision', and 'minimally invasive surgical procedure'. Studies reporting data about women who underwent duct excision surgery for pathological nipple discharge without clinical and radiological suspicion of breast cancer, as well as reporting data on women diagnosed with breast cancer after duct excision surgery, were included. A total of 318 titles were identified, of which nine publications were included in the analysis. This resulted in 1108 patients with pathological nipple discharge who underwent a duct excision. The weighted mean rate of malignancy after duct excision surgery was 8.1 per cent (ranging from 2.3 to 13.5 per cent). Three studies described the recurrence rate of pathological nipple discharge (ranging from 0 to 12 per cent) and two studies reported breast cancer development in the follow-up in a total of three patients (less than 1 per cent). The malignancy rate after duct excision surgery for pathological nipple discharge was low in patients with pathological nipple discharge without radiological and clinical abnormalities and approximately 9 of 10 patients undergo surgery for a benign cause. Improvement of the diagnostic and therapeutic workup is needed to prevent patients from undergoing (unnecessary) exploratory surgery.


Disengagement from mental health services. A literature review.
This paper reviews the literature on disengagement from mental health services examining how the terms engagement and disengagement are defined, what proportion of patients disengage from services, and what sociodemographic variables predict disengagement. Both engagement and disengagement appear to be poorly conceptualised, with a lack of consensus on accepted and agreed definitions. Rates of disengagement from mental health services vary from 4 to 46%, depending on the study setting, service type and definition of engagement used. Sociodemographic and clinical predictors of disengagement also vary, with only a few consistent findings, suggesting that such associations are complex and multifaceted. Most commonly reported associations of disengagement appear to be with sociodemographic variables including young age, ethnicity and deprivation; clinical variables such as lack of insight, substance misuse and forensic history; and service level variables such as availability of assertive outreach provision. Given the importance of continuity of care in serious mental disorders, there is a need for a consensual, validated and reliable measure of engagement which can be used to explore associations between patient, illness and service related variables and can inform service provision for difficult to reach patients.


[Current status and future direction of the treatment of CRPC (castration resistant prostate cancer)].
A new era of the treatment of prostate cancer has now come in Japan with the approval of several new agents for castration resistant prostate cancer (CRPC), which were delayed by 2-3 years compared to their introduction in Westerns. In addition to those development of new agents, a good news was presented in ASCO 2014 that is a successful phase III trial of chemo-hormonal therapy for hormone naïve (responsive) metastatic prostate cancer (HRPC). We must establish a reasonable treatment strategy for the advanced and high risk prostate cancer.


Fabrication of nano-hydroxyapatite/chitosan membrane with asymmetric structure and its applications in guided bone regeneration.
The development of guided bone regeneration (GBR) technique brings a promising alternative for bone defects and fracture healing. In this study, an asymmetric nano-hydroxyapatite/chitosan (n-HA/CS) composite GBR membrane was fabricated by means of solution-blending and solvent-evaporating in vacuum. The membranes were characterized using SEM, XPS and contact angle. It was found that the composite membrane displayed an asymmetric structure, in which the upper surface was CS and the under surface was a complex of n-HA and CS, and some interactions between n-HA and CS were also confirmed to exist. The contact angle testing showed that the under surface was more hydrophilic than the upper surface. The in vivo experiments demonstrated that the asymmetric composite membrane had the ability to make osteoblasts mineralize and promote loose bone calcified, and then accelerate the bone regeneration. Compared with CS membrane, the asymmetric composite membrane displays a better bone regeneration ability and is suitable for GBR membrane.


Parental perceptions, attitudes, and beliefs regarding vaccination of children aged 0-5 years: A qualitative study of hill-tribe communities, Thailand.
The widespread availability and use of vaccines have tremendously reduced morbidity and deaths related to infectious diseases globally. However, in hill-tribe communities in Northern Thailand, vaccination rates remain low, and there is limited literature on parental perceptions, attitudes, and beliefs about vaccination for children under five years of age. We conducted a qualitative study employing semi-structured interviews to understand parents' perceptions, attitudes, and beliefs about vaccinations. A purposive sample was used to recruit participants. Data were analyzed using thematic analysis. 74 hill-tribe parents (14 Akha, 11 Hmong, 12 Lahu, 13 Lisu, 12 Karen, and 12 Yao) were interviewed. Four themes emerged from the interviews: 1) traditional beliefs, and practices 2) traumatic experiences, 3) lack of information and effective communication, and 4) trust and support from the community. Findings highlight that it is crucial to build trust by providing knowledge, appropriate information, and advice about vaccinations in order to improve vaccine coverage in children under five years of age in the hill-tribe context.


Neurotrophin-3 is a novel angiogenic factor capable of therapeutic neovascularization in a mouse model of limb ischemia.
To investigate the novel hypothesis that neurotrophin-3 (NT-3), an established neurotrophic factor that participates in embryonic heart development, promotes blood vessel growth. We evaluated the proangiogenic capacity of recombinant NT-3 in vitro and of NT-3 gene transfer in vivo (rat mesenteric angiogenesis assay and mouse normoperfused adductor muscle). Then, we studied whether either transgenic or endogenous NT-3 mediates postischemic neovascularization in a mouse model of limb ischemia. In vitro, NT-3 stimulated endothelial cell survival, proliferation, migration, and network formation on the basement membrane matrix Matrigel. In the mesenteric assay, NT-3 increased the number and size of functional vessels, including vessels covered with mural cells. Consistently, NT-3 overexpression increased muscular capillary and arteriolar densities in either the absence or the presence of ischemia and improved postischemic blood flow recovery in mouse hind limbs. NT-3-induced microvascular responses were accompanied by tropomyosin receptor kinase C (an NT-3 high-affinity receptor) phosphorylation and involved the phosphatidylinositol 3-kinase-Akt kinase-endothelial nitric oxide synthase pathway. Finally, endogenous NT-3 was shown to be essential in native postischemic neovascularization, as demonstrated by using a soluble tropomyosin receptor kinase C receptor domain that neutralizes NT-3. Our results provide the first insight into the proangiogenic capacity of NT-3 and propose NT-3 as a novel potential agent for the treatment of ischemic disease.


Targeting cancer stem cells by using chimeric antigen receptor-modified T cells: a potential and curable approach for cancer treatment.
Cancer stem cells (CSCs), a subpopulation of tumor cells, have self-renewal and multi-lineage differentiation abilities that play an important role in cancer initiation, maintenance, and metastasis. An accumulation of evidence indicates that CSCs can cause conventional therapy failure and cancer recurrence because of their treatment resistance and self-regeneration characteristics. Therefore, approaches that specifically and efficiently eliminate CSCs to achieve a durable clinical response are urgently needed. Currently, treatments with chimeric antigen receptor-modified T (CART) cells have shown successful clinical outcomes in patients with hematologic malignancies, and their safety and feasibility in solid tumors was confirmed. In this review, we will discuss in detail the possibility that CART cells inhibit CSCs by specifically targeting their cell surface markers, which will ultimately improve the clinical response for patients with various types of cancer. A number of viewpoints were summarized to promote the application of CSC-targeted CART cells in clinical cancer treatment. This review covers the key aspects of CSC-targeted CART cells against cancers in accordance with the premise of the model, from bench to bedside and back to bench.