DFTB+, a software package for efficient approximate density functional theory based atomistic simulations.

DFTB+ is a versatile community developed open source software package offering fast and efficient methods for carrying out atomistic quantum mechanical simulations. By implementing various methods approximating density functional theory (DFT), such as the density functional based tight binding (DFTB) and the extended tight binding method, it enables simulations of large systems and long timescales with reasonable accuracy while being considerably faster for typical simulations than the respective ab initio methods. Based on the DFTB framework, it additionally offers approximated versions of various DFT extensions including hybrid functionals, time dependent formalism for treating excited systems, electron transport using non-equilibrium Green's functions, and many more. DFTB+ can be used as a user-friendly standalone application in addition to being embedded into other software packages as a library or acting as a calculation-server accessed by socket communication. We give an overview of the recently developed capabilities of the DFTB+ code, demonstrating with a few use case examples, discuss the strengths and weaknesses of the various features, and also discuss on-going developments and possible future perspectives.

Treatment Strategy for Persistent Sciatic Artery and Novel Classification Reflecting Anatomic Status.

BACKGROUND: Persistent sciatic artery (PSA) is a relatively rare congenital variant of the lower limb vasculature and can have highly variable clinical presentations. The purpose of this study was to analyze the relationship between PSA anatomy and clinical presentation, and to suggest an optimal management strategy. METHODS: Between 2001 and 2014, 24 PSAs in 19 patients were diagnosed by computed tomography and referred to the vascular surgery department. Patient demographics, types of PSA and femoral artery, aneurysmal changes, symptoms, and treatment methods were assessed. Additionally, all English literature from 1964 to 2014 was reviewed and compared using the PubMed database (224 PSAs in 171 patients). RESULTS: PSA was diagnosed in 10 men (52.6%) and nine women (47.4%). PSAs were bilateral in five patients (26.3%) and symptomatic in 12 patients, while in seven patients PSA was found incidentally. According to the Pillet-Gauffre classification, Type 2a was the most common variant (n = 15/24, 62.5%), with unclassifiable types in two limbs. Compared with cases in the literature, the PSA occlusion rate in this study was higher (n = 10/24, 41.7% vs. n = 54/224, 27.5%), but aneurysm incidence was higher in the literature cases (n = 5/24, 20.8% vs. n = 112/224; 50.7%). In this study, 16 limbs (66.6%) were treated conservatively, and six limbs were treated by open surgery, including four bypasses, one amputation, and one thrombo-embolectomy. Endovascular coil embolization was performed in one limb, and a hybrid procedure with stent graft was performed in one limb with PSA aneurysm. Based on the present series and the literature review, a new classification system and treatment option is proposed according to the anatomic status and the presence of aneurysm. According to the new classification, class III was the most common in both the present study (18/24; 75%) and the literature review, and the presence of aneurysm was the most important determinant of surgical treatment. CONCLUSIONS: The new classification system is simple and provides guidance for management. Limb anatomy of the femoral artery system and the presence of PSA aneurysm should be considered when selecting the optimal treatment. The risk of embolism from the presence of aneurysm is an important factor for treatment, and bypass surgery is mostly required in classes III and IV.

Safety and efficacy of plasmid DNA expressing two isoforms of hepatocyte growth factor in patients with critical limb ischemia.

VM202, a plasmid DNA that expresses two isoforms of hepatocyte growth factor, may elicit angiogenic effects that could benefit patients with critical limb ischemia (CLI). In a phase 2, double-blind trial in 52 CLI patients, we examined the safety and potential efficacy of intramuscular injections of low-dose (n=21) or high-dose (n=20) VM202 or placebo (n=11) in the affected limb (days 0, 14, 28 and 42). Adverse events and serious adverse events were similar among the groups; no malignancy or proliferative retinopathy was seen. In exploratory efficacy analyses, we found no differences in ankle or toe-brachial index, VAS, VascuQuol or amputation rate among the groups. Complete ulcer healing was significantly better in high-dose (8/13 ulcers; P<0.01) versus placebo (1/9) patients. Clinically meaningful reductions (>50%) in ulcer area occurred in high-dose (9/13 ulcers) and low-dose (19/27) groups versus placebo (1/9; P<0.05 and P<0.005, respectively). At 12 months, significant differences were seen in TcPO2 between the high-dose and placebo groups (47.5 ± 17.8 versus 36.6 ± 24.0 mm Hg, respectively; P<0.05) and in the change from baseline among the groups (P<0.05). These data suggest that VM202 is safe and may provide therapeutic bioactivity in CLI patients.

