HRAS-mutated primary thyroid malignant melanoma or medullary thyroid carcinoma with melanocytic dedifferentiation? A singular case with an ontogeny-phylogeny quandary.
Melanotic pigment in the thyroid is practically synonymous with chronic minocycline therapy and rare cases of melanotic medullary thyroid carcinoma. However, primary melanoma of the thyroid has not been reported yet. We report a rare case of a 25-year-old male with a locally aggressive thyroid mass and distant metastases at presentation. Radiologically, a 8.3×7.6-cm nodule was identified in the right thyroid lobe. Fine-needle aspiration cytology (FNAC) showed discohesive atypical plasmacytoid cells with prominent nucleoli and no cytoplasmic pigmentation. Serum calcitonin levels were normal. A trucut biopsy showed a malignant tumor with a similar cytomorphology, including marked nuclear pleomorphism. In addition, intracytoplasmic melanin was seen in <1% of cells. Tumor cells were immunonegative for AE1/AE3, TTF1, synaptophysin, and chromogranin while positive for SOX10, S100P, HMB45, and Melan A, confirming the diagnosis of malignant melanoma, without any detectable MTC component in the biopsy. An HRAS G13R mutation was detected on NGS, which, intriguingly, is a known mutation in MTC, and exceedingly rare in melanocytic lesions. No other clinically or radiologically apparent primary lesion was identified elsewhere in the patient. The unusual histology and hitherto unreported molecular findings make this case of primary thyroid melanocytic neoplasm worth reporting. Abstruse origin of melanoma cells in the thyroid gland with molecular signature suggestive of MTC in our case raises a nomenclature and management conundrum, prompting us to revisit the "ontogeny recapitulates phylogeny" theory.


Small molecules for combating multidrug-resistant superbug Candida auris infections.
Candida auris is emerging as a major global threat to human health. C. auris infections are associated with high mortality due to intrinsic multi-drug resistance. Currently, therapeutic options for the treatment of C. auris infections are rather limited. We aim to provide a comprehensive review of current strategies, drug candidates, and lead compounds in the discovery and development of novel therapeutic agents against C. auris. The drug resistance profiles and mechanisms are briefly summarized. The structures and activities of clinical candidates, drug combinations, antifungal chemosensitizers, repositioned drugs, new targets, and new types of compounds will be illustrated in detail, and perspectives for guiding future research will be provided. We hope that this review will be helpful to prompting the drug development process to combat this fungal pathogen.


Optimizing liver contrast in helical liver CT: value of a real-time bolus-triggering technique.
Optimal liver enhancement during portal venous-phase helical CT is crucial in the detection of parenchymal liver lesions. In the prospective study reported here we investigated the effects of a real-time bolus-tracking system on mean and maximal liver enhancement. In 79 patients referred to us for abdominal CT we injected 120 ml of non-ionic contrast (300 mg I/ml) at a rate of 3 ml/s. After a nonintravenous contrast upper abdominal scan a portal venous phase was performed. In 39 patients (mean weight 72.6 +/- 18.7 kg, range 48-139 kg) real-time bolus tracking was performed using the CARE Bolus software (Siemens, Erlangen, Germany). The software performs repetitive low-dose test scans in a preselected region of interest and measures the Hounsfield attenuation and liver enhancement in real-time. After a critical threshold (we selected 31 HU) is surpassed, the software starts diagnostic spiral scanning. Our control consisted of 40 patients weighing 51-100 kg (mean 73.2 +/- 11.1 kg) who were scanned with a fixed, preselected start delay of 80 s. Mean hepatic enhancement was 54.0 +/- 9.9 HU (range 33.3-74 HU) in 37 automatically triggered patients, mean peak hepatic enhancement 64.6 +/- 12.6 HU (range 42.0-91.8 HU). In 2 patients of the study group scanning had to be started manually. In the control group with fixed delay mean enhancement was 48.3 +/- 9.2 HU (range 33.8-71.6 HU) and peak enhancement 55.5 +/- 9.7 HU (range 39.7-81.0 HU). Differences were significant (p < 0.05, Student's t-test). Real-time bolus tracking significantly increased mean hepatic enhancement and may improve portal venous hepatic CT scanning.


Adjunctive radiotherapy with strontium-90 in the treatment of conjunctival squamous cell carcinoma.
Squamous cell carcinoma of the ocular conjunctiva is a relatively rare malignancy which is attended by a high rate of local recurrence following simple surgical excision. To date, the management of conjunctival squamous cell cancer has been controversial. From 1950 to 1985, 146 consecutive patients with superficial conjunctival squamous cell cancer were treated at the Queensland Radium Institute. All patients were treated by simple surgical excision of the visible conjunctival lesion followed by adjunctive radiotherapy. Of 140 patients with histologically confirmed squamous cell cancer, 123 were treated with a strontium-90 source, 10 with a radon "ring," and 7 with superficial X ray therapy. Standard policy since 1960 has been to deliver an incident dose of 30 Gy in a single fraction within the first 48 post-operative hours to the surgical bed using a strontium-90 source on a stand-off eye applicator. This report will largely focus on the 123 patients who were treated with a strontium-90 source, of whom 107 received 30 Gy, 14 received 40 Gy (pre 1960) and one patient each received 20 and 25 Gy incident dose. Of 131 evaluable patients, there were only 3 who developed local recurrence. All 3 local recurrences developed in elderly men who had presented with extensive superficial primary tumors. Two of the three recurrences occurred in the two patients who were treated with doses less than 30 Gy. Both early and late radiation-induced complications following ablative surgery and treatment with strontium-90 were very uncommon. Three patients developed unsightly conjunctival telangiectasia, 2 patients developed a persistent scleral ulcer and 2 patients developed clinically significant cataracts. This negligible degree of treatment-related side effects contrasts with the experience of 10 patients who had previously been treated with a radon ring, 8 of whom developed serious complications, although none developed local recurrence. On the basis of our excellent local control rates with minimal morbidity we would continue to advocate the use of simple surgical excision followed by 30 Gy beta radiation from a strontium-90 source as the definitive treatment for superficial conjunctival squamous cell cancer.


Self-powered photoelectrochemical aptasensor based on MIL-68(In) derived In2O3 hollow nanotubes and Ag doped ZnIn2S4 quantum dots for oxytetracycline detection.
A self-powered photoelectrochemical (PEC) aptasensor was constructed based on MIL-68(In) derived indium oxide hollow nanotubes (In2O3 HNs) and Ag-doped ZnIn2S4 quantum dots (QDs) as sensing matrix for the ultrasensitive detection of oxytetracycline (OTC). The hollow tube structure of the designed photoelectric active platform provided abundant active sites and a larger specific surface area for the immobilization of target recognition unit. The coupling of Ag:ZnIn2S4 QDs and In2O3 HNs can accelerate the transmit and separation of photoinduced charge, and thus greatly increasing the intensity of photocurrent signal. Then, the well-constructed OTC-aptamer was anchored on the modified photoelectrode as an accurate capturing element, achieving the specific detection of analyte. Under optimal conditions, the photocurrent intensity of the PEC aptasensor decreases linearly, with a linear response range of 10-4 -10 nmol/L, and a limit of detection (LOD) of 3.3 × 10-5 nmol/L (S/N = 3). The developed self-powered aptasensor with excellent reproducibility, stability, and selectivity, provides a potential way to detect antibiotic residues in environmental media.


Oligodendroglioma of the "widespread" type in the spinal cord.
The authors present clinical, radiological, and pathological features of the "widespread" type of primary spinal oligodendroglioma arising in a 12-year-old boy. The initial symptoms were gait disturbance, hypesthesia of the lower trunk, and scoliosis. Gadolinium-enhanced magnetic resonance imaging revealed an intramedullary tumor with syringomyelia. The tumor spread rapidly in a "widespread" pattern within the spinal cord between C7 and T12. One year after surgery the patient had made a poor neurological recovery despite the two-stage tumor resection. Only five cases of widespread tumors, including our case, have been described with discussion of their clinical manifestations.


Morbidity, mortality, and risk of general anesthesia in horses.
General anesthesia in horses carries an increased risk of morbidity and mortality compared with other species. In recent years the number and complexity of epidemiologic studies in equine anesthesia has increased. The ability to interpret such studies and understand epidemiologic terminology is vital for veterinarians for them to make potential improvements to their anesthetic practice and to allow them to communicate effectively the findings of such studies to colleagues and owners. This article provides the equine clinician with a basic understanding of the methodologies that can be used in observational epidemiologic studies, and reviews the literature on equine anesthetic morbidity, mortality, and risk.


Preparation of silica microspheres encapsulating phase-change material by sol-gel method in O/W emulsion.
Spherical silica microcapsules containing phase-change material (PCM) were prepared by the sol-gel method in O/W emulsion. This is the first time that inorganic encapsulation of PCM with core/shell structure has been studied. The results of this synthesis revealed that micron size (4 - 8 microm) silica microspheres encapsulating n-pentadecane can be successfully created from acidic solutions ([H+] > or = 1.44 N) by using cationic surfactants as the emulsifiers. The identification of the mechanisms for the formation of silica shell at the oil-water interface indicates that it should be the charge-controlled mechanism through S+X-I+ (positively charged surfactant-halide ion-positively charged silica species) electrostatic interactions or the reaction rates-controlled mechanism working on cationic emulsifiers.


A systematic morphosynthesis of barium sulfate in the presence of phosphonate inhibitor.
A systematic study of the influence of various experimental parameters on the morphology and size of BaSO4 crystals after crystallization from water in the presence of diethylenetriamine penta (methylphosphonic acid) (DETPMP) was presented. Depending on the experimental conditions, there are various crystal morphologies including flowers, ellipsoids, spheres, or conjoined spheres. The results indicated that the experimental parameters, such as the concentration of the inhibitor, the pH of solution, the aging of the particle growth, and the ratio [Ba2+]/[SO4(2-)], are important for the morphology and size of BaSO4. The morphogenesis of BaSO4 is controlled by the chelation of DETPMP with Ba2+ at the nucleation and the surface adsorption inhibition of crystal growth.


