Opinions on the Preclinical Evaluation of Novel Therapies for Spinal Cord Injury: A Comparison between Researchers and Spinal Cord-Injured Individuals

Abstract We previously conducted a survey to gather the opinions and perspectives of scientific and clinical researchers on what levels of preclinical evidence were needed to justify translating a promising neuroprotective or neuroregenerative therapy in spinal cord injury (SCI) into a human clinical trial (Kwon et al., 2010 ). Here we conducted an analogous survey of individuals living with SCI in which we gathered their expectations for the levels of preclinical evidence achieved by researchers in substantiating the neuroprotective and neuroregenerative therapies being offered to them in clinical trials. In total, 214 individuals with SCI completed the survey, and their responses were compared to the responses of the 235 scientists and clinicians who completed our previous survey. SCI individuals were more likely than SCI researchers to opine that demonstrating efficacy and safety in rodent models of SCI alone is sufficient to proceed with clinical trials. However, SCI individuals also reported strong support for large animal and primate model studies, and in the case of the latter, were actually more in agreement for the need for primate studies than researchers. SCI individuals also reported strong support for independent replication studies. In general, individuals with SCI had high expectations for the levels of preclinical evidence required to justify translating novel therapies into clinical trials. These expectations should be considered in the decisions to translate specific experimental therapies for SCI.     

The role of ultrasonography in the assessment of renal function in the elderly

BACKGROUND: Ageing is associated with a progressive loss of renal mass and kidney length and a decline in glomerular filtration rate (GFR). This study evaluated a possible correlation between renal function and kidney size measured by ultrasonography (US), and whether the latter helps estimate GFR in the elderly. METHODS: Twenty-five medically stable elderly patients (mean age 85 +/- 5 yrs) were examined in a geriatric ward at a university hospital. Blood samples were taken to determine serum creatinine (Cr) levels. On the same day, 51chromium ethylenediamine tetraacetic acid (51Cr-EDTA) clearance was performed as the gold standard of GFR. US measured kidney length, transverse and anteroposterior dimensions. RESULTS: Serum Cr (r=-0.67; p=0.0002), Cockcroft-Gault formula (r=0.82; p<0.0001), absolute length (r=0.51; p=0.008) and volume kidney (r=0.46; p=0.02) correlated significantly with GFR. After receiver operating curve (ROC) analysis, length was less specific than sensitive in detecting renal impairment. Adding length to the Cockcroft-Gault formula did not improve GFR estimation (p=0.44). In contrast, adding length to serum Cr levels improved GFR estimation (p=0.015). CONCLUSION: In the elderly, kidney length and volume significantly correlated with GFR. However, length has a low specificity in predicting renal impairment. Therefore, in clinical practice, serum Cr levels and calculated Cr clearance are more useful in predicting renal impairment. However, normal kidney length can help to exclude renal impairment in the elderly at risk of GFR underestimation by a calculated Cr clearance.     

Outcome in a post-cardiac surgery population with acute renal failure requiring dialysis: does age make a difference?

BACKGROUND: Acute renal failure (ARF), requiring dialysis (ARF-d), develops in 1-5% of patients undergoing cardiac surgery and is associated with higher in-hospital mortality. Age is one of the known risk factors for the development of ARF. As the ageing population is increasing, the nephrologist will be faced with a large population of elderly patients requiring dialysis following cardiac surgery. The aim of our study was to evaluate the influence of age on and the risk factors for in-hospital mortality. METHODS: Eighty-two patients with ARF following cardiac surgery and requiring dialysis between January 1997 and October 2001 were included. Two groups of patients were studied: the younger population (<70 years, 42 patients, mean age 59+/-10) and an elderly population (>/=70 years, 40 patients, mean age 76+/-4). Severity of disease was evaluated using the SAPS (Simplified Acute Physiology Score), the Liano score and the SHARF (Stuivenberg Hospital Acute Renal Failure) score. RESULTS: Overall mortality in the population with ARF-d was 56.1%. No difference in mortality rate was found between the younger (61.9%) and elderly patient group (50.0%). The two groups were very similar in baseline and procedural characteristics with exception of body weight (P=0.02) and preoperative glomerular filtration rate (P=0.0001). No significant difference was found in the scoring systems between the old and the young (SAPS P=0.52; Liano P=0.96; SHARF T0 P=0.06; SHARF T48 P=0.15). Mortality in the elderly was significantly correlated with hypotension before starting renal replacement therapy (RRT) (P=0.002), mechanical ventilation (P=0.002), presence of multiorgan failure (MOF) (P=0.0001) and higher scores in the severity models (SAPS: P=0.01; Liano: P<0.0001 and SHARF: P<0.0001). CONCLUSION: The outcome in the elderly requiring dialysis due to ARF post-cardiac surgery is comparable with the outcome in a younger population. No significant difference was found in severity of disease between the elderly and the younger. Variables predicting mortality in the elderly are the presence of MOF, mechanical ventilation and hypotension 24 h before starting RRT. These findings indicate that at the time the nephrologist is called for an elderly patient requiring dialysis due to ARF following cardiac surgery, age per se is not a reason to withhold RRT.     