Surgical treatment of middle aortic syndrome with Takayasu arteritis or midaortic dysplastic syndrome.

OBJECTIVE: Middle aortic syndrome (MAS) is a rare condition characterized by severe stenosis of the distal thoracic or abdominal aorta. The aims of this study are to define the anatomic characteristics of MAS and to review the various surgical methods and their outcomes in terms of long-term durability MATERIALS AND METHODS: Ten adult patients were diagnosed with MAS caused by Takayasu arteritis (TA) or midaortic dysplastic syndrome and underwent surgical treatment between July 1992 and January 2013. RESULT: The aortic lesions were mostly suprarenal (n = 7) and stenoses were commonly found in the celiac axis (n = 6), SMA (n = 7), and renal artery (n = 6). Indications for operation were uncontrolled hypertension in six patients and lower extremity claudication in four. Eight aortic bypasses, one supraceliac aortic interposition graft, and one bilateral aorto-renal bypass were performed. Adjunctive renal bypass with saphenous vein graft (n = 4) and IMA reimplantation (n = 2) were performed simultaneously. There was no post-operative mortality, and one complication of iliac dissection at the distal anastomosis site was detected and treated by stenting. Hypertension was cured or improved in five of the six patients, and lower extremity claudication improved in all of them. With a median follow up of 60 months (range, 12-263), all the aortic bypasses were patent and one adjunctive renal artery bypass graft with aortic bypass was occluded 29 months post-operatively. CONCLUSIONS: Aortic bypass for MAS is safe and shows excellent long-term durability. Considering the patients are relatively young with a long life expectancy, aggressive surgical treatment could be beneficial. Lifelong follow up to monitor complications and disease progression is necessary.

Repeated cessation and resumption of resistance training attenuates increases in arterial stiffness.

Although high-intensity resistance training (RT) increases arterial stiffness, removing weightlifting stimuli returns arterial stiffness to baseline levels within relatively short periods during 4-8 weeks. This study investigates the effects of repeated RT cessation and resumption on arterial stiffness. Eighteen young healthy subjects were randomly assigned to a group that performed continuous RT (CRT, n=9) and a group that performed periodic RT (PRT, n=9). Both groups performed RT at 75% of one repetition maximum for 3 days per week. The CRT group continuously trained for 16 weeks, whereas the PRT group performed 3 cycles of 4 weeks training, with 2 weeks detraining intervals between cycles. The carotid-femoral pulse wave velocity in the CRT group significantly increased (P<0.05) at 4, 6, 10, 12, 16 and 20 weeks from baseline, whereas in the PRT group it significantly increased (P<0.05) after 4, 10 and 16 weeks from baseline, and was significantly lower (P<0.05) than that of the CRT group after 6, 10, 12, 16 and 20 weeks. Muscle mass and strength in the both groups significantly increased after 16 weeks from baseline and persisted for 20 weeks (P<0.05). These results suggest that PRT, including short-term repeated cessation and resumption, attenuates increases in arterial stiffness.

The median effective dose of dexmedetomidine for laryngeal mask airway insertion with propofol 2.0 mg/kg.