The role of residential greenness levels, green land cover types and diversity in overweight/obesity among older adults: A cohort study.
Few studies have investigated the effects of greenness exposure, green land cover types and diversity and their interaction with particulate matter (PM) to adiposity. Cohort data were collected from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Baseline data on greenness levels, green land cover types and diversity were assessed by the Normalized Difference Vegetation Index (NDVI), three greenery types (trees, shrublands and grassland) and Shannon's diversity index, respectively. Body mass index (BMI) and waist circumference (WC) were separately used as dependent variables and represented for peripheral overweight/obesity and central obesity, respectively. The mixed Cox model with random intercept was used to estimate the effects of greenness levels, types and diversity on overweight/obesity using single and multiple exposure models. We also examined the interaction of PM and the aforementioned indicators on overweight/obesity on both additive and multiplicative scales. Single exposure models showed that higher levels of residential greenness, tree coverage and ratio of trees to shrublands/grassland were inversely associated with peripheral overweight/obesity and central obesity. An increase in shrublands, grassland and diversity of green was related to lower odds of peripheral overweight/obesity. Multiple exposure models confirmed the association between greenness levels and peripheral overweight/obesity. Males, educated participants and elderly who lived in southern regions and areas with cleaner air environments acquired more benefits from greenspace exposure. Single and multiple exposure models indicated that an antagonistic effect of increasing PM and decreasing greenness levels on peripheral overweight/obesity and central obesity. Single exposure models showed the potential interaction of tree coverage, ratio of trees to grassland and PM2.5 exposures on the risk of peripheral overweight/obesity. Increasing residential greenness and diversity of green were associated with healthy weight status. The relationship between greenery and overweight/obesity varied, and the effects of greenspace exposure on overweight/obesity were associated with air pollution.


Educational mobility and older adults' working memory updating ability: association and role of resilience.
Previous research revealed that a low childhood socioeconomic status, including low parental education, correlates with impaired executive functioning. However, there is a lack of research on the association of working memory updating (WMU) ability, which is one of the major components of executive functioning, and of resilience with educational mobility. The purpose of the present two studies was to further examine these associations. In Study 1, 180, 60-88-year old adults with different levels of educational mobility performed a WMU task. In Study 2, 130, 60-89-year old adults that had experienced different levels of upward educational mobility completed a WMU task and a resilience questionnaire. Study 1 revealed that extent of educational mobility was significantly positively associated with WMU ability. Study 2 revealed significant positive associations among extent of educational mobility, resilience, and WMU task performance. The results were discussed in terms of possible causal relations between the variables and implications for interventions that aim to enhance upward educational mobility and cognitive functioning in late adulthood.


Topically applied nitropyrenes are potent inducers of cutaneous and hepatic monooxygenases.
The inducibility of skin and liver microsomal cytochrome P-450 dependent aryl hydrocarbon hydroxylase and other monooxygenases by a mixture of nitropyrenes was assessed and compared with the parent non-nitrated compound, pyrene. A single topical application of nitropyrenes to neonatal rats resulted in highly significant induction of aryl hydrocarbon hydroxylase, ethoxycoumarin O-de-ethylase, and ethoxyresorufin O-de-ethylase activities in skin and liver after 24 hours. Inducibility of the skin and liver enzymes was 3.9-5.7 fold and 1.8-10.3 fold respectively. On the other hand, aminopyrine N-demethylase, benzphetamine N-demethylase and epoxide hydrolase activities in the liver were unaffected by topically applied nitropyrenes. Furthermore, treatment with nitropyrenes produced a 1 nm shift to the blue region in the wavelength maximum of hepatic microsomal cytochrome P-450. Topically applied pyrene produced only marginal or no effects on cutaneous and hepatic enzyme activities. Our results suggest that nitration of pyrene, a relatively ineffective enzyme inducer, produces nitropyrenes which are potent inducers of hepatic and cutaneous monooxygenases and they resemble 3-methylcholanthrene in this inducing effect.


[Comparative studies on lactate, proteins and enzymes in saliva of healthy and periodontitis sick juveniles].
Total protein, lactate and enzyme activity of alkaline and acid phosphatase and lactate dehydrogenase were determined in mixed non-stimulated saliva of healthy and periodontitis sick patients, aged from 15 to 17. Enzyme determination, expressed in U/l was performed with ready tests of Boehringer; total protein in g%--according to Netelsson, lactate--in mg/100 ml. Increased activity of alkaline phosphatase was observed, depending on the inflammatory processes of periodontium. With acid phosphatase the discrepancies were more negligible but with a marked tendency to increased enzyme activity. The changes in lactate quantity were also indicative. No statistically significant differences were established for lactate dehydrogenase and total protein. Conclusions have been drawn for the practice.


Use of talcum powder and endometrial cancer risk.
Use of talcum powder in the perineal area has been associated with an increased risk of ovarian cancer, and a recent cohort study found a positive association with endometrial cancer. We sought to confirm this association using data from the Australian National Endometrial Cancer Study (ANECS). ANECS was a population-based case-control study conducted from 2005 to 2007, in which 1,399 women with newly diagnosed histologically confirmed primary endometrial cancer and 740 control women provided risk factor information via telephone interview. Unconditional logistic regression was used to estimate odds ratios adjusting for potential confounders. We found no significant association between ever use of talc in the perineal area (OR 0.88, 95% CI: 0.68-1.14) or upper body area (OR 0.90, 95% CI: 0.71-1.14) and risk of endometrial cancer. The results were similar when stratified by subtype. Composite variables combining frequency and duration of talc use were also not significantly associated with risk (any perineal area use p = 0.07 and any upper body use p = 0.49). The absence of any increase in risk and the similarity of our results for talc use on the upper body and in the perineal area do not support the hypothesis that use of talc in the perineal area is associated with an increased risk of endometrial cancer. Our data do not confirm the positive association between perineal talc use and endometrial cancer observed in the only previous study.


Reimplantation of the ampulla of Vater after total pancreatectomy for nesidioblastosis.
Total pancreatectomy is often required to control hypoglycemic seizures in infants with nesidioblastosis. If duodenal devascularization results, reconstruction is difficult because standard biliary-intestinal anastomoses may reflux, or, in infants, become strictured. Therefore, surgeons are loath to perform such procedures. To avoid these complications, the common bile duct and the ampulla of Vater were implanted into the reconstructed duodenum.


Nifedipine blocks apamin-induced bursting activity in nigral dopamine-containing neurons.
Intrinsic sinusoidal oscillations in membrane potential, characteristic of nigral dopamine cells, are converted to plateau potentials following application of apamin, a potent antagonist of SK-type Ca2+-activated K+ channels. Blockade of these channels also changes neuronal firing pattern from a single-spike pacemaker discharge to a multiple spike bursting pattern. Nifedipine, a selective antagonist of L-type Ca2+ channels, blocks plateau potential generation; however, its effects on firing pattern have yet to be determined. In the present study, extracellular single unit recording techniques were used in conjunction with a brain slice preparation to determine whether nifedipine, in a concentration known to block plateau potential generation, also affects bursting activity. Nifedipine (30 microM) was equipotent in inhibiting the firing rate of control (51.2+/-10.8%) and apamin-treated (44.9+/-5.4%) neurons. Slow firing neurons (<2 Hz) were particularly sensitive to the inhibitory effects of the drug. Apamin-induced bursting was completely suppressed by nifedipine and accompanied by a significant increase in the regularity of firing. By contrast, pacemaker-like activity exhibited by control neurons was unaffected by the drug. These data demonstrate that the intrinsic plateau properties exhibited by DA neurons are responsible for the generation of phasic activity induced following blockade of apamin-sensitive Ca2+-activated K+ channels and provide further support for the involvement of an L-type Ca2+ conductance in mediating this type of activity.


Pelvic Floor Disorders/Obstetric Fistula.
Pelvic floor disorders (PFDs) and obstetric fistula (OF) are common across the globe. PFDs include stress and urge urinary incontinence, overactive bladder, pelvic organ prolapse, fecal incontinence, sexual dysfunction, and pelvic pain. Although PFD and OF are common in low- and middle-income countries (LMIC) there is a lack of awareness and constraints in health care resources. This article focuses on epidemiology, risk factors, assessment, and treatment of PFD and OF in resource-poor settings. Adherence to basic medical ethics principles has to be maintained at all times, coupled with knowledge of and respect for local cultures, traditions, and perceptions of health norms.


Inferotemporal neurons of the monkey responsive to auditory signal.
Responsiveness of single inferotemporal (IT) neurons to a tone as a start or warning signal in each test trial was investigated in monkeys performing visual discrimination of 4 patterns. It was found that the same IT neurons were responsive to both auditory signal and visual discriminanda with different response characteristics from each other. The activity of IT neurons for the auditory signal in the visual discrimination paradigm reflects an engagement process in attention to the visual discriminanda.


Dynamics of extended-spectrum cephalosporin resistance in pathogenic Escherichia coli isolated from diseased pigs in Quebec, Canada.
The aim of this study was to investigate the evolution with time of ceftiofur-resistant Escherichia coli clinical isolates from pigs in Québec, Canada, between 1997 and 2012 with respect to pathotypes, clones and antimicrobial resistance. Eighty-five ceftiofur-resistant E. coli isolates were obtained from the OIE (World Organisation for Animal Health) Reference Laboratory for Escherichia coli. The most prevalent pathovirotypes were enterotoxigenic E. coli (ETEC):F4 (40%), extraintestinal pathogenic E. coli (ExPEC) (16.5%) and Shiga toxin-producing E. coli (STEC):F18 (8.2%). Susceptibility testing to 15 antimicrobial agents revealed a high prevalence of resistance to 13 antimicrobials, with all isolates being multidrug-resistant. blaCMY-2 (96.5%) was the most frequently detected β-lactamase gene, followed by blaTEM (49.4%) and blaCTX-M (3.5%). Pulsed-field gel electrophoresis (PFGE) applied to 45 representative E. coli isolates revealed that resistance to ceftiofur is spread both horizontally and clonally. In addition, the emergence of extended-spectrum β-lactamase-producing E. coli isolates carrying blaCTX-M was observed in 2011 and 2012 in distinct clones. The most predominant plasmid incompatibility (Inc) groups were IncFIB, IncI1, IncA/C and IncFIC. Resistance to gentamicin, kanamycin and chloramphenicol as well as the frequency of blaTEM and IncA/C significantly decreased over the study period, whereas the frequency of IncI1 and multidrug resistance to seven antimicrobial categories significantly increased. These findings reveal that extended-spectrum cephalosporin-resistant porcine E. coli isolates in Québec belong to several different clones with diverse antimicrobial resistance patterns and plasmids. Furthermore, blaCMY-2 was the major β-lactamase gene in these isolates. From 2011, we report the emergence of blaCTX-M in distinct clones.


