Point and Interval Estimators of the Target Dose in Clinical Dose-Finding Studies with Active Control.

In a clinical dose finding study with active control a new drug with several dose levels is compared with an active comparator drug. The main focus of such studies often lies on the estimation of a target dose that leads to the same efficacy as the control. This article investigates the finite sample properties of the maximum likelihood estimation of the target dose and compares several approaches for constructing corresponding confidence intervals under the assumption of a linear dose-response curve and normal error terms. Furthermore, the impact of deviations from the model assumptions regarding the error distribution is explored.

Effects of transcutaneous spinal direct current stimulation in idiopathic restless legs patients.

BACKGROUND: Transcutaneous spinal direct current stimulation (tsDCS) is a new non-invasive technique to modulate spinal cord activity. The pathophysiological concept of primary RLS proposes increased spinal excitability. OBJECTIVE: This pilot study used tsDCS to reduce pathologically enhanced spinal excitability in RLS patients and to thereby ameliorate clinical symptoms. METHODS: 20 patients with idiopathic RLS and 14 healthy subjects participated in this double-blinded, placebo-controlled study. All participants received one session of cathodal, anodal and sham stimulation of the thoracic spinal cord for 15 min (2.5 mA) each, in randomized order during their symptomatic phase in the evening. The soleus Hoffmann-reflex with Hmax/Mmax-ratio and seven different H2/H1-ratios (of two H-reflex responses to double stimuli) were measured. The RLS symptoms were assessed by a visual analogue scale (VAS). All parameters were measured before and twice after tsDCS. RESULTS: RLS patients showed increased H2/H1-ratios during their symptomatic phase in the evening. Application of anodal stimulation led to a decreased H2/H1-ratio for 0.2 and 0.3 s interstimulus intervals in patients. Furthermore, application of anodal and cathodal stimulation led to a reduction in restless legs symptoms on the VAS, whereas application of sham stimulation had no effects on either the VAS or on the H2/H1-ratio in patients. VAS changes did not correlate with changes of H2/H1-ratios. CONCLUSIONS: This is the first tsDCS study in idiopathic RLS, which resulted in short-lasting clinical improvement. Furthermore, our results support the pathophysiological concept of spinal cord hyperexcitability in primary RLS and provide the basis for a new non-pharmacological treatment tool.

Discrepancies between medical oncologists and surgeons in assessment of resectability and indication for chemotherapy in patients with colorectal liver metastases.

BACKGROUND: Multidisciplinary discussion of the treatment of patients with colorectal liver metastases (CRLM) is advocated currently. The aim of this study was to investigate medical oncologists' and surgeons' assessment of resectability and indication for chemotherapy, and the effect of an educational intervention on such assessment. METHODS: Medical histories of 30 patients with CRLM were presented to ten experienced medical oncologists and 11 surgeons at an initial virtual tumour board meeting (TB1). Treatment recommendations were obtained from each participant by voting for standardized answers. Following lectures on the potential of chemotherapy and surgery, assessment was repeated at a second virtual tumour board meeting (TB2), using the same patients and participants. RESULTS: Overall, 630 answers (21 × 30) were obtained per tumour board meeting. At TB1, resectability was expected more frequently by surgeons. Participants changed 56·8 per cent of their individual answers at TB2. Assessment shifted from potentially resectable to resectable CRLM in 81 of 161 and from unresectable to (potentially) resectable CRLM in 29 of 36 answers. Preoperative chemotherapy was indicated more often by medical oncologists, and overall was included in 260 answers (41·3 per cent) at TB1, compared with only 171 answers (27·1 per cent) at TB2. Medical oncologists more often changed their decision to primary resection in resectable patients (P = 0·006). Postoperative chemotherapy was included in 51·9 and 52·4 per cent of all answers at TB1 and TB2 respectively, with no difference in changes between medical oncologists and surgeons (P = 0·980). CONCLUSION: Resectability and indication for preoperative chemotherapy were assessed differently by medical oncologists and surgeons. The educational intervention resulted in more patients deemed resectable by both oncologists and surgeons, and less frequent indication for chemotherapy.

Risk prediction of very early recurrence, death and progression after acute ischaemic stroke.

