Ultrasound guided quadratus lumborum block versus interlaminar epidural block for analgesia in pediatric abdominal surgery: a randomized controlled trial.

BACKGROUND: Although the efficacy and safety of epidural block (EB) are fairly high, complications such as inadvertent dural puncture may limit its use. Ultrasound-guided quadratus lumborum block (QLB) is a relatively new regional technique that provides perioperative somatic and visceral analgesia for pediatric patients. This trial compared the quality of pain relief in pediatric patients undergoing abdominal surgery who received either QLB or EB. METHODS: Patients were randomly allocated into two equal groups: Group E(n = 29): received EB; Group QL(n = 29): received QLB. Both groups were injected with 0.25% bupivacaine (0.5 ml/kg). Assessment of total analgesia consumption was the primary outcome measure, whereas the secondary outcome measures were assessment of postoperative analgesic effect by Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) and time of first analgesic request. RESULTS: Our study showed that the mean total fentanyl consumption was comparable between both groups(38.67 ± 5.02 and 36.47 ± 5.13 µg in the E and QL groups, respectively, P = 0.246). Only five patients did not require rescue analgesia (3 in the E group,2 in the QL group, P = 0.378). The mean duration of analgesia showed no significant difference between the two groups (9.9 ± 1.58 and 11.02 ± 1.74 h in the E and QL groups, respectively, P = 0.212). Evaluation of CHEOPS score values immediately in PACU and for the initial 24 h following operation showed no significant difference between the two study groups(P > 0.05). CONCLUSION: QLB can achieve analgesic effects comparable to those of EB as a crucial part of multimodal analgesia in children undergoing abdominal surgeries. CLINICAL TRIAL REGISTRATION NUMBER: PACTR202203906027106.

Deep Hypothermic Circulatory Arrest in the Pediatric Population Undergoing Cardiac Surgery With Electroencephalography Monitoring: A Systematic Review and Meta-Analysis.

OBJECTIVE: Cardiac surgery for repair of congenital heart defects poses unique hazards to the developing brain. Deep hypothermic circulatory arrest (DHCA) is a simple and effective method for facilitating a bloodless surgical field during congenital heart defect repair. There are, however, some concerns that prolonged DHCA increases the risk of nervous system injury. The electroencephalogram (EEG) is used in adult and, to a lesser extent, pediatric cardiac procedures as a neuromonitoring method. The present study was performed to assess outcomes following DHCA with EEG monitoring in the pediatric population. DESIGN: In this systematic review and meta-analysis, the PubMed, Cochrane Central Register of Controlled Trials, Scopus, Institute of Science Index, and Embase databases were searched from inception for relevant articles. A fixed- or random-effects model, as appropriate, was used. SETTING: Surgical setting. PARTICIPANTS: Pediatric population (≤18 y old). INTERVENTIONS: DHCA (18°C) with EEG monitoring. MEASUREMENTS AND MAIN RESULTS: Nineteen articles with 1,267 pediatric patients ≤18 years were included. The event rate of clinical and EEG seizures among patients who underwent DHCA was 12.9% and 14.9%, respectively. Mortality was found to have a 6.3% prevalence. A longer duration of DHCA was associated with a higher risk of EEG seizure and neurologic abnormalities. In addition, seizures were associated with increased neurologic abnormalities and neurodevelopmental delay. CONCLUSIONS: EEG and neurologic abnormalities were common after DHCA. A longer duration of DHCA was found to lead to more EEG seizure and neurologic abnormalities. Moreover, EEG seizures were more common than clinical seizures. Seizures were found to be associated with increased neurologic abnormalities and neurodevelopmental delay.

Efficacy of multi-wave locked system laser therapy on nerve regeneration after crushing in Wister rats.