Conformational stability of leukocyte lactate dehydrogenase in healthy men of different age.
Comparative analysis of cytosolic fraction distribution and conformational stability in lactate dehydrogenase (LDH) isozymes in healthy men of different age revealed significant differences indicating age-related characteristics of the enzyme. Activity of cytosolic fraction of LDH-1 and conformational stability of LDH-2 and LDH-3 in 40-year-old men were higher than in 20-year-olds. These data suggest age-related determination of conformational stability of individual LDH isozymes and functional heterogeneity of the enzyme within each isoform.


Overcoming a subclavian complete occlusion: Simple single lead extraction by the subclavian vein allowing implantation of two new leads and upgrade to CRT-P with multi-site pacing.
Central venous obstruction following pacemaker implantation is not uncommon, and can prove challenging in the case of system upgrade. We report a case of DDDR to CRT-P (with multi-site pacing) upgrade, where a subclavian occlusion was overcome resorting to an atrial lead extraction (using only a locking stylet). This allowed regaining of the venous access with subsequent implantation of not just one, but two new leads and subsequent successful upgrade.


Rhabdoid tumor of the liver: Report of 6 pediatric cases treated at a single institute.
Rhabdoid tumors (RTs) of the liver are rare, aggressive and nonsecreting malignancies occurring mainly during the first year of life. Definition of RT relies on characteristic morphology and on the inactivation of the SMARCB1 tumor suppressor gene. The aim of this study was to analyze clinical data, treatments and outcomes in our patients. 6 cases of patients treated in our institution for RT of the liver between January 2007 and January 2015 are reported. Variables examined included age at diagnosis, tumor stage, treatment and long-term survival. Median age at diagnosis was 5months (range: 4-23). Normal for age serum AFP levels was observed in all patients. No patient presented with metastasis at diagnosis. The diagnosis of RT based on the loss of SMARCB1 was made early in 4 patients. The 2 others were initially diagnosed as nonsecreting hepatoblastomas. Median follow-up was 6years (range: 2-9). All patients received chemotherapy, with variable regimens depending on initial diagnosis, followed by surgical resection. Three patients (50%) died of disease. Two of them were mistaken for nonsecreting hepatoblastomas at diagnosis and had recurrence shortly after completion of treatment. The third one presented a cardiac right atrium thrombus. Three patients (50%) are long-term survivors; they received multimodal therapy including chemotherapy according to protocol EpSSG NRSTS consisting of doxorubicin and surgical removal of the tumor performed within 3months after diagnosis. One patient had adjuvant radiotherapy. According to our results, search of SMARCB1 mutation or alternatively immunohistochemical assay for SMARCB1 in nonsecreting hepatoblastomas is mandatory to exclude RT. Chemotherapy according to EpSSG NRSTS protocol together with a surgical treatment seems justified to improve long-term survival. Retrospective study. Level IV.


Cinacalcet increases renal calcium excretion in PTHrP-mediated hypercalcemia: a case report.
In the acute setting, PTH-independent hypercalcemia is typically treated with anti-resorptive agents such as zoledronic acid or denosumab. When these agents are no longer able to control hypercalcemia, several case reports have shown the utility of cinacalcet. However, it is not known if cinacalcet can be effective in patients naïve to anti-resorptive therapy or how cinacalcet ameliorates the hypercalcemia. A 47-year-old male with a history of alcohol-induced cirrhosis was admitted for left cheek bleeding and swelling from an infiltrative squamous cell carcinoma of the oral cavity. On admission, he was found to have an elevated albumin-corrected serum calcium of 13.6 mg/dL, a serum phosphorus of 2.2 mg/dL and an intact PTH of 6 pg/mL (normal 18-90) with a PTHrP of 8.1 pmol/L (normal < 4.3), consistent with PTHrP-dependent hypercalcemia. Aggressive intravenous saline hydration and subcutaneous salmon calcitonin were initiated, but his serum calcium remained elevated. Given tooth extractions scheduled for the next day and possible irradiation to the jaw in the near future, alternatives to antiresorptive therapy were sought. Cinacalcet was initiated at 30 mg twice daily then increased to 60 mg twice daily the following day. The albumin-corrected serum calcium level decreased from 13.2 to 10.9 mg/dL within 48 h. The fractional excretion of calcium increased from 3.7 to 7.0%. This case demonstrates the utility of cinacalcet for the treatment of PTHrP-mediated hypercalcemia without prior anti-resorptive therapy via increased renal clearance of calcium.


Experience with the Kropp anti-incontinence procedure.
The experience of 2 surgeons working independently at separate institutions is reported to demonstrate the use of the Kropp urethral lengthening and implantation procedure. This experience includes 18 patients between 6 and 19 years old (median age 11.6 years) with neurogenic bladder dysfunction. The etiology of the neuropathic bladder was myelodysplasia in 16 patients and sacral agenesis in 2. There were 10 boys and 8 girls. All patients had failed trials of clean intermittent catheterization with adjunctive pharmacological manipulation. Incontinence was a significant social problem. Of the 18 patients 2 had undergone prior urinary diversion and the Kropp procedure was used as part of undiversion. One patient had had 2 previous failed attempts at continence using an artificial urinary sphincter. Augmentation cystoplasty was an adjunctive maneuver in 14 patients; ileum was used in 8, sigmoid in 4 and the ileocecum in 2 (both of whom had been diverted previously). The bladder capacity in the 4 patients in whom augmentation was not performed ranged from 200 to 450 ml. Of the 18 patients 17 achieved a good result and 14 were considered to have achieved an excellent result. The 1 failure is the patient who previously had failed to gain control with an artificial sphincter. Of the 4 patients who did not undergo bladder augmentation 3 required adjunctive anticholinergics to achieve continence.


Glaucoma Fellows-in-Training Recent Surgery Trends.
The volume of microinvasive glaucoma surgery (MIGS) has increased dramatically in recent years, from 31 059 in 2013 to 69 420 in 2018. We investigated the impact of this trend on trainees by determining the proportion of glaucoma surgeries performed by fellows-in-training comprised by MIGS, trabeculectomies, and aqueous shunts. Retrospective analysis. Fellows-in-training at Glaucoma Fellowship Programs certified by the Association of University Professors of Ophthalmology Fellowship Compliance Committee (AUPO-FCC) METHODS: We analyzed aggregate summaries of surgeries performed by fellows as reported to the AUPO-FCC from the academic years (AYs) beginning in 2014 through AY 2020. Each report lists the average number of procedures performed per surgery type per fellow. We combined these averages to create a sum "average number surgeries performed" across glaucoma surgeries and computed the proportion that each surgery type (MIGS, trabeculectomies, and aqueous shunts) represented within the total average number of surgeries performed per year. Average number of procedures performed for each surgery type as well as the proportion that each surgery type (MIGS, trabeculectomies, and aqueous shunts) represented within the total average number of procedures performed per year. Average number of MIGS performed is significantly greater in later years compared with earlier years (P < 0.001). The average number of trabeculectomies performed between AYs 2014 and AY 2020 ranged from 21.8 to 31.9 and decreased, on average, by - 0.80 year-to-year. The average number of aqueous shunts performed between AY 2014 and AY 2020 ranged from 44.7 to 49.5, with an average increase of + 0.8 year-to-year. The total average number of procedures performed (across all 3 surgical subtypes) increased on average by + 4.8 procedures each year. Since 2014, fellows are performing increasing numbers of MIGS procedures, whereas the total number of trabeculectomies and aqueous shunt surgeries performed each year remain similar, resulting in a net increase in total number of procedures performed per fellow each year. This suggests the increase in MIGS is not associated with a substantial decline in trabeculectomies or aqueous shunts performed by glaucoma fellows. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.


Dynamics of neocortical networks: connectivity beyond the canonical microcircuit.
The neocortical network consists of two types of excitatory neurons and a variety of GABAergic inhibitory interneurons, which are organized in distinct microcircuits providing feedforward, feedback, lateral inhibition, and disinhibition. This network is activated by layer- and cell-type specific inputs from first and higher order thalamic nuclei, other subcortical regions, and by cortico-cortical projections. Parallel and serial information processing occurs simultaneously in different intracortical subnetworks and is influenced by neuromodulatory inputs arising from the basal forebrain (cholinergic), raphe nuclei (serotonergic), locus coeruleus (noradrenergic), and ventral tegmentum (dopaminergic). Neocortical neurons differ in their intrinsic firing pattern, in their local and global synaptic connectivity, and in the dynamics of their synaptic interactions. During repetitive stimulation, synaptic connections between distinct neuronal cell types show short-term facilitation or depression, thereby activating or inactivating intracortical microcircuits. Specific networks are capable to generate local and global activity patterns (e.g., synchronized oscillations), which contribute to higher cognitive function and behavior. This review article aims to give a brief overview on our current understanding of the structure and function of the neocortical network.


Neoplasms of the central nervous system in Norway. V. Meningioma and cancer of other sites. An analysis of the occurrence of multiple primary neoplasms in meningioma patients in Norway from 1955 through 1986.
The association between meningioma and a primary malignant neoplasm at another site was studied. The data from the population-based Norwegian Cancer Registry were analysed according to whether the meningioma occurred before or after the malignant neoplasm. Male patients with meningioma showed a raised risk for developing a subsequent renal cancer. A significant association was found between meningioma and subsequent breast cancer in females 50-64 years old at time of meningioma diagnosis and between breast cancer and subsequent occurrence of meningioma. Breast cancer patients with symptoms of an intracranial neoplasm may therefore have a potentially curable meningioma and female meningioma patients over 50 years should be considered for breast cancer screening programmes.


Histone acetylation contributes to chromatin looping between the locus control region and globin gene by influencing hypersensitive site formation.
Chromatin loops are formed between enhancers and promoters and between insulators to regulate gene transcription in the eukaryotic genome. These transcription regulatory elements forming loops have highly acetylated histones. To understand the correlation between histone acetylation and chromatin loop formation, we inhibited the expression of histone acetyltransferase CBP and p300 in erythroid K562 cells and analyzed the chromatin structure of the β-globin locus. The proximity between the locus control region (LCR) and the active (G)γ-globin gene was decreased in the β-globin locus when histones were hypoacetylated by the double knockdown of CBP and p300. Sensitivity to DNase I and binding of erythroid specific activators were reduced in the hypoacetylated LCR hypersensitive sites (HSs) and gene promoter. Interestingly, the chromatin loop between HS5 and 3'HS1 was formed regardless of the hypoacetylation of the β-globin locus. CTCF binding was maintained at HS5 and 3'HS1 in the hypoacetylated locus. Thus, these results indicate that histone acetylation contributes to chromatin looping through the formation of HSs in the LCR and gene promoter. However, looping between insulators appears to be independent from histone acetylation.


