bluuebunny/crossref_metadata_2025 huggingface dataset:
T‐tube‐free single‐incision laparoscopic common bile duct exploration plus cholecystectomy: a single centre experience
Authors: Yao Chenhui , Tian Yu , Yao Dianbo , Han Jinyan , Wu Shuodong
Published: June 2019

Background

The present study aimed to explore the indications and feasibility of T‐tube‐free trans‐umbilical single‐incision laparoscopic common bile duct exploration (SILCBDE) plus laparoscopic cholecystectomy (LC) for treating choledocholithiasis.

Methods

Patients hospitalized in the Second Affiliated Hospital (Shengjing Hospital) of China Medical University from January 2010 to January 2017 with the diagnosis of common bile duct stones and treated with T‐tube‐free trans‐umbilical single‐incision LC plus common bile duct exploration were retrospectively analysed.

Results

A total of 37 male/female choledocholithiasis patients (mean age 65 years, range 29–86) were treated with T‐tube‐free trans‐umbilical SILCBDE plus LC. No intraoperative complication or conversion to open surgery occurred in any of the cases. The mean operative time was 99.8 min (range 84–125) for endoscopic nasobiliary drainage group (n = 6), 113.8 min (range 70–150) for endoscopic retrogradebiliary drainage group (n = 2), 131.1 min (range 75–161) for pigtail J‐tube group (n = 24), 113.7 min (range 100–150) for primary closure group (n = 5). The mean post‐operative hospital stay length was 5.5 days (range 4–7) for endoscopic nasobiliary drainage group, 12.5 days (range 10–15) for endoscopic retrogradebiliary drainage group, 6.5 days (range 4–10) for J‐tube group, 5.8 days (range 4–9) for primary closure group. Pancreatitis, bile leakage and peritonitis were not presented in any of the group. After 17–101 months follow‐up, three patients presented recurrent common bile duct stones.

Conclusion

In selected cases, T‐tube‐free trans‐umbilical SILCBDE plus LC is feasible and safe for experienced surgeons, and can achieve similar therapeutic effects as common LC plus common bile duct exploration procedures.
Dermal regeneration template and vacuum sealing drainage for treatment of traumatic degloving injuries of upper extremity in a single‐stage procedure
Authors: Lv Zhenmu , Yu Lili , Wang Qiusheng , Jia Rui , Ding Wenyuan , Shen Yong
Published: June 2019

Background

This study aimed to assess the efficacy and safety of a single‐stage procedure using single‐layer Pelnac and defatted avulsed skin for the management of degloving injuries of the forearm and hand.

Methods

This is a prospective study conducted from March 2013 to May 2017. A total of 15 consecutive patients with degloving injuries of the forearm and hand were treated with a single‐stage procedure using single‐layer Pelnac and defatted avulsed skin as a split‐thickness skin graft. Post‐operatively, scheduled follow‐up was conducted.

Results

The overall ‘take’ rate of the Pelnac dermal template and the skin graft was 85–100%. No infections, haematoma or seroma were observed during hospitalization and after discharge. At the final follow‐up, patients’ subjective satisfaction with the aesthetic appearance of the grafted areas was, on average, 71.0 (SD 8.0, range 55–92). The Vancouver Scar Scale value was 2.1 (SD 1.8, range 1.0–5.5), representing a good result. The response of ‘normal or near normal’ to the sensory recovery was obtained for 13 patients and ‘slight loss’ for two patients. The average Disabilities of the Arm, Shoulder and Hand score was 21.2 (SD 13.5, range 0–53), and most patients (14/15) regained the ability to perform the daily activities without pain or restriction by tissue adhesion.

Conclusion

This single‐stage procedure represents an effective technique for the management of degloving injuries of the forearm and hand and should be considered an alternative to other reconstructive procedures.
Development and validation of the Satisfaction with Treatment for Pain Questionnaire (STPQ) among patients with sickle cell disease
Authors: Elander James , Bij Deepali , Kapadi Romaana , Schofield Malcolm B. , Osias Arlene , Khalid Nosheen , Kaya Banu , Telfer Paul
Published: June 2019

A brief measure of patient satisfaction with treatment for pain is needed to help improve the treatment of painful episodes caused by sickle cell disease (SCD), especially during and after the transition from paediatric to adult care. Focus groups of 28 adolescent and adult patients were consulted about the content, clarity and relevance of 30 potential items, resulting in an 18‐item version. This was validated by analysing questionnaire responses from 120 patients aged 12–53 years. Confirmatory factor analysis and item analysis indicated five subscales with high internal reliability: ‘Communication and Involvement’ (6 items, α = 0·87); ‘Respect and Dignity’ (3 items, α = 0·82); ‘Pain Control’ (3 items, α = 0·91); ‘Staff Attitudes and Behaviour’ (4 items, α = 0·88); and ‘Overall Satisfaction’ (2 items, α = 0·85) plus a Total Satisfaction score (18 items, α = 0·96). High negative correlations with the Picker Patient Experience Questionnaire, a measure of problem experiences, indicated good convergent validity. Lower satisfaction scores among patients aged over 18 years, those admitted via the emergency department, those treated by non‐specialist hospital staff, and those reporting more breakthrough pain indicated good concurrent validity. The questionnaire provides a convenient brief measure that can be used to inform and evaluate improvements in healthcare for adolescent and adult patients with SCD, and could potentially be adapted for other painful conditions.
Distinct immunoglobulin heavy chain variable region gene repertoire and lower frequency of del(11q) in Taiwanese patients with chronic lymphocytic leukaemia
Authors: Huang Ying‐Jung , Kuo Ming‐Chung , Chang Hung , Wang Po‐Nan , Wu Jin‐Hou , Huang Yen‐Min , Ma Ming‐Chun , Tang Tzung‐Chih , Kuo Ching‐Yuan , Shih Lee‐Yung
Published: June 2019