[Purpose] To investigate the efficacy of the multi-wave locked system laser therapy on the regeneration of peripheral nerve injuries by evaluating the functional, electrophysiological, and morphological changes of the crushed sciatic nerve in Wistar rats. [Materials and Methods] Sixty male Wistar rats (200-250 g) were randomly assigned to control negative, control positive, or laser groups and subjected to no laser therapy or crushing, to crushing without laser therapy, or crushing followed by multi-wave locked system laser therapy five times/week for four weeks (power=1 W, energy density=10 J/cm2, total energy=100 J), respectively. Functional, electrophysiological, and morphometric analyses were performed before and 7, 15, 21, and 28 days after crushing. The sciatic functional index, compound motor action potential amplitude, motor nerve conduction velocity, and nerve and myelin sheath diameters were measured. [Results] The sciatic functional index value decreased significantly, while the compound motor action potential amplitude, motor nerve conduction velocity, nerve diameter, and myelin sheath diameter increased significantly in the laser group post-treatment compared to the values in the control groups. [Conclusion] Multi-wave locked system laser therapy was effective in accelerating the regeneration of crushed sciatic nerves in Wistar rats.

Dose-dependent effect of the pulsed Nd:YAG laser in the treatment of crushed sciatic nerve in Wister rats: an experimental model.

The objective of the study was to investigate the efficacy of three energy densities 4, 10, and 50 J/cm2 of pulsed Nd:YAG laser for the treatment of crushed sciatic nerve in Wister rats by evaluating changes in the sciatic functional index and the electrophysiology.A total of 180 Wistar rats were involved in the study. Rats were randomly assigned to five groups. Rats were subjected to the sciatic nerve crushing. Control negative (CONT-ve), which received no crushing; control positive (CONT+ve), which received crushing with no laser; and HILT-4, HILT-10, and HILT-50 groups, which received pulsed Nd:YAG laser (10 Hz, 360 mJ/cm2) with energy densities 4, 10, and 50 J/cm2, respectively. The SFI, the amilitude of compound motor action potential (CMAP) and sciatic motor nerve conduction velocity (MNCV) were measured before and after seven, 14, and 21 days after crushing. For the SFI and electrophysiological analysis, repeated measures ANOVA is used, followed by Bonferroni's repeated-measures test. Statistical significance was set at p < 0.05. After one week, there was no significant difference in SFI, CMAP, and MNCV among the three laser groups with significant changes between them and CONT-ve and CONT+ve groups. There was a significant increase in either CMAP amplitude or MNCV after 14 days with significant decrease in the SFI after 21 days among all treatment groups. The pulsed Nd:YAG laser applied with energy densities 4, 10, and 50 J/cm2 significantly decreased the SFI and increased the CMAP and MNCV of the crushed sciatic nerve in Wister rats. Among laser doses, the difference in the rate of recovery in the electrophysiology was found after two weeks while in the SFI after three weeks. The improvement after the nerve injury was time and dose dependent.

Anthropometric, biochemical and clinical assessment of malnutrition among Egyptian children with chronic liver diseases: a single institutional cross-sectional study.

BACKGROUND: Malnutrition is a common problem among children with chronic liver diseases (CLD). We aimed to assess the nutritional status of children with CLD and to correlate the anthropometric indices with the severity of liver disease, liver function tests, insulin growth factor-1 (IGF-1) and 25-hydroxy vitamin D (25- OH D). METHODS: A total of 69 patients with CLD and 50 healthy controls (6 months - 6 years) were included in the study. Nutritional status was assessed by anthropometric indices expressed in standard deviation score (Z score), biochemical, hematological and clinical parameters. RESULTS: We found 52.2% of CLD patients underweight by weight for age (W/A); 50.2% were stunted by height for age/ length for age (HAZ or LAZ); and 39% exhibited wasting by weight/height or (length) for age (W/HZ or W/LZ) z scores analysis. The mean values of z scores for all anthropometric parameters were significantly correlated with unconjugated and conjugated bilirubin and INR (p < 0.05), except HAZ or LAZ. Also, a significant correlation to albumin was found, except for W/HZ or (W/LZ) (p = 0.157). The z scores < - 2 SD based on W/ H versus arm indicators showed significant differences in MUAC, UAA and AMA (p < 0.001). We found no correlation between anthropometric z-scores and the mean IGF-1 and (25- OH D) values (p > 0.05). Malnutrition was directly correlated with the severity of hepatic dysfunction, particularly, Child-Pugh C cases. The mean IGF-1 and (25- OH D) values were significantly correlated with the severity of liver disease (p < 0.001). CONCLUSIONS: Our results identified anthropometric arm indicators and MUAC/A measurements as an effective applied methods for assessing nutritional status in CLD children. Moreover, Integrating comprehensive clinical assessment, anthropometric measurements and objective biochemical analyses is essential for evaluation, follow-up and management of CLD children with variable degree of malnutrition.