A rare cause of breast mass that mimics carcinoma: Foreign body reaction to amorphous surgical material.
A breast mass caused by foreign body type granulomatous reaction to surgical material is a very rare lesion and may mimic carcinoma. Reported foreign materials have included suture materials, silicone, paraffin, gunpowder and carbon particles used for localization of a nonpalpable breast lesions. To our knowledge, a foreign body reaction to gauze sponge has not been reported previously. A 58-year-old woman who had an enlarging mass that mimicked breast carcinoma, due to foreign body reaction to gauze sponge is presented here, and relevant literature is reviewed.


HER-2 pulsed dendritic cell vaccine can eliminate HER-2 expression and impact ductal carcinoma in situ.
HER-2/neu overexpression plays a critical role in breast cancer development, and its expression in ductal carcinoma in situ (DCIS) is associated with development of invasive breast cancer. A vaccine targeting HER-2/neu expression in DCIS may initiate immunity against invasive cancer. A HER-2/neu dendritic cell vaccine was administered to 27 patients with HER-2/neu-overexpressing DCIS. The HER-2/neu vaccine was administered before surgical resection, and pre- and postvaccination analysis was conducted to assess clinical results. At surgery, 5 of 27 (18.5%) vaccinated subjects had no evidence of remaining disease, whereas among 22 subjects with residual DCIS, HER-2/neu expression was eradicated in 11 (50%). When comparing estrogen receptor (ER)(neg) with ER(pos) DCIS lesions, vaccination was more effective in hormone-independent DCIS. After vaccination, no residual DCIS was found in 40% of ER(neg) subjects compared with 5.9% in ER(pos) subjects. Sustained HER-2/neu expression was found in 10% of ER(neg) subjects compared with 47.1% in ER(pos) subjects (P = .04). Postvaccination phenotypes were significantly different between ER(pos) and ER(neg) subjects (P = .01), with 7 of 16 (43.8%) initially presenting with ER(pos) HER-2/neu(pos) luminal B phenotype finishing with the ER(pos) HER-2/neu(neg) luminal A phenotype, and 3 of 6 (50%) with the ER(neg) HER-2/neu(pos) phenotype changing to the ER(neg) HER-2/neu(neg) phenotype. Results suggest that vaccination against HER-2/neu is safe and well tolerated and induces decline and/or eradication of HER-2/neu expression. These findings warrant further exploration of HER-2/neu vaccination in estrogen-independent breast cancer and highlight the need to target additional tumor-associated antigens and pathways.


Corneal Biomechanics Assessment with Ultra High Speed Scheimpflug Camera in Primary Open Angle Glaucoma Compared with Healthy Subjects: A meta-analysis of the Literature.
The aim of this meta-analysis of the literature is to provide a comprehensive analysis of the differences in Corvis ST dynamic corneal response (DCR) parameters between primary open-angle glaucoma (POAG) patients and healthy controls. A quantitative meta-analysis was conducted on articles published before September 10, 2021 identified by searching PubMed, EMBASE, and Web of Science. Prospective studies comparing DCR Corvis ST parameter in high tension POAG and healthy controls were included. The random-effects model was conducted. Assessment of heterogeneity was based on the calculation of I2. Funnel plots evaluation and meta-regression were performed in case of detection of high heterogeneity. The selection process resulted in the inclusion of six articles. Pooled analysis revealed that POAG corneas respond to mechanical stimulus with a smaller concavity, showing lower deformation amplitude (DA) (CI95% -0.991 to -0.578; p < .001; I2 = 0%), higher highest concavity radius (HCR; confidence interval [CI]95% -0.01 to 0.34; p = .058; I2 = 6.7%), and lower peak distance (PD; CI95% -1.06 to -0.024; p = .040; I2 = 86.5%). They also show a slower loading phase, with lower highest concavity time (HCT; CI95% -0.39 to -0.02; p = .029; I2 = 3.3%) and lower applanation velocity-1 (CI95% -0.641 to -0.127; p = .003; I2 = 34.6%), and a faster restoration to the original form, shown by lower applanation time-2 (CI95% -1.123 to -0.544; p = .001; I2 = 44.8%) compared to healthy subjects. High tension POAG patients are characterized by stiffer corneas compared to healthy controls. These differences are valid also after removing the effect of age, corneal thickness, and intraocular pressure (IOP).


[Criminalistic aspects of iatrogenic air embolism (author's transl)].
With reference to 7 cases of iatrogenic air embolism examined by autopsies at the Vienna Institute of Forensic Medicine between 1968 and 1977, the most important causes of such complications are discussed. The wide-spread use of intensive therapeutic methods has led to the tendency that an increasing number of air embolic incidents happens during intravenous infusions. Four cases are reported: two of them occurred by incorrect handling of an automatic infusion pump; two further complications followed insertion or use of central venous catheters. Frequently outward circumstances refer to an air embolism even ante obductionem. In our cases the suspected diagnosis was based on the following signs: air filled venous catheters remaining on the body [3], striking manipulations on infusion apparatus [2], premortal X-ray film [1], typical clinical picture [1]. The analytical-chemical part deals with the infrared and mass spectroscopic investigation of adhesive residues. The traces, which were detected on the housing of an infusion pump, originated from an adhesive tape used to hold down a push button to turn off the warning device. Comparing the spectra of known adhesive tapes it was possible to adjoin the incriminated residues to the adhesive component of 'Normaplast'.


Why don't children and young people engage with diabetes services?
The studySharpe D, Rajabi M, Harden A, et al. Supporting disengaged children and young people living with diabetes to self-care: a qualitative study in a socially disadvantaged and ethnically diverse urban area. BMJ Open 2021;11:e046989.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/why-dont-young-people-engage-with-diabetes-services/.


Phosphorylation of a 22,000-dalton component of the cardiac sarcoplasmic reticulum by adenosine 3':5'-monophosphate-dependent protein kinase.
Cardiac microsomes were incubated with [gamma-32P]ATP and a cardiac adenosine 3':5'-monophosphate (cyclic AMP)-dependent protein kinase in the presence of ethylene glycol bis(bets-aminoethyl ether)-N,N'-tetraacetic acid. After solubilization in sodium dodecyl sulfate and fractionation by polyacrylamide gel electrophoresis, a single microsomal protein component of approximately 22,000 daltons was found to bind most of the 32P label. The 32P labeling of this component increased several fold when NaF was included in the incubation medium. No other component of cardiac microsomes, including sarcoplasmic reticulum ATPase protein, contained significant amounts of 32P label. This 22,000-dalton phosphoprotein formed by cyclic AMP-dependent protein kinase had stability characteristics of a phosphoester rather than an acyl phosphate. Washing of microsomes with buffered KCl did not decrease the amount of 32P labeling to the 22,000-dalton protein, suggesting that this protein is associated with the membranes of sarcoplasmic reticulum rather than being a contaminant from other soluble proteins. The 22,000-dalton protein was susceptible to trypsin. Brief digestion with trypsin in the presence of 1 M sucrose did not significantly affect microsomal calcium transport activity, but prevented both subsequent phosphorylation of the 22,000-dalton protein and stimulation of calcium uptake by cyclic AMP-dependent protein kinase, suggesting that this protein is a modulator of the calcium pump. These results are consistent with previous findings (Kirchberger, M.A., Tada, M., and Katz, A.M. (1974) J. Biol. Chem. 249, 6166-6173; Tada, M., Kirchberger, M.A., Repke, D.I., and Katz, A.M. (1974) J. Biol. Chem. 249, 6174-6180) that cyclic AMP-dependent protein kinase-catalyzed phosphorylation is associated with stimulation of calcium transport in the cardiac sarcoplasmic reticulum, and further indicate that this phosphorylation occurs at a component of low mass (22,000 daltons) of the cardiac sarcoplasmic reticulum which, while separable from the calcium transport ATPase protein (100,000 daltons) by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, has the ability to regulate calcium transport by the cardiac sarcoplasmic reticulum.


Substance use disorders in an obsessive compulsive disorder clinical sample.
The prevalence and clinical correlates of substance use disorders (SUDs) were examined in a clinical sample of Obsessive Compulsive Disorder (OCD). As part of their intake interview into an observational study of the course of OCD, 323 participants completed a battery of standardized measures. Twenty-seven percent of the sample met lifetime criteria for a SUD. 70% of participants with comorbid SUDs reported that OCD preceded SUD onset by at least one year. Younger age at OCD onset and presence of Borderline Personality Disorder (BPD) were each associated with increased risk of alcohol use disorders but only BPD was associated with increased risk of drug use disorders. SUDs affect more than one-quarter of individuals who seek treatment for OCD. Individuals with a juvenile-onset of OCD or comorbid BPD may be especially vulnerable to SUDs. Further research is needed to identify risk factors for SUDs and to better understand their impact on OCD course.


Meloxicam in Combination with Mitoxantrone or Vinblastine as First-Line Treatment for Non-Resectable Urothelial Cell Carcinoma in Dogs.
Cyclooxygenase (COX) inhibitors have been demonstrated to have antitumour activity in canine urothelial cell carcinoma (UCC), given as a sole treatment or in combination with chemotherapy. The purpose of this retrospective multi-institutional study was to assess the efficacy of meloxicam in combination with mitoxantrone or vinblastine as a first-line treatment for non-resectable canine UCC. Gastrointestinal adverse effects (AEs) of these treatment combinations were also assessed. A total of 28 dogs met the inclusion criteria, 21/28 dogs received mitoxantrone and meloxicam, and 7/28 received vinblastine and meloxicam. Tumour response (TR) and AE were evaluated according to Veterinary Co-Operative Oncology Group (VCOG) criteria. The endpoint of the study was the time to tumour progression (TTP). The mitoxantrone-group induced 24% partial response and 62% stable disease, while the vinblastine-group induced 14% and 86%, respectively. Median TTP was 84 days (mitoxantrone and meloxicam, 70 days; and vinblastine and meloxicam, 178 days). The presence of metastatic disease significantly decreased TTP (p = 0.007). Gastrointestinal AEs were reported in 21.4% of the patients, with the most common being VCOG grade 1-2 diarrhoea. Meloxicam is a well-tolerated NSAID when combined with mitoxantrone or vinblastine as first-line treatment for non-resectable canine UCC.


