Primary Therapeutic Option Research Articles

Aspergillus fumigatus Cyp51A and Cyp51B Proteins Are Compensatory in Function and Localize Differentially in Response to Antifungals and Cell Wall Inhibitors.

Triazole antifungals are the primary therapeutic option against invasive aspergillosis. However, resistance to azoles has increased dramatically over the last decade. Azole resistance is known to primarily occur due to point mutations in the azole target protein Cyp51A, one of two paralogous 14-α sterol demethylases found in Aspergillus fumigatus Despite the importance of Cyp51A, little is known about the function of its paralog, Cyp51B, and the behavior of these proteins within the cell or their functional interrelationship. In this study, we addressed two important aspects of the Cyp51 proteins: (i) we characterized their localization patterns under normal growth versus stress conditions, and (ii) we determined how the proteins compensate for each other's absence and respond to azole treatment. Both the Cyp51A and Cyp51B proteins were found to localize in distinct endoplasmic reticulum (ER) domains, including the perinuclear ER and the peripheral ER. Occasionally, the Cyp51 proteins concentrated in the peripheral ER network of tubules along the hyphal septa and at the hyphal tips. Exposure to voriconazole, caspofungin, and Congo red led to significant increases in fluorescence intensity in these alternative localization sites, indicative of Cyp51 protein translocation in response to cell wall stress. Furthermore, deletion of either Cyp51 paralog increased susceptibility to voriconazole, though a greater effect was observed following deletion of cyp51A, indicating a compensatory response to stress conditions.

Current Treatment Options for Patulous Eustachian Tube: A Review of the Literature.

Patulous Eustachian tube (PET) is a clinical condition that is associated with troublesome aural symptoms and is difficult to be treated successfully. The purpose of this review is to examine the published literature regarding the therapeutic value of the current treatment options for PET. We searched Web of Science, PubMed and Medline from 1999 to 2019. The search focused on papers concerning the clinical evaluation of treatment methods in PET patients. Statistical techniques were not used. Prospective and retrospective case series were the types of trials available for review. We included 28 articles that evaluated the efficacy of various conservative and surgical therapeutic options. The recovery rates ranged from 50% to 100%. In most studies the assessment of efficacy was based on the subjective improvement of patient symptoms as there is no validated outcome tool available. No severe adverse events were observed in any study. On the basis of the available literature, it seems that conservative treatments can be considered as a primary therapeutic option for PET. Concerning the surgical interventions they seem to be a safe and valuable solution in patients with refractory disease. Finally, given the low level of evidence, prospective case-control studies with long follow-up and robust setting looking into the therapeutic approach of PET are required. The need for establishment of standard criteria of PET recovery should be underlined.

Investigation of Bladder Cancer Cell Response to Cryoablation and Adjunctive Cisplatin Based Cryo/Chemotherapy.