Fetal heart examination at the time of 13 weeks scan: a 5 years' prospective study.

Objective To evaluate our ability in classifying the fetal heart as normal or abnormal during the 1st trimester scan through fetal cardiac examination and determining the best time for this examination. Methods This was a prospective study performed on 3240 pregnant women to examine the fetal heart. Four chambers view and ventricular outflow tracts were mainly examined during the scan. We used grayscale and color mapping in the diagnosis. Color Doppler was used if additional information was needed, and all patients were rescanned during the 2nd trimester to confirm or negate our diagnosis. Results The cardiac findings were normal at both scans in 3108 pregnancies. The same cardiac abnormality was detected at both scans in 79 cases. In 36 cases there was false-positive diagnosis at the early scan; in 20 of these cases, there were mildly abnormal functional findings early in pregnancy with no abnormality found later. In 17 fetuses, there was discordance between the early and later diagnosis due to missed or incorrect diagnoses. The best time to do fetal heart examination during 1st trimester is between 13 and 13 + 6 weeks. Conclusion A high degree of accuracy in the identification of congenital heart disease (CHD) can be achieved by a 1st trimester fetal echocardiography.

H-reflex changes in adolescents with idiopathic scoliosis: a randomized clinical trial.

[Purpose] To detect H-reflex asymmetry and investigate the effect of direction sensitive exercise therapy protocol among patients with thoracolumbar and/or lumbar scoliosis. [Subjects and Methods] Fifty patients (10-17 years), Cobb's angle 10-20 degrees with thoracolumbar and lumbar scoliosis participated in the study. Soleus H-reflex was tested on both sides during prone lying position and standing position. Patients were randomly assigned into two groups. Group I received direction sensitive exercise therapy while the participants in group II received traditional exercise. Exercises were applied three times per week for twelve successive weeks. [Results] There were significant differences indicating asymmetry in the H-reflex amplitude on concave side. Cobb's angle significantly decreased and the H-reflex amplitude on concave side as well as H concave/convex ratios in both lying and standing significantly increased in both groups. Direction sensitive exercise therapy showed a more significant increase in the measured outcomes than traditional exercises therapy protocol. [Conclusion] H-reflex test was effective in discovering the asymmetry between concave and convex sides. Based on H-reflex test, direction-sensitive exercise therapy was more effective than traditional exercises in decreasing Cobb's angle and increasing H-reflex values as well as H/H percent in concave side in patients with adolescent idiopathic scoliosis.

Efficacy of high intensity laser therapy in the treatment of male with osteopenia or osteoporosis: a randomized placebo-controlled trial.

[Purpose] To investigate the effect of high intensity laser therapy, alone or combined with exercise on pain, health related quality of life and fall risk in male with osteopenia or osteoporosis. [Subjects and Methods] 100 male patients with osteopenia or osteoporosis participated in the study. They had T-scores ≤-1.5. Patients were randomly assigned into four groups and treated with laser plus exercise, placebo laser plus exercise, laser alone and placebo laser in groups I, II, III, and IV respectively. Laser was applied to the lower back and hip regions. Exercises included aerobic exercises, weight-bearing, flexibility, and strengthening and balance exercises. Treatment were performed 3 times/week for 12 weeks. The measured outcomes were pain, health related quality of life and fall risk. [Results] All measured outcomes were significantly decreased post-treatment in all treatment groups. Laser plus exercises showed a higher significant effect than exercises with a least significant effect in the laser group in reduction of pain and quality of life. [Conclusion] High intensity laser is an effective modality for male patients with osteopenia or osteoporosis. Laser combined with exercise is more effective than exercises or laser alone in decreasing pain, fall risk an increasing quality of life after 12 weeks of treatment.

Synthesis, Anticancer Activity, Effect on Cell Cycle Profile, and Apoptosis-Inducing Ability of Novel Hexahydrocyclooctathieno[2,3-d]pyrimidine Derivatives.

