Conducting polymer-based scaffolds for neuronal tissue engineering.

Neuronal tissue engineering has immense potential for treating neurological disorders and facilitating nerve regeneration. Conducting polymers (CPs) have emerged as a promising class of materials owing to their unique electrical conductivity and biocompatibility. CPs, such as poly(3,4-ethylenedioxythiophene) (PEDOT), poly(3-hexylthiophene) (P3HT), polypyrrole (PPy), and polyaniline (PANi), have been extensively explored for their ability to provide electrical cues to neural cells. These polymers are widely used in various forms, including porous scaffolds, hydrogels, and nanofibers, and offer an ideal platform for promoting cell adhesion, differentiation, and axonal outgrowth. CP-based scaffolds can also serve as drug delivery systems, enabling localized and controlled release of neurotrophic factors and therapeutic agents to enhance neural regeneration and repair. CP-based scaffolds have demonstrated improved neural regeneration, both in vitro and in vivo, for treating spinal cord and peripheral nerve injuries. In this review, we discuss synthesis and scaffold processing methods for CPs and their applications in neuronal tissue regeneration. We focused on a detailed literature review of the central and peripheral nervous systems.

Reasons for cessation of clean intermittent catheterization after spinal cord injury: Results from the Neurogenic Bladder Research Group spinal cord injury registry.

INTRODUCTION: Clean intermittent catheterization (CIC) is recommended for bladder management after spinal cord injury (SCI) since it has the lowest complication rate. However, transitions from CIC to other less optimal strategies, such as indwelling catheters (IDCs) are common. In individuals with SCI who stopped CIC, we sought to determine how individual characteristics affect the bladder-related quality of life (QoL) and the reasons for CIC cessation. METHODS: The Neurogenic Bladder Research Group registry is an observational study, evaluating neurogenic bladder-related QoL after SCI. From 1479 participants, those using IDC or urinary conduit were asked if they had ever performed CIC, for how long, and why they stopped CIC. Multivariable regression, among participants discontinuing CIC, established associations between demographics, injury characteristics, and SCI complications with bladder-related QoL. RESULTS: There were 176 participants who had discontinued CIC; 66 (38%) were paraplegic and 110 (63%) were male. The most common reasons for CIC cessation among all participants were inconvenience, urinary leakage, and too many urine infections. Paraplegic participants who discontinued CIC had higher mean age, better fine motor scores, and lower educational attainment and employment. Multivariable regression revealed years since SCI was associated with worse bladder symptoms (neurogenic bladder symptom score), ≥4 urinary tract infections (UTIs) in a year was associated with worse satisfaction and feelings about bladder symptoms (SCI-QoL difficulties), while tetraplegia was associated better satisfaction and feelings about bladder symptoms (SCI-QoL difficulties). CONCLUSIONS: Tetraplegics who have discontinued CIC have an improved QoL compared with paraplegics. SCI individuals who have discontinued CIC and have recurrent UTIs have worse QoL.

Synthetic, Structural, and Anticancer Activity Evaluation Studies on Novel Pyrazolylnucleosides.

The synthesis of novel pyrazolylnucleosides 3a-e, 4a-e, 5a-e, and 6a-e are described. The structures of the regioisomers were elucidated by using extensive NMR studies. The pyrazolylnucleosides 5a-e and 6a-e were screened for anticancer activities on sixty human tumor cell lines. The compound 6e showed good activity against 39 cancer cell lines. In particular, it showed significant inhibition against the lung cancer cell line Hop-92 (GI50 9.3 µM) and breast cancer cell line HS 578T (GI50 3.0 µM).

Gas in the kidney in asymptomatic Escherichia coli urinary tract infections in a patient with severe vesicoureteral reflex.

