Inhibition of mTOR affects protein stability of OGT.
Autophagy regulates cellular homeostasis through degradation of aged or damaged subcellular organelles and components. Interestingly, autophagy-deficient beta cells, for example Atg7-mutant mice, exhibited hypoinsulinemia and hyperglycemia. Also, autophagy response is diminished in heart of diabetic mice. These results implied that autophagy and diabetes are closely connected and affect each other. Although protein O-GlcNAcylation is up-regulated in hyperglycemia and diabetes, and O-GlcNAcylated proteins play an important role in metabolism and nutrient sensing, little is known whether autophagy affects O-GlcNAc modification and vice versa. In this study, we suppressed the action of mTOR by treatment of mTOR catalytic inhibitors (PP242 and Torin1) to induce autophagic flux. Results showed a decrease in global O-GlcNAcylation, which is due to decreased OGT protein and increased OGA protein. Interestingly, knockdown of ATG genes or blocking of lysosomal degradation enhanced protein stability of OGT. In addition, when proteasomal inhibitor was treated together with mTOR inhibitor, protein level of OGT almost recovered to control level. These data suggest that mTOR inhibition is a more efficient way to reduce protein level of OGT rather than that of CHX treatment. We also showed that not only proteasomal degradation regulated OGT stability but autophagic degradation also affected OGT stability in part. We concluded that mTOR signaling regulates protein O-GlcNAc modification through adjustment of OGT stability.


Flicker light-induced vasodilatation in the human retina: effect of lactate and changes in mean arterial pressure.
Diffuse luminance flicker light increases retinal and optic nerve head blood flow in animals and humans, but the exact mechanisms that mediate increased flow have yet to be identified. In the current study, the effect of increased plasma lactate levels on flicker-induced vasodilatation in the retina was investigated in three independent studies in healthy humans. In the first study, plasma lactate concentrations were increased by bicycle exercise in 12 volunteers, and the change in retinal vessel diameter to 8-Hz square-wave flicker stimulation was measured with the Zeiss Retinal Vessel Analyzer (Carl Zeiss Meditec, Oberkochen, Germany). In a different study, sodium lactate was administered intravenously, and flicker responses were measured in 12 subjects. As a control experiment accounting for pressure increases induced by exercise, the effect of elevated ocular perfusion pressure on the flicker response was investigated during tyramine infusion (n = 12). The increase in plasma lactate concentration during intravenous infusion from 1.3 +/- 0.4 to 6.3 mmol/L and during dynamic exercise from 1.2 +/- 0.3 to 9.4 mmol/L decreased flicker responses in retinal arteries from 5.3% +/- 0.9% to 1.7% +/- 0.6% (P < 0.001) and from 3.6% +/- 0.6% to 2.0% +/- 0.8% (P = 0.03), respectively. In contrast, an increase of mean blood pressure from 81 +/- 3 to 92 +/- 3 mm Hg after tyramine infusion had no significant effect on flicker-induced vasodilatation in retinal arteries and veins. The signaling between neuronal activity and flow response in the human retina is sensitive to changes in blood lactate levels, whereas changes in systemic blood pressure have no major effect. Whether an increased cytosolic redox impairment contributes to flicker-induced vasodilatation has yet to be clarified.


Overexpression of plastid transketolase in tobacco results in a thiamine auxotrophic phenotype.
To investigate the effect of increased plastid transketolase on photosynthetic capacity and growth, tobacco (Nicotiana tabacum) plants with increased levels of transketolase protein were produced. This was achieved using a cassette composed of a full-length Arabidopsis thaliana transketolase cDNA under the control of the cauliflower mosaic virus 35S promoter. The results revealed a major and unexpected effect of plastid transketolase overexpression as the transgenic tobacco plants exhibited a slow-growth phenotype and chlorotic phenotype. These phenotypes were complemented by germinating the seeds of transketolase-overexpressing lines in media containing either thiamine pyrophosphate or thiamine. Thiamine levels in the seeds and cotyledons were lower in transketolase-overexpressing lines than in wild-type plants. When transketolase-overexpressing plants were supplemented with thiamine or thiamine pyrophosphate throughout the life cycle, they grew normally and the seed produced from these plants generated plants that did not have a growth or chlorotic phenotype. Our results reveal the crucial importance of the level of transketolase activity to provide the precursor for synthesis of intermediates and to enable plants to produce thiamine and thiamine pyrophosphate for growth and development. The mechanism determining transketolase protein levels remains to be elucidated, but the data presented provide evidence that this may contribute to the complex regulatory mechanisms maintaining thiamine homeostasis in plants.


Boundary Between Bacterial Mesophilism and Thermophilism.
Bausum, Howard T. (Fort Detrick, Frederick, Md.), and Thomas S. Matney. Boundary between bacterial mesophilism and thermophilism. J. Bacteriol. 90:50-53. 1965.-The temperature boundary between bacterial mesophilism and thermophilism has been identified as 44 to 52 C. Facultative thermophiles growing in the mesophilic range require a brief period of adaptation at intermediate temperatures before gaining the capacity to initiate growth at thermophilic temperatures. Obligate mesophiles cannot grow in the thermophilic temperature range, but obligate thermophiles may show limited growth at temperatures as low as 41 C.


Skin layer in cyclic loading-cleaning of a nanofiber filter in filtering nano-aerosols.
Nano-aerosols from viruses to virgin pollutant particulates from combustion, 100 nm or smaller, are harmful to our health as they penetrate readily into our body causing various diseases. Nanofiber filter can capture effectively these nano-aerosols. However, over time the pressure drop increases dramatically and cleaning of the filter by backpulse/backblow is essential for filter reuse. The cyclic loading-and-cleaning of a nanofiber filter has been investigated for the first time experimentally and theoretically. The "skin" layer, a thin region upstream of the nanofiber filter, plays a pivoting role in controlling the pressure drop excursion of the filter. We model the skin layer to be made up of numerous fine capillaries and examine how continuous aerosols deposited in the capillaries affect rapid rise in pressure drop followed by bridging of aerosols across the capillary openings leading to more bridging and ultimately formation of cake on top of the bridges and filter surface. We have been able to describe the deposition of aerosols in the capillary pores for depth filtration, the deposition of aerosols in the cake (surface filtration), and the intermediate bridging regime between these two. We can depict the complete pressure drop excursion including the S-shaped curve behavior from depth filtration transiting to surface filtration for a filter with severe skin effect. Our prediction matches extremely well with the 6 cycles of loading/cleaning on a 280-nm nanofiber filter subject to challenging nano-aerosols, 50-400 nm. During cyclic loading and cleaning, the porosity and permeability in the skin layer for our experiment drop to 68% and 11-21% of their original values, respectively, and the effective pore diameter also drops from 1.2 to 0.6 μm.


The Extended Dwell Peripheral Intravenous Catheter Is an Alternative Method of NICU Intravenous Access.
Establishing vascular access is a common neonatal intensive care unit procedure. The extended dwell peripheral intravenous (EPIV) catheter is a 6-cm and 8-cm silicone catheter for peripheral vein insertion, which is a newer vascular access device than peripherally inserted central catheters (PICCs) and peripheral intravenous (PIV) catheter. Extended dwell peripheral intravenous catheters have been widely used in adults but evidence in neonates is lacking. To explore indwell time, success rate, catheter-associated complications, and cost among EPIV catheters, PICCs, and PIV catheters in neonates. We retrospectively compare patient demographics, indwell time, success rate, and catheter-associated complications, and analyze the rate of hyaluronidase-treated intravenous (IV) fluid extravasation on neonates who had an EPIV catheter, a PICC, or a PIV catheter in a level III neonatal intensive care unit. We also estimate the insertion cost of these 3 vascular access devices on the basis of our hospital charges. Extended dwell peripheral intravenous catheters were inserted in 432 neonates with an indwell time of 4.0 ± 2.3 (mean ± SD) days. Peripherally inserted central catheters were inserted in 202 neonates with an average indwell time of 7.3 ± 4.4 (mean ± SD) days, which was longer than EPIV catheters (P < .001). Peripherally inserted central catheters had a higher success rate of 83.6% than 71.7% of EPIV catheters, meaning succeeded in lasting through the completion of therapy (P = .001). Peripherally inserted central catheters were associated with 4 cases of life-threatening complications; none was seen in the EPIV catheter group. The incidence of hyaluronidase-treated IV fluid extravasation was less in EPIV catheter recipients (1.2%) than in the PIV catheter recipients (3.9%) (P = .004); none was in the PICC group. Cost savings were noted with using an EPIV catheter. Extended dwell peripheral intravenous catheter is a feasible option for neonatal vascular access. These data provide a baseline for future studies to explore the efficacy and effectiveness of EPIV catheter in the neonates.


Shyness and sociability among extremely low birth weight survivors in the third and fourth decades of life: Associations with relationship status.
We examined differences between the oldest known longitudinally followed cohort of extremely low birth weight survivors (ELBW; < 1,000 grams) and normal birth weight (NBW; > 2,500 grams) control participants on shyness and sociability, as well as conflicted shyness in adulthood across nearly a decade from their 20s to 30s. 100 ELBW survivors and 88 NBW control participants self-reported on shyness and sociability using the Cheek and Buss (1981; Cheek, 1983) shyness and sociability scale. Participants also self-reported on their relationship status. A composite measure of conflicted shyness was also computed (i.e., the product of shyness and sociability). We found that, in their 30s, ELBW survivors reported higher shyness, but similar levels of sociability and conflicted shyness compared to controls. However, the ELBW group exhibited a greater decrease in conflicted shyness than NBW controls from their 20s to their 30s. Greater decreases in conflicted shyness in both groups were associated with being male, as well as with changes in relationship status such as finding a partner or getting married. Relatively higher shyness among ELBW survivors in adulthood suggests that stressful pre- and early postnatal environments may have lasting effects on personality development. However, later social influences such as relationship status may attenuate some types of shyness in adulthood.