Due to a rising annual incidence of bladder cancer, there is a growing need for development of new strategies for treatment. In 2018, the World Cancer Research Fund and other groups reported that there were ~550,000 new cases worldwide of bladder cancer. It has been further estimated that >200,000 individuals die annually from bladder cancer worldwide. Various treatment options exist. However, many if not all remain suboptimal. While the preferred chemotherapeutic options have changed in the past few years there have been few advances in the bladder cancer medical device field. Cryoablation is now being evaluated as a new option for the treatment of bladder cancer. While several studies have shown cryoablation to be promising for the treatment of bladder cancer, a lack of basic information pertaining to dosing (minimal lethal temperature) necessary to destroy bladder cancer has limited its use as a primary therapeutic option. Concerns with bladder wall perforation and other side effects have also slowed adoption.In an effort to detail the effects of freezing on bladder cancer, two human bladder cancer cell lines, SCaBER and UMUC3, were evaluated in vitro. SCaBER, a basal subtype of muscle invasive bladder cancer, and UMUC3, an intermediate transitional cell carcinoma, are both difficult to treat but are reportedly responsive to most conventional treatments. SCaBER and UMUC3 cells were exposed to a range of freezing temperatures from −10 to −25°C and compared to non-frozen controls. The data show that a single 5 minute freeze to −10°C did not affect cell viability, whereas −15°C and −20°C results in a significant reduction in viability 1 day post freeze to <20%. These populations, however, were able to recover in culture. A complete loss of cell viability was found following a single freeze at −25°C. Application of a repeat (double) freeze resulted in complete cell death at −20°C. In addition to freezing alone, studies investigating the impact of adjunctive low dose (1 μM) cisplatin pre-treatment (30 minutes and 24 hours) in combination with freezing were conducted. The combination of 30 minute cisplatin pre-treatment and mild (−15°C) freezing resulted in complete cell death. This suggests that subclinical doses of cisplatin may be synergistically effective when combined with freezing.In summary, these in vitro results suggest that freezing to temperatures in the range of −20 to 25°C results in a high degree of bladder cancer cell destruction. Further, the data describe a potential combinatorial chemo/cryo therapeutic strategy for the treatment of bladder cancer.

Development and Validation of a Novel, Rapid Gradient HPLC Method for Simultaneous Estimation of Bioactive Marker Compounds in a Mixture of Convolvulus pluricaulis, Withania somnifera and Bacopa monnieri Extracts.

The use of herbs as medicine is an ancient form of healthcare known to mankind. Standardization of herbal medicines is however a challenging task and is the major bottleneck in their acceptance as the primary therapeutic option. The aim of this study was to develop and validate a simple, rapid HPLC method for standardizing the mixture of extracts of three Medhya Rasayanas (neurotonic), Convolvulus pluricaulis, Withania somnifera and Bacopa monnieri. Simultaneous estimation of the respective bioactive markers of these plants viz., scopoletin, withaferin A, bacoside A 3, bacopaside II, jujubogenin and bacosaponin C has been reported for the first time. The method was developed using Waters Hybrid X-Bridge shield with BEH technology 2.5μm, 4.6 × 75mm column and validated according to ICH guidelines. The 20minutes run time makes the method eco-friendly. The method was linear over a range of 12.5-400ng/10μL for scopoletin and 62.5-2,000ng/10μL for withaferin A, bacoside A 3, bacopaside II, jujubogenin and bacosaponin C with detection limits of 8.0, 48.3, 30.4, 40.7, 15.6 and 18.9ng/10μL and quantification limits of 24.5, 146.5, 92.2, 123.4, 47.4 and 57.4ng/10μL, respectively. The correlation coefficient for each analyte was >0.999. The intra-day and inter-day precision was <2%. These results confirmed the precision, accuracy and robustness of the proposed method.

Evaluation of telavancin susceptibility in isolates of Staphylococcus aureus with reduced susceptibility to vancomycin

Historically, vancomycin has been considered a primary therapeutic option for treating infections with Staphylococcus aureus, but isolates with reduced vancomycin susceptibility (SA-RVS) (MIC ≥ 4μg/mL) have emerged. Telavancin, a semisynthetic lipoglycopeptide, is an alternative treatment option for S. aureus, but data examining telavancin activity against SA-RVS are limited. In the present study, we characterize 300 isolates of S. aureus isolates (50 vancomycin-susceptible (VSSA) isolates and 250 SA-RVS isolates) from a large tertiary care, academic medical center, 51.8% of which were methicillin resistant (MRSA). Sixteen (6.4%) SA-RVS isolates were non-susceptible to telavancin, whereas all VSSA isolates were susceptible. Additionally, 3.6% of SA-RVS isolates were non-susceptible to daptomycin, with three (1.2%) isolates testing non-susceptible to both telavancin and daptomycin. When tested against other classes of antimicrobials, there were no statistical differences in susceptibility of VSSA and SA-RVS isolates, except for the fluoroquinolones (ciprofloxacin and moxifloxacin). Molecular characterization of the isolates showed that SCCmec types II and IV together represented over half of the SA-RVS isolates; 12.0% of the VSSA isolates were SCCmec type II. Using RepPCR, we detected 16 distinct strain types in this isolate collection, and tst-1 (gene encoding the Staphylococcus toxic shock syndrome super-antigen) carriage was low (5.4%). Overall, we show that in addition to reduced vancomycin susceptibility, a small, but clinically significant, proportion of SA-RVS isolates also demonstrate reduced susceptibility to both telavancin and daptomycin.