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in Western countries but very rare in Asia. Peripheral blood or bone marrow mononuclear cells obtained at initial diagnosis from 194 patients with CLL were analysed to determine the ethnic difference in genetic abnormalities. Mutated IGHV was detected in 71·2% of Taiwanese CLL and IGHV3‐23 was the most frequently used gene. Stereotyped BCR was present in 18·3% with subset 8 being the most frequent. All cases with subset 8 belonged to IGHV 4‐39 and were exclusively associated with un‐mutated IGHV and poor outcome. Mutation frequencies of SF3B1 (9·7%), NOTCH1 (8·6%), BIRC3 (1·1%), ATM (16·9%) or TP53 (8·1%), and frequencies of cytogenetic abnormalities including trisomy 12 (18·6%), del(17p) (10·4%), del(13q) (43·7%) and IGH translocation (10·1%) were comparable to those reported from Western countries, except del(11q) (6·9%) which was lower in our patients. Patients with un‐mutated IGHV, subset 8, disrupted TP53, trisomy 12, and SF3B1 mutations had a worse outcome compared to patients without these mutations. In conclusion, IGHV3‐23 usage, stereotyped subset 8 and lower frequency of del(11q) show an ethnicity‐dependent association in Taiwanese CLL patients.
Two‐part implant abutments with titanium and ceramic components: Surface modification affects retention forces—An in‐vitro study
Authors: Freifrau von Maltzahn Nadine , Bernard Sebastian , Kohorst Philipp
Published: June 2019

Objectives

Two‐part abutments consist of titanium base and ceramic coping. Their long‐term success is largely determined by the mechanical stability. The aim of the present study was to investigate the retention forces of two‐part implant abutments. The study included zirconia and lithium disilicate ceramics copings, with different surface treatments and resin‐based luting agents.

Material and Methods

The analysis of retention forces was based on a total of 70 test specimens. Seven surface modifications and three resin‐based luting agents were employed for the bonding of components in the seven groups (n = 70). All surfaces of titanium bases—except for a control—were pretreated with aluminum oxide blasting, either alone or in combination with surface activating primers. Surfaces of ceramic copings were also treated mechanically by sandblasting, either alone or with acid etching or different primers. All specimens underwent thermal aging (104 cycles, 5°C/55°C). The retention forces between the two parts were measured with a pull‐off test. The results were analyzed by two‐way ANOVA statistics. Fracture patterns were evaluated by light and scanning electron microscopy.

Results

No mechanical pretreatment of the titanium (group 2) base resulted in the lowest retention. The combination with Monobond plus leads to the highest pull‐off forces for both ceramic materials.

Conclusions

Surface modifications and resin‐based agents influence the retention of components of two‐part abutments. Lithium disilicate ceramic copings reached comparable results of retention to the typically used zirconia copings.
The management of suspected or confirmed laryngopharyngeal reflux patients with recalcitrant symptoms: A contemporary review
Authors: Lechien Jerome R. , Muls Vinciane , Dapri Giovanni , Mouawad François , Eisendrath Pierre , Schindler Antonio , Nacci Andrea , Barillari Maria R. , Finck Camille , Saussez Sven , Akst Lee M. , Sataloff Robert T.
Published: June 2019

Objective

To summarise current knowledge about the prevalence, aetiology and management of recalcitrant laryngopharyngeal reflux (LPR) patients—those who do not respond to anti‐reflux medical treatment.

Methods

A literature search was conducted following the PRISMA guidelines to identify studies that reported success of anti‐reflux medical treatment with emphasis on studies that attempted to be rigorous in defining a population of LPR patients and which subsequently explored the characteristics of non‐responder patients (ie aetiology of resistance; differential diagnoses; management and treatment). Three investigators screened publications for eligibility from PubMED, Cochrane Library and Scopus and excluded studies based on predetermined criteria. Design, diagnostic method, exclusion criteria, treatment characteristics, follow‐up and quality of outcome assessment were evaluated.

Results

Of the 139 articles screened, 45 met the inclusion criteria. The definition of non‐responder patients varied substantially from one study to another and often did not include laryngopharyngeal signs. The reported success rate of conventional therapeutic trials ranged from 17% to 87% and depended on diagnostic criteria, treatment scheme, definition of treatment failure and treatment outcomes that varied substantially between studies. The management of non‐responders differed between studies with a few differential diagnoses reported. No study considered the profile of reflux (acidic, weakly acid, non‐acid or mixed) or addressed personalised treatment with the addition of alginate or magaldrate, low acid diet, or other interventions that have emerging evidence of efficacy.

Conclusion

To date, there is no standardised management of LPR patients who do not respond to traditional treatment approached. A diagnostic and therapeutic algorithm is proposed to improve the management of these patients. Future studies will be necessary to confirm the efficacy of this algorithm through large cohort studies of non‐responder LPR patients.

Level of evidence

2a.
Empty pelvis syndrome: the use of breast prosthesis in the prevention of complications
Authors: Carboni F. , Federici O. , Giofre’ M. , Zazza S. , Valle M.
Published: June 2019

Aim

Empty pelvis syndrome and radiation‐induced bowel injury are two major clinical issues resulting from the pelvic dead space after pelvic exenteration (PE). In order to avoid these complications, different methods of pelvic floor reconstruction have been proposed. We report our experience on the use of breast prosthesis.

Method

Fifty‐three patients who underwent PE and three who underwent palliative surgery with silicone breast prosthesis placement were included.