Psychosocial work environment and psychological well‐being: assessment of the buffering effects in the job demand–control (–support) model in BELSTRESS

The Karasek Job Demand–Control model has as its central tenet the so‐called ‘strain hypothesis’, stating that the most adverse health outcomes are to be expected in ‘high strain’ jobs characterized by high job demands and low job control. Later, this model was elaborated, stating that ‘isolated’ high strain workers experiencing low worksite social support are even more worse off. This is labelled the ‘iso‐strain hypothesis’. However, in the literature, the question was raised whether a high level of job control may (1) mitigate or buffer the effects of high job demands on psychological well‐being, or alternatively whether (2) a high level of social support may buffer the negative impact of high strain on psychological well‐being. In this study among 16 335 male workers and 5084 female workers in Belgium, four indicators of psychological well‐being are considered: feelings of depression, feelings of fatigue, sleep problems and use of psychoactive drugs. Both in men and in women, the general strain hypothesis and the iso‐strain hypothesis alike are corroborated regarding the cross‐sectional associations adjusted for age, level of education and living situation. This is most clear with respect to feelings of depression, less so with respect to the use of psychotropic drugs. The buffer hypotheses however are definitely not supported by our data. Copyright © 2002 John Wiley & Sons, Ltd.     

The need for a revival of psychoanalytic investigations into premature ejaculation

Although psychoanalysis was the first-choice treatment for premature ejaculation (PE) between 1920 and 1960, hardly any reports on its efficacy have been published. Moreover, a scientific debate about its findings has never been fully developed. The recent progress that has been made in the classification of three different PE syndromes creates a new opportunity for psychoanalytic investigations of men with complaints of PE, distinguished by the actual duration of their intravaginal ejaculation latency time (IELT). The term premature-like ejaculatory dysfunction has been introduced to distinguish men with self-perceived PE at normal and long IELT durations from those men with lifelong, acquired and normal variable PE. Psychoanalytic research may contribute to a better understanding of the consequences of objective early ejaculations on the unconscious mental life of men with the four forms of PE. By integrating neurobiological, clinical and epidemiological data of ejaculatory performance, a revival of psychoanalytic research of PE in the four distinct, classified PE groups, will probably contribute to a deeper insight in to the unconscious mental life of men affected by PE.     

Adoption of Robotic vs Fluoroscopic Guidance in Total Hip Arthroplasty: Is Acetabular Positioning Improved in the Learning Curve?

Background

Acetabulum positioning affects dislocation rates, component impingement, bearing surface wear rates, and need for revision surgery. Novel techniques purport to improve the accuracy and precision of acetabular component position, but may have a significant learning curve. Our aim was to assess whether adopting robotic or fluoroscopic techniques improve acetabulum positioning compared to manual total hip arthroplasty (THA) during the learning curve.

Long-term reendothelialization of excimer laser-assisted nonocclusive anastomoses compared with conventionally sutured anastomoses in pigs