Diabetes mellitus (DM) is a common disease in Oman as in rest of Gulf Cooperation Council where metabolic syndrome is of high prevalence. DM is a foremost risk factor for urinary tract infections (UTIs). It is also linked to more complicated infections such as emphysematous pyelonephritis (EPN), emphysematous pyelitis (EP), renal/perirenal abscess, emphysematous cystitis, xanthogranulomatous pyelonephritis, and renal papillary necrosis. The diagnosis of these cases is frequently delayed because the clinical manifestations are generic and not different from the typical triad of upper UTI, which include fever, flank pain, and pyuria. A middle-aged female with DM and chronic kidney disease stage IV was admitted with recurrent UTI with extended-spectrum beta-lactamase-producing Escherichia coli. At presentation, she was afebrile, clinically stable, had no flank pain and there was no leukocytosis. Laboratory test for C- reactive protein done twice and was only mildly elevated at 7 and 11 mg/dL. A computed tomography scan of kidney-ureter-bladder (CT-KUB) was recommended and reported as "no KUB stone but small atrophic left kidney with dilatation of the pelvicalycial system and ureter and the presence of air in the collecting system suggestive of EP." Thus, commonly associated with DM, especially in females, debilitated immune-deficient individuals, and patients harboring obstructed urinary system with infective nidus. Air in the kidney is not always due to EPN. UTI with a gas-producing organism can ascend to the kidney in the presence of vesicoureteral reflux.

Patient Reported Bladder Related Symptoms and Quality of Life after Spinal Cord Injury with Different Bladder Management Strategies.

PURPOSE: Neurogenic bladder significantly impacts individuals after spinal cord injury. We hypothesized that there would be differences in bladder related symptoms and quality of life for 4 common bladder management methods. MATERIALS AND METHODS: In this prospective observational study we measured neurogenic bladder related quality of life after spinal cord injury. Study eligibility included age 18 years or greater and acquired spinal cord injury. Bladder management was grouped as 1) clean intermittent catheterization, 2) an indwelling catheter, 3) surgery (bladder augmentation, a catheterizable channel or urinary diversion) and 4) voiding (a condom catheter, involuntary leaking or volitional voiding). The primary outcomes were the NBSS (Neurogenic Bladder Symptom Score) and the SCI-QoL Difficulties (Spinal Cord Injury Quality of Life Measurement System Bladder Management Difficulties). Secondary outcomes were the NBSS subdomains and satisfaction with urinary function. Multivariable regression was done to establish differences between the groups, separated by level. RESULTS: Of the 1,479 participants enrolled in the study 843 (57%) had paraplegia and 894 (60%) were men. Median age was 44.9 years (IQR 34.4-54.1) and median time from injury was 11 years (IQR 5.1-22.4). Bladder management was clean intermittent catheterization in 754 cases (51%), an indwelling catheter in 271 (18%), surgery in 195 (13%) and voiding in 259 (18%). In regard to primary outcomes, in cases of paraplegia and tetraplegia an indwelling catheter and surgery were associated with fewer urinary symptoms on the NBSS compared to clean intermittent catheterization while voiding was associated with more symptoms. In paraplegia and tetraplegia cases surgery was associated with fewer bladder management difficulties according to the SCI-QoL Difficulties. In regard to secondary outcomes, surgery was associated with improved satisfaction in individuals with paraplegia or tetraplegia. CONCLUSIONS: In individuals with spinal cord injury fewer bladder symptoms were associated with an indwelling catheter and surgery, and worse bladder symptoms were noted in voiding individuals compared to those on clean intermittent catheterization. Satisfaction with the urinary system was improved after surgery compared to clean intermittent catheterization.

The effects of augmentation cystoplasty and botulinum toxin injection on patient-reported bladder function and quality of life among individuals with spinal cord injury performing clean intermittent catheterization.

