Onset of Kleine-Levin Syndrome in association with isotretinoin treatment.

UNLABELLED: The synthetic retinoid isotretinoin is an effective treatment option for severe forms of acne vulgaris. However, several reports indicate that some patients experience altered central nervous system functions in association with treatment. We present here the first description of the onset of Kleine-Levin Syndrome (KLS), a rare disorder characterised by periodic hypersomnia and cognitive and behavioural symptoms, in close temporal relation to the start of isotretinoin treatment. We also discuss the biological potential of retinoids to affect sleep. CONCLUSIONS: In light of a documented potential of retinoids to modulate sleep-wake regulation, the present case suggests that isotretinoin may rarely trigger the onset of KLS.

Substituent Pattern Effects on the Redox Potentials of Quinone-Based Active Materials for Aqueous Redox Flow Batteries.

Quinone-based, aqueous redox flow batteries are a promising technology for large-scale, low-cost energy storage. To understand the influence of substituent and substituent pattern effects of quinone-based derivatives on the redox potential, a screening study was performed that included benzoquinone, naphtaquinone, and anthraquinone derivatives. The order of substituent influence is -OH>-Me/-OMe for decreasing the redox potential and -F<-SO3 - <-CN, -NO2 for increasing the redox potential, which is in agreement with general expectations. We found that the consideration of resonance and inductive effects design strategies of redox-active materials can be extended by the ability of intramolecular hydrogen bond formation, steric hindrance, and energetic differences of conformers for oxidized and reduced species. Due to the complexity and overlap of these effects, theoretical screening studies can provide guidance for the design of new molecular materials. In addition to the redox potential, other parameters such as stability, solubility, and kinetic rate constant or synthetic accessibility are crucial to consider.

In vitro investigation of the geometric contraction behavior of chemo-mechanical P-protein aggregates (forisomes).

We investigated the contracting behavior of forisomes from Vicia faba by carrying out precise measurements of their changing geometric parameters in vitro in the absence and in the presence of dissolved oxygen. Furthermore, we investigated the fine structure of forisomes by scanning electron microscopy. For the first time, single forisomes were titrated with Ca(2+), protons, and hydroxide ions recording the complete progression of their contractions. An apparent Ca(2+)-binding constant of (22+/-3) muM was calculated from two complete titration curves. The forisomes also contracted in the presence of Ba(2+) and Sr(2+) ions, but the amplitudes of contraction were smaller under the same measuring conditions. The time taken to change from the longitudinally expanded into the longitudinally contracted state was up to 2 s shorter in 10 mM Ca(2+) in comparison to 0.2mM Ca(2+). However, the contraction time was prolonged by decreasing the Ca(2+) concentration. In the absence of dissolved oxygen, the transition between the two final states of the forisomes was almost reversible and the amplitude of contraction remained almost constant during the first 25 contraction cycles. In the presence of dissolved oxygen the forisomes denaturated after a few cycles and lost their ability to contract, just after only a few cycles with 10 min in the contracted state. Denaturation of the forisomes occurred appreciably in the contracted state. We propose a cycle process to explain the thermodynamic basis of the Ca(2+)-induced contraction and its reversal by EDTA. Reducing the pH-value from 7.3 to 4.0 caused the forisomes to shorten by approximately 15%, while increasing the pH to 11.0 caused them to shorten by 28 to 30%. In both cases, the increases of the forisomes volume were greater than during the Ca(2+) induced contraction. The pH values of 4.7+/-0.3, and 10.2+/-0.2 marked the inflection points of the acid base titration of different forisomes.

Calcium Microcrystal Formation in Recurrent Herniation Patients After Autologous Disc Cell Transplantation.

