Cocaine and Marijuana Use Among Young Adults With Myocardial Infarction

Background

Substance abuse is increasingly prevalent among young adults, but data on cardiovascular outcomes remain limited.

Sensitization of Pancreatic Cancers to Gemcitabine Chemoradiation by WEE1 Kinase Inhibition Depends on Homologous Recombination Repair

To improve the efficacy of chemoradiation therapy for locally advanced pancreatic cancer and begin to establish patient selection criteria, we investigated the combination of the WEE1 inhibitor AZD1775 with gemcitabine-radiation in homologous recombination (HR) repair proficient and deficient pancreatic cancers. Sensitization to gemcitabine-radiation by AZD1775 was assessed in pancreatic cancer cells by clonogenic survival and in patient-derived xenografts by tumor growth. The contributions of HR repair inhibition and G2 checkpoint abrogation to sensitization were assessed by γH2AX, BRCA2 manipulation, and RAD51 focus formation and pHistone H3 flow cytometry, respectively. We found that AZD1775 sensitized to gemcitabine-radiation in BRCA2 wild-type but not BRCA2 mutant pancreatic cancer cells. In all cells, AZD1775 caused inhibition of CDK1 phosphorylation and G2 checkpoint abrogation. However, sensitization by AZD1775 was associated with persistent γH2AX and inhibition of RAD51 focus formation. In HR-proficient (BRCA2 wild-type) or -deficient (BRAC2 null) isogenic cells, AZD1775 sensitized to gemcitabine-radiation in BRCA2 wild-type, but not in BRCA2 null cells, despite significant G2 checkpoint abrogation. In patient-derived pancreatic tumor xenografts, AZD1775 significantly inhibited tumor growth and impaired RAD51 focus formation in response to gemcitabine-radiation. In conclusion, WEE1 inhibition by AZD1775 is an effective strategy for sensitizing pancreatic cancers to gemcitabine chemoradiation. Although this sensitization is accompanied by inhibition of CDK1 phosphorylation and G2 checkpoint abrogation, this mechanism is not sufficient for sensitization. Our findings demonstrate that sensitization to chemoradiation by WEE1 inhibition results from inhibition of HR repair and suggest that patient tumors without underlying HR defects would benefit most from this therapy.Abbreviations: DSB, double-strand break; HR, homologous recombination; RER, radiation enhancement ratio; RT, radiation     

Paving the way towards green catalytic materials for green fuels: impact of chemical species on Mo-based catalysts for hydrodeoxygenation

A series of Mo-based catalysts were synthesized by tuning the sulfidation temperature to produce mixtures of MoO₃ and MoS₂ as active phases for the hydrodeoxygenation (HDO) of palmitic acid. Differences in the oxidation states of Mo, and the chemical species present in the catalytic materials were determined by spectroscopic techniques. Palmitic acid was used as a fatty-acid model compound to test the performance of these catalysts. The catalytic performance was related to different chemical species formed within the materials. Sulfidation of these otherwise inactive catalysts significantly increased their performance. The catalytic activity remains optimal between the sulfidation temperatures of 100 °C and 200 °C, whereas the most active catalyst was obtained at 200 °C. The catalytic performance decreased significantly at 400 °C due to a higher proportion of sulfides formed in the materials. Furthermore, the relative proportion of MoO₃ to MoS₂ is essential to form highly active materials to produce O-free hydrocarbons from biomass feedstock. The transition from MoS₂ to MoO₃ reveals the importance of Mo–S and Mo–O catalytically active species needed for the HDO process and hence for biomass transformation. We conclude that transitioning from MoS₂ to MoO₃ catalysts is a step in the right direction to produce green fuels.

A series of Mo-based catalysts were synthesized by tuning the sulfidation temperature to produce mixtures of MoO₃ and MoS₂ as active phases for the hydrodeoxygenation (HDO) of palmitic acid.     

Use of the levonorgestrel-releasing intrauterine system in renal transplant recipients: a retrospective case review

Our objective was to report on the use of the levonorgestrel-releasing intrauterine system (LNG-IUS, Mirena®) in renal transplant recipients.A retrospective case review was done to identify renal transplant recipients for whom a LNG-IUS had been inserted. All of the women had been seen in the Gynecology Department, Beaumont Hospital, during the period 2000 to 2010. Parameters including age, year of transplantation, indication for insertion, duration of use, discontinuation and complications were documented.The main outcome measure was discontinuation of the LNG-IUS due to pelvic infection.Eleven women were identified who had undergone renal transplantation and were using the LNG-IUS. The mean duration of use was 38 (range 1–84) months. Four women were using the LNG-IUS for contraception and seven were using it for the treatment of menorrhagia, either alone or in conjunction with endometrial ablative procedures. One woman discontinued use in order to conceive. There were no unplanned pregnancies. There were no documented cases of pelvic infection in women using the device.Renal transplant recipients have a critical need for safe and effective contraception. The use of the LNG-IUS has been avoided in the patients due to the theoretical risk of intrauterine device-related pelvic infection in immune-suppressed patients. However, on the basis of our results, we believe that it is acceptable to use the LNG-IUS in renal transplant recipients for both contraception and for the treatment of menorrhagia as the theoretical risk of infection in these immune-suppressed patients does not appear to be increased.     