Chemistry-specific surface adsorption of the barnacle settlement-inducing protein complex.
Gregarious settlement in barnacle larvae (cyprids) is induced by a contact pheromone, the settlement-inducing protein complex (SIPC). The SIPC has been identified both in the cuticle of adult barnacles and in the temporary adhesive secretion (footprint) of cyprids. Besides acting as a settlement inducer, the presence of the SIPC in footprints points to its additional involvement in the adhesion process. SIPC adsorption behaviour was therefore investigated on a series of self-assembled monolayers (SAMs) by surface plasmon resonance at the pH of seawater (8.3). Fibrinogen and α2-macroglobulin (A2M) (blood complement protease inhibitors with which the SIPC shares 29% sequence homology) were used in the adsorption experiments as positive and negative standards, respectively. The mass uptake of the SIPC was comparable to that of fibrinogen, with adsorption observed even on the protein-resistant oligo(ethylene glycol) surface. Notably, on the positively charged SAM the SIPC showed a kinetic overshoot, indicating a metastable configuration causing the amount of adsorbed protein to temporarily exceed its equilibrium value. A2M adsorption was low or negligible on all SAMs tested, except for the positively charged surface, indicating that A2M adsorption is mainly driven by electrostatics. Evaluation of SIPC non-specific adsorption kinetics revealed that it adsorbed irreversibly and non-cooperatively on all surfaces tested.


Fate of untreated asymptomatic osteonecrosis of the femoral head.
Magnetic resonance imaging has made it possible to detect asymptomatic lesions of osteonecrosis of the femoral head before abnormalities appear on plain radiographs. The extent of a necrotic lesion is known to be an important prognostic factor. In this study, we evaluated the fate of untreated asymptomatic osteonecrosis of the femoral head with an emphasis on the size of the lesion. We hypothesized that a lesion smaller than a certain size would not progress to symptomatic disease. One hundred and five initially asymptomatic hips of patients with bilateral nontraumatic osteonecrosis of the femoral head who had been followed without any treatment for at least five years or until pain developed were enrolled in this study. The extent of a lesion was estimated according to the area of the lesion based on a two-dimensional analysis on magnetic resonance images or on plain radiographs at the time of diagnosis. Sixty-two hips became symptomatic, and forty-three hips remained asymptomatic for more than five years (average, eight years and seven months). Of the twenty-one hips with a small necrotic lesion (<30% of the area of the femoral head), one became painful; of the twenty-four hips with a medium-sized necrotic lesion (30% to 50% of the area of the femoral head), eleven became painful; and of the sixty hips with a large necrotic lesion (>50% of the area of the femoral head), fifty became painful. Forty-six of the sixty-two hips that became symptomatic required surgery. Pain developed within five years after the diagnosis in fifty-eight (94%) of the sixty-two symptomatic hips. No treatment appears to be necessary for asymptomatic necrotic lesions with an area smaller than 30% of the femoral head, as the vast majority of these lesions will remain asymptomatic for more than five years.


Value of MR venography for detection of internal jugular vein anomalies in multiple sclerosis: a pilot longitudinal study.
CCSVI was recently described in patients with MS. CCSVI is diagnosed noninvasively by Doppler sonography and invasively by catheter venography. We assessed the role of conventional MRV for the detection of IJV anomalies in patients with MS diagnosed with CCSVI and in healthy controls who underwent MRV and Doppler sonography examinations during 6 months. Ten patients with MS underwent TOF, TRICKS, Doppler sonography, and catheter venography at baseline. They were treated at baseline with percutaneous angioplasty and re-evaluated 6 months' posttreatment with MRV and Doppler sonography. In addition, 6 healthy controls underwent a baseline and a 6-month follow-up evaluation by Doppler sonography and MRV. At baseline, the sensitivity, specificity, PPV, and NPV of Doppler sonography for detecting IJV abnormalities relative to catheter venography in patients with MS were calculated, respectively, at 82%, 100%, 99%, and 95%. The figures were 99%, 33%, 33%, 99% for TOF and 99%, 39%, 35%, and 99% for TRICKS. Venous anomalies included the annulus, septum, membrane, and malformed valve. No agreement was found between TOF and catheter venography in 70% of patients with MS and between TRICKS and catheter venography in 60% of patients with MS. At follow-up, 50% of the patients with MS presented with abnormalities on Doppler sonography but only 30% were diagnosed with restenosis. Conventional MRV has limited value for assessing IJV anomalies for both diagnostic and posttreatment purposes.


The effect of local application of insulin-like growth factor for prevention of inner-ear damage caused by electrode trauma.
Electrode insertion during cochlear implantation causes cochlear damage and apoptosis. Insulin-like growth factor applied locally was investigated in 21 rats. In the sham group, an intracochlear dummy electrode was inserted through the round window. In the control group, after the same insertion procedure, saline-soaked porcine skin gelatine was placed on the round window. In the study group, insulin-like growth factor 1 soaked gelatine was placed on the round window. Auditory brainstem response thresholds were measured and histopathological examination was performed. In the study group, at 2-4 kHz, one rat had deterioration, one showed improvement and the rest had stable thresholds 14 days after intervention. At 6 kHz, four rats showed improvement and the rest remained stable. At 8 kHz, four showed improvement, one had deterioration and two remained stable. In the other groups, hearing loss deteriorated in about half of the rats and remained stable in the rest. The mean post-operative 6 kHz threshold was significantly lower than that immediately after the intervention in the study group, contrary to the other groups. The study group had significantly better mean histopathological grading than the other groups. Local insulin-like growth factor 1 application may protect hearing after cochlear implantation.


Long-term Outcomes Following Radiotherapy for Adolescent Patients With Nonmetastatic WHO Type III Nasopharyngeal Carcinoma.
To report long-term results of primary radiotherapy for nasopharyngeal cancer (NPC) presenting in the adolescent group. Ten adolescent patients with World Health Organization (WHO) type III NPC were treated with primary radiotherapy at our institution between 1969 and 2007. Median age was 16.5 years (range, 11 to 21). Median radiotherapy dose to the primary target volume was 67.5 Gy (range, 60 to 74.8). The bilateral neck received 51.1 Gy (range, 50 to 60 Gy). Five patients were treated with once-daily radiotherapy and 5 received twice-daily radiotherapy. Three patients received neoadjuvant cisplatin and 5FU, and 1 patient received adjuvant maintenance cisplatin and 5FU. Median follow-up time was 9.5 years (range, 1.94 to 34.74). Fifteen-year overall survival, cause-specific survival, and progression-free survival rates were all 70%. Fifteen-year local and regional control rates were 100% and 90%. One patient recurred regionally and distantly simultaneously, and 2 patients developed distant metastases alone. All 3 died of their disease within 3 years. One patient died from multiple radiation-induced secondary meningiomas 34 years after radiotherapy. Five patients developed hypothyroidism, 3 developed sensorineural hearing loss, and 4 developed dental complications. The overall rates of CTCAE grade 3, 4, and 5 toxicity were 40%, 10%, and 10%, respectively. Despite high-radiation doses to the skull base, none of the patients in this study developed grade 3+ cognitive or vision toxicity. Radiotherapy achieves excellent local control in adolescent patients with unresectable WHO type III NPC. Our data support current protocols to systematically tailor treatment volumes and deescalate radiation doses to reduce treatment toxicity.


MicroRNA-454 inhibits tumor cell proliferation, migration and invasion by downregulating zinc finger E‑box‑binding homeobox 1 in gastric cancer.
Gastric cancer is the fourth most common malignancy and the third leading cause of cancer‑associated mortality globally. Accumulating studies have identified the involvement of microRNAs in the initiation and progression of gastric cancer. This study was aimed to investigate the expression, functional roles of microRNA‑454 (miR‑454) and its direct target gene in gastric cancer. According to the results, the expression level of miR‑454 was demonstrated to be reduced in gastric cancer tissues and cell lines compared with corresponding distant non‑tumor gastric tissues and human immortalized gastric epithelial, respectively. miR‑454 mimic transfection led to inhibition of gastric cancer cells proliferation, migration and invasion in vitro. Bioinformatic analysis predicated that zinc finger E‑box‑binding homeobox 1 (ZEB1) is a potential target gene of miR‑454. Luciferase reporter assays revealed that miR‑454 directly targeted the 3'UTR of ZEB1. miR‑454 overexpression significantly decreased the ZEB1 mRNA and protein expression levels. ZEB1 knockdown could mimic the tumor suppressive roles induced by miR‑454 overexpression on gastric cancer cell proliferation, migration and invasion. In conclusion, the present study suggested that miR‑454 under expression may be involved in gastric cancer initiation and progression, by promoting proliferation, migration and invasion by directly targeting ZEB1. miR‑454/ZEB1‑based targeted therapy may be a potential strategy for the treatment of gastric cancer.


Comparison of Long-Acting Injectable Antipsychotics With Oral Antipsychotics and Suicide and All-Cause Mortality in Patients With Newly Diagnosed Schizophrenia.
Schizophrenia is generally considered to be among the most severe psychiatric disorders because of the excessive mortality associated with it. Research to find means to reduce this excessive mortality is warranted. To investigate associations of long-acting injectable antipsychotics (LAIs) with all-cause, natural-cause, and suicide mortality risks as well as the impacts of early use of LAIs in patients with newly diagnosed schizophrenia. This cohort study used data from the Taiwan National Health Insurance Research Database to construct a population-based cohort of patients with schizophrenia who received oral antipsychotics (OAPs) from January 1, 2002, to December 31, 2017. Within this cohort, the LAI group was defined as patients who switched to LAIs and were prescribed LAIs at least 4 times within 1 year. The LAI group was propensity matched 1:1 to patients who continued receiving OAPs of the same compounds. All patients were followed up until switching the antipsychotic administration route, death, or the end of the study (December 31, 2018), whichever occurred first. Data analysis was performed from January 2002 to December 2018. All-cause mortality, natural-cause mortality, suicide mortality, and suicide attempts. In total, 2614 patients who switched to LAIs (median [interquartile range] {IQR} age, 30 [23-39] years) and 2614 who received OAPs (median [IQR] age, 30 [23-39] years) were included (1333 male patients [51.0%] in each group). During the 16-year follow-up period (median [IQR] follow-up of 14 [10-17] years), patients who switched to LAIs had lower risks of all-cause mortality (adjusted hazard ratio [aHR], 0.66; 95% CI, 0.54-0.81), natural-cause mortality (aHR, 0.63; 95% CI, 0.52-0.76), and suicide attempts (incidence rate ratio, 0.72; 95% CI, 0.55-0.93) compared with patients who received the corresponding OAPs. A 47% lower suicide mortality risk (aHR, 0.53; 95% CI, 0.30-0.92) was observed in patients who switched to LAIs within the first 2 years of OAP initiation. These findings suggest that LAI use in patients with newly diagnosed schizophrenia is associated with decreased all-cause mortality and suicide risk. Furthermore, early treatment with LAIs within the first 2 years of OAP initiation was associated with a decrease in suicide mortality risk. Thus, LAI use in the early stage of treatment should be actively considered for patients with newly diagnosed schizophrenia.