BACKGROUND AND PURPOSE: Early recurrent strokes lead to extended hospitalization and high number of complications. We investigated three stroke scores, the Essen Stroke Risk Score (ESRS), the ABCD(2) and the Recurrence Risk Estimator at 90 days (RRE-90) for their prognostic value to predict early recurrent stroke, death and progressive stroke. METHODS: Clinical and radiological data from 1727 consecutive patients with ischaemic stroke, being admitted to the stroke unit, were evaluated retrospectively. Predictive value of stroke scores was tested for early recurrence within 7 days, death and progressive stroke expressed as observational risk and area under the receiver operator curve (AUROC). RESULTS: Early recurrent stroke occurred in 56 patients (3.2%), 40 patients (2.3%) died within the first 7 days and 125 patients (7.2%) had a progressive stroke. ESRS was not predictive for early recurrence, death or progressive stroke. ABCD(2) score was predictive for death (P<0.01; χ(2); AUROC, 0.65; 0.58-0.72), and progressive stroke (P<0.001; χ(2); AUROC, 0.70; 0.66-0.74). RRE-90 predicted early recurrent stroke (P<0.001; χ(2); AUROC, 0.65; 0.58-0.73), early death (P<0.001; χ(2); AUROC, 0.72; 0.66-0.78) and progressive stroke (P<0.001; χ(2); AUROC, 0.66; 0.61-0.71). CONCLUSIONS: RRE-90 bears high potential to not only predict early recurrence but also death and progression after ischaemic stroke. ABCD(2) appears to be useful to predict risk of death and progression. These findings have relevant clinical implications for early triage of patients being admitted to stroke units.

Sodium caprate transiently opens claudin-5-containing barriers at tight junctions of epithelial and endothelial cells.

Claudin-5 is a tight junction (TJ) protein which limits the diffusion of small hydrophilic molecules. Thus, it represents a potential pharmacological target to improve drug delivery to the tissues protected by claudin-5-dependent barriers. Sodium caprate is known as an absorption enhancer which opens the paracellular space acting on TJ proteins and actin cytoskeleton. Its action on claudin-5 is not understood so far. Epithelial and endothelial systems were used to evaluate the effect of caprate on claudin-5 in TJ-free cells and on claudin-5 fully integrated in TJ. To this aim, confocal microscopy on live and fixed cells and isolated mouse brain capillaries, Western blotting and permeability assays were employed. Caprate reversibly reduced claudin-5 trans-interactions in TJ-free human embryonic kidney-293 cells expressing claudin-5-YFP. It decreased the membranous claudin-5 and the F-actin content in Madin-Darby canine kidney-II cells expressing Flag-claudin-5, thereby increasing the permeability to the small molecule lucifer yellow. Interestingly, zonula occludens protein 1 (ZO-1), which links transmembranous TJ proteins to the actin cytoskeleton, was not affected by caprate treatment. Similarly, endogenous claudin-5 in the membrane of brain endothelia was displaced together with F-actin, whereas ZO-1 remained unaffected. Caprate transiently opens the paracellular space, reducing the intercellular claudin-5/claudin-5 interactions and the polymerized actin at the perijunctional region of endothelial and epithelial cells. In conclusion, the study further elucidates the cellular effects of caprate at the tight junctions.

An appraisal of the current and potential value of web 2.0 contributions to continuing education in oral implantology.

OBJECTIVE: To systematically assess the informational value, quality, intention, source and bias of web 2.0 footage whose aim is peer-to-peer education about oral implantology. METHODS: YouTube (http://www.youtube.com) was scanned on 15 October 2010 for oral implantology-related videos using an adequately pre-defined search query. Search results were filtered with the system-generated category 'education' and the additional criterion 'most viewed'. Only those videos with at least 1000 views were included (total 124, of which 27 were excluded because they were not related to implantology). Filtered videos were discussed and rated with particular regard to the educational needs of potential groups of addressees [(i) undergraduates and laymen, (ii) dentists without or currently undergoing a specialisation in oral implantology and (iii) dentists who have completed a specialisation in the field of oral implantology] by a jury consisting of (i) an accredited post-graduate university instructor with 22 years of professional teaching experience in the field of implantology, (ii) a university lecturer in dentistry/orthodontics with 10 years teaching experience and (iii) a university haematologist/oncologist. They were required to fill out a questionnaire for each video. The data were statistically analysed using non-parametric ANOVA (α = 5%) and a sign test (α = 0.05/3 = 0.017). RESULTS: The YouTube scan produced 1710 results in the category 'EDU'. The analysis revealed that there is a wide range of instructional footage on this topic, but with highly variable range in quality and informational value. Footage intention was to large proportions (47.4%) a mixture of education and advertisement. Its usefulness differed significantly for the three groups of addressees, offering greater novelty to undergraduates and post-graduates. CONCLUSION: YouTube and similar social media websites may have a potential capacity and value in complementing continuing education in the technique of oral implantology. As a means of achieving an acceptable level of knowledge about the topic when used alone, it should not be considered to be suitable at this point in time.