AIMS: Clean intermittent catheterization (CIC) is recommended after spinal cord injury (SCI) because it has the least complications, however, CIC has a high discontinuation rate. We hypothesized that bladder botulinum toxin injection or augmentation cystoplasty may improve satisfaction with CIC. METHODS: The NBRG registry is a multicenter, prospective, observational study asking SCI participants about neurogenic bladder (NGB) related quality of life (QoL). In this study, participants performing CIC as primary bladder management were categorized into 3 groups: (1) CIC alone (CIC); (2) CIC with botulinum toxin (CIC-BTX); and (3) CIC with augmentation cystoplasty (CIC-AUG). Outcomes included primary: Neurogenic Bladder Symptom Score (NBSS) and SCI-QoL Bladder Management Difficulties, and secondary: NBSS subdomains (Incontinence, Storage & Voiding, Consequences) and the NBSS final question (satisfaction with urinary function). Multivariable regression, controlling for multiple factors was used to establish differences between the three groups. RESULTS: Eight hundred seventy-nine participants performed CIC as primary bladder management and had the following characteristics: mean age 43.4 (±12.9) and years from injury 13.7 (±10.7), tetraplegia in 284 (32%), and 543 (62%) were men. Bladder management was CIC in 593 (67%), CIC-BTX in 161 (19%), and CIC-AUG in 125(15%). Primary outcomes: CIC-AUG had associated improved total NBSS versus CIC(-3.2(-5.2 to -1.2), P = 0.001 and CIC-BTX(-3.9(-6.3 to -1.6), P = 0.001), CIC-AUG also had better SCI-QoL Difficulties scores versus CIC(-4(-5.48 to -2.53, P < 0.001) and CIC-BTX(-4.4(-6.15 to -2.65, P < 0.001). SECONDARY OUTCOMES: CIC-AUG had associated improved Incontinence and Satisfaction scores versus CIC and CIC-BTX. CONCLUSIONS: Compared to patients performing CIC with or without botulinum toxin treatment, those with augmentation cystoplasty had associated better urinary function and satisfaction with their urinary symptoms.

Elimination of BK viremia in renal transplant recipients by optimization of immunosuppressive medications without precipitating acute rejection.

BK Polyomavirus-associated nephropathy (BKVAN) has been recognized as an increasing threat in renal transplant patients (RTP) for more than a decade. Reduction in immunosuppression is the mainstay of treatment through various options of treatment has been suggested. Published reports on these protocols have shown mixed results, and no randomized controlled trials have compared one strategy with another. In this context, we hypothesize that the appearance of BKV in the blood compels one to optimize the immunosuppression with possible long-term beneficial effects. We conducted a retrospective study among the RTP being followed up by the Renal Medicine Department at Royal Hospital who tested positive for BKV-polymerase chain reaction and whose immunosuppression was altered with a final aim to get rid of BK viremia, yet avoiding acute rejection. Results were analyzed by the clinical and statistical approach. Extensive literature review was carried out to look into the prevalence, prognosis, and treatment of BKVAN. In all the patients in whom BKV was detected alteration in immunosuppression resulted in eliminating the virus without precipitating acute rejection. The study shows that in the exercise of eliminating BKV by alteration of immunosuppression, we have "tailored" the immunosuppression in each particular RTPs, without precipitating acute rejection.

Kinase-targeted cancer therapies: progress, challenges and future directions.

The human genome encodes 538 protein kinases that transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are associated with human cancer initiation and progression. The recent development of small-molecule kinase inhibitors for the treatment of diverse types of cancer has proven successful in clinical therapy. Significantly, protein kinases are the second most targeted group of drug targets, after the G-protein-coupled receptors. Since the development of the first protein kinase inhibitor, in the early 1980s, 37 kinase inhibitors have received FDA approval for treatment of malignancies such as breast and lung cancer. Furthermore, about 150 kinase-targeted drugs are in clinical phase trials, and many kinase-specific inhibitors are in the preclinical stage of drug development. Nevertheless, many factors confound the clinical efficacy of these molecules. Specific tumor genetics, tumor microenvironment, drug resistance, and pharmacogenomics determine how useful a compound will be in the treatment of a given cancer. This review provides an overview of kinase-targeted drug discovery and development in relation to oncology and highlights the challenges and future potential for kinase-targeted cancer therapies.

Persistent anemia in a kidney transplant recipient with parvovirus B19 infection.

Anemia after kidney transplant is not uncommon. This paper reports a case of unexplained anemia in a kidney transplant recipient that persisted for more than two months, and that did not respond to recombinant human erythropoietin treatment but was successfully treated after diagnosing Parvovirus B19 (ParvoV B19) infection. A middle-aged male underwent living-unrelated kidney transplantation from Pakistan in April 2015. He was on triple immuno-suppression therapy consisting of prednisolone, tacrolimus, and mycophenolate mofetil. He presented with anemia which persisted for more than two months that did not improve with Darbepoetin alpha and required blood transfusions. A bone marrow biopsy demonstrated pure erythroid hypoplasia and occasional giant pronormoblasts characteristic of a ParvoV B19 infection. The serum was highly positive for ParvoV B19 DNA polymerase chain reaction. The anemia resolved completely three weeks after the administration of intravenous immunoglobulin. ParvoV B19 infection should be considered in the differential diagnosis of kidney transplant recipients who present with anemia associated with a low reticulocyte count.