Autologous disc cell transplantation (ADCT) is a cell-based therapy aiming to initiate regeneration of intervertebral disc (IVD) tissue, but little is known about potential risks. This study aims to investigate the presence of structural phenomena accompanying the transformation process after ADCT treatment in IVD disease. Structural phenomena of ADCT-treated patients (Group 1, n = 10) with recurrent disc herniation were compared to conventionally-treated patients with recurrent herniation (Group 2, n = 10) and patients with a first-time herniation (Group 3, n = 10). For ethical reasons, a control group of ADCT patients who did not have a recurrent disc herniation was not possible. Tissue samples were obtained via micro-sequestrectomy after disc herniation and analyzed by micro-computed tomography, scanning electron microscopy, energy dispersive spectroscopy, and histology in terms of calcification zones, tissue structure, cell density, cell morphology, and elemental composition. The major differentiator between sample groups was calcium microcrystal formation in all ADCT samples, not found in any of the control group samples, which may indicate disc degradation. The incorporation of mineral particles provided clear contrast between the different materials and chemical analysis of a single particle indicated the presence of magnesium-containing calcium phosphate. As IVD calcification is a primary indicator of disc degeneration, further investigation of ADCT and detailed investigations assessing each patient's Pfirrmann degeneration grade following herniation is warranted. Structural phenomena unique to ADCT herniation prompt further investigation of the therapy's mechanisms and its effect on IVD tissue. However, the impossibility of a perfect control group limits the generalizable interpretation of the results.

Evaluation of the monothermal caloric test.

In 1970, Torok reported that patients with labyrinthine disease showed vestibular recruitment and that patients with retrolabyrinthine disease showed vestibular decruitment on the monothermal caloric test. Other investigators have failed to confirm these findings; however, their studies did not precisely replicate Torok's test procedure. Following Torok's procedure exactly, the monothermal caloric test was administered to normal individuals and to patients with well-documented vestibular lesions. Nine of ten normal persons showed normal responses and one person showed borderline decruitment. Six of eight patients who had lesions of the vestibular nerve or central vestibular pathways showed decruitment. Two patients with active Meniere's disease showed recruitment and one showed asymmetry. Two patients with Meniere's disease who had undergone endolymphatic sac operations showed normal responses. These findings support Torok's claim that the monothermal caloric test discriminates between labyrinthine and retrolabyrinthine vestibular pathology.

Risk factors for ototoxicity due to cisplatin.

OBJECTIVE: To determine whether abnormalities in routine blood tests were associated with increased susceptibility to hearing loss induced by cisplatin chemotherapy. DESIGN: Cohort study of patients with head and neck cancer receiving cisplatin chemotherapy who underwent audiometric testing. SETTING: A large, university-based hospital; part of a larger study regarding rehabilitation of patients with cancer. PATIENTS: Forty-two patients with head and neck cancer who agreed to participate underwent at least three serial treatments with high-dose cisplatin therapy. Routine blood tests and audiometric testing were performed before each course of chemotherapy. One hundred eighty audiograms were performed. OUTCOME MEASURES: A deterioration of auditory threshold of 15 dB or more at one frequency or of 10 dB or more at three or more frequencies was considered a significant loss. Only frequencies at and below 4000 Hz were considered. RESULTS: Multiple analysis of variance results indicated that decreased serum albumin level, hemoglobin level, red blood cell count, and hematocrit were associated with an increased likelihood of significant hearing loss during chemotherapy. CONCLUSIONS: Patients in poor general medical condition with low levels of red blood cells or serum proteins are at increased risk for development of hearing loss from cisplatin chemotherapy. We recommend that hearing be tested before chemotherapy begins and after the first course of cisplatin. If there is no significant hearing loss at or below 4000 Hz at that time, then subsequent audiometric testing is required only if symptoms of hearing loss develop.

The effect of swallowing bolus and head position on eustachian tube function via sonotubometry.

Eustachian tube function was evaluated by sonotubometry in otologically normal young adults. The purpose of the research was to determine if the incidence or duration of eustachian tube opening would be altered with changes in swallowing bolus volume or changes in head rotation. The subject performed multiple swallows of 10 cc water bolus and dry swallows (saliva), with the head in the straight-forward, turned right, and turned left positions. Both ears were evaluated. The average incidence and duration of eustachian tube opening for all swallows was 74% (398 msec). No significant differences were found with any combination of bolus type or head position, suggesting that neither liquid bolus volume nor head rotation need be controlled when sonotubometry is performed.