A new look at dry eye disease and its treatment.

This review examines the impact of moderate to severe dry eye disease on daily life and medical-resource utilization. The results suggest that current treatment paradigms can lead to unacceptable costs in both quality of life and progressive use of healthcare resources. Evidence linking this disease to T-cell-mediated inflammatory processes lays the foundation for understanding the clinical benefits of topical cyclosporine, an immunomodulatory and anti-inflammatory agent.

Calcific phacolysis.

BACKGROUND AND METHODS: The authors report the clinical and ocular histopathologic findings in three patients with longstanding unilateral post-traumatic blindness. After one or more decades, acute pain associated with conjunctival hyperemia and apparent keratoprecipitates or a hypopyon developed in the affected eye of each individual. Phacoanaphylaxis was diagnosed preoperatively in two patients. RESULTS: Calcified granular lens fragments were dispersed throughout all three eyes. The anterior chamber in all patients contained extracellular calcified lens particles, but only one eye contained conspicuous macrophages. Two eyes showed elevated intraocular pressure (IOP), and in one patient calcified particles extended into a glaucomatous optic nerve head. CONCLUSION: To the authors' knowledge, this is the first report describing a rare condition involving the intraocular dispersal of calcified lens particles after disruption of the lens capsule. The authors have designated this entity as calcific phacolysis.

Different proliferative potential of rat and pig hepatocytes in pure primary culture and coculture.

In the present study we have compared the growth potential of hepatocytes from rats and pigs and the influence of cocultivation between these hepatocytes and the rat liver epitheloid cell line RL-ET-14. Proliferation, i.e., DNA synthesis, was detected by autoradiography after exposure to [3H]thymidine. Rat hepatocytes cultured at low cell density showed a very low basal growth and responded to epidermal growth factor (EGF) and insulin by a considerable increase in DNA synthesis after 48 h leading to a labeling index (LI) of 33%. Cocultivation with RL-ET-14 cells almost completely blocked the basal as well as the growth factor stimulated proliferation of the rat hepatocytes. In contrast, pig hepatocytes cultured alone showed a much greater growth potential (basal: LI 11%; insulin/EGF:LI 67%) than rat hepatocytes and were further stimulated by cocultivation (basal: LI 39%; insulin/EGF: LI 89%). Density-dependent inhibition of cell growth was less pronounced with pig hepatocytes. Even after reaching confluency, they showed further strong proliferation in pure as well as in cocultures whereas the LI of the rapidly growing clone RL-ET-14 decreased to 40%. Use of conditioned medium from RL-ET-14 cells did not mimic the growth inhibition of rat hepatocytes in coculture indicating that no soluble growth inhibitors produced by the epitheloid cells are responsible for this effect. In particular, the differences between rat and pig hepatocytes in coculture are not simply due to production of TGF-beta by the epitheloid cells since the hepatocytes from both species were inhibited by TGF-beta to a similar extent.(ABSTRACT TRUNCATED AT 250 WORDS)

Stability of gentamicin sulfate and tobramycin sulfate in extemporaneously prepared ophthalmic solutions at 8 degrees C.

The stability of gentamicin sulfate and tobramycin sulfate in fortified ophthalmic solutions stored under refrigeration was studied. Fortified gentamicin ophthalmic solution and fortified tobramycin ophthalmic solution were prepared to a final theoretical concentration of 13.6 mg/mL by using commercially available ophthalmic and injectable solutions. Volumes of each solution were packaged in plastic bottles and refrigerated at 4-8 degrees C. Samples of each solution were analyzed by fluorescence polarization immunoassay on days 0 (before refrigeration), 1, 2, 3, 4, 7, 14, 28, 63, and 91. To validate the method, identical solutions were prepared, stored under refrigeration at 4-8 degrees C, and analyzed by a stability-indicating high-performance liquid chromatographic assay on days 0 (before refrigeration), 9, 28, 56, and 91. Fluorescence polarization immunoassay showed the mean concentrations of gentamicin and tobramycin on day 91 to be 104.4% and 97.4%, respectively, of the time 0 concentrations; the difference was not significant in either case. HPLC validated these results; the mean concentration of gentamicin and tobramycin on day 91 was 103.3% and 101.2%, respectively, of the mean day 0 concentrations. Gentamicin and tobramycin in ophthalmic solutions prepared by mixing ophthalmic and injectable products and stored in plastic bottles at 4-8 degrees C were stable for three months.