Results

Forty‐seven posterior PE, six total PE and three palliative procedures were identified. Sphincter preservation was feasible in 34 patients (62.3%). There were no deaths. Overall morbidity was 37.5%. There were no complications such as sepsis or obstruction related to the prosthesis. Adjuvant radiotherapy was delivered in 16 cases (30.1%) without any side‐effects. Reconstruction of intestinal continuity was possible in 12 patients (36.3%) with sphincter preservation and the prosthesis allowed a prompt identification of the rectal stump.

Conclusion

Breast prosthesis placement is a simple and safe method to minimize complications resulting from empty pelvis syndrome and can be adopted to exclude bowel loops from the radiation field. Reconstruction of intestinal continuity after resection is also simplified.
Prevention of parastomal hernia after abdominoperineal excision with a prophylactic three‐dimensional funnel mesh
Authors: López‐Borao J. , Madrazo‐González Z. , Kreisler E. , Biondo S.
Published: June 2019

Aim

A prophylactic three‐dimensional (3D) funnel mesh using the keyhole technique (intraperitoneal onlay mesh position) in abdominoperineal excision (APR) may significantly decrease the parastomal hernia (PSH) index without increasing morbidity. The aim of this retrospective observational study was to analyse the incidence of PSH and postoperative complications in patients who underwent permanent colostomy with the use of a prophylactic 3D preformed mesh compared with patients without a mesh.

Method

Patients who underwent an end‐colostomy after APR for primary or recurrent rectal cancer in a colorectal surgery unit were divided into two groups: group 1 without a prophylactic mesh and group 2 with a prophylactic synthetic mesh. The main end‐point was to analyse the incidence of PSH after a median follow‐up of 2.8 years.

Results

One hundred and ten patients (64 in group 1 and 46 in group 2, without significant clinical differences) underwent a permanent colostomy after APR. In group 1 70.3% developed a PSH, compared with 13% in group 2 (P < 0.001). Age (especially for patients ≥ 75 years) represented a significant risk factor for PSH. There were no differences in postoperative complications between the groups.

Conclusion

A prophylactic parastomal 3D mesh using the keyhole technique may reduce the incidence of PSH after permanent colostomy without an increase in postoperative complications.
Utility of arginine stimulation testing in preoperative assessment of children undergoing total pancreatectomy with islet autotransplantation
Authors: McEachron Kendall R. , Skube Mariya E. , Yang Yi , Hodges James S. , Wilhelm Joshua , Beilman Gregory , Chinnakotla Srinath , Schwarzenberg Sarah J. , Bellin Melena D.
Published: June 2019

Metabolic outcomes after total pancreatectomy with islet autotransplantation (TPIAT) are influenced by the islet mass transplanted. Preclinical and clinical studies indicate that insulin and C‐peptide levels measured after intravenous administration of the beta cell secretagogue arginine can be used to estimate the available islet mass. We sought to determine if preoperative arginine stimulation test (AST) results predicted transplanted islet mass and metabolic outcomes in pediatric patients undergoing TPIAT. We evaluated the association of preoperative C‐peptide and insulin responses to AST with islet isolation metrics using linear regression, and with postoperative insulin independence using logistic regression. Twenty‐six TPIAT patients underwent preoperative AST from 2015 to 2018. The acute C‐peptide response to arginine (ACRarg) was correlated with isolated islet equivalents (IEQ; r = 0.59, P = 0.002) and islet number (IPN; r = 0.48, P = 0.013). The acute insulin response to arginine (AIRarg) was not significantly correlated with IEQ (r = 0.38, P = 0.095) or IPN (r = 0.41, P = 0.071). Neither ACRarg nor AIRarg was associated with insulin use at 6 months postoperatively. Preoperative C‐peptide response to arginine correlates with islet mass available for transplant in pediatric TPIAT patients. AST represents an additional tool before autotransplant to provide counseling on likely islet mass and to inform quality improvements of islet isolation techniques.
Does ex vivo perfusion lead to more or less intimal thickening in the first‐year post–heart transplantation?
Authors: Sato Takuma , Azarbal Babak , Cheng Richard , Esmailian Fardad , Patel Jignesh , Kittleson Michelle , Czer Lawrence , Thottam Maria , Levine Ryan , Dimbil Sadia , Olymbios Michael , Anzai Toshihisa , Hamilton Michele A. , Khayal Tamer , Kobashigawa Jon A.
Published: June 2019

Background

The Organ Care System (OCS), an ex vivo heart perfusion platform, represents an alternative to the current standard of cold organ storage that sustains the donor heart in a near‐physiologic state. Previous reports showed that this system had significantly shortened the cold ischemic time from standard cold storage (CS). However, the effect of reduced ischemic injury against the coronary vascular bed has not been examined by intravascular ultrasound (IVUS).

Methods

Between August 2011 and February 2013, heart transplant (HTx) candidates enrolled in the PROCEED 2 trial were randomized to either CS or OCS. IVUS was performed at 4‐6 weeks (baseline) and repeated 1 year after transplantation. The change in maximal intimal thickness (MIT) and other clinical outcomes were examined.

Results

Thirty‐nine patients were randomized and underwent HTx by OCS (n=16) or CS (n=18). Of these, 18 patients (OCS: n=5, CS: n=13) with paired IVUS were examined. There were no significant differences in the change of MIT and other clinical outcomes between the groups.