Serine residues 338 and 339 in the carboxyl-terminal tail of the type II gonadotropin-releasing hormone receptor are critical for beta-arrestin-independent internalization

Cloned mammalian type II GnRH receptors have a carboxyl-terminal tail in contrast to the mammalian type I GnRH receptors, which uniquely lack a carboxyl-terminal tail. Because this domain mediates internalization of many serpentine receptors, the internalization pathway of the marmoset monkey type II GnRH receptor and the functional role of the carboxyl-terminal tail in internalization was studied. The internalization pathway of the type II GnRH receptor was investigated in COS-1 cells by coexpressing G protein-coupled receptor kinases (GRKs), dynamin-1, and beta-arrestins. Internalization of the receptor requires GRKs and dynamin but does not require beta-arrestin. The type II GnRH receptor can also internalize via beta-arrestin in the presence of exogenous beta-arrestins, suggesting that the receptor can use two distinct internalization pathways. Receptor internalization appears to occur via clathrin-coated pits and caveolae because disruption of either structure inhibits internalization. Progressive truncations of the carboxyl-terminal tail identified a region containing serine residues 338 and 339 as critical for receptor internalization. Substitution of these serine residues with alanine residues inhibited internalization, whereas substitutions with glutamic acid residues rescued internalization. Furthermore, a dominant-negative GRK2 did not inhibit internalization of receptors having these serine substitutions, although it inhibited internalization of the wild-type receptor. These results together identify serine residues 338 and 339 in the carboxyl-terminal tail as critical for internalization of the type II GnRH receptor and suggest that these residues undergo phosphorylation by GRKs. However, neither of these residues, nor the carboxyl-terminal tail, is required for beta-arrestin-dependent internalization.     

Acute Effects of Multisite Left Ventricular Pacing on Mechanical Dyssynchrony in Patients Receiving Cardiac Resynchronization Therapy

BackgroundA novel quadripolar left ventricular (LV) pacing lead has the ability to deliver multisite LV pacing (MSLV). We set out to characterize the safety and changes in acute mechanical dyssynchrony with MSLV in cardiac resynchronization therapy (CRT) patients.Methods and ResultsProspective multicenter study in 52 patients receiving CRT. An acute pacing protocol comprising 8 MSLV configurations covering a range of delays was compared with conventional CRT (baseline). Transthoracic tissue Doppler imaging (TDI) was used to measure the standard deviation of time to peak contraction of 12 LV segments (Ts-SD) and delayed longitudinal contraction. No ventricular arrhythmia occurred in any of the 52 patients. Complete TDI datasets were collected in 41 patients. Compared with baseline: 1) The mean Ts-SD was significantly lower for the optimal MSLV configuration (35.3 ± 36.4 vs 50.2 ± 29.1 ms; P < .001); 2) at least 1 MSLV configuration exhibited a significant dyssynchrony improvement in 63% of patients; and 3) the mean number of LV segments with delayed longitudinal contractions was significantly reduced with the optimal MSLV configuration (0.37 ± 7.99 vs 2.20 ± 0.19; P < .001).ConclusionsAcute MSLV was acutely safe, and a proportion of MSLV vectors resulted in a significant reduction in echocardiographic dyssynchrony compared with conventional CRT.     

Effect of maxillary and mandibular extrusion arches on dentoskeletal changes in adults with anterior open bite: a quantitative analysis

ObjectiveTo quantify dentoskeletal changes accompanying the use of extrusion arches during the treatment of anterior open bite (AOB) in adults.Materials and MethodsA total of 23 adult patients with an AOB of −3.05 mm ± 1.27 mm were treated with upper and lower extrusion arches after the alignment phase. Lateral cephalograms were taken before placement of the extrusion arch, immediately after closure of the open bite (T2), and at the end of orthodontic treatment (T3). Data were statistically analyzed using repeated-measures analysis of variance and the Bonferroni post hoc test for pairwise comparisons (α = 0.05).ResultsSuccessful closure of AOB, with an overall change in overbite of 4.73 ± 1.93 mm, was achieved in an average of 3.8 months and remained stable at T3. Upper and lower incisors were significantly extruded by 2.05 mm ± 0.72 mm and 2.54 mm ± 1.63 mm, respectively, and significantly retroclined by 6.36° ± 1.63° and 8.45° ± 3.83°, respectively, with a resultant increase in the interincisal angle of 12.80° ± 2.09°. Statistically significant intrusion and mesial tipping (P < .001) of the maxillary and mandibular first molars were observed at T2. Dentoskeletal changes remained stable at T3, except for a significant reduction of the mesial tipping of the maxillary and mandibular first molars.ConclusionsThe combined use of maxillary and mandibular extrusion arches resulted in significant favorable dentoskeletal changes that led to the successful closure of AOB during a short duration of treatment.     

10-Year Experience with the Modified Pectoralis Major Flap: The Use of the Deltopectoral Flap to Reduce Skin Tension

Purpose: Pectoralis major myocutaneous flap has been the work horse flap for head and neck reconstruction. However, due to the bulky nature of the pedicle it is not uncommon to struggle to achieve tension free closure of the neck skin incision. This case series presents a modified pectoralis major flap technique to overcome the difficulty of tight closure or the need to graft the residual cutaneous defect. Method: This 10-year study includes 73 patients who underwent modified pectoralis major flap reconstruction for complex laryngo-pharyngeal defects following resection of tumours involving larynx, hypopharynx oropharynx and cervical oesophagus. The modified technique involves accommodating a deltopectoral fasciocutaneous flap which rotates over the pedicle to insert into the neck incision providing extra tissue to achieve a tension free closure. Results: 73 patients underwent the procedure, 80% were male. Mean age of patients was 62.8years. Larynx was the most common site and the average size of the tumour was 34.8 mm. 13 patients developed minor complications such as wound dehiscence out of which 10 were managed conservatively, 3 patients required additional reconstructive procedures. 13 patients developed pharyngocutaneous fistula and 6 developed Neopharyngeal stenosis. 51 patients achieved good swallowing and 55 developed intelligible speech following recovery. Conclusion: We recommend the use of this technique as an effective method to achieve tension free neck incision closure and improved cosmetic results especially in centres which do not have free flap facility readily available.