Suicidal strangulation.
Self-strangulation for committing suicide by the use of ligature is admittedly rare. A suicidal strangulation case from Haryana State, India is discussed in the light of scene of occurrence, investigations of the ligature and its knot. Initially the case was suspected by the police to be a murder, but proved to be of suicidal strangulation.


Status and trends in biomedical engineering education.
An overview of graduate and undergraduate programs is given, including a brief history of each. With respect to undergraduate studies, the issues of accreditation, department status versus option programs, employment, registration, and medical and professional school opportunities are examined. Enrollment trends are examined. A survey of biomedical engineering textbooks and a bibliography containing 102 references are given in an appendix.


[The use of telephone for counseling diabetic patients: a descriptive and pedagogic approach].
This descriptive study of telephone interviews, conducted between the staff of a diabetes unit and patients, is intended to clarify a professional manner in which the telephone should be used as part of patient care. Having examined simulated calls from diabetic patients, analysis of the interviews conducted by the doctors, nurses and members of the office staff in a hospital unit demonstrates wide differences in the content, the quality of the content, and the interview strategy. An interpretation of the results signals the importance of the manner in which the staff member answers, a knowledge of patients' genuine needs, and an ability to adequately acknowledge the emotional state of the patient. Structuring telephone conversations, allowing sufficient time for patient responses, avoids over-long interviews. The decisions taken by the staff member answering the call, in terms of advice and suggestions of actions to take, must be systematically backed-up by ensuring that the patient has properly understood what has been said. The study poses a number of questions, notably concerning the specific requirements demanded by these new remote-care services in the organization of care within a hospital unit, and the professional approach to the use of the telephone as part of the relationship with patients. Recommendations are given concerning the general principles governing a telephone interview and the definition of training objectives for healthcare professionals.


Bioinspired Spatiotemporal Management toward RNA Therapies.
Ribonucleic acid (RNA)-based therapies have become an attractive topic in disease intervention, especially with some that have been approved by the FDA such as the mRNA COVID-19 vaccine (Comirnaty, Pfizer-BioNTech, and Spikevax, Moderna) and Patisiran (siRNA-based drug for liver delivery). However, extensive applications are still facing challenges in delivering highly negatively charged RNA to the targeted site. Therapeutic delivery strategies including RNA modifications, RNA conjugates, and RNA polyplexes and delivery platforms such as viral vectors, nanoparticle-based delivery platforms, and hydrogel-based delivery platforms as potential nucleic acid-releasing depots have been developed to enhance their cellular uptake and protect nucleic acid from being degraded by immune systems. Here, we review the growing number of viral vectors, nanoparticles, and hydrogel-based RNA delivery systems; describe RNA loading/release mechanism induced by environmental stimulations including light, heat, pH, or enzyme; discuss their physical or chemical interactions; and summarize the RNA therapeutics release period (temporal) and their target cells/organs (spatial). Finally, we describe current concerns, highlight current challenges and future perspectives of RNA-based delivery systems, and provide some possible research areas that provide opportunities for clinical translation of RNA delivery carriers.


[Cancer mortality in women from Cadiz. 1975-1983].
Both in Spain and in the rest of industrialized countries, cancer is the second caused mortality in accordance with its incidence. Respect to the different Autonomous Communities, Andalucia is that where men are at most unfavorable situation, and women are within the most unfavored. Out of all the Provinces which constituted this Community, mainly Cadiz attracted attention by its systematically and constantly growing rates of that tumors present in the most common localizations. The aim of the present work is to study, by means of death certificate dates, the mortality rate of women from Cadiz between 1975-1983. Mortality rate was 104.08 decease per 100,000 inhabitants. The cut off rate of female population older than 40 years was 287.77. The temporal trend of women cancer in our ambient was studied comparing the mortality rates with the incidence rates from some Spanish Populational-Based Cancer Registers (Granada, Murcia, Tarragona and Navarra). We conclude that in Cadiz Province there is a higher number of women decreased by cancer, mainly by liver cancers.


In vivo measurements of the internal and external diameters of the common bile duct in man.
As in other studies, it was not possible to define precisely the normal size of the common bile duct measured either externally or roentgenographically. However, the roentgenographically measured diameter of the common bile duct appears superior to the external width of the common bile duct in discriminating between patients with, and without, common bile duct disease. If the common bile duct was 1 centimeter or less roentgenographically, then only one of 78 patients studied had common bile duct disease, while all patients with common bile ducts 1.5 centimeters or larger had common bile duct disease. The range from 1.1 to 1.4 centimeters was indeterminate as a predictor of disease, since two of 19 patients in this group had common bile duct calculi. The utilization of the internal diameter instead of the external diameter of the common bile duct as a predictor of disease could be especially important in the clinical separation of patients with medical from surgical jaundice when noninvasive diagnostic tests, such as ultrasound and computerized tomography, are used.


Capacity and Utilization of Blood Culture in Two Referral Hospitals in Indonesia and Thailand.
It is generally recommended that sepsis patients should have at least two blood cultures obtained before antimicrobial therapy. From 1995 to 2015, the number of blood cultures taken each year in a 1,100-bed public referral hospital in Ubon Ratchathani northeast Thailand rose from 5,235 to 56,719, whereas the number received in an 840-bed referral public hospital in South Sulawesi, Indonesia, in 2015 was 2,779. The proportion of patients sampled for blood cultures out of all inpatients in South Sulawesi in 2015 (9%; 2,779/30,593) was lower than that in Ubon Ratchathani in 2003 (13%; 8,707/66,515), at a time when health expenditure per capita in the two countries was comparable. Under-use of bacterial cultures may lead to an underestimate and underreporting of the incidence of antimicrobial-resistant infections. Raising capacity and utilization of clinical microbiology laboratories in developing countries, at least at sentinel hospitals, to monitor the antimicrobial resistance situation should be prioritized.


Linking PBDEs in house dust to consumer products using X-ray fluorescence.
The indoor environment is an important source of exposure to polybrominated diphenyl ethers (PBDEs), a class of fire retardants used in many household products. Previous attempts to link PBDE concentrations in house dust to consumer products have been hampered by the inability to determine the presence of PBDEs in otherwise similar products. We used a portable X-rayfluorescence (XRF) analyzer to nondestructively quantify bromine concentrations in consumer goods. In the validation phase, XRF-measured bromine was highly correlated with GC/MS-measured bromine for furniture foam and plastic from electronics (n = 29, r = 0.93, p < 0.0001). In the field study phase, the XRF-measured bromine in room furniture was associated with pentaBDE concentrations in room dust in the bedroom (r = 0.68, p = 0.001) and main living area (r = 0.51, p = 0.02). We also found an association between XRF-measured bromine levels in electronics and decaBDE levels in dust, largely driven by the high levels in televisions (r = 0.64, p = 0.003 for bedrooms). For the main living area, predicting decaBDE in dust improved when we included an interaction effect between the bromine content of televisions and the number of persons in the house (p < 0.005), a potential surrogate for television usage.


Prostate Carcinoma Grade and Length But Not Cribriform Architecture at Positive Surgical Margins Are Predictive for Biochemical Recurrence After Radical Prostatectomy.
Postoperative biochemical recurrence occurs in up to 40% of prostate carcinoma patients treated with radical prostatectomy. Primary tumor grade and cribriform architecture are important parameters for clinical outcome; however, their relevance at positive surgical margins has not been completely elucidated yet. We reviewed 835 radical prostatectomy specimens and recorded pT-stage, surgical margin status, Grade Group, and cribriform architecture of the primary tumor and at positive surgical margins. Clinicopathologic parameters and biochemical recurrence-free survival (BCRFS) were used as endpoints. Positive surgical margins were present in 284 (34%) patients, with a median cumulative length of 5.0 mm. In 46%, the Grade Group at the margin was equal to the primary tumor grade, while being lower in 42% and higher in 12%. In multivariable analysis, Grade Group at the margin outperformed the Grade Group of the primary tumor in predicting BCRFS. Among primary Grade Group 2 patients, 56% had Grade Group 1 disease at the margin. Multivariable analysis identified cumulative length, Grade Group at the margin, and lymph node metastasis as independent predictors for BCRFS, while percentage Gleason pattern 4, tertiary Gleason pattern 5 of the primary tumor, and cribriform architecture at the margin were not. In conclusion, the Grade Group at the positive surgical margin was dissimilar to the primary tumor grade in 54% and better predicted BCRFS than the primary tumor grade. Cumulative length and tumor grade at the margin were independent predictors for BCRFS, whereas cribriform architecture at the margin was not.


[A case study of anaphylaxis in a pregnant woman].
We report a case of anaphylaxis in a 35+5 week of pregnancy patient who came to the Emergency Room with shortness of breath, hypotension and loss on fetal wellbeing. Due to her medical history and given the clinical picture at that time, an anaphylactic shock was suggested as the most probable diagnose. The administration of dexchlorpheniramine and methylprednisolone resulted in an immediate and positive reaction. Simultaneously, an improvement in the fetus cardiotocographic record was objectified. The patient was hospitalized for 48 hours, after which she was discharged. In case of suspicion of anaphylaxis in a pregnant woman, four aspects should be handled: the severity of the anaphylaxis chart, individual complications regarding a pregnant woman, unfavorable effects of the regularly used treatment during that specific gestation, and the need of fetal extraction based of gestational age.


Spontaneous osteonecrosis of the knee. Treatment and evolution.
We performed a retrospective study on 21 patients affected by unilateral spontaneous osteonecrosis of the femoral condyle. Fifteen were women and 6 men. Their average age was 66.9 years. In ten cases the onset of pain was sudden, with a clear previous history of trauma in two of them. Gait pain, effusion, and joint locking were the most frequent clinical symptoms. At the time of diagnosis, 7 patients presented with grade I necrosis, 8 grade II, 1 grade III, and 5 grade IV, following Koshino's classification [11]. The average percentage of osteonecrosis was 36.8%. Six patients underwent conservative treatment with physical exercises and nonsteroidal anti-inflammatory drugs. We performed arthroscopy alone in 4 patients, arthroscopy and drilling in 8, valgus high tibial osteotomy in 2, and total knee arthroplasty in 1. The overall results after an average follow-up 41 months were excellent and good in 76.2% of the cases, fair in 14.3%, and poor in 9.5%. An associated medial meniscus tear was found in half of the patients who underwent surgery. In patients diagnosed with grade III and IV osteonecrosis, no increase in the percentage of necrosis was observed.