Conclusion

The incidence of cardiac allograft vasculopathy in donor hearts preserved with the OCS versus CS was similar. These results suggest that this ex vivo allograft perfusion system is a promising and valid platform for donor heart transportation.
Long‐term impact of dialysis‐requiring AKI during the perioperative period of liver transplantation on postdischarge outcomes
Authors: Lee Soojin , Park Sehoon , Kang Min Woo , Yoo Hai‐Won , Han Kyungdo , Kim Yaerim , Lee Jung Pyo , Joo Kwon Wook , Lim Chun Soo , Kim Yon Su , Kim Hyeongsu , Kim Dong Ki
Published: June 2019

Background

Patients undergoing liver transplantation (LT) are prone to dialysis‐requiring acute kidney injury (AKI‐D). However, long‐term prognoses among them need further investigation, as overall survival after LT is improving.

Methods

A nationwide, population‐based cohort study was conducted using the data of Korean National Health Insurance System between 2006 and 2015. The patients who received dialysis during the perioperative period of LT were in the AKI‐D group, and the control group included those who did not undergo dialysis.

Results

Among the 6879 patients who underwent LT, 968 were in the AKI‐D group. All‐cause mortality [adjusted hazard ratio (HR): 1.52 (1.26‐1.83), P < 0.001], end‐stage renal disease (ESRD) progression [adjusted HR: 2.93 (2.34‐3.66), P < 0.001], and ICU readmission [adjusted HR: 1.70 (1.44‐2.01), P < 0.001] within and after 90 days from discharge were increased in the AKI‐D group. When analyzed among those who recovered from dialysis at discharge, overall outcomes were similar to those of the AKI‐D group, except the long‐term mortality.

Conclusions

AKI‐D during the perioperative period of LT was associated with worse mortality, ESRD progression, and ICU readmission risk. The results of renal‐recovered patients could indicate clinicians that achievement of dialysis independence is important to gain favorable long‐term postdischarge survival.
Post‐transplant lymphoproliferative disorders, Epstein‐Barr virus infection, and disease in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice
Authors: Allen Upton D. , Preiksaitis Jutta K. ,   the AST Infectious Diseases Community of Practice
Published: June 2019

These updated guidelines from the American Society of Transplantation Infectious Diseases Community of Practice review the diagnosis, management, and prevention of post‐transplant lymphoproliferative disorders (PTLD) and other Epstein‐Barr virus (EBV) syndromes after solid organ transplantation. PTLD are a heterogeneous spectrum of predominantly B‐cell disorders, often extra‐nodal, with complex distinct pathogeneses and variable clinical presentations determined by pathologic subtype. Recent epidemiologic studies report a decrease in early EBV‐positive (+) PTLD and an increase in late EBV‐negative (−) PTLD. Pre‐transplant EBV‐seronegativity and primary EBV infection, often from donor‐transmitted infection, are an important risk factors for EBV syndromes and early EBV + PTLD. Low‐quality evidence supports preemptive prevention strategies for early EBV + PTLD in EBV‐seronegative recipients that involve EBV DNA measurement in peripheral blood using assays requiring further result harmonization, combined with interventions to lower viral load. Reduction in immunosuppression (RIS) is the best validated intervention. WHO pathology classification of a tissue biopsy remains the gold standard for PTLD diagnosis; optimal staging procedures are uncertain. Treatment of CD20+ PTLD with the response‐dependent sequential use of RIS, rituximab, and cytotoxic chemotherapy is recommended. Evidence gaps requiring future research and alternate treatment strategies including immunotherapy are highlighted.
Cognitive decline in association with hyposmia in idiopathic rapid eye movement sleep behavior disorder: a prospective 2‐year follow‐up study
Authors: Shin C. , Lee J.‐Y. , Kim Y. K. , Nam H. , Yoon E. J. , Shin S. A. , Kim H.‐J. , Jeon B.
Published: June 2019

Background and purpose

The aim was to analyze the characteristics and progression of cognitive dysfunction in non‐demented idiopathic rapid eye movement sleep behavior disorder (iRBD) patients with baseline olfactory function.

Methods

From a prospective polysomnography‐confirmed iRBD cohort, 25 patients (16 patients in 2‐year follow‐up) and 13 normal controls were included. Initial and 2‐year follow‐up cognitive functions were analyzed with olfactory function and 18F‐fluorinated‐N‐3‐fluoropropyl‐2β‐carboxymethoxy‐3β‐(4‐iodophenyl)‐nortropane (18F‐FP‐CIT) uptake in deep nuclei initially.

Results

Idiopathic RBD patients had impaired attention, memory and executive function compared to controls. Baseline cognitive tests were comparable between the iRBD subgroups with and without hyposmia. 18F‐FP‐CIT uptake tended to be lower in the hyposmic group than in the normosmic group. The olfactory test score was positively correlated with amygdala uptake in iRBD patients (P = 0.027). After 2 years, visuospatial and verbal memory dysfunction worsened more in hyposmics than in normosmics. Lower initial olfactory test score was associated with more severe declines in verbal memory function.

Conclusions

Hyposmia may be a predictive sign of cognitive decline in iRBD patients.
Cash holdings in family firms: CEO identity and implications for firm value
Authors: Caprio Lorenzo , Del Giudice Alfonso , Signori Andrea
Published: June 2019

We investigate the cash holdings policy of family firms and examine potential value implications. Family firms hold more cash than other firms, with an average difference of 2.3% of total assets. This result is driven by firms managed by heir CEOs. While the cash holdings policy of first‐generation family firms is more sensitive to firm risk, consistent with founders’ increased risk aversion, that of later‐generation firms is more sensitive to information asymmetry and agency conflicts. Heir CEOs’ cash policies destroy value, as the marginal value of an additional Euro suffers from a 38.3‐cent discount, on average, relative to non‐family firms.
A 10‐year study of arthroscopic surgery in racing Thoroughbreds and Quarter Horses with osteochondral fragmentation of the carpus
Authors: Graham R. J. T. Y. , Rosanowski S. M. , McILWRAITH C. W.
Published: June 2019

Background

Osteochondral fragmentation of the carpus is a common cause of lameness in racehorses. Prognosis following arthroscopic removal of the fragments was reported in 1987, but little is known of recent success rates.