Study protocol: patient reported outcomes for bladder management strategies in spinal cord injury.

BACKGROUND: The majority of spinal cord injury (SCI) patients have urinary issues, such as incontinence, retention, and frequency. These problems place a significant burden on patients' physical health and quality of life (QoL). There are a wide variety of bladder management strategies available to patients with no clear guidelines on appropriate selection. Inappropriate bladder management can cause hospitalizations and serious complications, such as urosepsis and renal failure. Patients believe that both independence and ability to carry out daily activities are just as important as physical health in selecting the right bladder-management strategy but little is known about patient's QoL with different bladder managements. Our study's aim is to assess patient reported QoL measures with various bladder managements after SCI. This manuscript describes the approach, study design and common data elements for our central study. METHODS: This is a multi-institutional prospective cohort study comparing three different bladder-management strategies (clean intermittent catheterization, indwelling catheters, and surgery). Information collected from participants includes demographics, past medical and surgical history, injury characteristics, current and past bladder management, and SCI /bladder-related complications. Patient reported outcomes and QoL questionnaires were administered at enrollment and every 3 months for 1 year. Aims of this study protocol are: (1) to assess baseline QoL differences between the three different bladder-management strategies; (2) determine QoL impact when those using either form of catheter management undergo a surgery over the 1 year of follow-up among patients eligible for surgery; (3) assess the effects of changes in bladder management and complications on QoL over a 1-year longitudinal follow-up. DISCUSSION: By providing information about patient-reported outcomes associated with different bladder management strategies after SCI, and the impact of bladder management changes and complications on QoL, this study will provide essential information for shared decision-making and guide future investigation. TRIAL REGISTRATION: Trial registration number: www.clinicaltrials.gov : Identifier: NCT0261608; U.S. National Library of Medicine, wwwcf.nlm.nih.gov : Identifier: HSRP20153564.

Mending Gaps in Knowledge: Collaborations in Neurogenic Bladder Research.

Patient-reported outcomes and quality of life assessments are essential to studying conditions such as neurogenic bladder in which multiple management strategies are approximately equally efficacious. Innovations for the treatment of neurogenic bladder need to be guided by both clinical and patient-reported outcomes that are rigorously tested via high-quality prospective cohort or randomized studies. Collaborative research groups in reconstructive urology are critical to the study of uncommon disease processes because they allow studies to be powered adequately, foster innovative treatment strategies through collaboration, and help moderate the risk of investigator and or institutional biases.

Early clinical manifestations and laboratory findings before and after treatment of cytomegalovirus infection in kidney transplant patients.

Cytomegalovirus (CMV) is one of the most frequently encountered opportunistic viral pathogens in kidney transplant recipients. In this study, we retrospectively reviewed all living related and unrelated kidney transplant recipients on regular follow-up from January 2006 to June 2015, who were suspected to have CMV clinically and confirmed by DNA polymerase chain reaction (PCR). CMV PCR was detected in 102 kidney transplant recipients. The median time of detection after kidney transplant was 21 months, ranging from 15 days to 84 months. There were 58 male and 44 female patients. The induction immunosuppression in living related kidney transplants was with antithymocyte globulin or basiliximab, whereas the most common maintenance immunosuppressive regimen was with cyclosporine, mycophenolate mofetil, and prednisolone. Most of the transplant recipients were asymptomatic at the time of detection of CMV PCR (67%). Fever, mainly low grade, was the main presentation in 16% of patients, followed by diarrhea (15%) and pneumonitis (2%). The most common hematological abnormality was lymphopenia seen in 46% of patients, followed by anemia (40%) and thrombocytopenia (14%). The common biochemical abnormalities found were elevated alanine aminotransaminase (18%) and hyperbilirubinemia (9%). The serum creatinine was found to be above baseline in 72% of patients. All patients with CMV infection were treated with intravenous ganciclovir, 2.5-5 mg/kg q 12 hourly, according to creatinine clearance, for 21 days. The treatment was successful in all but two patients, who died during the treatment period. There was a significant improvement in the kidney and liver functions after successful treatment of CMV infection. Our study shows that CMV infection should be considered in a patient presenting with unexplained rise in serum creatinine, low-grade fever, diarrhea, or anemia. A significant improvement in kidney and liver functions was observed after successful treatment of the infection.