Effect of Er:YAG laser on removal of fibre posts from root canal.
The aim of this study was to evaluate the efficiency of Er:YAG laser in translucent fibre post removal. 60 human single-rooted anterior teeth were divided into three groups (n = 20) according to post diameters (Exacto1-E1, Exacto2-E2, Exacto3-E3) and subdivided according to laser application. Fibre posts were cemented to endodontically treated teeth, and the specimens were sliced with a thickness of 1.0 ± 0.2 mm. Er:YAG laser was applied and the push out bond strength test was performed. Two-way analysis of variance was used to perform the statistical analysis. Push out bond strengths at apical area were significantly lower in all test groups (p < 0.05). Laser application caused increase in all radicular thirds, but it was significant for E1 and E3 groups. Laser application to the post-dentine interface enhances the connection between post and dentine.


Endoscopic retrograde cholangiopancreatography (ERCP) approach for patients with Roux-en-Y gastric bypass: a comparative study between four ERCP techniques with proposed management algorithm.
Endoscopic retrograde cholangiopancreatography (ERCP) is technically challenging in patients with Roux-en-Y gastric bypass (RYGB) due to altered anatomy. To compare the procedural and clinical outcomes of 4 different ERCP techniques in RYGB patients. Academic tertiary referral center in the United States. A retrospective cohort study including patients with RYGB anatomy who underwent an ERCP between January 2015 and September 2020. We compared procedural success and adverse events (AEs) rates of balloon-assisted enteroscopy (BAE), gastrostomy-assisted ERCP (GAE), endoscopic ultrasound (EUS)-directed transgastric ERCP (EDGE), and rendezvous guidewire-assisted ERCP (RGA). Seventy-eight RYGB patients underwent a total of 132 ERCPs. The mean age was 60 ± 11.8 years, with female predominance (85.7%). The ERCP procedures performed were BAE (n = 64; 48.5%), GAE (n = 18; 13.7%), EDGE (n = 25; 18.9%), and RGA (n = 25; 18.9%), with overall procedure success rates of 64.1%, 100%, 89.5%, and 91.7%, respectively. All approaches were superior to BAE (GAE versus BAE, P = .003; EDGE versus BAE, P = .034; RGA versus BAE, P = .011). The overall AE rates were 10.9%, 11.1%, 15.8 %, and 25.0%, respectively. There was no statistical difference in AEs. There were also no differences in bleeding, post-ERCP pancreatitis, and perforation rates between the 4 approaches. Procedure success was similar between GAE, RGA, and EDGE, but superior to BAE. AE rates were similar between approaches.


Difficult Intubation and Ventilation in an Infant With Retropharyngeal Abscess With Mediastinal Extension.
A previously healthy 7-month-old male infant presented for evaluation of fever, deceased oral intake, and intermittent noisy breathing. Physical examination revealed neck tenderness. Soft tissue neck radiographs and computed tomography (CT) scan supported a diagnosis of retropharyngeal swelling with extension to the superior mediastinum. Surgical exploration was planned, and endotracheal intubation was performed in the operating room. Significant cardiorespiratory derangements developed immediately after the tracheal tube was inserted, including hypotension, hypoxia, and bradycardia with signs of cardiac ischemia. The patient was resuscitated with intravenous fluids, vasopressors, and bronchodilators; his condition improved after resuscitation and surgical evacuation of purulent material. A combination of mediastinal mass effect, aspiration, and bronchospasm likely contributed to the patient's deterioration. The subsequent clinical course was uneventful. The patient was extubated in a delayed fashion and discharged on the fourth postoperative day. This case highlights the importance of preparing for a difficult airway in cases of retropharyngeal abscesses that necessitate tracheal intubation. A multidisciplinary approach is best suited to manage the airway, preferably in the operating room.


[T4 tracheo-bronchial carcinoma: clinical evaluation of 48 sleeve pneumonectomies].
The aim of the study was to verify the indications for surgery in T4 tracheo-bronchial carcinomas. Forty-eight tracheal-sleeve pneumonectomies for T4 bronchogenic carcinoma were performed in our unit from 1986 to 2003. The patients were 42 males and 6 females. A postero-lateral thoracotomy was preferred (46 right, 2 left). Bronchial reimplantation was performed additionally (tracheal-sleeve lobectomy) in 2 patients on the right side. The morbidity was 25% and the mortality 6.2% (1 acute respiratory distress syndrome, 1 myocardial infarction, 1 anastomotic fistula). Twenty-three cases were sT4N2M0, 14 sT4N1M0, and 11 sT4N0M0. The sT4N2M0 and sT4N1M0 cases were not associated with more than 3 year survival, despite adjuvant therapies; sT4N0M0 squamous cell carcinomas, on the other hand, had > 40% 10-year survival with no adjuvant therapy. Associated prosthetic replacement of the superior vena cava neither affected the risk nor improved the prognosis. Surgery for T4 tracheo-bronchial carcinoma appears feasible for well differentiated sT4N0 squamous cell carcinomas; at more advanced stages this procedure is no more than a dangerous form of palliation.


Toward precision medicine with next-generation EGFR inhibitors in non-small-cell lung cancer.
The use of genomics to discover novel targets and biomarkers has placed the field of oncology at the forefront of precision medicine. First-generation epidermal growth factor receptor (EGFR) inhibitors have transformed the therapeutic landscape of EGFR mutant non-small-cell lung carcinoma through the genetic stratification of tumors from patients with this disease. Somatic EGFR mutations in lung adenocarcinoma are now well established as predictive biomarkers of response and resistance to small-molecule EGFR inhibitors. Despite early patient benefit, primary resistance and subsequent tumor progression to first-generation EGFR inhibitors are seen in 10%-30% of patients with EGFR mutant non-small-cell lung carcinoma. Acquired drug resistance is also inevitable, with patients developing disease progression after only 10-13 months of antitumor therapy. This review details strategies pursued in circumventing T790M-mediated drug resistance to EGFR inhibitors, which is the most common mechanism of acquired resistance, and focuses on the clinical development of second-generation EGFR inhibitors, exemplified by afatinib (BIBW2992). We discuss the rationale, mechanism of action, clinical efficacy, and toxicity profile of afatinib, including the LUX-Lung studies. We also discuss the emergence of third-generation irreversible mutant-selective inhibitors of EGFR and envision the future management of EGFR mutant lung adenocarcinoma.


[Role of diagnostic imaging in chronic recurrent parotitis in childhood].
Chronic recurrent parotitis represents a disease of still uncertain etiology that can be divided into a childhood and an adult form. Sialography is still the imaging procedure of choice. We report about a nine-year-old girl who had had six episodes of parotitis in the past two years. MR sialography is presented as an alternative to conventional sialography. MR was performed with a 1.5 T wholebody tomograph using a high resolution 3D-CISS sequence. MR sialography does not require any contrast medium. It primarily images liquid structures, and the flow of saliva can be adequately demonstrated after stimulation with ascorbic acid. These special features of MR sialography allow its use also during acute episodes of sialadenitis, thus providing a significant improvement over conventional sialography. Furthermore, no overlapping occurs as in conventional summation images, due to the multiplanar reconstruction features.


Assessment of occupational risk for hantavirus infection in Arizona and New Mexico.
Differentiating occupational exposure from other potential domestic or recreational exposure(s) for Sin Nombre virus (SNV) infection is an epidemiologic challenge. Interviews on work-related activities were conducted, and serum specimens were obtained from 494 workers in Arizona and New Mexico. These workers may have been exposed to rodents and rodent excreta at work, but their primary occupation did not require rodent contact (National Park Service [n = 193]; Navajo Agricultural Product Industry [n = 65], utility companies [n = 169] and plumbing and heating contractors [n = 67]. Within each occupational group (farm workers [n = 57], laborers [n = 20], professionals [n = 70], repairers [n = 211], service industry workers [n = 83], and technicians [n = 53], the majority of workers reported working in areas that had rodent droppings (range, 75 to 95%); 70% of laborers and 64% of service industry workers reported handling rodents. More than 60% of workers in each group, except technicians, reported reopening and cleaning or working in closed spaces. Approximately 90% of laborers, repairers, and farm workers reported hand-plowing. Although the risk for occupationally related SNV infection appears to be low, workers frequently performed risk activities associated with hantavirus pulmonary syndrome (HPS). All workers were seronegative for SNV by enzyme-linked immunoassay or Western blot testing. These findings, the known occupational exposure of some HPS cases, and the high HPS case-fatality rate (52%) support the need for recommendations to reduce human contact with rodents in the workplace. Increased understanding of hantavirus transmission to humans will help focus future recommendations to minimize human exposures effectively.


Perceived coercion and the therapeutic relationship: a neglected association?
Increasing patient autonomy and decreasing coercion are frequently cited goals in mental health care. Research suggests that the therapeutic relationship and patients' experiences of coercion may be associated. This study investigated the association between the therapeutic relationship and perceived coercion in psychiatric admissions. Associations between perceived coercion and the therapeutic relationship and sociodemographic and clinical variables were examined by using data from structured interviews with 164 patients consecutively admitted to two psychiatric hospitals in Oxford, England. High levels of coercion were experienced by 48% of voluntarily and 89% of involuntarily admitted patients. A high perceived coercion score was significantly associated with involuntary admission and a poor rating of the therapeutic relationship. The therapeutic relationship confounded legal status as a predictor of perceived coercion. Similar factors may influence patients' experience of both coercion and the therapeutic relationship during psychiatric hospital admission. Hospitalization, even when voluntary, was viewed as more coercive when patients rated their relationship with the admitting clinician negatively. Interventions to improve the therapeutic relationship may reduce perceptions of coercion.


Defects in mitochondrial metabolism and cancer.
Cancer is a heterogeneous set of diseases characterized by different molecular and cellular features. Over the past decades, researchers have attempted to grasp the complexity of cancer by mapping the genetic aberrations associated with it. In these efforts, the contribution of mitochondria to the pathogenesis of cancer has tended to be neglected. However, more recently, a growing body of evidence suggests that mitochondria play a key role in cancer. In fact, dysfunctional mitochondria not only contribute to the metabolic reprogramming of cancer cells but they also modulate a plethora of cellular processes involved in tumorigenesis. In this review, we describe the link between mutations to mitochondrial enzymes and tumor formation. We also discuss the hypothesis that mutations to mitochondrial and nuclear DNA could cooperate to promote the survival of cancer cells in an evolving metabolic landscape.