BACKGROUND: Dexmedetomidine can be used as a co-induction agent to facilitate laryngeal mask airway (LMA) insertion with minimal effect on respiratory function. The purpose of the study was to determine the median effective dose (ED50) of dexmedetomidine to facilitate LMA insertion during anaesthesia induction with propofol 2.0 mg/kg without neuromuscular blockade. METHODS: Twenty-two patients, whose American Society of Anesthesiologists physical status was I or II with ages between 18 and 60 years undergoing minor orthopaedic or gynaecological surgery, were enrolled. After an injection of pre-determined bolus dose of dexmedetomidine over 2 min, anaesthesia was induced with propofol 2.0 mg/kg. The modified Dixon's up-and-down method was used to determine the bolus dose of dexmedetomidine, starting from 0.5 µg/kg (step size; 0.1 µg/kg). LMA insertion was conducted 90 s after the propofol injection, and the response of patients was categorized as either 'success' or 'failure.' RESULTS: Insertion of the LMA was unsuccessful in 12 of 22 patients. The ED50 (95% confidence interval) of dexmedetomidine for successful LMA insertion with propofol 2.0 mg/kg was 0.55 (0.44-0.66) µg/kg. Bradycardia occurred in four patients, and seven patients had an apneic episode. CONCLUSION: The single dose of dexmedetomidine for successful LMA insertion to be feasible in 50% of patients was 0.55 µg/kg during anaesthesia induction with propofol 2 mg/kg.

Conversion of twice-daily tacrolimus to once-daily tacrolimus formulation in stable pediatric kidney transplant recipients: pharmacokinetics and efficacy.

The pharmacokinetics, efficacy and safety of once-daily tacrolimus formulation (Tac-OD) were assessed in 34 stable pediatric kidney transplant recipients. Enrolled patients received their dose of twice-daily tacrolimus formulation (Tac-BID) on study Days 0 through 7. On the morning of study Day 8, the total daily doses for patients were converted to Tac-OD on a 1:1 basis and maintained on a once-daily morning dosing regimen. Tacrolimus pharmacokinetic profiles were obtained on study Days 7, 14 and 28 (after dose adjustment). Although the mean C0 concentrations (4.10 ± 1.16-3.53 ± 1.10 ng/mL, p = 0.004), and AUC0-24 (151.8 ± 41.6-129.8 ± 39.3 ng h/mL, p < 0.001) were decreased significantly after a 1:1 based conversion, there was high interindividual variability. The dose of Tac-OD was decreased in 26.5% and increased in 44.1% of patients. The resultant tacrolimus dose and pharmacokinetic profiles on study Day 28 were comparable to those on Day 7. There were no serious adverse events. In conclusion, Tac-BID can be safely converted to Tac-OD in stable pediatric kidney transplant patients with the heightened therapeutic drug monitoring. Effects of drug conversion on the cardiovascular risk factors, neurological side effects and adherence should be further evaluated.

Characterization of NODs and TLRs in innate immune response of human cementoblast cells.

OBJECTIVES: Microbial Pattern-recognition receptors (PRRs), such as Toll-like receptors (TLRs) and the nucleotide-binding oligomerization domains (NODs), are essential for mammalian innate immune response. In this study, we examined the characterization of NODs and TLRs on innate immune responses in human cementoblast (HCEM) cells. MATERIALS AND METHODS: The gene expression of NODs and TLRs was examined by RT-PCR. Interleukin-6 (IL-6) and Interleukin-8 (IL-8) productions in culture supernatants were measured by ELISA. Western blot analysis was performed to determine the degradation of IκB-α and Mitogen activated protein kinase (MAPK) activation in response to their agonist. RESULTS: The levels of NODs and TLRs were apparently expressed in HCEM cells. Although a few gene levels were weak in intact cells, the stimulation by their agonists increased the gene expression of TLRs. NODs and TLRs led to the production of IL-6 or IL-8 and the degradation of IκB-α and MAPK activation in HCEM cells. Combination treatment of NOD1 or NOD2 agonists with TLRs agonists did not influence the production of IL-6 and IL-8 in HCEM cells. CONCLUSIONS: Our results indicate that NODs and TLRs are functionally expressed in HCEM cells and can trigger innate immune responses. However, NOD1 and NOD2 may not be cooperated with TLRs to elicit an immune response in HCEM cells.

A laminin-2-derived peptide promotes early-stage peripheral nerve regeneration in a dual-component artificial nerve graft.