A novel series of hexahydrocyclooctathieno[2,3-d]pyrimidines was synthesized. Investigation of the anticancer activity of these derivatives revealed that compounds 2a and b showed broad-spectrum anticancer activity in nanomolar to micromolar concentrations. In particular, compound 2b showed a concentration required for 50% inhibition of cell growth (GI50) value of less than 1 µM against 20 cancer cell lines. Compounds 2a and b induced G2/M- and S-phase cell cycle arrest in human colon adenocarcinoma (HCT116) and human breast adenocarcinoma (MCF7) cell lines with a concomitant increase in the pre-G cell population in a time-dependent manner. Furthermore, compound 2b increased the nuclear expression of the proapoptotic protein cleaved caspase-3, indicating that apoptosis has an important role, at least in part, in the cancer cell death induced by the new compounds.

Effect of magnesium sulphate on bi-spectral index (BIS) values during general anesthesia in children.

BACKGROUND: Magnesium was reported to reduce both the anesthetic requirements and the period needed to reach a bi-spectral index value of 60 when used intra-operatively (Br J Anaesth 83:302-20, 1999; Anesth Analg 20:1273-5, 1988; Br J Anaesth 89:594-8, 2002; Anesth Analg 87:206-10, 1998; Br J Anaesth 89:594-8, 2002; Br J Anaesth 94:438-41, 2005) and to minimize the emergence agitation (Anaesthesia 61:1058-63, 2006). Previous studies examined the influence of magnesium on the anesthetic requirements while the bi-spectral Index values were kept within a constant range. We evaluated the effect of intraoperative magnesium on the bi-spectral index values during pediatric anesthesia while we kept other anesthetic variables unchanged. METHODS: Eighty pediatric patients with ASA physical status I, age 2-8 years and scheduled for minor infra-umbilical elective procedures included in a prospective randomized controlled study. We randomly divided patients into two groups. Group I (40 patients); received a bolus dose 50 mg/kg of magnesium sulphate followed by an infusion at rate of 15 mg/kg/h throughout the procedure. Group II (40 patients); received the same amount in the form of ringer acetate for blinding. We compared between the groups regarding: 1) BIS values. 2) Hemodynamic parameters. 3) Arterial oxygen saturation 4) End-tidal CO2 5) Respiratory rate and 6) Tidal volume. RESULTS: Magnesium group (Group I) showed significantly lower BIS values and shorter time to achieve BIS values below 60. Respiratory parameters (tidal volume and respiratory rate) were significantly lower in the magnesium group. Otherwise, no significant differences between the study group and the control group were detected. DISCUSSION: Our study has the advantage of evaluating the direct effect of magnesium sulphate on the Bi-spectral index scale with keeping other intraoperative factors almost constant (as the type of operations, induction and maintenance techniques, end-tidal anesthetic concentration, analgesia and mode of ventilation) for accurate assessment. CONCLUSION: Magnesium produced significantly lower BIS values, less time to reach BIS values below 60, lower tidal volume and lower respiratory rate during pediatric general anesthesia. TRIAL REGISTRATION: Pan African Clinical Trial Registry, www.pactr.org , PACTR201312000666231 . Registered at 6 October 2013.

Metabolic engineering of Propionibacterium freudenreichii: effect of expressing phosphoenolpyruvate carboxylase on propionic acid production.

Propionic acid is currently produced mainly via petrochemicals, but there is increasing interest in its fermentative production from renewable biomass. However, the current propionic acid fermentation process suffers from low product yield and productivity. In this work, the gene encoding phosphoenolpyruvate carboxylase (PPC) was cloned from Escherichia coli and expressed in Propionibacterium freudenreichii. PPC catalyzes the conversion of phosphoenolpyruvate to oxaloacetate with the fixation of one CO2. Its expression in P. freudenreichii showed profound effects on propionic acid fermentation. Compared to the wild type, the mutant expressing the ppc gene grew significantly faster, consumed more glycerol, and produced propionate to a higher final titer at a faster rate. The mutant also produced significantly more propionate from glucose under elevated CO2 partial pressure. These effects could be attributed to increased CO2 fixation and resulting changes in the flux distributions in the dicarboxylic acid pathway.

The clinical impact of orthotic correction of lower limb rotational deformities in children with cerebral palsy: a randomized controlled trial.