Is cis-platinum vestibulotoxic?

Serial vestibular testing was performed on 34 patients undergoing cis-platinum chemotherapy and 12 age-matched normal subjects. Vestibular testing comprised caloric and low-frequency, sinusoidal rotational testing (0.01 to 0.16 Hz). Test-retest variability in the caloric and rotational vestibular assessment of the normal subjects formed the basis for evaluation of subclinical loss of vestibular function within our patient population. In spite of high-dose cis-platinum chemotherapy (100 mg/m2) with cumulative dosages to 1600 mg, no clear evidence of vestibular toxicity was found.

The "plateau effect" of cis-platinum-induced hearing loss.

Cis-platinum-induced hearing loss has been reported to exhibit a "plateau effect" over the 2 to 8 kHz range. We examined serial audiometry data from 27 patients treated with cis-platinum. Although a plateau at 60 to 70 dB HL often occurred, this hearing loss was clearly exceeded in a number of patients. We identified 14 patients with sufficient cis-platinum-induced sensorineural hearing loss to evaluate a plateau limit to hearing loss over the 4 to 8 kHz range. Half of these 14 patients had hearing losses that exceeded the plateau level. More severe 4 to 8 kHz hearing losses did not correlate with number of treatments, cumulative dosages of cis-platinum, pre-existing hearing loss, radiation therapy, other chemotherapeutic agents, or even hearing losses below 4 kHz. Although cis-platinum therapy can induce a plateau of moderate hearing impairment for some patients over the 4 to 8 kHz range, a significant proportion of patients will experience more severe hearing impairment in this range, even after only one or two courses of cis-platinum.

Pseudohypacusis.

This article provides the basis for the techniques and interpretation of audiologic tests useful in evaluation of the patient with pseudohypacusis. Differences between the childhood and adult forms of the problem are discussed. The indications for currently popular conventional and special tests are presented. These include both behavioral and electrophysiologic measures for assessing auditory function.

Audiometric test criteria in the detection of cisplatin ototoxicity.

Audiometric criteria establishing the ototoxic effects of cisplatin (CDDP) vary widely in the literature. Normal test-retest variability in audiometric thresholds resulting from serial audiometry is likely a confounding variable in the over-reporting of ototoxic effects. This study investigated the variability of serial audiometry for a group of 21 head and neck cancer patients receiving no known ototoxic drugs in an effort to establish guidelines for determining reasonable audiometric criteria for CDDP therapy. Comparison of this group to a similar group of 31 patients receiving high dose (100+ mg/m2) bolus administration of CDDP suggests that audiometric shift criteria developed from Receiver Operating Characteristic analysis and employing multiple frequency averaging above 1000 Hz may lead to more universally accepted audiometric criteria for ototoxicity, which should in turn lead to more reliable reports of disease incidence.

Comparison of palmar fixed-angle plate fixation with K-wire fixation of distal radius fractures (AO A2, A3, C1) in elderly patients.

The objective of this prospective, randomized, controlled trial was to compare the results of two operative techniques used for the treatment of unstable distal radius fractures in elderly patients classified as AO types A2, A3, and C1. Patients were treated with either fixed-angle volar plates or K-wires using a combined Kapandji and Willenegger technique. The functional results were determined after 3, 6, and 12 months. We included 40 patients aged over 65 years. Twenty-one patients were treated with plate fixation and 19 with K-wire fixation. The functional results, after 1 year, were nearly the same in both treatment groups, suggesting that either method is suitable for the treatment of unstable distal radius fractures of AO types A2, A3, and C1 in elderly patients. Sixteen of 21 patients with plate fixation and 17 of 19 patients with K-wire fixation present good results as assessed by the Castaing score. The median DASH score was three in both groups after 1 year. The patients with plate fixation were able to resume activities of daily living 4 weeks earlier. The most common complication was an intermediate post-traumatic median nerve irritation. Both methods are suitable for the treatment of elderly patients with unstable distal radius fractures of AO types A2, A3, and C1. If early functional post-operative care is important, palmar fixed-angle plate fixation is an ideal treatment approach. Otherwise, K-wire fixation is an effective, minimally invasive method with comparable clinical results.