The DLTIDDSYWYRI motif (Ln2-P3) of human laminin-2 has been reported to promote PC12 cell attachment through syndecan-1; however, the in vivo effects of Ln2-P3 have not been studied. In Schwann cells differentiated from skin-derived precursors, the peptide was effective in promoting cell attachment and spreading in vitro. To examine the effects of Ln2-P3 in peripheral nerve regeneration in vivo, we developed a dual-component poly(p-dioxanone) (PPD)/poly(lactic-co-glycolic acid) (PLGA) artificial nerve graft. The novel graft was coated with scrambled peptide or Ln2-P3 and used to bridge a 10 mm defect in rat sciatic nerves. The dual-component nerve grafts provided tensile strength comparable to that of a real rat nerve trunk. The Ln2-P3-treated grafts promoted early-stage peripheral nerve regeneration by enhancing the nerve regeneration rate and significantly increased the myelinated fibre density compared with scrambled peptide-treated controls. These findings indicate that Ln2-P3, combined with tissue-engineering scaffolds, has potential biomedical applications in peripheral nerve injury repair.

Direct peroral cholangioscopy using an ultraslim upper endoscope for management of residual stones after mechanical lithotripsy for retained common bile duct stones.

BACKGROUND AND STUDY AIMS: The incidence of residual stones after mechanical lithotripsy for retained common bile duct (CBD) stones is relatively high. Peroral cholangioscopy using a mother-baby system may be useful for confirming complete extraction of stones, but has several limitations regarding routine use. We evaluated the role of direct peroral cholangioscopy (DPOC) using an ultraslim upper endoscope for the evaluation and removal of residual CBD stones after mechanical lithotripsy. PATIENTS AND METHODS: From August 2006 to November 2010, 48 patients who had undergone mechanical lithotripsy for retained CBD stones with no evidence of filling defects in balloon cholangiography were recruited. The bile duct was inspected by DPOC after balloon cholangiography. Detected residual CBD stones were directly retrieved with a basket or balloon catheter under DPOC. The incidence of residual stones detected by DPOC, and the success rate of residual stone retrieval under DPOC were investigated. RESULTS: DPOC was successfully performed in 46 of the 48 patients (95.8%). Of these, 13 patients (28.3%) had residual CBD stones (mean number 1.4, range 1-3; mean diameter 4.5 mm, range 2.3-9.6). The residual stones were removed directly under DPOC in 11 of these patients (84.6%). There were no complications associated with DPOC or stone removal. CONCLUSION: DPOC using an ultraslim upper endoscope is a useful endoscopic procedure for the evaluation and extraction of residual stones after mechanical lithotripsy for retained CBD stones.

Limited maximal flow rate of target-controlled remifentanil infusion and induced cough.

This study evaluated the effect of limiting maximal infusion-pump flow rate on suppression of remifentanil-induced cough during target-controlled infusion. Two hundred and ten patients were randomly assigned to receive remifentanil at an effect-site concentration of 4.0 ng.ml(-1) with maximal flow rate limited to 100 (group R(100)), 200 (group R(200)), or 1200 ml.h(-1) (group R(1200)). The number of episodes of cough were recorded and graded as mild (1-2), moderate (3-4), or severe (5 or more). The incidence of cough was 2.9% in group R(100), 5.7% in group R(200) and 25.7% in group R(1200). Patients in group R(100) and R(200) had a significantly lower incidence of cough than those in group R(1200) (p < 0.05). Zero, two and five patients coughed a moderate amount in groups R(100), R(200) and group R(1200), respectively (p < 0.05). Limiting maximal infusion rate during remifentanil TCI suppressed remifentanil-induced cough.

Preoperative determination of anatomic variations of the small saphenous vein for varicose vein surgery by three-dimensional computed tomography venography.

OBJECTIVE: To define the anatomical variations of small saphenous vein (SSV) for varicose vein (VV) surgery by three-dimensional computed tomography venography (3D-CTV) and to analyse the impact of this preoperative evaluation on surgical outcomes. METHODS: A total of 120 consecutive limbs with SSV insufficiency having undergone VV surgery from January 2005 until December 2007 were enrolled. The medical records and images were analysed retrospectively. RESULTS: The relationship between SSV and gastrocnemial vein (GNV) were categorized into two: (a) SSV and GNV drained to popliteal vein (PV) separately (100 limbs, 87%) and (b) SSV and GNV made common channel which drained to PV (15 limbs, 13%). Saphenopopliteal junction morphology was normal (75 limbs), severe tortuosity near PV (19 limbs), ampullary ectasia (4 limbs) and duplicated drainage to PV (2 limbs). No recurrence of VV was noted. CONCLUSIONS: CTV can provide thorough preoperative anatomic information of the SSV variations and reduce the recurrence of VV.