Endoscopic endonasal transpterygoid transnasopharyngeal management of petroclival chondrosarcomas without medial extension.

Chondrosarcomas of the skull base are malignant tumors for which surgery is the primary therapeutic option. Gross-total resection has been demonstrated to improve survival in patients with these tumors. Chondrosarcomas arising from the petroclival synchondrosis harbor particularly unique anatomical considerations that have long been a barrier to achieving such a resection. Endoscopic endonasal transpterygoid approaches have been recently used to gain improved access to such lesions; however, these approaches have classically relied on a medial to lateral transclival trajectory, which provides limited exposure for complete resection of lateral disease. In this paper the authors describe an endoscopic endonasal transpterygoid transnasopharyngeal approach that provides comprehensive access to the petroclival region through dissection of the eustachian tube with resection of the cartilaginous torus tubarius. Of note, the authors have previously demonstrated the superior outcomes and validity of this approach relative to other cranial base techniques for petroclival chondrosarcomas. Surgical outcomes in 5 cases of chondrosarcoma without medial extension are detailed. Gross-total resection was achieved in 4 of 5 patients. Postoperative complications included transient palatal numbness in all patients and eustachian tube dysfunction due to the approach. With tympanostomy tube placement, no patient had persistent hearing loss. Overall, this approach appears to be a safe and effective technique for resection of petroclival chondrosarcomas.

Surgical approaches and long-term outcomes of intramedullary spinal cord cavernous malformations: a single-center consecutive series of 219 patients.

Optimal surgical strategies for intramedullary spinal cord cavernous malformations (ISCCMs) are not optimized and remain problematic. In this study the authors identify rational surgical strategies for ISCCMs and predictors of outcomes after resection. A single-center study was performed with 219 consecutive surgically treated patients who presented from 2002 to 2017 and were analyzed retrospectively. The American Spinal Injury Association (ASIA) Impairment Scale was used to evaluate neurological functions. Patient characteristics, surgical approaches, and immediate and long-term postoperative outcomes were identified. The average ISCCM size was 10.5 mm. The spinal level affected was cervical in 24.8% of patients, thoracic in 73.4%, and lumbar in 1.8%. The locations of the lesions in the horizontal plane were 30.4% ventral, 41.6% dorsal, and 28.0% central. Of the 214 patients included in the cohort for operative evaluation, 62.6% had superficially located lesions, while 37.4% were embedded. Gross-total resection was achieved in 98.1% of patients. The immediate postoperative neurological condition worsened in 10.3% of the patients. Multivariate logistic regression identified mild preoperative function (p = 0.014, odds ratio [OR] 4.5, 95% confidence interval [CI] 1.4-14.8) and thoracolumbar-level lesions (p = 0.01, OR 15.7, 95% CI 1.9-130.2) as independent predictors of worsening. The mean follow-up duration in 187 patients was 45.9 months. Of these patients, 63.1% were stable, 33.2% improved, and 3.7% worsened. Favorable outcomes were observed in 86.1% of patients during long-term follow-up and were significantly associated with preoperative mild neurological and disability status (p = 0.000) and cervically located lesions (p = 0.009). The depths of the lesions were associated with worse long-term outcomes (p = 0.001), and performing myelotomy directly through a yellowish abnormal surface in moderate-depth lesions was an independent predictor of worsening (p = 0.023, OR 35.3, 95% CI 1.6-756.3). Resection performed with an individualized surgical approach remains the primary therapeutic option in ISCCMs. Performing surgery in patients with mild symptoms at the thoracolumbar level and embedded located lesions requires more discretion.