Mecamylamine reversal by nicotine and by a partial alpha7 nicotinic acetylcholine receptor agonist (GTS-21) in rabbits tested with delay eyeblink classical conditioning.
The aim of this experiment was to investigate the effects of nicotinic acetylcholine receptor (nAChR) agonism and antagonism on learning. Eyeblink classical conditioning (750ms delay procedure) was tested for 15 daily sessions in a total of 82 young rabbits: 58 rabbits were tested in the paired procedure when the conditioned stimulus (CS) was always followed by the unconditioned stimulus (US), and 24 rabbits were tested in the explicitly unpaired procedure in which CS and US presentations were independent. We used the nAChR agonists nicotine and GTS-21 (a selective alpha7 nAChR partial agonist that antagonizes alpha4beta2 nAChRs) and the relatively nonselective nAChR antagonist, mecamylamine. Groups of young rabbits were injected with 0.5mg/kg mecamylamine alone and in combination with two doses of nicotine or GTS-21 and compared to vehicle-treated rabbits. Explicitly unpaired control groups received vehicle, mecamylamine plus the highest nicotine dose, or mecamylamine plus the highest GTS-21 dose. Both GTS-21 and nicotine reversed the deleterious effect of mecamylamine on the acquisition of conditioned responses. Combinations of GTS-21 or nicotine and mecamylamine did not cause sensitization or habituation in the unpaired condition. Reversal of mecamylamine-induced learning deficits by nicotine and GTS-21 suggests that nAChR agonists may have efficacy in ameliorating deficits caused by the loss of some types of nAChRs in diseases such as AD.


Global Preconception and Contraception Care: Using a Life-Course Approach to Improve Health Outcomes in Lower-Resource Settings.
A life-course approach incorporating appropriate preconception and contraception care is key to achieving optimal maternal, neonatal, and child health outcomes. In low- and middle-income countries (LMIC), there is a large unmet need for contraception and an estimated 49% of pregnancies are unintended. In this article, we discuss preconception and contraception care in LMIC settings including key recommendations for content and service delivery. We discuss barriers and facilitators to contraceptive provision, discuss considerations for providers who may practice in LMIC settings, and highlight strategies for achieving increased contraceptive uptake including several examples of successful programs.


An investigation into the relationship between input-output nonlinearities and rate-induced nonlinearities of click-evoked otoacoustic emissions recorded using maximum length sequences.
The maximum length sequence (MLS) technique allows otoacoustic emissions (OAEs) to be recorded using clicks presented at very high presentation rates. It has previously been found that increasing the click presentation rate leads to increasing suppression (termed "rate-suppression") of the MLS evoked OAE (Hine, J.E., Thornton, A.R.D., 1997. Transient evoked otoacoustic emissions recorded using maximum length sequences as a function of stimulus rate and level. Ear Hear. 18, 121-128). It has been suggested that the source of rate-suppression arises from the same nonlinear processes that give rise to the well-known nonlinear growth of OAEs. Based on this assumption, a simple model of rate-suppression (Kapadia, S., Lutman, M.E., 2001. Static input-output nonlinearity as the source of nonlinear effects in maximum length sequence click-evoked OAEs. Br. J. Audiol. 35, 103-112) predicts that both input-output (I/O) nonlinearity and rate-suppression can be unified by characterising the stimulus in terms of its acoustic power which, at high rates, is proportional to the click presentation rate. The objective of this study was to test this simple model by recording MLS OAEs from a group of normally hearing adults over a range of stimulus rates from 40 to 5000 clicks/s, and of stimulus levels from 45 to 70dB peSPL. The results are broadly in agreement with the predictions from the model, though there appears to be some tendency for the model to slightly overestimate the degree of rate-suppression for a given degree of I/O nonlinearity. It is also suggested that the model may break down more significantly in the presence of spontaneous OAEs.


Electropolymerization and characterization of polyaniline films using a spectroelectrochemical flow cell.
A new spectroelectrochemical flow cell is presented and its capability to provide a better understanding of reaction mechanisms is illustrated with the study of the electrosynthesis and characterization of a conducting polymer, polyaniline (PANI). A spectroelectrochemical study of electropolymerization of aniline under flow conditions has been performed for the first time. The significant influence that the flow rate of feeding monomer solution has on the electropolymerization process and, consequently, on the electrochromic properties of the resulting polymer has been demonstrated.


Fast beta-emitter Monte Carlo simulations and full patient dose calculations of targeted radionuclide therapy: introducing egs_mird.
Targeted radionuclide therapy (TRT) is a fast-growing field garnering much interest, with several clinical trials currently underway, that has a steady increase in development of treatment techniques. Unfortunately, within the field and many clinical trials, the dosimetry calculation techniques used remain relatively simple, often using a mix of S-value calculations and kernel convolutions. The common TRT calculation techniques, although very quick, can often ignore important aspects of patient anatomy and radionuclide distribution, as well as the interplay there-in. This paper introduces egs_mird, a new Monte Carlo (MC) application built in EGSnrc which allows users to model full patient tissue and density (using clinical CT images) and radionuclide distribution (using clinical PET images) for fast and detailed dose TRT calculation. The novel application egs_mird is introduced along with a general outline of the structure of egs_mird simulations. The general structure of the code, and the track-length (TL) estimator scoring implementation for variance reduction, is described. A new egs++ source class egs_internal_source, created to allow detailed patient-wide source distribution, and a modified version of egs_radionuclide_source, changed to be able to work with egs_internal_source, are also described. The new code is compared to other MC calculations of S-values kernels of 131 I, 90 Y, and 177 Lu in the literature, along with further self-validation using a histogram variant of the electron Fano test. Several full patient prostate 177 Lu TRT prostate cancer treatment simulations are performed using a single set of patient DICOM CT and [18 F]-DCFPyL PET data. Good agreement is found between S-value kernels calculated using egs_mird with egs_internal_source and those found in the literature. Calculating 1000 doses (individual voxel uncertainties of ∼0.05%) in a voxel grid Fano test for monoenergetic 500 keV electrons and 177 Lu electrons results in 94% and 99% of the doses being within 0.1% of the expected dose, respectively. For a hypothetical 177 Lu treatment, patient prostate, rectum, bone marrow, and bladder dose volume histograms (DVHs) results did not vary significantly when using the TL estimator and not modeling electron transport, modeling bone marrow explicitly (rather than using generic tissue compositions), and reducing activity to voxels containing partial or full calcifications to half or none, respectively. Dose profiles through different regions demonstrate there are some differences with model choices not seen in the DVH. Simulations using the TL estimator can be completed in under 15 min (∼30 min when using standard interaction scoring). This work shows egs_mird to be a reliable MC code for computing TRT doses as realistically as the patient Computed Tomography (CT) and Positron Emission Tomography (PET) data allow. Furthermore, the code can compute doses to sub-1% uncertainty within 15 min, with little to no optimization. Thus, this work supports the use of egs_mird for dose calculations in TRT.


Platelet aggregation in whole blood is a paradoxical predictor of ischaemic stroke: Caerphilly Prospective Study revisited.
The Caerphilly Prospective Study demonstrates a paradoxical association of increased ischaemic stroke risk with decreased whole blood adenosine diphosphate (ADP) induced platelet sensitivity. A reanalysis of this association examines whether other haematological indices and prevalent disease at baseline may explain this finding. There were 1506 men free of clinical cardiovascular disease at baseline, with 85 men manifesting a first ischaemic stroke event over 8.3 years of follow-up in this population-based prospective cohort study. Using two different approaches, the paradoxical findings are confirmed and associations are slightly stronger after accounting for red cell, platelet, and white cell indices. A U-shaped relation of stroke with platelet count is noted. These findings are consistent with the existence of sub-clinical endothelial disease and compensatory mechanisms down-regulating ADP-induced aggregation sensitivity. They support an allostasis model of causality for understanding the paradox. A public health approach to prevention could have measurable impact if intervention strategies can be developed to alter early stages of disease appropriate to such mechanisms of causation.


Anti-inflammatory Effects of Siponimod in a Mouse Model of Excitotoxicity-Induced Retinal Injury.
Glaucoma is a leading cause of permanent blindness worldwide and is characterized by neurodegeneration linked to progressive retinal ganglion cell (RGC) death, axonal damage, and neuroinflammation. Glutamate excitotoxicity mediated through N-methyl-D-aspartate (NMDA) receptors plays a crucial role in glaucomatous RGC loss. Sphingosine 1-phosphate receptors (S1PRs) are important mediators of neurodegeneration and neuroinflammation in the brain and the retina. Siponimod is an immunomodulatory drug for multiple sclerosis and is a selective modulator of S1PR subtypes 1 and 5 and has been shown to have beneficial effects on the central nervous system (CNS) in degenerative conditions. Our previous study showed that mice administered orally with siponimod protected inner retinal structure and function against acute NMDA excitotoxicity. To elucidate the molecular mechanisms behind these protective effects, we investigated the inflammatory pathways affected by siponimod treatment in NMDA excitotoxicity model. NMDA excitotoxicity resulted in the activation of glial cells coupled with upregulation of the inflammatory NF-kB pathway and increased expression of TNFα, IL1-β, and IL-6. Siponimod treatment significantly reduced glial activation and suppressed the pro-inflammatory pathways. Furthermore, NMDA-induced activation of NLRP3 inflammasome and upregulation of neurotoxic inducible nitric oxide synthase (iNOS) were significantly diminished with siponimod treatment. Our data demonstrated that siponimod induces anti-inflammatory effects via suppression of glial activation and inflammatory singling pathways that could protect the retina against acute excitotoxicity conditions. These findings provide insights into the anti-inflammatory effects of siponimod in the CNS and suggest a potential therapeutic strategy for neuroinflammatory conditions.


Specific antibodies reacting with simian virus 40 capsid protein mimotopes in serum samples from healthy blood donors.
Simian virus 40 (SV40), a small DNA tumor virus, was inadvertently administered to human populations with the use of contaminated vaccines. SV40 sequences have mainly been detected in healthy individuals and cancer patients using polymerase chain reaction techniques. However, some studies have failed to reveal the presence of SV40 in human specimens. These conflicting results indicate the need for new research to verify whether SV40 is circulating in humans. Mimotopes from SV40 structural peptides were tested to investigate for specific reactions to human sera antibodies. An indirect enzyme-linked immunosorbent assay with synthetic peptides from SV40 viral capsid proteins 1-2-3 (VPs 1-2-3) was set up and employed to test 855 serum samples from healthy blood donors. Data from immunologic assays indicate that serum antibodies against SV40 VP mimotopes are detectable, although with a low titer, in blood donors 18 to 65 years old. The overall prevalence of serum samples that reacted with the 2 SV40 VP peptides was 18%. The strong points for this novel method include the simplicity of its approach and the potential to discriminate between SV40-specific antibody responses and to draw correlations between responses to the 2 independent SV40 peptides. These data suggest that SV40, or a yet undetected closely related polyomavirus, is circulating in human populations, but with lower prevalence than that of the ubiquitous BK and JC human polyomaviruses.