Embolization of giant renal angiomyolipomas: technique and results.
To evaluate the efficacy and safety of prophylactic embolization of angiomyolipomas (AMLs) larger than 10 cm. Sixteen patients (mean age, 41.2 years; 14 women and two men) underwent embolization for 23 AMLs larger than 10 cm. All lesions were embolized by using microcatheters with ethanol and ethiodized oil mixed to a ratio of 7(ethanol) to 3(ethiodized oil). Data collected included pre- and posttreatment AML size, creatinine level, technical success, volume of embolic material used, clinical success, and complications. The mean AML size before treatment was 15 cm (range, 10-25 cm). Ten of the 16 patients (62%) had all their AMLs treated in one session, whereas six (38%) required multiple sessions. A mean volume of 8.6 mL of the ethanol-ethiodized oil mixture (range, 2-20 mL) was administered per lesion. Patients were followed up for a mean of 29 months (range, 1-80 months). No patient had an increase of 0.2 mg/dL (17.7 mumol/L) or greater in mean serum creatinine level during the follow-up period. Two of the 16 patients (12%) required repeat embolization due to AML regrowth (n = 1) or reperfusion (n = 1) seen at surveillance imaging. One of the 16 patients (6.2%) had an AML hemorrhage 59 months after AML embolization. Embolization of giant renal AMLs to decrease the risk of bleeding can be done safely without loss of renal function. Although recurrence was infrequent, additional treatment may be necessary and giant renal AMLs should be followed up with serial imaging studies.


Process evaluation of a randomised controlled trial of PBS-based staff training for challenging behaviour in adults with intellectual disability.
Positive Behaviour Support (PBS) for challenging behaviour is a complex intervention. Process evaluation is pivotal in fully understanding the mechanisms and contextual factors that impact on participant outcomes. To conduct a process evaluation of a national clinical trial investigating the impact of PBS-based staff training on the level of challenging behaviour in adults with intellectual disability. The Medical Research Council guidance for process evaluation of complex interventions was followed. Semi-structured interviews with 62 stakeholders from the intervention arm (service users, family and paid carers, service managers, staff who delivered the intervention and PBS trainers), quantitative data from the study database and an external evaluation of the quality of the PBS plans were used. Twenty-one health staff volunteered to be trained in delivering PBS. Available log data from 17 therapists revealed that they worked with 63 participants a median of 11.50 hours (IQR 8-32). Only 33 out of 108 reports had included all elements of the intervention. Another 47 reports had some elements of the intervention. All PBS plans were rated weak, indicating insufficient quality to impact challenging behaviour. Stakeholders reported an appreciation of PBS and its potential to impact quality of care and engagement with the participant. However, they also identified important challenges including managing PBS-related caseloads, paid carer turnover and service commitment to the delivery of PBS. PBS-based staff training was well received, but therapists found it difficult to undertake all the elements of the intervention in routine care. Implementing a workforce training strategy is important to better define the active components of PBS, and resource implications if the intervention is no better than usual care.


Effect of Reaction Media on Photosensitized [2+2]-Cycloaddition of Cinnamates.
The outcome of photosensitized [2+2]-cycloaddition reactions of various cinnamates has been compared in different reaction media, including homogeneous organic solutions under inert conditions, degassed water, and aerated physical gels. The reactions were performed under LED blue light (λmax=455 nm) irradiation and [Ir{dF(CF3)ppy}2(dtb-bpy)]PF6 (1.0 mol%) as photocatalyst. The processes were optimized taking into consideration solvent, gelator, and substrate. Comparative kinetics analyses, as well as the effect of the reaction media on the diastereoselectivity of the process, were evaluated during this investigation. In a number of cases, carrying out the reaction in a less polar solvent, like toluene or highly polar solvent, like water had a tremendous impact on the diastereoselectivity of the process, pointing towards an effect on the stabilization of the putative diradical intermediate in this medium. Moreover, while for reactions run in homogeneous solution oxygen needs to be excluded, no erosion in yield is observed when the photoadditions were run in aerated gel media.


Transcription efficiency of human polymerase III genes in vitro does not depend on the RNP-forming autoantigen La.
Transcription of class III genes is conducted by multi-protein complexes consisting of polymerase III itself and several transcription factors. We established a reconstituted in vitro transcription system from which the autoantigen La was removed by immunodepletion. This system showed no RNP formation, but was still fully active in transcription. Supplementing such La-free transcription reactions with recombinant La restored the formation of La complexes with the newly synthesised RNA, but did not lead to enhanced transcription efficiency. Furthermore, we developed a technique for the generation and isolation of transcription complexes, assembled from purified transcription factors and isolated by glycerol centrifugation. These complexes were fully competent to re-initiate RNA synthesis but they were not associated with La and their transcription rate could not be stimulated by addition of recombinant La. Therefore, we conclude that La does not act as a human polymerase III transcription factor.


The influence of timing and the addition of urea to supplements containing DL-methionine on ruminal fermentation and cow weight change in beef cows.
A study was conducted to determine an optimal time for supplementation of DL-methionine in relation to time of forage intake by mature British breed-type crossbred cows, and two other experiments were conducted to determine whether ruminal ammonia concentration limited changes in disappearance rates in situ and ruminal functions caused by supplements containing DL-methionine. Experiments 1 and 2 used 4 x 4 Latin square designs with four cows in each experiment. Treatments in Exp. 1 were no supplement (CON), DL-methionine at feeding (0800), DL-methionine 4 h after feeding (1200), and DL-methionine 7 h after feeding (1500). Treatments in Exp. 2 were .5 kg of beet pulp (CON), .5 kg of beet pulp plus 16.5 g of DL-methionine (MET), .5 kg of beet pulp plus 16.5 g of DL-methionine and 55 g of urea (METU), and .4 kg of soybean (SOY). Experiment 3 was conducted in a 326-ha pasture with treatments of no supplement (CON), .5 kg of beet pulp plus 12.5 g of DL-methionine and 30 g of urea (METU), and .4 of kg soybean meal (SOY). In Exp. 1, in situ NDF disappearance rates of cows supplemented at 1200 and 1500 were greater (P less than .01) than those of cows supplemented at 0800. In Exp. 2, ruminal ammonia concentration was greatest (P less than .001) for METU (5.2 mg/dl) and least for CON (1.5 mg/dl). Disappearance rates in situ for DM differed (P less than .01) among treatments; METU was similar (P greater than .2) to SOY but faster (P less than .01) than MET. Disappearance rates of NDF were greatest (P less than .001) for METU-supplemented cows. In Exp. 3, DM and NDF disappearance rates were faster (P less than .10) for SOY than for METU. Cow BW change was positive for METU and SOY, and decrease in condition score was least (P less than .10) for METU- and SOY-treated cows. These studies indicate favorable ruminal responses to DL-methionine supplementation; however, the response depended on time of supplementation and ruminal ammonia concentration.


Retinal detachment in the eye with the choroidal coloboma.
Choroidal coloboma is a congenital defect caused by an inadequate closure of embryonic fissure. About 40% of the eyes with the choroidal coloboma (CHC) develop the retinal detachment (RD). It is extremely difficult to manage these cases due to the lack of pigmentation at the site of choroidal coloboma. This is a case series of five patients with CHC and RD who were successfully operated using one of two different surgical techniques: pars plana vitrectomy (PPV)+silicone oil internal tamponade and/or scleral buckle with encircling band with laser photocoagulation (SB+EB+LPC) around the coloboma. The purpose of this paper is to present how to successfully handle patients with CHC, who have concurrent retinal detachment in the same eye and to compare two different techniques and indications for the predominant use of one of them in a specific case. Both surgical techniques can be applied with equal success in the operation of retinal detachment in eyes with the chorioidal coloboma. Which one will be used depends only of the posterior segment of eye findings. We use scleral buckling in cases with RD accompanied by CHC when the peripheral break is evident and there are no breaks in the coloboma itself. We also perform, 2-3 days after surgery, laser burns around the coloboma, which is our modification of this technique. In all other cases it is indicated to perform PPV+silicon oil internal tamponade.


A novel imaging approach for early detection of prostate cancer based on endogenous zinc sensing.
The early detection of prostate cancer is a life-saving event in patients harboring potentially aggressive disease. With the development of malignancy, there is a dramatic reduction in the zinc content of prostate tissue associated with the inability of cancer cells to accumulate the ion. In the current study, we used endogenous zinc as an imaging biomarker for prostate cancer detection and progression monitoring. We employed a novel fluorescent sensor for mobile zinc (ZPP1) to detect and monitor the development of prostate cancer in a transgenic mouse model of prostate adenocarcinoma, using in vivo optical imaging correlated with biological fluid-based methods. We showed that the progression of prostate cancer could be monitored in vivo judging by the decreasing zinc content in the prostates of tumor-bearing mice in an age-dependent manner. In a novel quantitative assay, we determined the concentration of mobile zinc in both prostate cell lysates and mouse prostate extracts through simple titration of the ZPP1 sensor. Our findings fulfill the promise of zinc-based prostate cancer diagnostics with the prospect for immediate clinical translation.


[Treatment of cavernous venous incompetence by insertion of a pericavernous prosthetic band].
The authors present a series of 30 patients treated by pericavernoplasty involving insertion of a prosthetic venous tourniquet. At 1 year, 60% of the patients obtained a good result. The preoperative selection criteria were: impossibility of penetration without manual assistance, normal arterial Doppler and hormone assays, high erection induction and maintenance flow rates, failure of simple medical treatments and perineal rehabilitation. The current problem concerns the objective evaluation of the compliance of erectile tissues. A possible approach in the future could be cavernous biopsy, which would allow the proposal of either venous surgery or the immediate insertion of a prosthesis.


Population genetic analysis of Propionibacterium acnes identifies a subpopulation and epidemic clones associated with acne.
The involvement of Propionibacterium acnes in the pathogenesis of acne is controversial, mainly owing to its dominance as an inhabitant of healthy skin. This study tested the hypothesis that specific evolutionary lineages of the species are associated with acne while others are compatible with health. Phylogenetic reconstruction based on nine housekeeping genes was performed on 210 isolates of P. acnes from well-characterized patients with acne, various opportunistic infections, and from healthy carriers. Although evidence of recombination was observed, the results showed a basically clonal population structure correlated with allelic variation in the virulence genes tly and camp5, with pulsed field gel electrophoresis (PFGE)- and biotype, and with expressed putative virulence factors. An unexpected geographically and temporal widespread dissemination of some clones was demonstrated. The population comprised three major divisions, one of which, including an epidemic clone, was strongly associated with moderate to severe acne while others were associated with health and opportunistic infections. This dichotomy correlated with previously observed differences in in vitro inflammation-inducing properties. Comparison of five genomes representing acne- and health-associated clones revealed multiple both cluster- and strain-specific genes that suggest major differences in ecological preferences and redefines the spectrum of disease-associated virulence factors. The results of the study indicate that particular clones of P. acnes play an etiologic role in acne while others are associated with health.