Effect-site concentration of remifentanil for nasotracheal versus orotracheal intubation during target-controlled infusion of propofol.

The concentration of remifentanil required for acceptable nasotracheal intubation in adults after target-controlled infusion (TCI) of propofol without neuromuscular blockade was compared with that required for orotracheal intubation. Twenty-five patients undergoing oral and maxillofacial surgery received nasotracheal intubation and 25 undergoing ear, nose and throat surgery received orotracheal intubation. Anaesthesia was induced with propofol TCI at a target effect-site concentration of 5.0 µg/ml. The 50% and 95% effective concentrations (EC(50) and EC(95), respectively) for remifentanil, calculated using isotonic regression, were 5.40 and 6.85 ng/ml, respectively, in the orotracheal group and 5.75 and 7.43 ng/ml in the nasotracheal group. The EC(50) (± SD) values for remifentanil, calculated using a modified Dixon's up-and-down method, were 6.08 ± 0.75 and 5.58 ± 0.75 ng/ml for nasotracheal and orotracheal intubation, respectively. Effect-site remifentanil concentrations did not differ significantly between the two groups of patients. Coadministration of propofol and remifentanil can provide acceptable conditions for nasotracheal intubation without neuromuscular blockade.

Bolus effective dose of ketamine for preventing withdrawal movement on injection of rocuronium in paediatric patients.

The bolus effective dose of ketamine required to prevent withdrawal movement on injection of rocuronium was determined in 27 paediatric patients undergoing elective surgery. A predetermined dose of ketamine was given intravenously on arrival in the operating room and anaesthesia (2.5% thiopental, 5 mg/kg) was administered 1 min later. After loss of consciousness, 1% rocuronium at 0.6 mg/kg was injected over 5 s and the presence or absence of withdrawal movement recorded. The effective dose of ketamine was determined using a modified Dixon up-and-down method with a step size of 0.1 mg/kg, successful prevention of withdrawal movement being defined as no response or movement at the wrist only. The bolus effective dose of ketamine for preventing withdrawal movement after injection of rocuronium following thiopental anaesthesia in 50% of paediatric patients (ED(50)) was 0.21 mg/kg according to the modified Dixon up-and-down method. Probit analysis indicated an ED(50) of 0.18 mg/kg and an ED(95) of 0.33 mg/kg. The latter was the most satisfactory dose in the clinical setting.

Reduction of microemulsion propofol-induced injection pain via target-controlled remifentanil infusion.

The intravenous injection of microemulsion propofol to induce anaesthesia causes more intense and frequent pain than lipid emulsion propofol. This study investigated whether different target effect-site concentrations of remifentanil could prevent pain due to microemulsion propofol injection. In total, 96 patients were randomly assigned to one of three groups receiving target effect-site concentrations of remifentanil 0 (control group), 4 or 6 ng/ml, followed by injection with microemulsion propofol. Remifentanil pretreatment significantly reduced the incidence and severity of injection pain compared with the control group. Although no difference in pain reduction between the two remifentanil-treated groups was observed, those receiving a target effect-site concentration of 6 ng/ml exhibited an increased rate of complications, compared with those receiving 4 ng/ml. In conclusion, prior administration of remifentanil at a target effect-site concentration of 4 ng/ml is a useful strategy to decrease the injection pain of microemulsion propofol.

Effect-site concentration of propofol for reduction of remifentanil-induced cough.

SUMMARY: This study examined the effectiveness of different propofol infusion target concentrations on cough suppression, during a target-controlled remifentanil infusion. Four hundred patients were randomly assigned to receive propofol target effect-site concentrations of 0, 3.0, 4.5, or 6.0 microgxml(-1). When the propofol effect-site concentration reached the target, remifentanil was administered at a target effect-site concentration of 4.0 ngxml(-1). Episodes of cough were recorded over a 2-min period after remifentanil commencement, and graded as mild (1-2), moderate (3-4), or severe (5 or more). The overall incidence of cough was significantly decreased in by propofol 6.0 microgxml(-1) compared with 0 or 3.0 microgxml(-1) propofol (p < 0.001). The incidence of severe cough was significantly lower with propofol 6.0 microgxml(-1) compared with 3.0 microgxml(-1) (p = 0.03). A propofol target effect-site concentration of 6.0 microgxml(-1) effectively suppressed remifentanil-induced cough when remifentanil was administrated at a target effect-site concentration of 4.0 ngxml(-1).

