A 24-week, randomized, controlled trial of rivastigmine patch 13.3 mg/24 h versus 4.6 mg/24 h in severe Alzheimer's dementia

AIMS: The 24-week, prospective, randomized, double-blind ACTION study investigated the efficacy, safety, and tolerability of 13.3 versus 4.6 mg/24 h rivastigmine patch in patients with severe Alzheimer's disease (AD). METHODS: Patients had probable AD and Mini-Mental State Examination scores ≥3-≤12. Primary outcome measures were as follows: Severe Impairment Battery (SIB) and AD Cooperative Study-Activities of Daily Living scale-Severe Impairment Version (ADCS-ADL-SIV). Secondary outcomes were as follows: ADCS-Clinical Global Impression of Change (ADCS-CGIC), 12-item Neuropsychiatric Inventory (NPI-12), and safety/tolerability. RESULTS: Of 1014 patients screened, 716 were randomized to 13.3 mg/24 h (N = 356) or 4.6 mg/24 h (N = 360) patch. Baseline characteristics/demographics were comparable. Completion rates were as follows: 64.3% (N = 229) with 13.3 mg/24 h and 65.0% (N = 234) with 4.6 mg/24 h patch. The 13.3 mg/24 h patch was significantly superior to 4.6 mg/24 h patch on cognition (SIB) and function (ADCS-ADL-SIV) at Week 16 (P < 0.0001 and P = 0.049, respectively) and 24 (primary endpoint; P < 0.0001 and P = 0.025). Significant between-group differences (Week 24) were observed on the ADCS-CGIC (P = 0.0023), not NPI-12 (P = 0.1437). A similar proportion of the 13.3 mg/24 h and 4.6 mg/24 h patch groups reported adverse events (AEs; 74.6% and 73.3%, respectively) and serious AEs (14.9% and 13.6%). CONCLUSIONS: The 13.3 mg/24 h patch demonstrated superior efficacy to 4.6 mg/24 h patch on SIB and ADCS-ADL-SIV, without marked increase in AEs, suggesting higher-dose patch has a favorable benefit-to-risk profile in severe AD

Botulinum toxin treatment of urethral and bladder dysfunction.

Tremendous excitement has been generated by the use of botulinum toxin for the treatment of various types of urethral and bladder dysfunction over the past several years. Botulinum toxin is the most lethal naturally occurring toxin known to mankind. Why, then, would an urologist want to use this agent to poison the bladder or urethral sphincter? In this review article we will examine the mechanisms underlying the effects of botulinum toxin treatment. We will discuss the current use of this agent within the urologic community and will provide perspectives on future targets of botulinum toxin.</p

Removal of urothelium affects bladder contractility and release of ATP but not release of NO in rat urinary bladder

<p>Abstract</p> <p>Background</p> <p>The objective of our work was to investigate both the contractile function and the release of ATP and NO from strips of bladder tissue after removal of the urothelium.</p> <p>Methods</p> <p>The method of removal was a gentle swabbing motion rather than a sharp surgical cutting to separate the urothelium from the smooth muscle. The contractile response and ATP and NO release were measured in intact as well as on swabbed preparations. The removal of the urothelial layer was affirmed microscopically.</p> <p>Results</p> <p>After the swabbing, the smaller contractions were evoked by electrical as well as by chemical stimulation (50 μM carbachol or 50 μM α, β meATP). Electrical stimulation, carbachol and substance P (5 μM) evoked lower release of ATP in the swabbed strips than in intact strips. Although release of NO evoked by electrical stimulation or substance P was not changed, release of NO evoked by carbachol was significantly less in the swabbed preparations.</p> <p>Conclusion</p> <p>Since swabbing removes only the urothelium, the presence of the suburothelial layer may explain the difference between our findings and those of others who found an increase in contractility. Evoked release of ATP is reduced in swabbed strips, indicating that ATP derives solely from the urothelium. On the other hand, electrical stimulation and substance P evoke identical degrees of NO release in both intact and swabbed preparations, suggesting that NO can be released from the suburothelium. Conversely, carbachol-induced release of NO is lower in swabbed strips, implying that the cholinergic receptors (muscarinic or nicotinic) are located in the upper layer of the urothelium.</p