OBJECT: In contrast to conventional anastomosis methods, the excimer laser-assisted nonocclusive anastomosis (ELANA) technique involves a platinum ring and intima-adventitia apposition with a rim of medial and adventitial layers exposed to the bloodstream. The authors assessed the reendothelialization of porcine carotid arteries through ELANA compared with conventional anastomosis by using scanning electron microscopy. METHODS: In 28 pigs a bypass with one ELANA and one conventional anastomosis was made on the left common carotid artery. All patent anastomoses were evaluated intraoperatively with the aid of an ultrasonographic flowmeter and postoperatively by using scanning electron microscopy at 2 weeks, 2 months, 3 months, and 6 months thereafter. Twenty-four of 28 bypasses (48 of 56 end-to-side anastomoses) were fully patent at the time of evaluation. On scanning electron microscopic evaluation of the bypasses, all 48 patent anastomoses showed complete reendothelialization, including all 24 ELANAs in which the endothelium covered the rim and the laser-ablated edge completely. No endothelial difference was observed between conventional anastomoses and ELANAs, aside from the obvious anatomical differences like the platinum ring, which had been completely covered with endothelium. At 6 months postsurgery, remodeling of the ELANA was observed, leaving the ring covered with a layer of endothelium as the most narrow part of the anastomosis. CONCLUSIONS: In long-term experiments, ELANA allows reendothelialization comparable to that achieved with conventional anastomosis. Considering its nonocclusive and high-flow characteristics, the ELANA technique is preferable in cerebral revascularization procedures.     

Thyroid hormone, but not parathyroid hormone, partially restores glucocorticoid-induced growth retardation

Growth retardation is a serious side effect of long-term glucocorticoid (GC) treatment. In order to prevent or diminish this deleterious effect, a combination therapy including growth hormone (GH), a stimulator of bone growth, is often recommended. Parathyroid hormone (PTH) and thyroid hormone (T₄) are important hormonal regulators of bone growth, and might also be helpful anabolic agents for counteracting the negative effects of GCs. Therefore, we studied the interaction of GCs in combination with a single dose of either PTH or T₄ on GC-induced growth retardation. Dexamethasone (Dex) treatment of mice for four weeks induced a significant growth inhibition of body length and weight and weights of several organs. PTH or T₄ alone did not affect the normal growth pattern. However, T₄ could partially restore the Dex-induced growth inhibition, whereas PTH could not. Although PTH did not affect total body growth, it did affect the height of the proliferative zone, which could be counteracted by Dex. This contrasts with T₄ treatment alone or in combination with Dex, which both resulted in a disturbed morphology of the growth plate. IGF-I mRNA, one of the mediators of longitudinal bone growth, was present in proliferative and hypertrophic chondrocytes. However, its expression was not affected by any of the treatments. In conclusion, T₄ but not PTH can partially counteract the effects of Dex on general body growth, with possible implications for future treatments of GC-induced growth retardation. Additionally, both T₄ and PTH, alone or in combination with Dex, have differential effects on the morphology of the growth plate.This work was presented in part at the IPNA Seventh Symposium on Growth and Development in Children with Chronic Kidney Disease: The Molecular Basis of Skeletal Growth, 1–3 April 2004, Heidelberg, Germany     

Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine

Background: Remifentanil-induced secondary hyperalgesia has been documented experimentally in both animals and healthy human volunteers, but never clinically. This study tested the hypotheses that increased pain sensitivity assessed by periincisional allodynia and hyperalgesia can occur after relatively large-dose intraoperative remifentanil and that small-dose ketamine prevents this hyperalgesia.

Methods: Seventy-five patients undergoing major abdominal surgery were randomly assigned to receive (1) intraoperative remifentanil at 0.05 [mu]g [middle dot]kg-1 [middle dot]min-1 (small-dose remifentanil); (2) intraoperative remifentanil at 0.40 [mu]g [middle dot]kg-1 [middle dot]min-1 (large-dose remifentanil); or (3) intraoperative remifentanil at 0.40 [mu]g [middle dot]kg-1 [middle dot]min-1 and 0.5 mg/kg ketamine just after the induction, followed by an intraoperative infusion of 5 [mu]g [middle dot] kg-1 [middle dot] min-1 until skin closure and then 2 [mu]g [middle dot]kg-1 [middle dot]min-1 for 48 h (large-dose remifentanil-ketamine). Pain scores and morphine consumption were recorded for 48 postoperative hours. Quantitative sensory tests, peak expiratory flow measures, and cognitive tests were performed at 24 and 48 h.

Results: Hyperalgesia to von Frey hair stimulation adjacent to the surgical wound and morphine requirements were larger (P < 0.05) and allodynia to von Frey hair stimulation was greater (P < 0.01) in the large-dose remifentanil group compared with the other two groups, which were comparable. There were no significant differences in pain, pressure pain detection threshold with an algometer, peak flow, cognitive tests, or side effects.