Effect of cell membrane thiols and reduction-triggered disassembly on transfection activity of bioreducible polyplexes

Bioreducible polyplexes are promising vectors for delivery of nucleic acids due to low toxicity and favorable transfection activity. The often improved transfection is usually explained by enhanced intracellular reductive disassembly of the polyplexes. This study evaluated the effect of enhanced reductive disassembly on transfection activity of plasmid DNA and antisense oligonucleotide (AON) polyplexes based on a series of bioreducible poly(amido amine)s (PAA). We found that the presence of disulfide bonds in PAA had no effect on nucleic acid binding, hydrodynamic size and zeta potential of polyplexes. Increasing the disulfide content in PAA increased susceptibility to reduction-triggered DNA and AON release from the polyplexes. Increasing the disulfide content in PAA increased DNA transfection but had no effect on AON transfection. Plasma membrane protein thiols played a key role in the observed enhancement of DNA transfection. The presence of disulfide bonds in PAA had no significant effect on the rate of intracellular DNA clearance, suggesting that enhanced intracellular disassembly of the bioreducible polyplexes is not a major contributing factor to the improved transfection activity.     

Laparoscopic ureterocystoplasty before kidney transplantation

PURPOSE: To describe the technique of total laparoscopic ureterocystoplasty. MATERIALS AND METHODS: Laparoscopic ureterocystoplasty was performed to optimize the bladder function before kidney transplantation in a 23-year-old man. This patient had undergone bilateral cutaneous ureterostomy with fulguration of a posterior urethral valve at the age of 11 months. He underwent open surgical removal of multiple renal stones at age 10. He progressed to chronic renal failure at the age of 20, at which time hemodialysis was initiated. Because of grade IV vesicoureteral reflux and a poorly compliant bladder, the patient underwent laparoscopic ureterocystoplasty. RESULTS: The patient's lower urinary tract symptoms improved, and a urodynamic study performed after 6 months revealed a compliant bladder. Subsequently, a right nephrectomy and a live-donor renal transplantation from his mother were performed. At 1-year follow-up, his renal parameters were within normal range, he does not have any significant residual urine or urinary symptoms. CONCLUSION: Laparoscopic ureterocystoplasty is an excellent option for a poorly compliant bladder, especially when a patient has had multiple open surgeries and is awaiting renal transplantation.     

Raynaud's phenomenon secondary to erenumab in a patient with chronic migraine

Raynaud''s phenomenon is a rare side effect of CGRP monoclonal antibodies. These molecular treatments are a relatively new class of drugs for the prevention of migraine. It is likely that we will see this side effect more often in the future. Patients with a background of Raynaud''s phenomenon may experience worsening of their symptoms if started on these treatments.     

Activity of telithromycin against key pathogens associated with community-acquired respiratory tract infections

OBJECTIVES: To investigate the correlation between in vitro susceptibility of isolates and clinical outcomes with telithromycin in respiratory tract infections. METHODS: The activity of telithromycin was determined by in vitro susceptibility testing of key respiratory tract pathogens isolated from patients with community-acquired pneumonia, acute exacerbations of chronic bronchitis or acute maxillary sinusitis enrolled in 14 Phase III/IV clinical trials evaluating the clinical efficacy of telithromycin. RESULTS: In this pooled analysis, telithromycin mode minimum inhibitory concentration (MIC) and MIC90, respectively, were: 0.016 and 0.03 mg/l against Streptococcus pneumoniae (n=626); 0.03 and 0.5 mg/l for penicillin-resistant S. pneumoniae (n=56); 0.03 and 1 mg/l for erythromycin-resistant S. pneumoniae (n=81); 2 and 4 mg/l against Haemophilus influenzae (including beta-lactamase producers; n=627); both 0.12 mg/l for Moraxella catarrhalis (n=159) and both 0.25 mg/l for Staphylococcus aureus (n=124). Telithromycin (5 or 7-10 days) resulted in overall clinical and bacteriologic success rates of 88.1% (1593/1808) and 89% (1593/1789), respectively. CONCLUSIONS: High levels of in vitro susceptibility to telithromycin are paralleled by high rates of clinical cure and bacteriologic eradication.     

Voice abnormality in adults with congenital and adult-acquired growth hormone deficiency

CONTEXT: Adult males with congenital, untreated, severe GH deficiency (GHD) due to genetic GHRH receptor deficiency exhibit distinctive, high-pitched, and raspy voice characteristics. OBJECTIVE/DESIGN: To determine the physical underpinning of this phenomenon, we performed voice recordings, translarynx impedance measurements, spectral analysis, and estimates of spectral complexity [approximate entropy (ApEn)] in four affected men. Results were compared with those obtained in four men with untreated adult-onset GHD and a normal male population. RESULTS: Congenital GHD subjects had a high-pitched voice with a fundamental frequency typical of normal females (174-266 Hz). Their frequency spectra were characterized by abnormal harmonics, with reversal/interruption of the normal amplitude decay among higher-order harmonics, findings consistent with a creaky quality of the voice. Patients with adult-onset GHD, acquired at ages 31, 38, and 40 yr, had a normal male pitch (fundamental frequency, 117-154 Hz) but pathologically low ApEn values, corresponding to a breathy quality of the voice and suggesting abnormal vocal fold function. A fourth patient who acquired GHD at age 22 yr had a pitch intermediate between male and female, high ApEn, and a spectral pattern similar to the congenital GHD patients. CONCLUSIONS: This study demonstrates an effect of GH on laryngeal size and vocal fold compliance that results in a high pitch and disordered spectral quality. The time of onset of GHD determines which type of abnormality predominates.     

Endothelial cell-specific overexpression of endothelial nitric oxide synthase in Ins2Akita mice exacerbates diabetic nephropathy

Previous studies demonstrated that global deficiency of eNOS in diabetic mice exacerbated renal lesions and that overexpression of eNOS may protect against tissue injury. Our study revealed for the first time overexpression of eNOS leads to disease progression rather than protection. Transgenic mice selectively expressing eNOS in endothelial cells (eNOSTg) were cross bred with Ins2Akita type-1 (AK) diabetic mice to generate eNOS overexpressing eNOSTg/AK mice. Wild type, eNOSTg, AK and eNOSTg/AK mice were assessed for kidney function and blood glucose levels. Remarkably, overexpressing eNOSTg mice showed evidence of unpredicted glomerular injury with segmental mesangiolysis and occasional microaneurysms. Notably, in eNOSTg/AK mice overexpression of eNOS led to increased glomerular/endothelial injury that was associated with increased superoxide levels and renal dysfunction. Results indicate for the first time that overexpressing eNOS in endothelial cells cannot ameliorate diabetic lesions, but paradoxically leads to progression of nephropathy likely due to eNOS uncoupling and superoxide upsurge. This novel finding has a significant impact on current therapeutic strategies to improve endothelial function and prevent progression of diabetic renal disease. Further, the eNOSTg/AK model developed in this study has significant translational potentials for elucidating the underlying mechanism implicated in the deflected function of eNOS in diabetic nephropathy.