Comparing Clinical Profiles in Alzheimer\u27s Disease and Parkinson\u27s Disease Dementia

BACKGROUND: Greater understanding of differences in baseline impairment and disease progression in patients with Alzheimer\u27s disease (AD) and Parkinson\u27s disease dementia (PDD) may improve the interpretation of drug effects and the design of future studies. METHODS: This was a retrospective analysis of three randomized, double-blind rivastigmine databases (one in PDD, two in AD). Impairment on the Alzheimer\u27s Disease Assessment Scale-cognitive subscale (ADAS-cog), Alzheimer\u27s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, 10-item Neuropsychiatric Inventory (NPI-10) and the ADCS-Clinical Global Impression of Change (CGIC) was compared [standardized difference (Cohen\u27s d), similar if \u3c0.1]. RESULTS: Patients with AD or PDD had similar levels of impairment on the ADAS-cog and NPI-10. Scores on the ADCS-ADL scale (standardized difference = 0.47) and the ADAS-cog memory domain (total, 0.33; items, 0.10-0.58) were higher in AD; PDD patients were more impaired in the language (0.23) and praxis (0.34) domains. AD patients receiving placebo showed greater deterioration on the ADAS-cog (0.14) and improvement on the NPI-10 (0.11) compared with patients with PDD. CONCLUSION: Differing patterns of impairment occur in AD and PDD

Is abdominal wall contraction important for normal voiding in the female rat?

BACKGROUND: Normal voiding behavior in urethane-anesthetized rats includes contraction of the abdominal wall striated muscle, similar to the visceromotor response (VMR) to noxious bladder distension. Normal rat voiding requires pulsatile release of urine from a pressurized bladder. The abdominal wall contraction accompanying urine flow may provide a necessary pressure increment for normal efficient pulsatile voiding. This study aimed to evaluate the occurrence and necessity of the voiding-associated abdominal wall activity in urethane-anesthetized female rats METHODS: A free-voiding model was designed to allow assessment of abdominal wall activity during voiding resulting from physiologic bladder filling, in the absence of bladder or urethral instrumentation. Physiologic diuresis was promoted by rapid intravascular hydration. Intercontraction interval (ICI), voided volumes and EMG activity of the rectus abdominis were quantified. The contribution of abdominal wall contraction to voiding was eliminated in a second group of rats by injecting botulinum-A (BTX, 5 U) into each rectus abdominis to induce local paralysis. Uroflow parameters were compared between intact free-voiding and BTX-prepared animals. RESULTS: Abdominal wall response is present in free voiding. BTX preparation eliminated the voiding-associated EMG activity. Average per-void volume decreased from 1.8 ml to 1.1 ml (p < 0.05), and reduced average flow from 0.17 ml/sec to 0.11 ml/sec (p < 0.05). Intercontraction interval (ICI) was not changed by BTX pretreatment. CONCLUSION: The voiding-associated abdominal wall response is a necessary component of normal voiding in urethane anesthetized female rats. As the proximal urethra may be the origin of the afferent signaling which results in the abdominal wall response, the importance of the bladder pressure increment due to this response may be in maintaining a normal duration intermittent pulsatile high frequency oscillatory (IPHFO)/flow phase and thus efficient voiding. We propose the term Voiding-associated Abdominal Response (VAR) for the physiologic voiding-associated EMG/abdominal wall response, to distinguish it from the visceromotor response (VMR) to noxious bladder distension

Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020

We show the distribution of SARS-CoV-2 genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three available genomic nomenclature systems for SARS-CoV-2 to all sequence data from the WHO European Region available during the COVID-19 pandemic until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation. We provide a comparison of the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2.Peer reviewe