Sudden Cardiac Death in Brugada Syndrome.

The Brugada syndrome is an inherited channelopathy that alters the main transmembrane ion currents that constitute the cardiac action potential. These changes not only modify the resting electrocardiogram but also predispose patients to develop malignant ventricular tachyarrhythmias that can lead to syncope, cardiac arrest, and sudden cardiac death. This syndrome is responsible for nearly 20% of all sudden cardiac deaths in patients with structurally normal hearts and up to 12% of all sudden cardiac deaths. Brugada syndrome is diagnosed by its characteristic electrocardiogram consisting of a coved-type ST-segment elevation of at least 2 mm followed by a negative T wave in either one of the right precordial leads. These changes can be observed spontaneously or after administration of a sodium channel blocker. While our understanding of this disease has increased tremendously since its first description in 1992, the primary therapeutic option remains implantation of an implantable cardioverter-defibrillator to avoid sudden cardiac death. Therefore, tremendous effort is being made to effectively risk stratify patients to determine who would benefit from implantable cardioverter-defibrillator implantation.

Treatment of ovarian endometrial cysts in the context of recurrence and fertility.

An approach to ovarian endometrial cysts has changed considerably during recent years, especially in regard to treatment of recurrent endometriosis, fertility sparing and infertility management. Surgical treatment is the primary therapeutic option. The most efficient types of treatment are radical procedures involving adhesiolysis, removal of the cyst along with its capsule and any remaining endometriotic foci. However, small asymptomatic cysts should not be treated surgically, especially in patients older than 35 years. Surgical treatment can be considered in infertile women and those who failed to get pregnant despite 1-1.5 years of trials, as well as in cases in which in vitro fertilization is not an option. Also large cysts, with more than 4 cm in diameter, should be treated surgically due to the risk of their rupture or torsion. The most efficient preventive measure for recurrent ovarian endometriosis is unilateral oophorectomy with sparing the contralateral ovary. Such a procedure should be considered in women who are no longer interested in childbearing or present with another endometriotic cyst in the same ovary. The role of pharmacotherapy is fairly limited; it should be considered in patients in whom diffuse endometriosis is associated with pain. Therapeutic agents from the following groups can be used: estrogen-progestin preparation, gestagens, including progesteronereleasing intrauterine systems and gonadotropin-releasing hormone agonists. Women with infertility should get pregnant as soon as possible, and in patients who failed to get pregnant and/or are older than 35 years, in vitro fertilization should be the treatment of choice.

Gemcitabine: A Review of Chemoresistance in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma, an exocrine tumor, is the most common type of cancer of the pancreas and one of the top five most prominent causes of cancer-associated mortality worldwide. The survival rate for pancreatic cancer is sadly less than 8%. The high fatality rate is partly related to late diagnosis and partly to the aggressive nature of malignant cells that disseminate to nearby tissues at an early stage of the disease, making treatment difficult. Available treatment choices consist of both medical and surgical: removal of the tumor, use of various medications like chemotherapeutic drugs and immunotherapeutic agents, radiation therapy, and targeted drug therapy. Since most patients suffer from advanced cancer at the time of diagnosis, chemotherapy becomes the primary therapeutic option in such cases. Drugs like Gemcitabine, Abraxane, FOLFIRINOX, and newer combination therapies are all effective in management, either curatively or palliatively. However, chemoresistance poses a significant challenge. Several factors, both intrinsic and acquired, are involved in drug resistance. Here, we review the mechanism of action of the first-line chemotherapy drugs in pancreatic cancer and various factors associated with cancer chemoresistance.