Objective

To identify associations between the severity and location of osteochondral fragments in the carpus, and to describe the racing performance of horses pre‐ and post‐surgery in Thoroughbreds and Quarter Horses. To identify factors associated with a horse racing post‐surgery.

Study design

Retrospective study of clinical records (2006–2016).

Methods

Surgical and racing records for racehorses undergoing arthroscopic surgery of the carpus were collated during the 10‐year study period. Signalment, location of osteochondral fragmentation and grade of defect left after removal and debridement identified and racing performance pre‐ and post‐surgery were described, stratified by breed. Logistic regression analysis was used to identify factors associated with unsuccessful return to racing.

Results

In total, 828 horses (n = 416 Quarter Horses; n = 412 Thoroughbreds) underwent 880 carpal arthroscopies after fragments were found on radiography. Sixty‐five percent (n = 289) and 27% (n = 118) of the lesions were bilateral in Quarter Horses and Thoroughbreds respectively (P<0.001). In both breeds, the most commonly affected bone was the dorsodistal radial carpal bone (n = 320/659; 48.6%). Overall, 82% (n = 686; n = 358 Quarter Horses, n = 328 Thoroughbreds) of horses raced post‐surgery, with 69.5% (n = 476; n = 228 Quarter Horses, n = 248 Thoroughbreds) racing at the same or a higher level of competition. Factors associated with horses not returning to racing post‐surgery were increasing horse age, female horses, and a lesion grade of 4, while racing pre‐surgery was protective.

Main limitations

This study does not include a control population for comparison.

Conclusions

There were significant differences between the location and severity of lesions in Quarter Horses, when compared to Thoroughbreds. The majority of horses return to racing following surgery, although performance was influenced by lesion severity.

The Summary is available in Portuguese ‐ see Supporting information
Adrenoceptor‐related decrease in serum triglycerides is independent of PPARα activation
Authors: Konstandi Maria , Kypreos Kyriakos E. , Matsubara Tsutomu , Xepapadaki Eva , Shah Yatrik M. , Krausz Kristopher , Andriopoulou Christina E. , Kofinas Aristeidis , Gonzalez Frank J.
Published: June 2019

Adrenoceptor (AR)‐linked pathways belong to the major components of the stress response system and are associated with the pathophysiology of diseases within the spectrum of metabolic syndrome. In this study, the role of adrenoceptor stimulation in serum triglyceride (TG) regulation in mice was investigated. For this purpose, α1‐ARs were activated with phenylephrine (PH) and β1/2‐ARs with isoprenaline (ISOP). Both AR agonists markedly reduced serum TG levels independently of PPARα activation. These drugs also significantly activated the hormone‐sensitive lipase in the white adipose tissue indicating increased mobilization of TGs in this tissue. In addition, PH and ISOP up‐regulated Lpl, Nr4A, Dgat1, Mttp, Aadac and Cd36 genes, critical in TG regulation, whereas the observed decrease in serum TG levels was independent of the hepatic very low‐density lipoprotein (VLDL)‐TG secretion. Interestingly, PH and ISOP also inactivated the hepatic insulin/PI3k/AKT/FoxO1 signaling pathway, holding a critical role in the regulation of genes involved in TG synthesis. Taken together, the findings of the present study indicate that stimulation of α1‐ and β1/2‐ARs markedly reduced serum TG steady‐state levels as a result of alterations in TG synthesis, uptake, transport, hydrolysis, metabolism and clearance, an effect induced by PPARα independent mechanisms.
Proteoglycans and glycosaminoglycans as regulators of cancer stem cell function and therapeutic resistance
Authors: Vitale Daiana , Kumar Katakam Sampath , Greve Burkhard , Jang Bohee , Oh Eok‐Soo , Alaniz Laura , Götte Martin
Published: June 2019

In contrast to the bulk of the tumor, a subset of cancer cells called cancer stem cells (CSC; or tumor‐initiating cells) is characterized by self‐renewal, unlimited proliferative potential, expression of multidrug resistance proteins, active DNA repair capacity, apoptosis resistance, and a considerable developmental plasticity. Due to these properties, CSCs display increased resistance to chemo‐ and radiotherapy. Recent findings indicate that aberrant functions of proteoglycans (PGs) and glycosaminoglycans (GAGs) contribute substantially to the CSC phenotype and therapeutic resistance. In this review, we summarize how the diverse functions of the glycoproteins and carbohydrates facilitate acquisition and maintenance of the CSC phenotype, and how this knowledge can be exploited to develop novel anticancer therapies. For example, the large transmembrane chondroitin sulfate PG NG2/CSPG4 marks stem cell (SC) populations in brain tumors. Cell surface heparan sulfate PGs of the syndecan and glypican families modulate the stemness‐associated Wnt, hedgehog, and notch signaling pathways, whereas the interplay of hyaluronan in the SC niche with CSC CD44 determines the maintenance of stemness and promotes therapeutic resistance. A better understanding of the molecular mechanisms by which PGs and GAGs regulate CSC function will aid the development of targeted therapeutic approaches which could avoid relapse after an otherwise successful conventional therapy. Chimeric antigen receptor T cells, PG‐primed dendritic cells, PG‐targeted antibody–drug conjugates, and inhibitory peptides and glycans have already shown highly promising results in preclinical models.
Diminished inhibition and facilitated activation of RyR2‐mediated Ca2+ release is a common defect of arrhythmogenic calmodulin mutations
Authors: Søndergaard Mads T. , Liu Yingjie , Brohus Malene , Guo Wenting , Nani Alma , Carvajal Catherine , Fill Michael , Overgaard Michael T. , Chen S. R. Wayne
Published: June 2019