Curcumin: Not So Spicy After All.

BACKGROUND: This is a short review on the most recent studies on curcumin and its analogs, including the studies from the laboratories of authors. The diverse medicinal properties of curcumin itself reported in the recent years are reviewed. Although curcumin has shown great potential in treating various diseases, it has not been approved as a clinical drug candidate because of its poor pharmacokinetics. METHOD: The recent methods developed to solve this problem are briefly described. CONCLUSION: The biological and other properties of synthetic curcumin analogs (diarylheptanoids and diarylpentanoid monocarbonyl derivatives) reported in the recent literature are also presented.

Convenient access to 5-arylisoindolo[2,1- α]quinolin-11(6a H)-ones.

Substituted isoindoloquinolinones were obtained from N-aryl-3-hydroxyisoindolinones and aryl alkynes under Lewis acid-catalyzed conditions in 30-99% yields.

Curcumin-inspired cytotoxic 3,5-bis(arylmethylene)-1-(N-(ortho-substituted aryl)maleamoyl)-4-piperidones: A novel group of topoisomerase II alpha inhibitors.

Three series of novel 3,5-bis(arylmethylene)-1-(N-(ortho-substituted aryl)maleamoyl)-4-piperidones, designed as simplified analogs of curcumin with maleic diamide tether, were synthesized and bioevaluated. These compounds displayed potent cytotoxicity towards human Molt 4/C8 and CEM T-lymphocytes as well as murine L1210 leukemic cells. In contrast, the related N-arylmaleamic acids possessed little or no cytotoxicity in these three screens. Design of these compounds was based on molecular modeling studies performed on a related series of molecule in a previous study. Representative title compounds were found to be significantly potent in inhibiting the activity of topoisomerase II alpha indicating the possible mode of action of these compounds. These compounds were also potent antioxidants in vitro and attenuated the AAPH triggered peroxyl radical production in human fibroblasts. Various members of these series were also well tolerated in both in vitro and in vivo toxicity analysis.

Novel carbocyclic curcumin analog CUR3d modulates genes involved in multiple apoptosis pathways in human hepatocellular carcinoma cells.

Anticancer activity of a novel curcumin analog (E)-2-(4-hydroxy-3-methoxybenzylidene)-5-((E)-3-(4-hydroxy-3-methoxyphenyl)acryloyl)cyclopentanone (CUR3d) was studied using a human hepatocellular carcinoma cell line (HepG2). The results showed that CUR3d completely inhibits the tumor cell proliferation in a dose- and time-dependent manner. CUR3d at 100 µmol/L activated the pro-apoptotic caspase-3 along with downregulation of anti-apoptotic BIRC5 and Bcl2. CUR3d treatment controlled the cancer cell growth by downregulating the expression of PI3K/Akt (Akt1, Akt2) pathway along with NF-κB. CUR3d down-regulated the members of epidermal growth receptor family (EGFR, ERBB3, ERBB2) and insulin like growth receptors (IGF1, IGF-1R, IGF2). This correlated with the downregulation of G-protein (RHOA, RHOB) and RAS (ATF2, HRAS, KRAS, NRAS) pathway signaling. CUR3d also arrested cell cycle via inhibition of CDK2, CDK4, CDK5, CDK9, MDM2, MDM4 and TERT genes. Cell cycle essential aurora kinases (AURKα, AURKß) and polo-like kinases (PLK1, PLK2, PLK3) were also modulated by CUR3d. Topoisomerases (TOP2α, TOP2ß), important factors in cancer cell immortality, as well as HIF-1α were downregulated following CUR3d treatment. The expression of protein kinase-C family (PRKC-A, PRKC-D, PRKC-E) was also attenuated by CUR3d. The downregulation of histone deacetylases (Class I, II, IV) and PARP I further strengthened the anticancer efficacy of CUR3d. Downregulation of carcinogenic cathepsins (CTSB, CTSD) and heat shock proteins exhibited CUR3d's potency as a potential immunological adjuvant. Finally, the non-toxic manifestation of CUR3d in healthy liver and lung cells along with downregulation of drug resistant gene ABCC1 further warrant need for advance investigations.