Characterization of a microbial transglutaminase cross-linked type II collagen scaffold.
This study investigated the effect on the mechanical and physicochemical properties of type II collagen scaffolds after cross-linking with microbial transglutaminase (mTGase). It is intended to develop a collagen-based scaffold to be used for the treatment of degenerated intervertebral discs. By measuring the amount of epsilon-(gamma-glutamyl)lysine isodipeptide formed after cross-linking, it was determined that the optimal enzyme concentration was 0.005% (w/v). From the production of covalent bonds induced by mTGase cross-linking, the degradation resistance of type II collagen scaffolds can be enhanced. Rheological analysis revealed an almost sixfold increase in storage modulus (G') with 0.005% (w/v) mTGase cross-linked scaffolds (1.31 +/- 0.03 kPa) compared to controls (0.21 +/- 0.01 kPa). There was a significant reduction in the level of cell-mediated contraction of scaffolds with increased mTGase concentrations. Cell proliferation assays showed that mTGase crosslinked scaffolds exhibited similar cytocompatibility properties in comparison to non-cross-linked scaffolds. In summary, cross-linking type II collagen with mTGase imparted more desirable properties, making it more applicable for use as a scaffold in tissue engineering applications.


The role of one-shot learning in #TheDress.
#TheDress is remarkable in two aspects. First, there is a bimodal split of the population in the perception of the dress's colors (white/gold vs. black/blue). Second, whereas interobserver variance is high, intra-observer variance is low, i.e., the percept rarely switches in a given individual. There are two plausible routes of explanations: either one-shot learning during the first presentation of the image splits observers into two different, stable populations, or the differences are caused by stable traits of observers, such as different visual systems. Here, we hid large parts of the image by white occluders. The majority of naïve participants perceived the dress as black and blue. With black occluders, the majority of observers perceived the dress as white and gold. The percept did not change when we subsequently presented the full image, arguing for a crucial role of one-shot learning. Next, we investigated whether the first fixation determines the perceived color in naïve observers. We found no such effect. It remains thus a puzzling question where the source of variability in the different percepts comes from.


Does the A9285G Polymorphism in Collagen Type XII α1 Gene Associate with the Risk of Anterior Cruciate Ligament Ruptures?
One of the most severe injuries sustained by athletes is rupture of the anterior cruciate ligament (ACL). Recent investigations suggest that a predisposition for ACL rupture may be the result of specific genetic sequence variants. In light of this, we decided to investigate whether the COL12A1 A9285G polymorphism was associated with ACL ruptures in Polish football players. We compared genotypic and allelic frequencies of the COL12A1 A9285G polymorphism in two groups of athletes: 91 male football players (23 ± 3 years) with surgically diagnosed primary ACL ruptures who qualified for ligament reconstruction (cases) and 143 apparently healthy, male football players of the same ethnicity, a similar age category, and a comparable level of exposure to ACL injury, who were without any self-reported history of ligament or tendon injury (controls). DNA samples extracted from the oral epithelial cells were genotyped by using a real-time polymerase chain reaction (Ri-Ti-PCR) method. The genotype distribution in the cases were not different from those in controls (p = 0.70). The frequency of the G allele was lower in the cases (18.1%) but not statistically significant (p = 0.40) when compared with controls (21.3%). Our results are in contradiction to the hypothesis that the COL12A1 A9285G polymorphism is associated with a predisposition for ACL injury. However, these conclusions should be supported with more experimental studies on COL12A1 polymorphisms.


Pesticide use among farmers in the Amazon basin of Ecuador.
Pesticide use is one of the most significant occupational exposures for agricultural workers in the Amazon basin of Ecuador. A structured questionnaire was developed focusing on sociodemographic characteristics, knowledge and experience of adverse health effects related to pesticide use, details of work practices, and an inventory of pesticides used on the farm. Of the 112 farmers interviewed, 111 (99.1%) used pesticides. Paraquat was most commonly used (77.4%), followed by glyphosate (65.7%). Respondents had good knowledge about the acute health effects of pesticides and their exposure routes. Risk behaviors were identified as frequent pesticide use, washing pesticide equipment in water sources used by humans, inadequate disposal of empty pesticide containers, eating and drinking during pesticide application, and using inadequate protective clothing. Training and educational campaigns on pesticide use should be encouraged for this cohort, along with suggestions for alternative methods of pest control.


Art Rounds: teaching interprofessional students visual thinking strategies at one school.
The Art Rounds program uses visual thinking strategies (VTS) to teach visual observation skills to medical and nursing students at the University of Texas Health Science Center San Antonio. This study's goal was to evaluate whether students' exposure to VTS would improve their physical observation skills, increase tolerance for ambiguity, and increase interest in learning communication skills. In January 2010, 32 students attended three, 90-minute sessions at which they observed and commented on three pieces of art in small groups led by museum educators. Pre and posttest evaluations included Geller and colleagues' version of Budner's Tolerance of Ambiguity Scale, the Communication Skills Attitudes Scale, and free responses to art and patient images. Statistical analyses compared pre and post time looking at images, number of words used to describe images, and number of observations made according to gender and discipline. Students significantly increased the amount of time they spent looking at art and patient images (P = .007), the number of words they used to describe art (P = .002) and patient images (P = .019), and the number of observations made of art (P = .000) and patient images (P = .001). Females increased the time spent observing significantly more than did males (P = .011). Students significantly increased their tolerance for ambiguity (P = .033) and positive views toward health care professional communication skills (P = .001). The authors speculate that these improved skills may help in patient care and interprofessional team interactions.


An α helix to β barrel domain switch transforms the transcription factor RfaH into a translation factor.
NusG homologs regulate transcription and coupled processes in all living organisms. The Escherichia coli (E. coli) two-domain paralogs NusG and RfaH have conformationally identical N-terminal domains (NTDs) but dramatically different carboxy-terminal domains (CTDs), a β barrel in NusG and an α hairpin in RfaH. Both NTDs interact with elongating RNA polymerase (RNAP) to reduce pausing. In NusG, NTD and CTD are completely independent, and NusG-CTD interacts with termination factor Rho or ribosomal protein S10. In contrast, RfaH-CTD makes extensive contacts with RfaH-NTD to mask an RNAP-binding site therein. Upon RfaH interaction with its DNA target, the operon polarity suppressor (ops) DNA, RfaH-CTD is released, allowing RfaH-NTD to bind to RNAP. Here, we show that the released RfaH-CTD completely refolds from an all-α to an all-β conformation identical to that of NusG-CTD. As a consequence, RfaH-CTD binding to S10 is enabled and translation of RfaH-controlled operons is strongly potentiated. PAPERFLICK:


Glucose transport in vesicles reconstituted from Saccharomyces cerevisiae membranes and liposomes.
Glucose transport activity was reconstituted into liposomes by the freeze-thaw-sonication procedure from unextracted Saccharomyces cerevisiae membranes and preformed phospholipid liposomes. Fluorescence-dequenching measurements with octadecylrhodamine B chloride (R18)-labeled membranes showed that the yeast membrane lipids are diluted by the liposome lipids after the freeze-thaw-sonication procedure. At lipid-to-protein ratios greater than 75:1, vesicles with single transporters were formed. Reconstituted specific activity was increased at least twofold if the liposomes contained 50 mol% cholesterol. A further increase in specific activity, from 3- to 10-fold, was achieved by fractionation of the membranes on a Renografin gradient before reconstitution. Examination of the fractions from the Renografin gradient by sodium dodecyl sulfate-gel electrophoresis showed a parallel enrichment of glucose transport activity and a number of proteins including one with an apparent Mr of ca. 60,000, which might be the glucose transporter. Finally, preliminary kinetic analysis of glucose transport activity in vesicles reconstituted at a high lipid-to-protein ratio gave a Vmax of ca. 2.8 mumol/mg of protein per min at 23 degrees C and a Km of ca. 8 mM. The latter value corresponds to the kinase-independent, low-affinity component of glucose transport observed in wild-type cells.


Optical activity in twisted solid-core photonic crystal fibers.
In this Letter we show that, in spectral regions where there are no orbital cladding resonances to cause transmission loss, the core mode of a continuously twisted photonic crystal fiber (PCF) exhibits optical activity, and that the magnitude of the associated circular birefringence increases linearly with twist rate and is highly reproducible. In contrast to previous work on twist-induced circular birefringence, PCF has zero linear birefringence and an on-axis core, making the appearance of circular birefringence rather unexpected. A theoretical model based on symmetry properties and perturbation theory is developed and used to show that both spin and orbital angular momentum play a role in this effect. It turns out that the degenerate left- and right-circularly polarized modes of the untwisted PCF are not 100% circularly polarized but carry a small amount of orbital angular momentum caused by the interaction between the core mode and the hollow channels.


EDTA conditioning of circumpulpal dentine induces dentinogenic events in pulpotomized miniature swine teeth.
To investigate pulp responses after pulpotomy and EDTA conditioning of pulp chamber dentinal walls with or without the placement of a collagenous scaffold in the experimental model of miniature swine teeth. Forty-two fully developed permanent premolars and molars of healthy miniature swines were used. After preparation of pulp exposures through Class I cavities, the tissue of the pulp chamber was completely removed. The haemorrhage was controlled, and the root pulp was protected using a polyurethane film. The circumpulpal pulp chamber dentine was treated for 3 min with normal saline (group 1), or 17% EDTA solution (groups 2 and 3). The film was removed, and the pulp chamber cavities were left empty (groups 1 and 2), or filled with swine collagenous sponge (group 3). The access cavities were restored with a Teflon disc and glass ionomer. Teeth were evaluated histo-morphologically after 10 weeks. Data were compared using the nonparametric Fisher's exact test. Teeth after treatment of dentine with saline (group 1) were associated with no or only traces of hard tissue formation along the root canal walls. Atubular tertiary dentine deposition in the form of matrix deposition along root canal walls, or dentine bridge formation at the orifice of root canals or complete pulp canal obliteration, was found after treatment of dentine with EDTA in both experiments (groups 2 and 3). Significantly different types of mineralization in the root canals of groups 2 and 3 were seen (P = 0.001). Tissue changes in the pulp cavity, characterized by soft tissue growth and osteodentine or atubular tertiary dentine formation, were only seen after EDTA conditioning of dentine, in 6.2% of the teeth without scaffold and 64.7% of the teeth with scaffold application. Newly deposited mineralized matrix in the pulp chamber was always in continuation with hard tissue deposited in the root canals. The EDTA conditioning of pulp cavity dentinal walls after pulpotomy induced dentinogenic events in the root pulp. Application of collagenous scaffold in the pulp chamber enhanced soft tissue growth and mineralized tissue formation along the treated circumpulpal dentine.