Review. Gastrointestinal Surgery in Neonates: Practice, Facts, and Trends

The author presents an overview of the current trends in acute neonatal gastrointestinal surgery. Necrotizing enterocolitis and focal intestinal perforation are disorders of different etiology, appearance, and prognosis. In neonates with focal perforation, a good prognosis can be expected. Primary anastomosis is a valid option for primary surgery. Meconium ileus is based on obstruction of the terminal ileum. Medical treatment is the primary therapeutic option, although surgery may be required. In contrast, meconium plug syndrome is based on stool plugging in the left colon, and surgery is not appropriate. Hirschsprung’s disease is confirmed on the basis of representative biopsy of the rectum just above the dentate line. There is a trend toward a single-step pull-through operation without protective stoma. Open hernia repair in small neonates can be performed via a mini-incision and without opening the external inguinal ring. Laparoscopic hernia repair has some advantages, especially in girls. In infants with pyloric stenosis, laparoscopic pyloromyotomy is a first line option for treatment. There is a general trend toward single-stage procedures and laparoscopic reconstructive surgery for gastrointestinal malformations. With the exception of tracheoesophageal fistula and low bowel obstruction, the vast majority of upper gastrointestinal malformations can be identified using prenatal ultrasound examination. One-stage repair with excellent results is even possible in neonates below 1000 g. Surgery of duodenal or small bowel atresia can be performed following the postnatal adaptation period. For some forms of anorectal malformation, the need for a protective stoma has been questioned in the last decade. Posterior sagittal anorectoplasty remains the standard procedure for the majority of cases. Midgut or segmental volvulus affects different groups of infants. If a neonate is suspected of having any type of volvulus, urgent surgery is required. Intestinal duplication carries a high risk for complications, and surgery should be performed on an elective basis.

MAP2K6 is associated with radiation resistance and adverse prognosis for locally advanced nasopharyngeal carcinoma patients.

BackgroundAlthough radiotherapy is the primary therapeutic option for nasopharyngeal carcinoma (NPC), local recurrence and distant metastasis caused by radioresistance are still the major barriers for some NPC patients who cannot benefit from radiotherapy. In this study, we analyzed the association between MAP2K6 expression and radioresistance in patients with locally advanced NPC.MethodsWe collected 120 NPC patients who received radiotherapy in the Xiangya Hospital of Central South University from August 2008 to July 2012. The clinical data and tissue samples of patients were collected. Detection of MAP2K6 was performed using immunohistochemical staining.ResultsThe rates of two groups were 19.4% and 4.2%, and significant difference was observed between MAP2K6 high expression group and low expression group (χ2=5.817, P=0.016). The Kaplan–Meier analysis suggested a significant difference in the survival rate between two groups (P<0.05). The results from multivariate Cox regression indicated that the MAP2K6 was independently related to adverse prognosis in NCP patients (HR =3.40, 95% CI =1.13–10.26, P=0.030).ConclusionThe present study indicated that MAP2K6 was correlated with radioresistance, and the elevated expression of MAP2K6 predicted poor prognosis in NPC patients. MAP2K6 may be a new therapy target for radioresistance of NPC.

STAPHYLOCOCCUS AUREUS: PATHOGENICITY, ANTIMICROBIAL RESISTANCE AND CLINICAL IMPLICATIONS

Objective: To conduct a reflection about the pathogenicity, antimicrobial resistance, and clinical implications of the infections caused by Staphylococcus aureus . Method: Reflexive analysis, supported by theoretical references about the pathogenicity, antimicrobial resistance, and clinical implications of the staphylococcal infections. Results: The pathogenesis of S. aureus infections is complex and depends on the host characteristics, expression of virulence factors and ability to develop resistance to antimicrobials. Methicillin-resistant S. aureus (MRSA) is related to an advancement of healthcare- and community-acquired infections, being vancomycin the primary therapeutic option. Infections caused by S. aureus with reduced vancomycin susceptibility (hVISA/VISA) have been associated with treatment failures and increased mortality. Conclusion: With the evolution of S. aureus to MRSA, hVISA and VISA, the treatment of staphylococcal infections has become a major challenge for the medical clinic, and an adequate and early antibiotic therapy is essential for decreasing morbidity and mortality rates related to this microorganism.