OBJECTIVE: This study aimed to evaluate the effectiveness of a static ground reaction ankle foot orthosis and strapping system on improving gait parameters in children with spastic diplegic cerebral palsy. SETTING: The current study was conducted at the physical therapy faculty of Cairo University, Egypt. SUBJECTS: This study included 57 children of both sexes, aged 6 to 8 years. STUDY DESIGN: Three-armed randomized control trial. INTERVENTION: Participants in all groups received a traditional neuro-developmental physical therapy program that included standing and gait training exercises. Children in group A performed the training program without any orthotic management, in group B with the TheraTogs strapping system, and in group C with the TheraTogs strapping system and static ground reaction ankle foot orthoses. Children underwent treatment for two hours daily, except on weekends, for twelve successive weeks. MAIN MEASURE: Gait speed, cadence, stride length, and hip and knee flexion angles in the mid-stance phase were evaluated pre-and post-treatment using a three-dimensional motion analysis system (pre-reflex system). RESULTS: Statistically significant differences were recorded among the three groups post-treatment in gait speed, cadences, and stride length. The P-values for these variable differences were 0.03, 0.011, and 0.001 respectively. Significant post-treatment differences were also recorded for bilateral hip-and knee-flexion angles. For all measured parameters, better significant results were registered for group C than for the other groups. CONCLUSION: Orthotic intervention composed of a static ground reaction ankle foot orthosis combined with the TheraTogs strapping system improves gait more than conventional treatment with or without TheraTogs in children with spastic diplegic cerebral palsy.

Free-hand placement of occipital condyle screws: a cadaveric study.

PURPOSE: Cranio-vertebral junction fixation is challenging due to the complex topographical anatomy and the presence of important anatomical structures. There are several limitations to the traditional occipital squama fixation methods. The purpose of this work is to assess the safety and feasibility of a new optimum trajectory of occipital condyle (OC) screws for occipitocervical fixation via a free-hand technique. METHODS: Eight different parameters of OC morphology were studied in fifty adult skulls. Free-hand placement of OC screws was performed in five cadavers using 3.5-mm titanium polyaxial screws and a 3-mm rod construct (C0-C1-C2). Postoperative computed tomography was performed to determine the success of the screw placement and their angulation, length and effect on hypoglossal canal volume. RESULTS: The average length, width and height of the OC were 24.2 ± 3.6, 14.2 ± 1.9, and 10.7 ± 2 mm, respectively. The average medio-lateral, hypoglossal canal and atlanto-occipital joint angles were 38.8° medially ±5°, 7.4° rostrally ±1.9° and 23.4° caudally ±3.5°, respectively. The ten screws were successfully inserted using a free-hand technique with bicortical purchase. There was no vertebral artery injury or breach of the hypoglossal canal in any specimen. The average screw length was 22.2 ± 3.9 mm. The average medio-lateral angle was 30° medially ±6.7°. The average cranio-caudal angle was 4° caudally ±6.2°. CONCLUSIONS: The free-hand technique of OC screw placement is a safe and viable option for occipitocervical fixation and may be a preferred alternative in selected cases. However, further studies are needed to compare its safety and reliability to other more established methods.

Effect of rowing on pulmonary functions in children with Down syndrome.

PURPOSE: To examine effects of a rowing exercise regimen versus a chest physical therapy program on pulmonary function in children with Down syndrome. METHODS: Twenty-nine participants of both sexes, between 8 to 12 years of age, participated in this study. They were assigned randomly into 2 study groups. The first group (A) received a chest physical therapy program, while the second group (B) received an aerobic exercise regimen using a rowing ergometer. Vital capacity, forced vital capacity, forced expiratory volume after 1 second, and peak expiratory flow rate were measured before and after 12 successive weeks of treatment. RESULTS: Significant improvements in all measured variables were found posttreatment in both study groups. No significant difference between the 2 groups was found posttreatment. CONCLUSION: Rowing exercise could be effective in improving pulmonary functions in children with Down syndrome.

Spiral strapping for improving upper extremity motor functions in individuals with stroke: A randomized controlled trial.