Expression of two distinct T cell receptor alpha/beta heterodimers by an antigen-specific T cell clone.
A cytochrome c-specific, MHC-restricted T cell clone with two complete rearrangements of the same V beta 1 gene element was shown to express two different TCR alpha/beta heterodimers. Antipeptide antisera specific for TCR C beta 1 and C beta 2 peptides each immunoprecipitated distinct disulfide-linked cell surface heterodimers. The clone was derived from immunized allogeneic chimeric mice, and displayed multiple Ia specificities, including the ability to recognize antigen in association with both I-Ek and I-Es Ia molecules, as well as alloreactivity to the I-Eb molecule. It will be important to determine whether each receptor contributes independently to the overall specificity of the clone.


[Clonogenic capacity and proliferative activity of the cells of malignant tumors of the bones].
The authors presented their first results of tumor cell cloning in 48 patients with malignant bone tumors. Colony growth was observed in 32 patients. Colony formation efficacy, expressed in the number of grown colonies per 10(5) tumor cells incubated in the culture, varied greatly (from 0.4 to 90.7) in different patients. Rather a high colony forming capacity of tumor cells was prognostically unfavorable. Tumor cells in the patients with malignant bone tumors were characterized by a low proliferative activity: the ratio of DNA-synthesizing cells evaluated by immunofluorescence or flow cytometry in 14 examinees was an average of 3.3% varying in different patients from 0 to 8.0%. No distinct correlation between tumor cell colony forming capacity and proliferative activity was revealed in the patients.


Sequential Acquisition of Virulence and Fluoroquinolone Resistance Has Shaped the Evolution of Escherichia coli ST131.
Escherichia coli ST131 is the most frequently isolated fluoroquinolone-resistant (FQR) E. coli clone worldwide and a major cause of urinary tract and bloodstream infections. Although originally identified through its association with the CTX-M-15 extended-spectrum β-lactamase resistance gene, global genomic epidemiology studies have failed to resolve the geographical and temporal origin of the ST131 ancestor. Here, we developed a framework for the reanalysis of publically available genomes from different countries and used this data set to reconstruct the evolutionary steps that led to the emergence of FQR ST131. Using Bayesian estimation, we show that point mutations in chromosomal genes that confer FQR coincide with the first clinical use of fluoroquinolone in 1986 and illustrate the impact of this pivotal event on the rapid population expansion of ST131 worldwide from an apparent origin in North America. Furthermore, we identify virulence factor acquisition events that predate the development of FQR, suggesting that the gain of virulence-associated genes followed by the tandem development of antibiotic resistance primed the successful global dissemination of ST131. Escherichia coli sequence type 131 (ST131) is a recently emerged and globally disseminated multidrug-resistant clone frequently associated with human urinary tract and bloodstream infections. In this study, we have used two large publically available genomic data sets to define a number of critical steps in the evolution of this important pathogen. We show that resistance to fluoroquinolones, a class of broad-spectrum antibiotic used extensively in human medicine and veterinary practice, developed in ST131 soon after the introduction of these antibiotics in the United States, most likely in North America. We also mapped the acquisition of several fitness and virulence determinants by ST131 and demonstrate these events occurred prior to the development of fluoroquinolone resistance. Thus, ST131 has emerged by stealth, first acquiring genes associated with an increased capacity to cause human infection, and then gaining a resistance armory that has driven its massive population expansion across the globe.


High-resolution mass spectrometry elucidates metabonate (false metabolite) formation from alkylamine drugs during in vitro metabolite profiling.
In vitro metabolite profiling and characterization experiments are widely employed in early drug development to support safety studies. Samples from incubations of investigational drugs with liver microsomes or hepatocytes are commonly analyzed by liquid chromatography/mass spectrometry for detection and structural elucidation of metabolites. Advanced mass spectrometers with accurate mass capabilities are becoming increasingly popular for characterization of drugs and metabolites, spurring changes in the routine workflows applied. In the present study, using a generic full-scan high-resolution data acquisition approach with a time-of-flight mass spectrometer combined with postacquisition data mining, we detected and characterized metabonates (false metabolites) in microsomal incubations of several alkylamine drugs. If a targeted approach to mass spectrometric detection (without full-scan acquisition and appropriate data mining) were employed, the metabonates may not have been detected, hence their formation underappreciated. In the absence of accurate mass data, the metabonate formation would have been incorrectly characterized because the detected metabonates manifested as direct cyanide-trapped conjugates or as cyanide-trapped metabolites formed from the parent drugs by the addition of 14 Da, the mass shift commonly associated with oxidation to yield a carbonyl. This study demonstrates that high-resolution mass spectrometry and the associated workflow is very useful for the detection and characterization of unpredicted sample components and that accurate mass data were critical to assignment of the correct metabonate structures. In addition, for drugs containing an alkylamine moiety, the results suggest that multiple negative controls and chemical trapping agents may be necessary to correctly interpret the results of in vitro experiments.


Differences in early gesture explain SES disparities in child vocabulary size at school entry.
Children from low-socioeconomic status (SES) families, on average, arrive at school with smaller vocabularies than children from high-SES families. In an effort to identify precursors to, and possible remedies for, this inequality, we videotaped 50 children from families with a range of different SES interacting with parents at 14 months and assessed their vocabulary skills at 54 months. We found that children from high-SES families frequently used gesture to communicate at 14 months, a relation that was explained by parent gesture use (with speech controlled). In turn, the fact that children from high-SES families have large vocabularies at 54 months was explained by children's gesture use at 14 months. Thus, differences in early gesture help to explain the disparities in vocabulary that children bring with them to school.


Effects of injected Alzheimer beta-amyloid cores in rat brain.
Although amyloid deposits have long been known to accumulate in Alzheimer disease (AD) brain, their origin and significance remain speculative. Because of the lack of an in vivo model where amyloid deposits can be induced, the relationship of the extracellular beta-amyloid deposits to other AD pathology has never been directly investigated. Therefore, we injected SDS-isolated amyloid cores into rat cortex and hippocampus. Similarly isolated lipofuscin fractions from control human brains were injected on the contralateral side. Rats were perfused and brains were examined immunohistochemically at 2 days, 7 days, and 1 month after injection. Alz-50, a monoclonal antibody against abnormally phosphorylated tau proteins, stained neurons along the cortical needle track at 2 but not 7 days after injection of either amyloid or lipofuscin. At 1 month, however, ubiquitin, Alz-50 antigen, and silver-positive structures were observed only in response to amyloid. In 7 of 10 animals, there was considerable neuronal loss in the hippocampal layers. In each instance, these effects were in the immediate vicinity of beta-protein immunoreactive material. Marked neuronal loss was never observed at any time after lipofuscin injection. These results indicate a neuronal response to amyloid. When preparations of mature plaque amyloid isolated from the AD brain are injected into the rat brain, they exert neurotoxic effects and induce antigens found in the AD brain.


Aspirin: its effect on platelet glycolysis and release of adenosine diphosphate.
Incubation of human platelets with aspirin inhibited glycolysis and produced a fall in the concentration of adenosine triphosphate. When platelets were exposed to collagen there was an increase in glycolysis and release of adenosine diphosphate. Prior incubation of the platelets with aspirin for 5 minutes did not totally suppress the increase in glycolysis after exposure to collagen but completely inhibited the collagen-induced reaction of the release of adenosine diphosphate. It is suggested that aspirin acts on human platelets by inhibiting both release of adenosine diphosphate and the transport of glucose across the platelet membrane.


Addition of sunitinib to cetuximab and irinotecan in patients with heavily pre-treated advanced colorectal cancer.
Results of continuous sunitinib, in combination with cetuximab and irinotecan every other week (SIC) for compassionate use in heavily pre-treated patients with mCRC are presented. Patients with mCRC resistant to oxaliplatin, irinotecan, 5-FU and cetuximab received SIC at two Danish oncologic departments. The regimen consisted of sunitinib given as a continuous-dosing in combination with cetuximab and irinotecan every other week (CetIri). The first six patients started with a daily oral dose of sunitinib of 12.5 mg. Subsequent patients started at a daily dose of 25 mg with the possibility to escalate to 37.5 mg. Twenty-nine patients received SIC. No patient had an objective response, but 13 patients had subjective relief and 42% had stable disease. The median time to progression was 3.2 months and median overall survival was 7.4 months. Fatigue and leukopenia were the most frequently reported severe adverse event (18% grade 3 and 18% grade 3/4, respectively). Sunitinib continuous-dosing with 25 mg/day can safely be combined with CetIri administered every other week.


Metagenomic Survey Reveals More Diverse and Abundant Antibiotic Resistance Genes in Municipal Wastewater Than Hospital Wastewater.
Alongside antibiotic resistance, co-selection of antibiotics, biocides, and metal resistance is a growing concern. While hospital wastewater is considered a hotspot for antibiotic-resistant bacteria (ARB) and genes (ARGs), the scenario in India, one of the biggest consumers of antibiotics, remains poorly described. In this study, we used metagenomic sequencing to characterize ARGs and biocide/metal resistance genes (BMRGs) in four wastewater treatment plants (WWTPs) in Jaipur City of India. We observed a significantly lower richness and abundance of ARGs in the influent of a WWTP exclusively receiving hospital wastewater when compared to other three WWTPs involving municipal wastewater treatment. Several tetracycline and macrolide-lincosamide-streptogramin resistance genes were enriched in influents of these three municipal wastewater-related treatment plants, whereas hospital wastewater had a higher abundance of genes conferring resistance to disinfectant-related compounds such as synergize and wex-cide-128, reflecting the patterns of antibiotic/disinfectant use. Of note, in the wastewater system with more chemicals, there was a strong correlation between the numbers of ARGs and BMRGs potentially harbored by common hosts. Our study highlights significant influxes of ARGs from non-hospital sources in Jaipur City, and thus more attention should be paid on the emergence of ARGs in general communities.