Comparison of Selection and Long-term Clinical Outcomes Between Chemotherapy and Radiotherapy as Primary Therapeutic Modality for Ocular Adnexal MALT Lymphoma

BackgroundThe choice of a primary treatment for ocular adnexal mucosa-associated lymphoid tissue lymphoma (OAML) depends on the extent of tumor spread. However, radiotherapy is commonly used as a first-line therapy despite ophthalmic complications, because most OAMLs are in a limited stage of progression. However, the initial therapeutic modality, including chemotherapy and treatment of the advanced stage, has not been fully established for OAML. Therefore, we evaluated the optimal therapeutic options and survival outcome-related parameters for patients with primary OAML. MethodsWe evaluated 208 consecutive patients with primary OAML who were diagnosed at the Catholic University Lymphoma Group between January 2004 and April 2015. FindingsDuring a median follow-up of 70.0 months (range, 3.2–182.0 months) in 208 patients with primary OAML, most patients were female and the median age was 46 years old. Overall survival (OS) and progression-free survival (PFS) at 13 years were excellent (92.7% and 69.7%, respectively). Of the 117 patients who received the first-line radiotherapy, 92% achieved complete remission (CR), usually by being treated with less than 30 Gy. Radiation-related ophthalmic complications including dry eye syndrome (59%) and cataract (22%) caused a decline in the quality of life (QoL). Chemotherapy alone was used to treat 86 OAML patients, with 84.9% achieving CR and 12.8% achieving partial remission with tolerable toxicities. There were no differences in survival outcomes between patients treated with radiotherapy versus those treated with rituximab-containing chemotherapy, although the latter group had more advanced stages of OAML (OS, p = 0.057; PFS, p = 0.075). InterpretationOAML patients were predominantly female and relatively young, and radiotherapy as a primary therapeutic option was more likely to lead to radiation-related complications, resulting in lower QoL. On the other hand, frontline chemotherapy showed consistent therapeutic outcomes with tolerable toxicities compared to radiotherapy, and there were no long-term or delayed adverse events. Therefore, when considering therapeutic efficacy and therapy-related QoL, chemotherapy is recommended for younger patients, and radiotherapy is recommended for older and chemotherapy-ineligible patients. FundingA National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (No. NRF-2016R1A2B4007282).

Surgical treatment options for cervical paragangliomas

The therapies available for the rare tumor entity of cervical paraganglioma (PG) are currently undergoing aparadigm shift. The treatment of choice for small carotid body tumors, malignant and active endocrine tumors is surgical resection; however, for locally advanced carotid body tumors and vagal PG, surgical therapy should be critically evaluated. Due to the immediate proximity of these hypervascularized tumors to the caudal cranial nerves, there is a risk of severe nerve damage with a significant impairment of quality of life after resection, particularly for locally advanced cervical PG, emphasizing further the importance of arestrictive surgical strategy. External radiotherapy can provide an equivalent primary therapeutic option with respect to the rate of recurrence and is accompanied by alower morbidity. The slow rate of tumor progression and the multifocality of the familial variant of cervical PG or significant comorbidities in older, asymptomatic patients warrant aless aggressive treatment strategy for these tumors. When await and scan approach is implemented, aclosely monitored radiological and clinical re-evaluation is of upmost importance. In amultidisciplinary approach the following critical points require consideration before atherapy is implemented,: size and location of the tumor, progression rate, genetic background, patient age and general condition, relevant comorbidities, the presence of synchronous PG and/or vasoactive catecholamine-producing tumors. Although best practice algorithms for the treatment of cervical PG have already been devised, recent innovative developments have led to more patient-tailored, individualized treatment approaches.