Eye injury: prevalence and prognosis by setting.

Although an estimated 1 million Americans suffer ocular injuries each year, the setting of injury and its prognostic implications have not been closely examined. Using data compiled by the Eye Injury Registry of Alabama (EIRA) from 514 cases of serious eye injury, we examined the demographics and prognosis of ocular injury by setting of injury. Work-related injuries accounted for only 28% of total injuries, and injuries occurring at home accounted for 27%, followed by situations related to recreation (25%), assault (11%), travel (5%), and "other" (school, unknown, etc) (4%). The poorest initial vision, poorest final vision, and highest rate of enucleation occurred in patients injured by assault, whereas the lowest rate of enucleation and loss of light perception was found in patients who had work-related injuries. Patients in the "other" category had the highest rate of return to 20/100 or better vision.

Eye Injury Registry of Alabama (preliminary report): demographics and prognosis of severe eye injury.

Each year an estimated 1.3 million Americans suffer eye injuries. There is little information in the literature regarding the prevalence, demographic characteristics, and prognosis of these patients. The Eye Injury Registry of Alabama (EIRA) serves as the first and only statewide system of its kind for the collection of information on serious eye injuries. We have analyzed 736 cases of serious eye injury (injury involving permanent structural or functional change) accumulated by the EIRA between August 1982 and May 1986. Prognosis was found to be related to early diagnosis and initial vision. Individuals with follow-up vision of 20/40 or better were found in all early diagnostic groups, and 13% of patients with no light perception on initial examination had some improvement on follow-up. The worst visual prognosis was among those patients suffering blunt eyeball rupture, of whom 40% had no light perception and 25% regained vision of 20/100 or better.

Complications following enucleation and implantation of multiple glass spheres in the orbit.

The technique of subperiosteal implantation of multiple, small glass beads for correction of enophthalmos associated with anophthalmos was first described in 1967. Reported complications of this procedure include ptosis, anesthesia of the distribution of the supraorbital or infraorbital nerve, and migration of the implants into the orbit or sinuses. A case of orbital cellulitis has been reported. We now report a case in which the extremely serious complication of intracranial migration of glass bead implants, with subsequent cerebrospinal fluid leak, occurred 17 years postimplantation.

[Axe blow injuries caused by reflex action?]. / Beilhiebverletzung durch "reflektorisches Nachgreifen"?

In cases of questionable insurance fraud through self mutilation axe blows now as before play an important role. Occasionally it is alleged that the billet began to totter during the stroke and that the left hand responded to this stimulus by an unwilled movement to the billet. By this the thumb or forefinger was placed unfortunately on the upper surface of the timber and hit by the chopper. According to the literature and on the basis of own experiments we estimate the reaction time, i.e. initiation time plus movement time, at 700 msec., at least, whereas the stroke needs only 220-290 msec. (chopper), and 280-380 msec. (axe), respectively, as could be shown in further experiments. That means, that the left hand can only touch the billet when the blow already has reached the goal. Hence unwilling finger mutilations can scarcely be the result of a "reflex action" of this kind.

Effects of ethyl alcohol on VECP.

Previous studies have demonstrated that ethyl alcohol ingestion affects the clinically recorded visually evoked cortical potential (VECP). However these studies have not related the possible relevance of such alcohol-induced VECP changes to visual performance. We studied the flash and pattern-reversal monopolar VECP recorded at the occiput before and after alcohol ingestion and compared the recordings with psychophysical parameters (e.g. contrast sensitivity) also measured before and after alcohol intake. Results are presented, and the potential usefulness of VECP alterations in predicting alcohol-induced effects on visual performance is evaluated. We found no clear, consistent effect of blood alcohol levels ranging from 0.05% to 0.15% on the parameters tested.