Concise synthesis of 12a-methyl-11-aryl-1,2-dihydrobenzo[f]pyrrolo[1,2-a]quinolin-3(12aH)-ones as racemic 14-azaestrogen analogs.

A concise method for the synthesis of 14-azasteroid analogs with angular methyl group at C-13 of the steroidal nucleus has been reported in this paper. We have developed an interesting cascade reaction of arylacetylenes and N-(naphthalen-2-yl)pent-4-ynamides under gold (III)-catalysis to produce novel tetracyclic 12a-methyl-11-aryl-1,2-dihydrobenzo[f]pyrrolo[1,2-a]quinolin-3(12aH)-ones which may be viewed as 14-azaestrogen analogs.

Investigation of fatty acid conjugates of 3,5-bisarylmethylene-4-piperidone derivatives as antitumor agents and human topoisomerase-IIα inhibitors.

A series of five 3,5-bisarylidene-4-piperidones designed as analogs of curcumin and their twenty five fatty acid conjugates were synthesized as candidate anticancer agents. The fatty acid conjugates were designed for efficient delivery of these compounds at the targeted cancer sites. The cytostatic potential of these compounds was evaluated against three representative cancer cell lines namely murine leukemic L1210 cells, and human T-lymphocyte CEM cells and cervical HeLa cells. Most compounds were found to exhibit significant anti-cancer activity in vitro. QSAR studies indicated electrophilicity of these compounds towards cellular nucleophiles may have a key role to play in their cytostatic activity. Representative compounds were also tested for topoisomerase IIα inhibitory potential, which indicated strong catalytic inhibition of the enzyme in vitro. The data showed that the fatty acid conjugates also possessed robust antioxidant activity in multiple analyses. This study also indicated that these compounds prompted significantly lower cellular damage in human fibroblasts than a currently used cancer drug sorafenib in vitro. The wide spectrum of anticancer action, supplemented with antioxidant potential along with non-toxic manifestations, certainly augment the anticancer candidacy of the novel fatty acid conjugates.

Design, synthesis and bioevaluation of novel 6-(4-Hydroxypiperidino)naphthalen-2-ol-based potential Selective Estrogen Receptor Modulators for breast cancer.

In a study directed towards development of novel Selective Estrogen Receptor Modulators (SERMs), 1-(4-(2-(dialkylamino)ethoxy)benzyl)-6-(4-hydroxypiperidin-1-yl)-2-naphthol and corresponding aryl methyl ethers were synthesized and bioevaluated against the estrogen-responsive human MCF-7 breast cancer cell line. The phenolic analogs displayed little or no activity, but aryl methyl ether analogs showed significant cytotoxic potency. Also, representative compounds from the aryl methyl ether series showed significant binding and antagonistic activity against ERα. Two representative compounds were also evaluated for in vitro membrane permeability, plasma stability as well as in-vivo toxicity in mice. The compounds displayed well-acceptable drug-like in vitro membrane permeability as well as plasma stability and were well-tolerated in experimental mice at 300 mg/kg dose.

All trans 1-(3-arylacryloyl)-3,5-bis(pyridin-4-ylmethylene)piperidin-4-ones as curcumin-inspired antineoplastics.

A series of eleven N-acryloyl/N-cinnamoyl 3,5-bis(pyridin-4-yl)methylene-4-piperidones were synthesized as curcumin-based candidate antineoplastic agents. The cytostatic potency of these compounds was evaluated against three representative cell lines and all compounds were found to exhibit significant anti-cancer cell activity in vitro. QSAR studies using several physicochemical parameters and 50% inhibitory concentration (IC50) values resulted in certain important correlations which will aid design of more potent analogs. Representative test compounds were investigated in the NCI 60-cell line panel where they were found to display a profound cytotoxicity. These compounds were also potent anti-oxidants and inhibitors of human topoisomerase IIα. Representative compounds were well-tolerated by human fibroblasts and by mice during the survival/toxicity studies.