BACKGROUND: The rehabilitation process for the upper extremities of individuals with stroke requires therapists to use splints for supportive and corrective purposes. The aim of this study was to assess the effectiveness of spiral strapping in inhibiting spasticity and improving the upper extremity motor functions of individuals with chronic stroke. METHODS: Forty Saudi individuals aged 50-60 years with chronic stroke participated in this study. Their degrees of spasticity according to the Modified Ashworth Scale ranged across grades 1, 1+, and 2. Participants were randomly assigned to experimental and control groups. Participants in both groups received 1 h of conventional physical therapy for 3 d/wk to improve the motor functions of their upper extremities. In addition, participants in the experimental group wore an upper-limb spiral strapping with a hand splint 10 h/d for 6 d/wk. The treatment program for both groups was delivered for 4 weeks. Changes in the scores of Action Research Arm Test for elbow joint spasticity, active range of motion of the shoulder, elbow, and forearm joints, and hand grip strength were evaluated before and after treatment in both groups. RESULTS: Significant improvements in all measured variables after treatment were reported in both groups, except for elbow joint spasticity in the control group. The experimental group showed significant post-treatment improvement in the scores for all measured variables compared with the control group. CONCLUSIONS: Spiral strapping was beneficial in inhibiting mild degrees of spasticity and improving the motor functions of the upper extremities of stroke patients.

C-Mill Virtual Reality/Augmented Reality Treadmill Training for Reducing Risk of Fall in the Elderly: A Randomized Controlled Trial.

Objective: Falling is considered one of the major problems that may affect the elderly, leading to multiple health issues. Walking adaptability to environmental demands is essential for safe walking in the elderly. The aim of this study was to evaluate the efficacy of virtual reality (VR)/augmented reality (AR) treadmill training on balance performance and the risk of falls in the elderly. Materials and Methods: Sixty Saudi elderly individuals of both genders, aged between 60 and 70 years, participated in the study. The participants were categorized into two groups: the experimental and the control groups. Both groups received 1 hour of training: 30 minutes of conventional exercises and 30 minutes of gait training on the C-Mill VR/AR treadmill. The experimental group used the C-Mill treadmill with VR and AR games therapy. The control group had gait training on the C-Mill treadmill without VR and AR. The training for both groups was conducted for 6 successive weeks/three times a week. The changes in the scores of the following variables were recorded at baseline, after 6 weeks of training, and 4 weeks after the completion of training. These variables involved the time needed for completing the Timed Up and Go (TUG) test, overall stability indices of the Fall Risk (FR) test and Limit of Stability (LOS) test evaluated using the Biodex Balance System (BBS), and the time required for completing the LOS test. Results: Both groups demonstrated significant improvement in all measured variables immediately post-training, and this improvement persisted for 4 weeks after completing the training. The experimental group exhibited greater improvement in the recorded values of all measured variables compared with the control group following the training. Conclusions: This study concluded that C-Mill VR/AR treadmill training is effective in improving balance control and reducing the fall risk in the elderly.

Effect of Different Primers on the Shear Bond Strength of Orthodontic Brackets Bonded to Reinforced Polyetheretherketone (PEEK) Substrate.

This in vitro study assessed the effect of different primers on the shear bond strength (SBS) and adhesive remnant index (ARI) of orthodontic brackets bonded to reinforced polyetheretherketone (PEEK) substrate. A total of 40 specimens were randomly distributed to two groups based on the primer used for orthodontic bonding: group 1 (control)-Transbond XT adhesive with Visio.link primer and group 2 (test)-orthodontic adhesive (Transbond XT) with traditional orthodontic primer. After bonding, specimens were thermocycled followed by SBS testing and ARI scoring of debonded specimens. Data were analyzed using the unpaired independent t-test and the Chi-square test. Group 1 specimens showed significantly higher SBS values (21.38 ± 1.48 MPa) compared to group 2 specimens (18.63 ± 1.29 MPa) (p < 0.0001). Adhesive remnant index scores showed no significant variations in bond failure modes and distributions between groups. The SBS obtained by the tested primers exceeded the clinically recommended value. Consequently, there is a comparable clinical application for both tested primers in orthodontic bonding, especially the traditional orthodontic primer, where the availability of Visio.link in clinical practice is not ensured.