Optimal bolus dose of alfentanil for successful tracheal intubation during sevoflurane induction with and without nitrous oxide in children.

BACKGROUND: The goals of this study were to determine the effective bolus dose of alfentanil required for successful tracheal intubation during inhalation induction using sevoflurane 5% without neuromuscular block in children, and whether nitrous oxide reduces these doses. METHODS: Fifty paediatric patients, aged 3-10 yr, were randomly assigned to one of the two groups. Subjects received either sevoflurane 5% in oxygen 100% (O(2) group, n=25) or sevoflurane 5% in oxygen 40% and nitrous oxide 60% (N(2)O group, n=25) through a face mask. One minute after inhalation induction, a predetermined dose of alfentanil was injected over 15 s. The alfentanil dose was determined using Dixon's up-and-down method, starting from alfentanil 14 microg kg(-1). The trachea was intubated 3 min after inducing anaesthesia. RESULTS: The ED(50) [95% confidence interval (CI)] of alfentanil for successful tracheal intubation was 11.5 (9.9-13.1) and 8.6 (7.4-9.8) microg kg(-1) in the O(2) and N(2)O groups, respectively. The ED(50) of the N(2)O group was significantly lower than that of the O(2) group (P=0.0146)(.) From isotonic regression, 50% effective dose (ED(50)) (95% CI) of alfentanil in the O(2) and N(2)O groups was 11.4 (9.9-13.0) and 6.5 (5.0-8.1) microg kg(-1), respectively. CONCLUSIONS: The effective bolus dose of alfentanil for successful tracheal intubation was 11.5 microg kg(-1) in 50% of children during inhalation induction using sevoflurane 5% without neuromuscular blocking agent. Addition of nitrous oxide 60% in oxygen reduced the effective alfentanil dose by 25%.

N(1)-guanyl-1,7,-diamineoheptane, an inhibitor of deoxyhypusine synthase, suppresses differentiation and induces apoptosis via mitochondrial and AMPK pathways in immortalized and malignant human oral keratinocytes.

BACKGROUND: Although N(1)-guanyl-1,7,-diamineoheptane (GC7), an inhibitor of deoxyhypusine synthase, has been shown to inhibit cell growth, the mechanism of its action is not completely understood. In this study, we investigated the mechanisms of the effects of GC7 on cell growth, differentiation and apoptosis in relation to adenosine monophosphate-activated protein kinase (AMPK) activation, as AMPK is known to be a possible target for cancer treatment. METHODS: The effects of GC7 on the growth of immortalized human oral keratinocytes (IHOK) and primary oral cancer cells (HN4), was investigated using MTT assay, Western blotting, cell cycle analysis, DNA fragmentation and expression of apoptotic pathway proteins. RESULTS: N(1)-guanyl-1,7,-diamineoheptane inhibited cell proliferation in a time- and dose-dependent manner in IHOK and HN4 cells. GC7 treatment decreased the expression of differentiation markers, such as involucrin, CK13 and CK19. The major mechanism of growth inhibition by GC7 treatment was induction of apoptosis, which is supported by sub-G(1) phase arrest, annexin V-FITC staining and DNA fragmentation analysis. GC7 treatment increased the cytosolic level of cytochrome c and resulted in caspase-3 activation. GC7 treatment also resulted in a strong activation of AMPK. Furthermore, specific AMPK activator blocked the GC7-induced growth inhibition effect, as well as apoptosis. CONCLUSION: These results demonstrate that GC7 blocks immortalized and malignant keratinocyte cell proliferation and differentiation by inducing apoptosis through the mitochondrial and AMPK pathways. On the basis of these observations, we propose that a strategy combining GC7 and AMPK inhibition could be developed into a novel chemotherapeutic modality in oral cancer.