A number of calmodulin (CaM) mutations cause severe cardiac arrhythmias, but their arrhythmogenic mechanisms are unclear. While some of the arrhythmogenic CaM mutations have been shown to impair CaM‐dependent inhibition of intracellular Ca2+ release through the ryanodine receptor type 2 (RyR2), the impact of a majority of these mutations on RyR2 function is unknown. Here, we investigated the effect of 14 arrhythmogenic CaM mutations on the CaM‐dependent RyR2 inhibition. We found that all the arrhythmogenic CaM mutations tested diminished CaM‐dependent inhibition of RyR2‐mediated Ca2+ release and increased store‐overload induced Ca2+ release (SOICR) in HEK293 cells. Moreover, all the arrhythmogenic CaM mutations tested either failed to inhibit or even promoted RyR2‐mediated Ca2+ release in permeabilized HEK293 cells with elevated cytosolic Ca2+, which was markedly different from the inhibitory action of CaM wild‐type. The CaM mutations also altered the Ca2+‐dependency of CaM binding to the RyR2 CaM‐binding domain. These results demonstrate that diminished inhibition, and even facilitated activation, of RyR2–mediated Ca2+ release is a common defect of arrhythmogenic CaM mutations.
Apoptotic cell death regulation in neurons
Authors: Hollville Emilie , Romero Selena E. , Deshmukh Mohanish
Published: June 2019

Apoptosis plays a major role in shaping the developing nervous system during embryogenesis as neuronal precursors differentiate to become post‐mitotic neurons. However, once neurons are incorporated into functional circuits and become mature, they greatly restrict their capacity to die via apoptosis, thus allowing the mature nervous system to persist in a healthy and functional state throughout life. This robust restriction of the apoptotic pathway during neuronal differentiation and maturation is defined by multiple unique mechanisms that function to more precisely control and restrict the intrinsic apoptotic pathway. However, while these mechanisms are necessary for neuronal survival, mature neurons are still capable of activating the apoptotic pathway in certain pathological contexts. In this review, we highlight key mechanisms governing the survival of post‐mitotic neurons, while also detailing the physiological and pathological contexts in which neurons are capable of overcoming this high apoptotic threshold.
Crystal structure of CagV, the Helicobacter pylori homologue of the T4SS protein VirB8
Authors: Wu Xiuling , Zhao Yanhe , Sun Lifang , Jiang Meiqin , Wang Qin , Wang QianChao , Yang Wendi , Wu Yunkun
Published: June 2019

The VirB/D type IV secretion system (T4SS) plays an essential role in materials transport between host cells and pathogenic Helicobacter pylori and is considered the major pathogenic mediator of H. pylori‐associated gastric disease. VirB8, an inner membrane protein that interacts with many other proteins, is a crucial component for secretory function. Here, we present a crystal structure of the periplasmic domain of CagV, the VirB8 counterpart in the H. pylori Cag‐T4SS. The structure reveals a fold similar to that of other VirB8 members except for the absence of the α5 helix, a discontinuous β1 strand, a larger angle between the α2 and α3 helices, a more hydrophobic surface groove, but exhibits a different dimer interface. Whether the dimerization occurs in solution was proved by mutagenesis, size‐exclusion chromatography and cross‐linking assays. Unlike the classical dimerization mode, the interface of the CagV dimer is principally formed by several hydrogen bonds, which indicates instability of dimerization. The structure here demonstrates the difference in dimerization among VirB8 homologues and indicates the considerable compositional and functional diversity of them in T4SS.

Database

Coordinates and structure factors have been deposited in the Protein Data Bank under accession codes 6IQT.
Impaired calcium homeostasis via advanced glycation end products promotes apoptosis through endoplasmic reticulum stress in human nucleus pulposus cells and exacerbates intervertebral disc degeneration in rats
Authors: Luo Rongjin , Song Yu , Liao Zhiwei , Yin Huipeng , Zhan Shengfeng , Wang Kun , Li Shuai , Li Gaocai , Ma Liang , Lu Saideng , Zhang Yukun , Yang Cao
Published: June 2019

Previous studies identified advanced glycation end products (AGEs) accumulation in the intervertebral disc (IVD) as an essential risk factor associated with IVD degeneration via accelerated cell apoptosis and impeded extracellular‐matrix metabolism; however, the underlying mechanisms have not been fully elucidated. Here, we investigated the effects and mechanisms of AGEs‐mediated apoptosis in vitro and in vivo. We evaluated the effects of AGEs on endoplasmic reticulum (ER) stress, apoptosis, and subcellular calcium (Ca2+) redistribution. Our data indicated time‐ and concentration‐dependent upregulation of ER‐stress responses in AGEs‐treated nucleus pulposus (NP) cells. Additionally, we observed marked suppression of AGEs‐mediated apoptosis following the inhibition of ER stress using 4‐phenylbutyric acid. Moreover, AGEs‐induced sustained cytosolic Ca2+ ([Ca2+]c) elevation and ER luminal Ca2+ ([Ca2+]er) depletion in a concentration‐ and time‐dependent manner in NP cells. Furthermore, we observed significant increases and decreases in levels of the ER‐resident Ca2+‐release channels inositol 1,4,5‐triphosphate receptor and ryanodine receptor and ER Ca2+‐reuptake pumps sarco/endoplasmic reticulum Ca2+‐ATPase, respectively. Pharmacologically blocking ER Ca2+ release using Ca2+ antagonists significantly ameliorated Ca2+ dyshomeostasis, ER stress, and subsequent apoptosis in NP cells and partially attenuated the progression of IVD degeneration in vivo. These results demonstrated that impaired Ca2+ homeostasis plays an essential role in AGEs‐mediated ER stress and subsequent apoptosis in NP cells, with blockage of ER Ca2+ release partially ameliorating subcellular Ca2+ redistribution, ER stress, and apoptosis. Our findings provide novel mechanistic insight into the role of AGEs in the pathogenesis of IVD degeneration and a potential therapeutic strategy.
Mutational profiling of poorly differentiated and anaplastic thyroid carcinoma by the use of targeted next‐generation sequencing
Authors: Duan Huanli , Li Yan , Hu Peizhen , Gao Jie , Ying Jianming , Xu Wanni , Zhao Danhui , Wang Zhe , Ye Junyi , Lizaso Analyn , He Yangzhige , Wu Huanwen , Liang Zhiyong
Published: June 2019