Metabolic engineering of Propionibacterium freudenreichii for n-propanol production.

Propionibacteria are widely used in industry for manufacturing of Swiss cheese, vitamin B12, and propionic acid. However, little is known about their genetics and only a few reports are available on the metabolic engineering of propionibacteria aiming at enhancing fermentative production of vitamin B12 and propionic acid. n-Propanol is a common solvent, an intermediate in many industrial applications, and a promising biofuel. To date, no wild-type microorganism is known to produce n-propanol in sufficient quantities for industrial application purposes. In this study, a bifunctional aldehyde/alcohol dehydrogenase (adhE) was cloned from Escherichia coli and expressed in Propionibacterium freudenreichii. The mutants expressing the adhE gene converted propionyl- coenzyme A, which is the precursor for propionic acid biosynthesis, to n-propanol. The production of n-propanol was limited by NADH availability, which was improved significantly by using glycerol as the carbon source. Interestingly, the improved propanol production was accompanied by a significant increase in propionic acid productivity, indicating a positive effect of n-propanol biosynthesis on propionic acid fermentative production. To our best knowledge, this is the first report on producing n-propanol by metabolically engineered propionibacteria, which offers a novel route to produce n-propanol from renewable feedstock, and possibly a new way to boost propionic acid fermentation.

Design and synthesis of novel cytotoxic fluoroquinolone analogs through topoisomerase inhibition, cell cycle arrest, and apoptosis.

To exploit the advantageous properties of approved drugs to hasten anticancer drug discovery, we designed and synthesized a series of fluoroquinolone (FQ) analogs via functionalization of the acid hydrazides of moxifloxacin, ofloxacin, and ciprofloxacin. Under the NCI-60 Human Tumor Cell Line Screening Assay, (IIIf) was the most potent among moxifloxacin derivatives, whereas (VIb) was the only ofloxacin derivative with significant effects and ciprofloxacin derivatives were devoid of activity. (IIIf) and (VIb) were further selected for five-dose evaluation, where they showed potent growth inhibition with a mean GI50 of 1.78 and 1.45 µM, respectively. (VIb) elicited a more potent effect reaching sub-micromolar level on many cell lines, including MDA-MB-468 and MCF-7 breast cancer cell lines (GI50 = 0.41 and 0.42 µM, respectively), NSCLC cell line HOP-92 (GI50 = 0.50 µM) and CNS cell lines SNB-19 and U-251 (GI50 = 0.51 and 0.61 µM, respectively). (IIIf) and (VIb) arrested MCF-7 cells at G1/S and G1, respectively, and induced apoptosis mainly through the intrinsic pathway as shown by the increased ratio of Bax/Bcl-2 and caspase-9 with a lesser activation of the extrinsic pathway through caspase-8. Both compounds inhibited topoisomerase (Topo) with preferential activity on type II over type I and (VIb) was marginally more potent than (IIIf). Docking study suggests that (IIIf) and (VIb) bind differently to Topo II compared to etoposide. (IIIf) and (VIb) possess high potential for oral absorption, low CNS permeability and low binding to plasma proteins as suggested by in silico ADME calculations. Collectively, (IIIf) and (VIb) represent excellent lead molecules for the development of cytotoxic agents from quinolone scaffolds.

Deep and lasting response and acquired resistance to BRAFV600E targeting in a low-grade ovarian cancer patient.

The treatment of BRAFV600E mutant melanoma has been revolutionized by BRAF inhibitors. Furthermore, the BRAF/MEK combination has shown further improvement in clinical outcomes in advanced and in adjuvant melanoma patients. In low-grade ovarian tumors, BRAF inhibitor use has been also proposed. Here we present a patient with an excellent, lasting response to BRAF therapy alone. At first progression, after more than two years on BRAF monotherapy, we could not identify any molecular mechanisms explaining resistance. After a switch to dual BRAF/MEK therapy, the patient responded. However, despite the initial response clinical the patient again progressed, this time with the appearance of a KRAS G12C mutation, which could not be overcome by BRAF/MEK therapy. We provide evidence that BRAF inhibitor alone can be highly beneficial in BRAF mutant low-grade ovarian tumors and the resistance mechanisms are similar to that of other BRAF mutant tumors, including in melanoma.