The impact of environmental sounds on food reward.
Wanting and liking are both components of food reward, but they manifest in fundamentally different neural substrates. While wanting denotes anticipatory and motivational behaviors, liking is associated with consummatory and hedonic experiences. These distinct constructs have also been quantitatively dissociated in behavioral paradigms. Indeed, internal, physiological, and interoceptive states affect the degree to which the food presented is valued. However, how contextual sensory cues might impact these appetitive and rewarding responses to food remains unexplored. In light of the increasing empirical focus on sound in food research, we investigated the influence of environmental soundscapes on explicit liking, explicit wanting, implicit wanting, choice frequency, and reaction time of healthy/unhealthy food using an online version of the Leeds Food Preference Questionnaire (LFPQ). Soft nature sounds and loud restaurant noises were employed to induce emotional relaxation and arousal respectively. One hundred and one healthy university students completed a repeated-measure design of the LFPQ; once with each soundscape playing in the background. Generalized linear mixed model analyses detected a significant interaction effect between soundscape and food type on choice frequency, yet the post hoc analyses did not reach significance. No interaction effects between soundscape and food type on wanting or liking were discovered. However, hypothesis-driven analyses found that nature sounds increased explicit liking of healthy (vs. unhealthy) foods, while no effect of soundscape on any wanting measures (explicit or implicit) were observed. Finally, exploratory analyses indicated that restaurant noise (vs. nature sound) induced faster response times for both healthy and unhealthy foods. The study exemplifies that in an online setting, contextual auditory manipulation of certain food reward measures and decision processes is feasible.


The C-terminal domain of 72 kDa gelatinase A is not required for catalysis, but is essential for membrane activation and modulates interactions with tissue inhibitors of metalloproteinases.
Recombinant 72 kDa gelatinase A and a truncated form lacking the C-terminal domain were shown to be activated by organomercurials and to possess similar activities towards a number of substrates. The truncated proenzyme differed from the full-length gelatinase in that it could not be activated by a membrane activator and did not bind tissue inhibitor of metalloproteinase (TIMP)-2. Kinetic studies also showed that the inhibition of the activated truncated enzyme, by both TIMP-1 and TIMP-2, was considerably decreased compared with the full-length enzyme. We conclude that the C-terminal domain plays an important role in the regulation of gelatinase A by a potential physiological activator and inhibitors.


Erratum: Enhanced detection of single-cell-secreted proteins using a fluorescent immunoassay on the protein-G-terminated glass substrate [Corrigendum].
[This corrects the article on p. 7197 in vol. 10, PMID: 26648723.].


The Most Probable Curve method - A robust approach to estimate kinetic models from low plate count data resulting in reduced uncertainty.
A novel method is proposed for fitting microbial inactivation models to data on liquid media: the Most Probable Curve (MPC) method. It is a multilevel model that makes a separation between the "true" microbial concentration according to the model, the "actual" concentration in the media considering chance, and the actual counts on the plate. It is based on the assumptions that stress resistance is homogeneous within a microbial population, and that there is no aggregation of microbial cells. Under these assumptions, the number of colonies in/on a plate follows a Poisson distribution with expected value depending on the proposed kinetic model, the number of dilutions and the plated volume. The novel method is compared against (non)linear regression based on a normal likelihood distribution (traditional method), Poisson regression and gamma-Poisson regression using data on the inactivation of Listeria monocytogenes. The conclusion is that the traditional method has limitations when the data includes plates with low (or zero) cell counts, which can be mitigated using more complex (discrete) likelihoods. However, Poisson regression uses an unrealistic likelihood function, making it unsuitable for survivor curves with several log-reductions. Gamma-Poisson regression uses a more realistic likelihood function, even though it is based mostly on empirical hypotheses. We conclude that the MPC method can be used reliably, especially when the data includes plates with low or zero counts. Furthermore, it generates a more realistic description of uncertainty, integrating the contribution of the plating error and reducing the uncertainty of the primary model parameters. Consequently, although it increases modelling complexity, the MPC method can be of great interest in predictive microbiology, especially in studies focused on variability analysis.


Increased wheat yield and soil C stocks after silica fertilization at the field scale.
Increased crop production is a main goal to feed the predicted human population in future. The current management practice is, however, not sustainable as it depends on high amounts of fertilizer application and is highly vulnerable to decreased soil water availability. At the same time it becomes more and more crucial to reduce or even mitigate anthropogenic greenhouse gas (GHG) emissions. A possible way to enable this, might be the increase of the soil C sequestration and thus the C sink function of arable lands. A recent and potentially more sustainable idea is the single time fertilization with amorphous silicon (ASi) which is known to increase both nutrient and water availability. Here we show for the first time on the basis of a field plot experiment how a fertilization with ASi is affecting both, crop yield and the C sequestration of the soils in an agricultural system cultivating wheat. We found a strong increase in wheat yield and biomass production after ASi fertilization by increasing soil moisture during the whole growing season. Additionally, despite a relatively short growing season, Si fertilization increased the net C uptake by soils, i.e., C sequestration with both Si fertilized treatments showing a negative net ecosystem C balance (soil C gain) during the measurement period, while the control showed a small positive net ecosystem C balance (soil C loss). To our best knowledge, this is the first time such effect has ever been observed. In summary, our study demonstrates a new management strategy for crop production increasing yield and biomass production as well as soil C uptake on a more sustainable basis, by a single time fertilization with ASi.


Low concentrations of UD-CG 212 enhance myocyte contractility by an increase in calcium responsiveness in the presence of inorganic phosphate.
Recent data show that UD-CG 212 in nanomolar concentrations increases myofibrillar Ca++ responsiveness of chemically skinned cardiac preparations in the presence of elevated inorganic phosphate. We studied the effects of UD-CG 212 on cell shortening of intact myocytes and in addition measured the intracellular calcium transients with the aid of INDO-1 fluorescence in the presence of 5 mM inorganic phosphate. The validity of our experimental system was first tested with the calcium channel opener Bay k 8644. Bay k 8644 at 10(-8) M did not significantly influence myocyte shortening (+ 13.9 +/- 4.6%, n = 9) but at 10(-7) M and 10(-6) M significantly increased contraction by 40.1 +/- 13.6% and 52.5 +/- 17.0% respectively. Bay k 8644 at 10(-8) M increased the INDO-1 fluorescence ratio by 17.3 +/- 4.7% (P < 0.01; n = 9), and at 10(-7) M by 21.5 +/- 4.3% (P < 0.01; n = 9), whereas 10(-6) M Bay k 8644 had no significant effect on peak INDO-1 ratio. However, 10(-7) and 10(-6) M Bay k 8644 accelerated and broadened the calcium transients.(ABSTRACT TRUNCATED AT 250 WORDS)


Prevalence and influencing factors of hyperuricemia in middle-aged and older adults in the Yao minority area of China: a cross-sectional study.
Hyperuricemia (HUA) endangers human health, and its prevalence has increased rapidly in recent decades. The current study investigated HUA's prevalence and influencing factors in Gongcheng, southern China. A cross-sectional investigation was conducted; 2128 participants aged 30-93 years were included from 2018 to 2019. Univariate and multivariate logistic regression models were used to screen HUA variables. A Bayesian network model was constructed using the PC algorithm to evaluate the association between influencing factors and HUA. The prevalence of HUA was 15.6% (23.2% in men, 10.7% in women). After screening the variables using a logistic regression analysis model, fatty liver disease (FLD), dyslipidemia, abdominal obesity, creatinine (CREA), somatotype, bone mass, drinking, and physical activity level at work were included in the Bayesian network model. The model results showed that dyslipidemia, somatotype, CREA, and drinking were directly related to HUA. Bone mass and FLD were indirectly associated with HUA by affecting the somatotype. The prevalence of HUA in Gongcheng was high in China. The prevalence of HUA was related to somatotype, drinking, bone mass, physical activity level at work, and other metabolic diseases. A good diet and moderate exercise are recommended to maintain a healthy somatotype and reduce the prevalence rate of HUA.


Investigation of Dientamoeba fragilis and Blastocystis in patients from Turkey with ulcerative colitis and irritable bowel syndrome: Any relation with genotypes?
Blastocystis sp. and Dientamoeba fragilis are two most common protists worldwide, whose pathogenic potentials are a matter of debate since their discovery. This study aims to investigate the relationship between the activation of ulcerative colitis (UC) and irritable bowel syndrome (IBS) with these protists. A total of 100 patients (35 IBS, 35 active UC, and 30 remittent UC), diagnosed at Hacettepe University Adult Hospital (Ankara, Turkey), were screened for D. fragilis and Blastocystis sp. with microscopic examination using the methods of wet mount, trichrome staining, conventional PCR, nested PCR, real-time PCR and genotyping. Eight patients (4 IBS, 2 active, and 2 remittent UC patients) were found to be D. fragilis positive. 18S rRNA region of the parasite was amplified in four of the patients, whereas cathepsin L-like cysteine peptidase; clan Sc, family S9, serine peptidase; and clan MH, family M20 metallopeptidase in six different patients. All isolates were Genotype 1. Sequence results showed very limited diversity. A total of nine patients (3 IBS, 5 active UC, 1 remittent UC) were found to be positive for Blastocystis sp., all of which were Subtype 3. One active UC and one IBS patient were found to be positive for both parasites. No statistically significant difference was detected between the patient groups in means of parasite detection. D. fragilis was found to be related to older age (p=0,045). In our study, no significant correlation was identified between D. fragilis and Blastocystis sp., and the activation of UC and IBS. More studies are needed on the host-parasite relationship, including the role of gut microbiota, together with transcriptomic and metabolomic assessments to unveil the pathogenicity of both protists.