Aims

To characterise the mutational profiles of poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) and to identify markers with potential diagnostic, prognostic and therapeutic significance.

Methods and results

Targeted next‐generation sequencing with a panel of 18 thyroid carcinoma‐related genes was performed on tissue samples from 41 PDTC and 25 ATC patients. Genetic alterations and their correlations with clinicopathological factors, including survival outcomes, were also analysed. Our results showed that ATC had significantly higher mutation rates of BRAF, TP53, TERT and PIK3CA than PDTC (P = 0.005, P = 0.007, P = 0.005, and P = 0.033, respectively). Nine (69%) ATC cases with papillary thyroid carcinoma (PTC) components harboured BRAF mutations, all of which coexisted with a late mutation event (TP53, TERT, or PIK3CA). Nine cases with oncogenic fusion (six RET cases, one NTRK1 case, one ALK case, and one PPARG case) were identified in 41 PDTCs, whereas only one case with oncogenic fusion (NTRK1) was found among 25 ATCs. Moreover, all six cases of RET fusion were found in PDTC with PTC components, accounting for 33%. In PDTC/ATC patients, concurrent TERT and PIK3CA mutations were associated with poor overall survival after adjustment for TNM stage (P = 0.001).

Conclusions

ATC with PTC components is typically characterised by a BRAF mutation with a late mutation event, whereas PDTC with PTC components is more closely correlated with RET fusion. TERT and concurrent PIK3CA mutations predict worse overall survival in PDTC/ATC patients.
Topical monomethylsilanetriol can deliver silicon to the viable skin
Authors: Polonini H. C. , Ferreira A. O. , Brandão M. A. F. , Raposo N. R. B.
Published: June 2019

Objective

Organic silicon has been linked to positive effects on the skin rejuvenation, mainly by the oral route. Thus, the main objective of the present study was to assess whether monomethylsilanetriol (MMST, a source of organic silicon) can deliver silicon to the epidermis and dermis, when applied topically in a cream. Once the hypothesis was confirmed, the present study also evaluated whether the product was toxic to keratinocytes; additionally, its possible antioxidant activity was assessed.

Methods

The ex vivo skin permeation profile was determined using human skin in Franz‐cells equipment; cytotoxicity was assessed using HaCaT keratinocytes. Antioxidant capacity was determined as scavenging activity, measured according to the 1,1‐diphenyl‐2‐picrylhydrazil free radical method.

Results

The permeation percentage was almost 60% of the applied MMST, with a large quantity of drug found in the viable epidermis and dermis. The cell viability assay showed no significant difference in the percentage of viable keratinocytes among the treated groups at the doses used. In terms of antioxidant activity, the IC50 value obtained was 2400 μg mL−1. Low antioxidant activity, negligible toxicity for keratinocytes and a significant percentage of permeation were observed.

Conclusion

We provide evidence that MMST applied topically can deliver silicon to the skin in biorelevant levels for cosmetic purposes.
Spatially varying relationships between municipal operating expenditure and its determinants: The case of South Africa
Authors: Mulamba Kabeya C. , Tregenna Fiona
Published: June 2019

We apply the geographically weighted regression to investigate spatial variability (nonstationarity) in the relationships between municipal operating expenditure (in total and for a separate component thereof) and the determinants of this expenditure, in South Africa. The empirical findings indicate that some of these relationships are spatially varying for the period under consideration. The global model (i.e., least square regression) cannot take account of the unequal environment in which South African municipalities operate. One implication of our findings is that a “one‐size‐fits‐all” approach in the design of policies targeting municipal finances may not be appropriate for municipalities in South Africa, and indeed in other contexts in which such heterogeneity is found. Instead, policy formulation should explicitly consider relevant differences in local conditions.
Carbon monoxide‐releasing molecule‐3 (CORM‐3) offers protection in an in vitro model of compartment syndrome
Authors: Bihari Aurelia , Chung Kyukwang (Akira) , Cepinskas Gediminas , Sanders David , Schemitsch Emil , Lawendy Abdel‐Rahman
Published: June 2019

Objective

Limb compartment syndrome (CS), a complication of trauma, results in muscle necrosis and cell death; ischemia and inflammation contribute to microvascular dysfunction and parenchymal injury. Carbon monoxide‐releasing molecule‐3 (CORM‐3) has been shown to protect microvascular perfusion and reduce inflammation in animal models of CS. The purpose of the study was to test the effect of CORM‐3 in human in vitro CS model, allowing exploration of the mechanism(s) of CO protection and potential development of pharmacologic treatment.