A natural molecule, urolithin A, downregulates androgen receptor activation and suppresses growth of prostate cancer.

Androgen ablation therapy is the primary therapeutic option for locally advanced and metastatic castration-resistant prostate cancer (CRPC). We investigated therapeutic effect of a dietary metabolite Urolithin A (UroA) and dissected the molecular mechanism in CRPC cells. Treatment with UroA inhibited cell proliferation in both androgen receptor-positive (AR+ ) (C4-2B) and androgen receptor-negative (AR- ) (PC-3) cells however, AR+ CaP cells were more sensitive to UroA treatment as compared with AR- CaP cells. Inhibition of the AR signaling was responsible for the UroA effect on AR+ CaP cells. Ectopic expression of AR in PC-3 cells sensitized them to UroA treatment as compared to the vector-expresseing PC-3 cells, which suggests that AR could be a target of UroA. Similarly, in enzalutamide-resistant C4-2B cells, a downregulation of AR expression also suppressed cell proliferation which was observed with the UroA treatment. Oral administration of UroA significantly suppressed the growth of C4-2B xenografts (P = 0.05) compared with PC-3 xenografts (P = 0.069) without causing toxicity to animals. Immunohistochemistry analysis confirmed in vitro findings such as downregulation of AR/pAKT signaling in UroA-treated C4-2B tumors, which suggests that UroA may be a potent chemo-preventive and therapeutic agent for CRPC.

Effect of Silver nanoParticles on Carbapenem Resistant Gram-negative Bacteria

Background: Gram-negative bacteria are common causes of both community-acquired and hospital-acquired infections. β-Lactam drugs are often the primary therapeutic option for serious infections, and carbapenems in particular are often considered agents of last resort. Thus, the emergence and spread of carbapenem-resistant (CR) bacteria are a significant public health concern. Infections with these resistant bacteria are associated with higher mortality rates than those for infections caused by carbapenem susceptible organisms. There have been considerable efforts to develop new antimicrobials drug against this type of resistant bacteria. Silver Nanoparticles (AgNPs) have emerged as promising weapons in the anti-microbial arsenal. Their anti-microbial efficacy is attributable to multiple mechanism of action. Objective: The aim of this study was to evaluate effect of AgNPs on CR Gram-negative bacteria. Materials and Methods: Effect of AgNPs on CR Gram-negative bacteria alone and in combination with carbapenems. 50 CR Gram-negative bacterial samples were included in this study. They were divided into 4 types; Acinetobacter, E. coli, klebseilla and P. aeruginosa. Each type was divided into (subtypes) metalo and non metalo carbapenemase producers. Results: There was statistically significant difference between all types of CR Gram-negative bacteria with AgNPs alone and some of them with AgNPs plus antibiotic (P-value < 0.05). A comparison of the effect of AgNPs alone between different types of detected CR Gram-negative bacteria showed different levels of response. Lowest response was observed with klebsiella (metalo), while highest was remarked with P. aeruginosa (metalo). Highest synergy with highly statistically significant difference (P-value < 0.001) occurred with Meropenem in P. aeruginosa Conclusion: AgNPs showed anti-microbial effect against CR Gram-negative bacteria alone and synergistic effect against some of detected CR Gram-negative bacteria with certain antibiotics.