Palbociclib in combination with chemotherapy in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia and lymphoma: A Children's Oncology Group study (AINV18P1).
Cyclin D has been shown to play an essential role in acute lymphoblastic leukemia (ALL) initiation and progression, providing rationale for targeting the CDK4/6-cyclin D complex that regulates cell cycle progression. The Children's Oncology Group AINV18P1 phase 1 trial evaluated the CDK4/6 inhibitor, palbociclib, in combination with standard four-drug re-induction chemotherapy in children and young adults with relapsed/refractory B- and T-cell lymphoblastic leukemia (ALL) and lymphoma. Palbociclib (50 mg/m2 /dose) was administered orally once daily for 21 consecutive days, first as a single agent (Days 1-3) and subsequently combined with re-induction chemotherapy. This two-part study was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D), followed by an expansion pharmacokinetic cohort. Twelve heavily pretreated patients enrolled, all of whom were evaluable for toxicity. One dose-limiting hematologic toxicity (DLT) occurred at the starting dose of 50 mg/m2 /dose orally for 21 days. No additional DLTs were observed in the dose determination or pharmacokinetic expansion cohorts, and overall rates of grade 3/4 nonhematologic toxicities were comparable to those observed with the chemotherapy platform alone. Five complete responses were observed, two among four patients with T-ALL and three among seven patients with B-ALL. Pharmacokinetic studies showed similar profiles with both liquid and capsule formulations of palbociclib. Palbociclib in combination with re-induction chemotherapy was well tolerated with a RP2D of 50 mg/m2 /day for 21 days. Complete responses were observed among heavily pretreated patients.


Iatrogenic pyogenic spondylodiscitis: a case report and a review of literature.
Iatrogenic Pyogenic Spondylodicitis is a disease not commonly reported probably because of the way it is acquired, from the health practitioner. The case of a 62 year old man that presented in our outpatient department with features of spondylodiscitis after several attempts at spinal anaesthesia at a rural hospital was reported and the literature reviewed. The patient showed remarkable improvement few days with parenteral antibiotics and made complete recovery subsequently. Adequate asepsis is required for spinal anaesthesia and parenteral antibiotics given presumptively following numerous attempts at spinals.


Hybrid Palliation for Ductal-Dependent Systemic Circulation.
We reviewed our hybrid palliation experience for 91 neonates, with ductal-dependent systemic circulation, born between August 2007 and October 2015. For analysis, we stratified the 91 patients by a risk factor (RF) score and divided them into three groups: (1) high-risk two-functional ventricles (2V) median RF score of 3 (N = 20); (2) low-risk one-functional ventricle (1V) RF score 0-1 (N = 32); and (3) high-risk 1V RF score ≥2 (N = 39). Midterm survival (median 4 years) by group was: (1) 95 %, (2) 91 %, and (3) 15 %, (p = 0.001). In conclusion, hybrid palliation was associated with excellent midterm results for high-risk 2V and low-risk 1V patients with ductal-dependent systemic circulation. In contrast, high-risk 1V patients had significantly worse outcomes.


PULMONARY ALVEOLAR MICROLITHIASIS. DISCREPANCIES BETWEEN RADIOLOGICAL FINDINGS AND CLINICAL PATTERN- CASE STUDY.
Pulmonary alveolar microlithiasis is a rare genetic disorder, inherited autosomally recessively, which is characterized by intra-alveolar deposition of microliths built mostly of calcium salts and phosphorus. This case study describing management of patient with pulmonary alveolar microlithiasis. A 49-year-old woman, diagnosed with pulmonary microlithiasis in 1979 was admitted to Pneumology Department due to increased dyspnea. On admission there were no clinical signs of active infection. The chest computer tomography scan confirmed the presence of advanced microlithiasis. Pulmonary function test revealed mild restriction with moderate diffusion impairment, due to severe hypoxemia present on 6-minute walking test patient was sent for specific assessment to local lung transplant team in Zabrze for consideration for lung transplantation. According to International Society for Heart & Lung Transplantation guidelines the patient was observed in 6 months intervals to reveal whether further disease progression will be observed. Clinical condition of our patient does not correlate with radiological scans, severe respiratory symptoms and cardiological complications. Computer tomography scan should not be the only indication for lung transplant.


Assessment of sarcopenia: longitudinal versus cross sectional body composition data.
An accurate diagnosis of sarcopenia is required. The aim of this study is to correlate the results of two methods to define sarcopenia using cross sectional body composition data, with actual loss of fat free mass. Healthy older subjects (926 females and 381 males aged 70 years or more) and healthy young adults (425 females and 151 males aged 20 to 40 years) were studied. Body composition was assessed by double beam X ray absorptiometry (DEXA). Among older subjects, a contemporary subsample of 148 females and 45 males had two or more measurements, separated by 4.8+/-1.5 years and loss of fat free mass per year was calculated. In the whole sample, total and appendicular lean body mass index were calculated as total or appendicular lean body mass/height. Using data from young people, sex specific t scores were obtained. In older subjects residuals were derived from a regression equation, using total or appendicular fat free mass as the dependent variable and height, fat free mass and age as independent variables. The concordance between residuals and t scores to define sarcopenia was 68 and 72%, respectively. Among subjects with two or more measurements, men and women lost a mean of 521+/-454 and 221+/-399 g/year of fat free mass, respectively. The odds ratio of losing more than 822 g lean body mass /year among men or 514 g lean body mass /year among women was 2.63 and 2.64 for subjects classified in the two lowest quintiles of sarcopenia, using t scores or residuals, respectively. Cross sectional body composition data can predict loss of fat free mass among older people.


Assessment of knowledge among caregivers of diabetic patients in insulin dosage regimen and administration.
Inadequate production of Insulin can lead to a complex metabolic disorder named Diabetes Mellitus that is characterized by hyperglycaemia. Diabetes is leading metabolic disease that causes major disability and increased death-rate world-wide. Diabetes can cause neuropathy, blindness, ischaemic heart disease, peripheral vascular disease, increased risk of stroke, and renal diseases. Since the management of diabetes mellitus is complex, the reliance of some patients on their caregivers has increased. In this study, a caregiver is a family member or a paid helper who is willing to provide long-term assistance to a child, an older adult, or a person with a disability. The knowledge of caregivers about insulin doses (administration and adjustment) is determined and to study the correlation between the demographic data (age, gender, and marital status) and the knowledge of caregivers. This is a cross sectional type of descriptive study. A questionnaire was built based on literature review and was reviewed and validated by 17 arbitrators and modified accordingly. A pilot study was performed on 5 people of the targeted population to assess the feasibility, duration, and clarity of the data collection tool. The questionnaire was distributed online and had some extra questions to exclude non-relevant responses. A total of 819 participants filled the online questionnaire. Out of these, 83.6% were female and 16.4% were male. The good knowledge was significantly associated with caregivers who had patients diagnosed with diabetes since less than 6 months when compared with others. Caregivers who reported that they do not live with the healthcare receiver had less knowledge compared with those they live, and it is statically significant association. 55% were satisfied with their level of knowledge about insulin doses management. This study indicates who lives with patient has caregiver's knowledge on inulin dosages administration 1.766 times from who don't have.


Plasma concentrations of arginine vasopressin, oxytocin and angiotensin in patients with hymenoptera venom anaphylaxis.
The plasma concentrations of arginine vasopressin, oxytocin, angiotensin I and II were studied in patients with hymenoptera venom anaphylaxis (n = 50) and healthy volunteers (n = 25). There was no difference in arginine vasopressin: 5.52 +/- 0.45 fmol/ml vs. 3.99 +/- 0.41 fmol/ml or oxytocin: 28.10 +/- 1.13 fmol/ml vs. 26.24 +/- 1.80 fmol/ml between patients and controls. No correlation between the severity of clinical symptoms and the plasma levels of arginine vasopressin and oxytocin was found in patients. However, patients with a history of hymenoptera venom anaphylaxis showed significantly reduced angiotensin I and angiotensin II plasma levels as compared to controls (ANG I: 9.51 +/- 0.61 fmol/ml vs. 22.91 +/- 1.73 fmol/ml; ANG II: 2.84 +/- 0.16 fmol/ml vs. 6.95 +/- 0.33 fmol/ml). A significant inverse correlation between the severity of clinical symptoms and the plasma levels of angiotensin I and angiotensin II was observed; the lower the concentrations the more severe the clinical symptoms. Oxytocin immunoreactivity eluted from the HPLC column as a single peak with the same retention time as synthetic oxytocin. The vasopressin immunoreactive material could be characterized on HPLC as arginine-vasopressin and two other peptides of unknown nature which crossreacted with the vasopressin antibody. These findings suggest a possible role of angiotensin I and angiotensin II in hymenoptera venom anaphylaxis while arginine vasopressin and oxytocin are most likely not involved.


Angiotensin-converting enzyme inhibitors.
There is convincing evidence that ACE inhibitors, alone or in combination with a diuretic, effectively lower blood pressure in patients with all grades of essential or renovascular hypertension and that they are of particular benefit as adjunctive therapy in patients with congestive heart failure. The hemodynamic, hormonal and clinical effects of the presently available ACE inhibitors, captopril and enalapril, are comparable and their side effect profiles are extremely favorable. One important difference between the two oral ACE inhibitors, however, is their pharmacokinetics; enalapril's action is slower to begin and is of longer duration. Compared with other agents, ACE inhibitors offer important advantages, among them an improved feeling of well being. It is, therefore, expected that ACE inhibitors will gain greater acceptance by patients and physicians in the future.


Comparison of the results of radical hysterectomy: sequential observations in each period.
The efficacy of drains and of antibiotics for prophylaxis of postoperative retroperitoneal infections following radical hysterectomy with systematic lymphadenectomy has not yet been adequately investigated. Patients who had just undergone radical hysterectomy were divided into three groups. We used a retroperitoneal drain transvaginally for Groups A (n = 54) and B (n = 55) and transabdominally for Group C (n = 103). Group A was administered a first- and Groups B and C a second- or third-generation cephem antibiotic as the prophylactic antibiotic. We compared the surgery time, blood loss, fever index and febrile morbidity in these three groups. The average surgery time was Group A 344.2 +/- 13.7 min (mean +/- SE), Group B 425.6 +/- 11.0 min and Group C 528.2 +/- 10.9 min. A significant difference was observed among the groups (p < 0.05). In terms of blood loss during surgery, a significant increase (p < 0.05) occurred in Groups B (2400 +/- 196 g) and C (2373 +/- 130 g) compared with Group A (1820 +/- 122 g). For fever index, Group A showed a value of 36.1 +/- 2.7 dh, Group B 19.9 +/- 2.4 dh and Group C 8.8 +/- 1.5 dh. A significant difference was observed among the groups (p < 0.01). In terms of febrile morbidity, significant differences (p < 0.01, p < 0.0001) were observed between Groups B (14.6%) and C (8.7%) in comparison with Group A (44.4%), respectively. In radical hysterectomy with systematic lymphadenectomy, it may be preferable to choose transabdominal drains in the retroperitoneal space and second-generation cephem antibiotics for prophylaxis of postoperative retroperitoneal infections.