Methods

Confluent human vascular endothelial cells (HUVECs) were stimulated for 6 h with serum isolated from patients with CS. Intracellular oxidative stress (production of reactive oxygen species (ROS)) apoptosis, transendothelial resistance (TEER), polymorphonuclear leukocyte (PMN) activation and transmigration across the monolayer in response to the CS stimulus were assessed. All experiments were performed in the presence of CORM‐3 (100 μM) or its inactive form, iCORM‐3.

Results

CS serum induced a significant increase in ROS, apoptosis and endothelial monolayer breakdown; it also increased PMN superoxide production, leukocyte rolling and adhesion/transmigration. CORM‐3 completely prevented CS‐induced ROS production, apoptosis, PMN adhesion, rolling and transmigration, while improving monolayer integrity.

Conclusion

CORM‐3 offers potent anti‐oxidant and anti‐inflammatory effects, and may have a potential application to patients at risk of developing CS.
YY males of the dioecious plant Mercurialis annua are fully viable but produce largely infertile pollen
Authors: Li Xinji , Veltsos Paris , Cossard Guillaume G. , Gerchen Jörn , Pannell John R.
Published: June 2019

The suppression of recombination during sex‐chromosome evolution is thought to be favoured by linkage between the sex‐determining locus and sexually antagonistic loci, and leads to the degeneration of the chromosome restricted to the heterogametic sex. Despite substantial evidence for genetic degeneration at the sequence level, the phenotypic effects of the earliest stages of sex‐chromosome evolution are poorly known.

Here, we compare the morphology, viability and fertility between XY and YY individuals produced by crossing seed‐producing males in the dioecious plant Mercurialis annua, which has young sex chromosomes with limited X−Y sequence divergence.

We found no significant difference in viability or vegetative morphology between XY and YY males. However, electron microscopy revealed clear differences in pollen anatomy, and YY males were significantly poorer sires in competition with their XY counterparts. Our study suggests either that the X chromosome is required for full male fertility in M. annua, or that male fertility is sensitive to the dosage of relevant Y‐linked genes.

We discuss the possibility that the maintenance of male‐fertility genes on the X chromosome might have been favoured in recent population expansions that selected for the ability of females to produce pollen in the absence of males.
At the intersection of exocytosis and endocytosis in plants
Authors: Zhang Liang , Xing Jingjing , Lin Jinxing
Published: June 2019

Vesicle exocytosis and endocytosis control the activities and turnover of plasma membrane proteins required for signaling triggering or attenuating at the cell surface. In recent years, the diverse exocytic and endocytic trafficking pathways have been uncovered in plants. The balance between conventional and unconventional protein secretion provides an efficient strategy to respond to stress conditions. Similarly, clathrin‐dependent and ‐independent endocytosis cooperatively regulate the dynamics of membrane proteins in response to environmental cues. In fact, many aspects of plant growth and development, such as tip growth, immune response, and protein polarity establishment, involve the tight deployment of exo–endocytic trafficking. However, our understanding of their intersection is limited. Here, we discuss recent advances in the molecular factors coupling plant exo–endocytic trafficking and the biological significance of balance between exocytosis and endocytosis in plants.
Role of cis‐zeatin in root responses to phosphate starvation
Authors: Silva‐Navas Javier , Conesa Carlos M. , Saez Angela , Navarro‐Neila Sara , Garcia‐Mina Jose M. , Zamarreño Angel M. , Baigorri Roberto , Swarup Ranjan , del Pozo Juan C.
Published: June 2019

Phosphate (Pi) is an essential nutrient for all organisms. Roots are underground organs, but the majority of the root biology studies have been done on root systems growing in the presence of light.

Root illumination alters the Pi starvation response (PSR) at different intensities. Thus, we have analyzed morphological, transcriptional and physiological responses to Pi starvation in dark‐grown roots.

We have identified new genes and pathways regulated by Pi starvation that were not described previously. We also show that Pi‐starved plants increase the cis‐zeatin (cZ) : trans‐zeatin (tZ) ratio. Transcriptomic analyses show thattZpreferentially represses cell cycle andPSRgenes, whereascZinduces genes involved in cell and root hair elongation and differentiation. In fact,cZ‐treated seedlings show longer root system as well as longer root hairs compared withtZ‐treated seedlings, increasing the total absorbing surface. Mutants with lowcZconcentrations do not allocate free Pi in roots during Pi starvation.

We propose that Pi‐starved plants increase thecZ : tZratio to maintain basal cytokinin responses and allocate Pi in the root system to sustain its growth. Therefore,cZacts as a PSR hormone that stimulates root and root hair elongation to enlarge the root absorbing surface and to increase Pi concentrations in roots.
Skin‐resident memory T cells as a potential new therapeutic target in vitiligo and melanoma
Authors: Willemsen Marcella , Linkutė Rugile , Luiten Rosalie M. , Matos Tiago R.
Published: June 2019

Tissue‐resident memory T (TRM) cells are abundant in the memory T cell pool and remain resident in peripheral tissues, such as the skin, where they act as alarm sensors or cytotoxic killers. TRM cells persist long after the pathogen is eliminated and can respond rapidly upon reinfection with the same antigen. When aberrantly activated, skin‐located TRM cells have a profound role in various skin disorders, including vitiligo and melanoma. Autoreactive TRM cells are present in human lesional vitiligo skin and mouse models of vitiligo, which suggests that targeting these cells could be effective as a durable treatment strategy for vitiligo. Furthermore, emerging evidence indicates that induction of melanoma‐reactive TRM cells is needed to achieve effective protection against tumor growth. This review highlights seminal reports about skin‐resident T cells, focusing mainly on their role in the context of vitiligo and melanoma, as well as their potential as therapeutic targets in both diseases.