Effect of Silver nanoParticles on Carbapenem Resistant Gram-negative Bacteria

Background: Gram-negative bacteria are common causes of both community-acquired and hospital-acquired infections. β-Lactam drugs are often the primary therapeutic option for serious infections, and carbapenems in particular are often considered agents of last resort. Thus, the emergence and spread of carbapenem-resistant (CR) bacteria are a significant public health concern. Infections with these resistant bacteria are associated with higher mortality rates than those for infections caused by carbapenem susceptible organisms. There have been considerable efforts to develop new antimicrobials drug against this type of resistant bacteria. Silver Nanoparticles (AgNPs) have emerged as promising weapons in the anti-microbial arsenal. Their anti-microbial efficacy is attributable to multiple mechanism of action. Objective: The aim of this study was to evaluate effect of AgNPs on CR Gram-negative bacteria. Materials and Methods: Effect of AgNPs on CR Gram-negative bacteria alone and in combination with carbapenems. 50 CR Gram-negative bacterial samples were included in this study. They were divided into 4 types; Acinetobacter, E. coli, klebseilla and P. aeruginosa. Each type was divided into (subtypes) metalo and non metalo carbapenemase producers. Results: There was statistically significant difference between all types of CR Gram-negative bacteria with AgNPs alone and some of them with AgNPs plus antibiotic (P-value < 0.05). A comparison of the effect of AgNPs alone between different types of detected CR Gram-negative bacteria showed different levels of response. Lowest response was observed with klebsiella (metalo), while highest was remarked with P. aeruginosa (metalo). Highest synergy with highly statistically significant difference (P-value < 0.001) occurred with Meropenem in P. aeruginosa Conclusion: AgNPs showed anti-microbial effect against CR Gram-negative bacteria alone and synergistic effect against some of detected CR Gram-negative bacteria with certain antibiotics.

Radical cystectomy and urinary diversion-what is important ?

In Germany, radical cystectomy with urinary diversion is the primary therapeutic option for localized muscle invasive urothelial bladder cancer. Modifications in the pre-, peri-, and postoperative phase have significantly improved outcomes. Different factors and parameters are directly associated with patients' outcome. An overview on how to best approach this procedure is provided in this article. The data regarding preparation and the procedure for the radical cystectomy followed by urinary diversion are separately analyzed. During the preoperative phase, Fast Track and ERAS (Enhanced Recovery after Surgery) concepts should be an integral part of therapeutic management. Different aspects of such models are presented and discussed. Comorbidities such as diabetes mellitus, hypertension, malnutrition or anemia should also be treated early. In the perioperative phase, optimized fluid management and close interaction with the anesthesiologist are needed. Use of vasopressors during surgery and controlled hypotension (about80 mm Hg) help reduce perioperative blood loss. Blood product use should be minimized. The use of epidural anesthesia to improve the stress reaction of the body improves pain management and functional recovery. Radical cystectomy is associated with the best oncological outcome, preserving functional structures to maintain agood quality of life. Nerve-sparing procedures in men and women should be used where appropriate. The use of robotic assisted radical cystectomy (RARC) is also discussed. The ileum conduit is still the most common urinary diversion worldwide. However, numerous other urinary diversions to provide patients with the highest quality of life are available. Centers with ahigh case load seem to be associated with an improved outcome.

Molecular and cellular mechanisms of castration resistant prostate cancer.

With increases in the mortality rate and number of patients with prostate cancer (PCa), PCa, particularly the advanced and metastatic disease, has been the focus of a number of studies globally. Over the past seven decades, androgen deprivation therapy has been the primary therapeutic option for patients with advanced PCa; however, the majority of patients developed a poor prognosis stage of castration resistant prostate cancer (CRPC), which eventually led to mortality. Due to CRPC being incurable, laboratory investigations and clinical studies focusing on CRPC have been conducted worldwide. Clarification of the molecular pathways that may lead to CRPC is important for discovering novel therapeutic strategies to delay or reverse the progression of disease. A sustained androgen receptor (AR) signal is still regarded as the main cause of CRPC. Increasing number of studies have proposed different potential mechanisms that cause CRPC, and this has led to the development of novel agents targeting the AR-dependent pathway or AR-independent signaling. In the present review, the major underlying mechanisms causing CRPC, including several major categories of AR-dependent mechanisms, AR bypass signaling, AR-independent mechanisms and other important hypotheses (including the functions of autophagy, PCa stem cell and microRNAs in CRPC progression), are summarized with retrospective pre-clinical or clinical trials to guide future research and therapy.