Microporous calcium phosphate ceramics as tissue engineering scaffolds for the repair of osteochondral defects: biomechanical results.

This work investigated the suitability of microporous ß-tricalcium phosphate (TCP) scaffolds pre-seeded with autologous chondrocytes for treatment of osteochondral defects in a large animal model. Microporous ß-TCP cylinders (Ø 7 mm; length 25 mm) were seeded with autologous chondrocytes and cultured for 4 weeks in vitro. Only the upper end of the cylinder was seeded with chondrocytes. Chondrocytes formed a multilayer on the top. The implants were then implanted in defects (diameter 7 mm) created in the left medial femoral condyle of ovine knees. The implants were covered with synovial membrane from the superior recess of the same joint. For the right knees, an empty defect with the same dimensions served as control. Twenty-eight sheep were split into 6-, 12-, 26- and 52 week groups of seven animals. Indentation tests with a spherical (Ø 3mm) indenter were used to determine the biomechanical properties of regenerated tissue. A software-based limit switch was implemented to ensure a maximal penetration depth of 200 µm and maximal load of 1.5 N. The achieved load, the absorbed energy and the contact stiffness were measured. Newly formed cartilage was assessed with the International Cartilage Repair Society Visual Assessment Scale (ICRS score) and histomorphometric analysis. Results were analysed statistically using the t-test, Mann-Whitney U-test and Wilcoxon test. Statistical significance was set at p<0.05. After 6 weeks of implantation, the transplanted area tolerated an indentation load of 0.05±0.20 N. This value increased to 0.10±0.06 N after 12 weeks, to 0.27±0.18 N after 26 weeks, and 0.27±0.11 N after 52 weeks. The increase in the tolerated load was highly significant (p<0.0001), but the final value was not significantly different from that of intact cartilage (0.30±0.12 N). Similarly, the increase in contact stiffness from 0.87±0.29 N mm-(1) after 6 weeks to 3.14±0.86 N mm(-1) after 52 weeks was highly significant (p<0.0001). The absorbed energy increased significantly (p=0.02) from 0.74×10(-6)±0.38×10(-6) Nm after 6 weeks to 2.83×10(-6)±1.35×10(-6) Nm after 52 weeks. At 52 weeks, the International Cartilage Repair Society (ICRS) scores for the central area of the transplanted area and untreated defects were comparable. In contrast, the score for the area from the edge to the centre of the transplanted area was significantly higher (p=0.001) than the score for the unfilled defects. A biomechanically stable cartilage was built outside the centre of defect. After 52 weeks, all but one empty control defect were covered by bone and a very thin layer of cartilage (ICRS 7 points). The empty hole could still be demonstrated beneath the bone. The histomorphometric evaluation revealed that 81.0±10.6% of TCP was resorbed after 52 weeks. The increase in TCP resorption and replacement by spongy bone during the observation period was highly significant (p<0.0001). In this sheep trial, the mechanical properties of microporous TCP scaffolds seeded with transplanted autologous chondrocytes were similar to those of natural cartilage after 52 weeks of implantation. However, the central area of the implants had a lower ICRS score than healthy cartilage. Microporous TCP was almost fully resorbed at 52 weeks and replaced by bone.

A novel MSC-seeded triphasic construct for the repair of osteochondral defects.