Serum proteins as carriers of amino acids to and from the hindlimbs of fed and fasted calves.
Venoarterial differences in the amino acid composition of serum proteins were measured across the hindlimbs of growing Holstein steer calves (147 kg) surgically fitted with abdominal aorta and caudal vena cava cannulae. Steers were maintained in near steady-state metabolism by feeding at hourly intervals in a continuously lighted environment. The steady-state blood samples were obtained 10 d post-surgery; then the steers were fasted and resampled. Arterial and venous serum proteins were chromatographically separated into four fractions and the amino acid composition of each was determined. Under steady-state conditions, there appeared to be a tendency for serum protein amino acids to appear on the venous side of the tissue in either greater or lesser concentrations than on the arterial side, depending upon the protein fraction. However, after the steers had fasted for 72 h, virtually all amino acids from all protein fractions were present in greater concentrations in venous serum than in arterial serum. Furthermore, the quantitative differences were several-fold larger than during steady-state sampling. It appears that serum proteins may contribute to the transport of amino acids to and from peripheral tissues. Data further suggest that all serum proteins do not appear to function in the same manner, and physiological state influences this process.


The 3-4 loop of an archaeal glutamate transporter homolog experiences ligand-induced structural changes and is essential for transport.
Glutamatergic synaptic transmission is terminated by members of the excitatory amino acid transporter (EAAT) family of proteins that remove glutamate from the synaptic cleft by transporting it into surrounding glial cells. Recent structures of a bacterial homolog suggest that major motions within the transmembrane domain translocate the substrate across the membrane. However, the events leading to this large structural rearrangement are much less clear. Two reentrant loops have been proposed to act as extracellular and intracellular gates, but whether other regions of these proteins play a role in the transport process is unknown. We hypothesized that transport-related conformational changes could change the solvent accessibilities of affected residues, as reflected in protease sensitivity or small-molecule reactivity. In the model system Glt(Ph), an archaeal EAAT homologue from Pyrococcus horikoshii, limited trypsin proteolysis experiments initially identified a site in the long extracellular loop that stretches between helices 3 and 4 that becomes protected from proteolysis in the presence of a substrate, L-aspartate, or an inhibitor, DL-TBOA in the presence of Na(+), the cotransported ion. Using a combination of site-directed cysteine-scanning mutagenesis and fluorescein-5-maleimide labeling we found that positions throughout the loop experience these ligand-induced conformational changes. By selectively cleaving the 3-4 loop (via introduced Factor Xa sites) we demonstrate that it plays a vital role in the transport process; though structurally intact, the cleaved proteins are unable to transport aspartate. These results inculcate the 3-4 loop as an important player in the transport process, a finding not predicted by any of the available crystal structures of Glt(Ph).


Correction to: Dehydroepiandrosterone sulphate (DHEAS) concentrations stringently regulate fertilization, embryo development and IVF outcomes: are we looking at a potentially compelling 'oocyte-related factor' in oocyte activation?
Erratic oocyte-activation affects fertilization and embryo development. Dehydro-epiandrosterone sulphate (DHEAS) is present in theca/cumulus-granulosa cells, regulates the same calcium-pumps that cause calcium-oscillations in mice and its levels are altered in women with no or low fertilization rates. Yet no study has explored correlation of DHEAS with oocyte-activation. We proposed to implicate DHEAS as an oocyte-related factor in oocyte-activation by demonstrating that rectification of deviated (both lower/and higher than normal) DHEAS concentrations to normal post-treatment improves fertilization, embryo development rates. Prospective Closed-Cohort. Recruited n = 750 (150 women/subgroup) in previously classified Low(A), Average/Control(B), High(C) D3-serum DHEAS groups. 50% women in both A and C groups received 3-months exposure to oral DHEAS and Metformin respectively. Also measured Follicular-fluid DHEAS levels. Compared embryologic, clinical outcomes: DHEAS untreated (A1) vs. treated (A2); metformin untreated (C1) vs. treated (C2) and A1/A2/C1/C2 against normal-control-B group. Also compared serum vs. FF-group results. Significantly improved embryologic, clinical parameters in treated A2/C2 compared to untreated A1/C1 subgroups respectively. Post-treated improved parameters in A2/C2 were comparable with, whereas untreated A1/C1 sub-groups had significantly lower values than, normal-control B-group. Parameters differed significantly between Low, Medium, High FF-DHEAS groups. Results in serum vs. FF: A1 vs. LowFF, C1 vs. HighFF and A2/C2/B vs. MediumFF were comparable. Odds of fertilization, live-births increased in post-treatment A2/C2 subgroups. Fertilization rates strongly correlated with FF-DHEAS. Rectification of deviated DHEAS levels post-treatment significantly improves outcomes, comparable with those exhibited by normal-control DHEAS thresholds. DHEAS is the most promising endogenous oocyte-related factor influencing embryologic, clinical IVF outcomes possibly by affecting oocyte-activation.


Indaziflam herbicidal action: a potent cellulose biosynthesis inhibitor.
Cellulose biosynthesis is a common feature of land plants. Therefore, cellulose biosynthesis inhibitors (CBIs) have a potentially broad-acting herbicidal mode of action and are also useful tools in decoding fundamental aspects of cellulose biosynthesis. Here, we characterize the herbicide indaziflam as a CBI and provide insight into its inhibitory mechanism. Indaziflam-treated seedlings exhibited the CBI-like symptomologies of radial swelling and ectopic lignification. Furthermore, indaziflam inhibited the production of cellulose within <1 h of treatment and in a dose-dependent manner. Unlike the CBI isoxaben, indaziflam had strong CBI activity in both a monocotylonous plant (Poa annua) and a dicotyledonous plant (Arabidopsis [Arabidopsis thaliana]). Arabidopsis mutants resistant to known CBIs isoxaben or quinoxyphen were not cross resistant to indaziflam, suggesting a different molecular target for indaziflam. To explore this further, we monitored the distribution and mobility of fluorescently labeled CELLULOSE SYNTHASE A (CESA) proteins in living cells of Arabidopsis during indaziflam exposure. Indaziflam caused a reduction in the velocity of YELLOW FLUORESCENT PROTEIN:CESA6 particles at the plasma membrane focal plane compared with controls. Microtubule morphology and motility were not altered after indaziflam treatment. In the hypocotyl expansion zone, indaziflam caused an atypical increase in the density of plasma membrane-localized CESA particles. Interestingly, this was accompanied by a cellulose synthase interacting1-independent reduction in the normal coincidence rate between microtubules and CESA particles. As a CBI, for which there is little evidence of evolved weed resistance, indaziflam represents an important addition to the action mechanisms available for weed management.


The neurology of ageing: what is normal?
Ageing is associated with changes in the nervous system with consequent alterations in some neurological examination findings: understanding what is 'normal' at different ages is essential when evaluating patients. In seminal papers published in 1931, Dr MacDonald Critchley summarised his observations and the prevailing evidence on the effects of ageing on, among others, sensation, reflexes, ocular function, olfaction, movement and cognition. In this review, these observations are re-evaluated in light of contemporary evidence. Factors influencing the measurement and interpretation of these clinical findings are then discussed, including reproducibility, the influence of comorbidities, secular trends, how 'normality' should best be defined, the problems of extrapolating group data to individuals and the influence of presymptomatic neurodegenerative disease states. The case is made that context is critical, and that combining life course data with detailed clinical and biomarker phenotyping is required to understand the determinants of normal neurological function associated with ageing.


Eltrombopag therapy in newly diagnosed steroid non-responsive ITP patients.
Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterised by isolated thrombocytopenia (peripheral blood platelet count <100 × 10(9)/L) in the absence of other causes or disorders that may be associated with thrombocytopenia. The upfront treatment in newly diagnosed ITP patients is steroids; however, about one-third patients do not respond, and require other treatment, including IVIg, anti-D, or splenectomy. Previous studies have shown decreased platelet production in some ITP patients, aside from the evidence of enhanced platelet destruction. Thrombopoietin receptor agonists (TPO-RA), such as eltrombopag have been shown to provide good response in steroid non-responsive chronic ITP patients. We have studied response to eltrombopag in 25 newly diagnosed steroid non-responsive ITP patients; 80 % patients showed response at the end of 1 month, and 76 % sustained response at the end of 3 months. The platelet count rose from a mean value of 17.5 ± 3.6-152.5 ± 107.9 × 10(9)/L at the end of 1 month. Our results suggest a possible role of eltrombopag in newly diagnosed steroid non-responsive ITP patients. However, our study is limited in that it is a single-centre study, with a small sample size, and lacks a long-term safety profile. Our findings highlight the potential value of a larger prospective study on the upfront use of TPO-RA in patients of ITP.


Ginsenoside Rh2 Inhibited Proliferation by Inducing ROS Mediated ER Stress Dependent Apoptosis in Lung Cancer Cells.
Ginsenoside Rh2 (G-Rh2), a component extracted from roots of ginseng, exhibited anti-cancer pharmacological activities by inhibiting proliferation and inducing apoptosis in lung cancer cells. However, the mechanisms of G-Rh2 suppressing lung cancer development remained elusive. This study tried to investigate the possible mechanism involved in anti-proliferative effect of G-Rh2 in lung cancer cells. As results, G-Rh2 inhibited the proliferation of H1299 cells in a dose-dependent manner by inducing cell apoptosis. Activating transcription factor 4 (ATF4), CCAAT/enhancer-binding protein homologous protein (CHOP), and caspase-4 were involved in G-Rh2-induced apoptosis of H1299 cells. It was also found that G-Rh2 could up-regulate expressions of ATF4, CHOP and caspase-4 in H1299 cells in a dose-dependent manner. In addition, NAC (N-acetylcysteine, a reactive oxygen species (ROS) scavenger) treatment dramatically decreased ROS generation in H1299 cells; both of NAC and 4-PBA (4-phenylbutyrate, a specific endoplasmic reticulum (ER) stress inhibitor) administration impaired apoptosis and expression levels of ATF4, CHOP and caspase-4 in G-Rh2 incubated H1299 cells. In vivo assays extended the significance of these results, showing that G-Rh2 inhibited lung cancer growth and the inhibition effects of G-Rh2 in tumor growth were significantly reduced by inhibition of ER stress. In conclusion, G-Rh2 inhibited proliferation of H1299 cells by inducing ROS mediated ER stress dependent cell apoptosis.