Optimization-based artificial neural networks to fit the isotherm models parameters of aqueous-phase adsorption systems.
An artificial neural network (ANN) hybrid structure was proposed that, unlike the standard ANN structure optimization, allows the fit of several adsorption curves simultaneously by indirectly minimizing the real output error. To model a case study of 3-aminophenol adsorption phenomena onto avocado seed activated carbon, a hybrid ANN was applied to fit the parameters of the Langmuir and Sips isotherm models. Network weights and biases were optimized with two different methods: particle swarm optimization (PSO) and genetic algorithm (GA), due to their good convergence in large-scale problems. In addition, the data were also fitted with the Levenberg-Marquardt feedforward optimization method to compare the performance between a standard ANN model and the hybrid model proposed. Results showed that the ANN-isotherm hybrid models with both PSO and GA were able to accurately fit the experimental equilibrium adsorption capacity data using the Sips isotherm model, obtaining Pearson's correlation coefficient (R) of the order of 0.9999 and mean squared error (MSE) around 0.5, very similar to the performance of standard ANN using Levenberg-Marquardt optimization. On the other hand, the results with Langmuir isotherm models were quite inferior in the ANN-isotherm hybrid models with both PSO and GA, with R and MSE of around 0.944 and 4.04 × 102, respectively. The proposed ANN-isotherm hybrid structure was successfully applied to estimate the parameters of adsorption isotherms, reducing the computational demand and the exhausting task of estimating the parameters of each adsorption curve individually.


Normal values and differences between intraperitoneal and subcutaneous microdialysis in patients after non-complicated gastrointestinal surgery.
Visceral ischemia is an early event in the development of shock and organ failure. Microdialysis has been presented as a promising method for detection of visceral hypoxia and ischemia. The aim of this study was to investigate differences in the metabolic response measured by microdialysis between intraperitoneal and subcutaneous locations and to estimate normal values of lactate/pyruvate ratio, glucose and glycerol. Intraperitoneal and subcutaneous metabolic responses were compared regarding lacate/pyruvate ratio, glucose and glycerol, during 45 postoperative hours in 33 patients undergoing various non-complicated elective major gastrointestinal surgery. Intraperitoneal lactate/pyruvate ratio started around 15 and decreased over time, while subcutaneous levels were stable around 9. Glucose levels were higher intraperitoneally and increased rapidly during the first 9 h to 8.6 mM, while the subcutaneous levels increased during 21 h to 7.5 mM. Intraperitoneal glycerol levels were stable around 100 microM, while subcutaneous values started around 230 microM and then increased. In a non-complicated postoperative course the lactate/pyruvate ratio and glucose levels are higher intraperitoneally, suggesting a higher postoperative intraperitoneal metabolism. Glycerol levels are higher and increase subcutaneously, suggesting increased postoperative energy demand, particularly in the visceral organs, as being responsible for the lipolysis seen in the subcutaneous tissue.


Natural death in the setting of autoerotic practice.
Deaths in an autoerotic setting are usually due to accidental asphyxia, in which the individual accidently hangs or strangles themselves while inducing hypoxia for the purpose of heightened arousal. Death occurs when the level of hypoxia causes the individual to lose consciousness and is thus unable to prevent the neck compression from becoming lethal. In some cases there is an "escape" mechanism incorporated into the set-up which may fail. In rare cases, death is not as an immediate result of the autoerotic activity and is as a result of natural causes, which may or may not be related to the process. This case demonstrates the death of a 69 year old male which has occurred in the setting of a complex autoerotic environment, not as a result of asphyxiation, but rather as a result of natural causes which is likely to have been brought about by repeated similar activity. The autopsy revealed pulmonary emboli and lower limb deep vein thrombosis. There was no other natural disease of note and no features considered typical of asphyxiation.


Myocardial Induction of Type 3 Deiodinase in Dilated Cardiomyopathy.
The thyroid hormone-inactivating enzyme type 3 deiodinase (D3) is induced during hypertrophic and ischemic cardiomyopathy, leading to a state of local cardiac hypothyroidism. Whether D3 induction occurs in dilated cardiomyopathy is unknown. This study characterized changes in cardiac D3 and thyroid hormone signaling in a transgenic model of progressive dilated cardiomyopathy (TG9 mice). Cardiac D3 was dramatically induced 15-fold during the progression of dilated cardiomyopathy in TG9 mice. This D3 induction localized to cardiomyocytes and was associated with a decrease in myocardial thyroid hormone signaling. Cardiac D3 is induced in a mouse model of dilated cardiomyopathy, indicating that D3 induction may be a general response to diverse forms of cardiomyopathy.


Late progamic phase and fertilization affect calreticulin expression in the Hyacinthus orientalis female gametophyte.
Calreticulin expression is upregulated during sexual reproduction of Hyacinthus orientalis, and the protein is localized both in the cytoplasm and a highly specialized cell wall within the female gametophyte. Several evidences indicate calreticulin (CRT) as an important calcium (Ca(2+))-binding protein that is involved in the generative reproduction of higher plants, including both pre-fertilization and post-fertilization events. Because CRT is able to bind and sequester exchangeable Ca(2+), it can serve as a mobile intracellular store of easily releasable Ca(2+) and control its local cytosolic concentrations in the embryo sac. This phenomenon seems to be essential during the late progamic phase, gamete fusion, and early embryogenesis. In this report, we demonstrate the differential expression of CRT within Hyacinthus female gametophyte cells before and during anthesis, during the late progamic phase when the pollen tube enters the embryo sac, and at the moment of fertilization and zygote/early endosperm activation. CRT mRNA and the protein localize mainly to the endoplasmic reticulum (ER) and Golgi compartments of the cells, which are involved in sexual reproduction events, such as those in sister synergids, the egg cell, the central cell, zygote and the developing endosperm. Additionally, immunogold research demonstrates selective CRT distribution in the filiform apparatus (FA), a highly specific component of the synergid cell wall. In the light of our previous data showing the total transcriptional activity of the Hyacinthus female gametophyte and the results presented here, we discuss the possible functions of CRT with respect to the critical role of Ca(2+) homeostasis during key events of sexual plant reproduction. Moreover, we propose that the elevated expression of CRT within the female gametophyte is a universal phenomenon in the cells involved in double fertilization in higher plants.


Recent advances in high resolution scanning electrochemical microscopy of living cells--a review.
This review discusses advances in the field of high resolution scanning electrochemical microscopy (HR-SECM) and scanning ion conductance microscopy (SICM) to study living cells. Relevant references from the advent of this technique in the late 1980s to most recent contributions in 2012 are presented with special discussion on high resolution images. A clear progress especially within the last 5 years can be seen in the field of HR-SECM. Furthermore, we also concentrate on the intrinsic properties of SECM imaging techniques e.g. different modes of image acquisition, their advantages and disadvantages in imaging living cells and strategies for further enhancement of image resolution, etc. Some of the recent advances of SECM in nanoimaging have also been discussed which may have potential applications in high resolution imaging of cellular processes.


Should Ovarian Tissue Cryopreservation in Pediatric Patients with Turner Syndrome Be Limited to the Research Setting?
Now that ovarian tissue cryopreservation (OTC) has become standard of care for patients receiving gonadotoxic therapies, discussion has turned toward offering OTC to pediatric patients with Turner syndrome outside of research. Although patients with Turner syndrome have unmet fertility needs and the authors support efforts for fertility preservation in these individuals, safety and efficacy data about OTC in this population are limited. Building on longstanding debates around offering experimental therapies as research or outside of research (as "innovative therapy"), we considered the suitability of offering OTC for patients with Turner syndrome as innovative therapy. On the basis of pathophysiology and preliminary research data, we argue that there is significant uncertainty about whether the risk-benefit profile of OTC for patients with Turner syndrome is favorable. This reduces the weight of arguments in favor of offering it as innovative therapy. Furthermore, as Turner syndrome is rare, widespread availability of OTC could make it difficult to develop generalizable knowledge. The benefits of innovative therapy for acquiring experience from use in humans and avoiding research-related procedures are of limited importance too, as OTC is already an established procedure, and current studies involve limited procedures that restrict access. OTC should therefore only be offered to patients with Turner syndrome in research settings until additional data suggest that the risk-benefit profile is likely favorable.


Balance of Treg vs. T-helper cells in the transition from symptomless to lesional psoriatic skin.
In the pathogenesis of psoriasis, proinflammatory T cells are strongly involved in the inflammatory process, where regulatory T-cell (Treg) function is impaired. As effective Treg function is associated with a numerical balance between Treg and effector T cells, we wondered whether Treg/T-helper cell ratios may be associated with certain stages of the inflammatory process. We opted for the margin zone model as a dynamic approach. From nine patients with chronic plaque psoriasis, 3-mm punch biopsies were obtained from the centre and margin of the lesion, perilesional skin and distant uninvolved skin. Skin biopsies of 10 healthy volunteers were included as a control. Samples were analysed using immunohistochemistry and immunofluorescence. In the transition from symptomless to lesional skin, a significant increase of CD3+, CD4+ and Foxp3+ cells was found. In seven of nine patients the ratio of Treg (Foxp3+) vs. CD4+ T cells was higher in the distant uninvolved skin than in the perilesional and lesional skin. Interestingly, the Foxp3/CD4 ratio in the distant uninvolved skin was even higher than in the skin of healthy controls. Notably, we found that most of the interleukin (IL)-17 expression was not related to CD4+ cells, but to mast cells. The relatively high Foxp3/CD4 ratio in symptomless skin of patients with psoriasis suggests an active immune controlling mechanism distant from the psoriatic plaque. In the margin and centre of the plaque the ratio appears skewed towards effector cells associated with inflammation. IL-17, an important driver of the psoriatic process, is mostly related to mast cells, and only sporadically to T cells.


Management of difficult intracranial aneurysms by deep hypothermia and elective cardiac arrest using cardiopulmonary bypass.
Giant anterior circulation aneurysms and some basilar aneurysms can cause problems due to their size, the presence of clot in the aneurysm and the difficulty of applying a clip without kinking the perforating vessels. By utilising cardiopulmonary bypass via the femoro-femoral perforating vessels. By utilising cardiopulmonary bypass via the femoro-femoral route the patient can be cooled to below 20 degrees C allowing the circulation to be stopped for up to 3/4 hour. This will enable the neurosurgeon to unhurriedly dissect out the aneurysm without fear of rupture and where necessary open the aneurysm to remove clot and clip the aneurysm. By draining the circulating volume into the venous reservoir of the pump, a large aneurysm may collapse thus enabling it to be clipped more easily. It is, therefore, a useful technique for difficult aneurysms. We present here a series of 11 patients who underwent this procedure with excellent results in 7. All patients had aneurysms which would otherwise have been either inoperable or very risky to tackle.