Mesenchymal stem cells (MSC) are increasingly replacing chondrocytes in tissue engineering based research for treatment of osteochondral defects. The aim of this work was to determine whether repair of critical-size chronic osteochondral defects in an ovine model using MSC-seeded triphasic constructs would show results comparable to osteochondral autografting (OATS). Triphasic implants were engineered using a beta-tricalcium phosphate osseous phase, an intermediate activated plasma phase, and a collagen I hydrogel chondral phase. Autologous MSCs were used to seed the implants, with chondrogenic predifferentiation of the cells used in the cartilage phase. Osteochondral defects of 4.0 mm diameter were created bilaterally in ovine knees (n = 10). Six weeks later, half of the lesions were treated with OATS and half with triphasic constructs. The knees were dissected at 6 or 12 months. With the chosen study design we were not able to demonstrate significant differences between the histological scores of both groups. Subcategory analysis of O'Driscoll scores showed superior cartilage bonding in the 6-month triphasic group compared to the autograft group. The 12-month autograft group showed superior cartilage matrix morphology compared to the 12-month triphasic group. Macroscopic and biomechanical analysis showed no significant differences at 12 months. Autologous MSC-seeded triphasic implants showed comparable repair quality to osteochondral autografts in terms of histology and biomechanical testing.

Micromechanical measurements on P-protein aggregates (forisomes) from Vicia faba plants.

Forisomes are chemomechanically active P-protein aggregates found in the phloem of legumes. They can convert chemical energy into mechanical work when induced by divalent metal ions or changes in pH, which control the folding state of individual forisome proteins. We investigated the changing geometric parameters of individual forisomes and the strength and dynamics of the forces generated during this process. Three different divalent ions were tested (Ca2+, Sr2+ and Ba2+) and were shown to induce similar changes to the normalized length and diameter. In the concentration range from 0.1 to 4 M, K+ and Cl(-) ions had no influence on the contraction behaviour of the forisomes induced by 10 mM Ca2+. In the absence of dissolved oxygen, these changes were independent of the radius of the metal ion, water uptake and the strength of binding between the selected metal ions and those protein molecules responsible for forisome conformational transformation. In the absence of any load, bound Ca2+, Sr2+ and Ba2+ ions showed apparent and averaged dissociation constants of 14, 62 and 1070 microM, respectively. Various forisomes generated bending on a quartz glass fibre with a diameter of 9 microm. The fibre bending was measured microscopically also by correlation between the digital patterns of a predefined window of observation before and after bending. Similar bending forces of approximately 90 nN were measured for a single forisome sequentially exposed to 10 mM Ca2+, Sr2+ and Ba2+. In the absence of dissolved oxygen, the same conditions resulted in averaged bending forces of (93+/-40) nN, (58+/-20) nN, and (91+/-20) nN after contacting different forisomes with 10 mM Ca2+, 10 mM Sr2+, and 10 mM Ba2+ respectively, demonstrating that the force generated was independent on ion concentrations above a certain threshold value.

Do film cuts facilitate the perceptual and cognitive organization of activity sequences?

Film depictions of activities possess two kinds of structures--namely, the structural features of the depicted activities themselves and a formal structure defined by film cuts. The former structure is used by everyday observers for perceptually and cognitively unitizing the continuous flow of events into comprehensible entities. It seems conceivable that cuts can serve a similar unitizing purpose for film viewers. For each of two different activity sequences, two film versions were produced. Throughout each film version, cuts were placed either at breakpoints or at nonbreakpoints. In a 2 x 2 (activity sequence x film version) factorial design, 40 subjects segmented the film during viewing and recalled the film content after viewing in a detailed protocol. Segmentation behavior depended primarily on the occurrence of breakpoints and was largely unaffected by the occurrence of cuts. Cuts accompanying a breakpoint lead to more detailed recall protocols for these sections of the film.

The dichotic rhyme task: results in split-brain patients.

Monosyllabic rhyme words were dichotically presented to normal and complete split-brain subjects. In the normal adult population, only one of the words in the dichotic condition was identified. Hence, normal performance was about 50%, with a small but significant right-ear advantage. The split-brain patients yielded the expected marked left deficit, as seen on other dichotic speech tests, and demonstrated a right-ear enhancement, producing a large interear difference. This right-ear enhancement on the dichotic rhyme task (DRT) may suggest a release from central auditory competition in the left hemisphere. The dichotic rhyme task's normative data results and sensitivity to lack of callosal transmission make it worthy of further clinical and basic research.