Spider silk nerve graft promotes axonal regeneration on long distance nerve defect in a sheep model.

Peripheral nerve injuries with substantial tissue loss require autologous nerve transplantation or alternatively reconstruction with nerve conduits. Axonal elongation after nerve transection is about 1 mm/day. The precise time course of axonal regeneration on an ultrastructural level in nerve gap repair using either autologous or artificial implants has not been described. As peripheral nerve regeneration is a highly time critical process due to deterioration of the neuromuscular junction, this in vivo examination in a large animal model was performed in order to investigate axonal elongation rates and spider silk material degradation in a narrowly delimited time series (20, 30, 40, 50, 90, 120, 150 and 180 days) by using a novel spider silk based artificial nerve graft as a critical prerequisite for clinical translation. Autologous nerves or artificial nerve conduits based on spider silk of the spider species Trichonephila edulis were transplanted in a 6.0 cm nerve defect model in the black headed mutton. At each of the post-implant time point, electrophysiology recordings were performed to assess functional reinnervation of axonal fibers into the implants. Samples were analyzed by histology and immunofluorescence in order to verify the timeline of axonal regeneration including axonal regeneration rates of the spider silk implant and the autologous transplant groups. Spider silk was degraded within 3 month by a light immune response mainly mediated by Langhans Giant cells. In conjunction with behavioral analysis and electrophysiological measurements, the results indicate that the spider silk nerve implant supported an axonal regeneration comparable to an autologous nerve graft which is the current gold standard in nerve repair surgery. These findings indicate that a biomaterial based spider silk nerve conduit is as effective as autologous nerve implants and may be an important approach for long nerve defects.

[Reducing tinnitus intensity : Pilot study to attenuate tonal tinnitus using individually spectrally optimized near-threshold noise]. / Reduktion der Tinnituslautstärke : Pilotstudie zur Abschwächung von tonalem Tinnitus mit schwellennahem, individuell spektral optimiertem Rauschen.

BACKGROUND: Around 15% of the general population is affected by tinnitus, but no real cure exists despite intensive research. Based on our recent causal model for tinnitus development, we here test a new treatment aimed at counteracting the perception. This treatment is based on the stochastic resonance phenomenon at specific auditory system synapses that is induced by externally presented near-threshold noise. OBJECTIVE: This pilot study will investigate whether individually spectrally adapted noise can successfully reduce chronic tonal/narrow-band tinnitus during stimulation. MATERIALS AND METHODS: Hearing loss (HL) as well as tinnitus pitch (TP) and loudness (TL) were audiometrically measured in 22 adults (46.6±16.3 years; 4 women) with tinnitus. Based on these measurements, up to eight different noise stimuli with five intensities (-20 to +20 dB SL) were generated. These were presented for 40 s each via audiologic headphones in a soundproof chamber. After each presentation, the change in TL was rated on a five-level scale (-2 to +2). RESULTS: We found patients (n = 6) without any improvement in their TL perception as well as patients with improvement (n = 16), where stimulation around the TP was most effective. The groups differed in post-hoc analysis of their audiograms: the effectiveness of our new therapeutic strategy obviously depends on the individual HL, and was most effective in normal-hearing tinnitus patients and those with mild HL. CONCLUSION: Subjective TL could be reduced in 16 out of 22 patients during stimulation. For a possible success of a future therapy, the HL seems to be of relevance.

Support of a patient-specific therapeutical acoustic stimulation in tinnitus by numerical modeling.

The pathogenesis of tinnitus involves multiple hierarchical levels of auditory processing and appraisal of sensory saliency. Early tinnitus onset is most likely attributed to homeostatic plasticity in the periphery, while the chronification and decompensation are tightly linked to brain areas for the allocation of attentional resources, such as e.g., the thalamocortical feedback loops and the limbic system. Increased spontaneous firing after sensory deafferentation might be sufficient to generate a phantom perception, yet the question why not every peripheral hearing loss automatically elicits a tinnitus sensation is still to be addressed. Utilizing quantitative modeling of multiple hierarchical levels in the auditory pathway, we demonstrate the effects of lateral inhibition on increased spontaneous firing and the resulting elevation of firing regularity and synchronization of neural activity. The presented therapeutical approach is based on the idea of disrupting the heightened regularity of the neural population response in the tinnitus frequency range. This neural activity regularity depends on lateral dispersion of common noise and thus is susceptible for edge effects and might be influenced by a change in neural activity in bordering frequency ranges by fitted acoustical stimulation. We propose the use of patient specifically adapted tailor-made notched acoustic stimulation, utilizing modeling results for the optimal adjustment of the stimulation frequencies to archive a therapeutical edge-effect.

On the matching of top-down knowledge with sensory input in the perception of ambiguous speech.

BACKGROUND: How does the brain repair obliterated speech and cope with acoustically ambivalent situations? A widely discussed possibility is to use top-down information for solving the ambiguity problem. In the case of speech, this may lead to a match of bottom-up sensory input with lexical expectations resulting in resonant states which are reflected in the induced gamma-band activity (GBA). METHODS: In the present EEG study, we compared the subject's pre-attentive GBA responses to obliterated speech segments presented after a series of correct words. The words were a minimal pair in German and differed with respect to the degree of specificity of segmental phonological information. RESULTS: The induced GBA was larger when the expected lexical information was phonologically fully specified compared to the underspecified condition. Thus, the degree of specificity of phonological information in the mental lexicon correlates with the intensity of the matching process of bottom-up sensory input with lexical information. CONCLUSIONS: These results together with those of a behavioural control experiment support the notion of multi-level mechanisms involved in the repair of deficient speech. The delineated alignment of pre-existing knowledge with sensory input is in accordance with recent ideas about the role of internal forward models in speech perception.

Identification of age-structured models: cell cycle phase transitions.

A methodology is developed that determines age-specific transition rates between cell cycle phases during balanced growth by utilizing age-structured population balance equations. Age-distributed models are the simplest way to account for varied behavior of individual cells. However, this simplicity is offset by difficulties in making observations of age distributions, so age-distributed models are difficult to fit to experimental data. Herein, the proposed methodology is implemented to identify an age-structured model for human leukemia cells (Jurkat) based only on measurements of the total number density after the addition of bromodeoxyuridine partitions the total cell population into two subpopulations. Each of the subpopulations will temporarily undergo a period of unbalanced growth, which provides sufficient information to extract age-dependent transition rates, while the total cell population remains in balanced growth. The stipulation of initial balanced growth permits the derivation of age densities based on only age-dependent transition rates. In fitting the experimental data, a flexible transition rate representation, utilizing a series of cubic spline nodes, finds a bimodal G(0)/G(1) transition age probability distribution best fits the experimental data. This resolution may be unnecessary as convex combinations of more restricted transition rates derived from normalized Gaussian, lognormal, or skewed lognormal transition-age probability distributions corroborate the spline predictions, but require fewer parameters. The fit of data with a single log normal distribution is somewhat inferior suggesting the bimodal result as more likely. Regardless of the choice of basis functions, this methodology can identify age distributions, age-specific transition rates, and transition-age distributions during balanced growth conditions.

Top-down knowledge supports the retrieval of lexical information from degraded speech.

How is it that the human brain is capable of making sense from speech under many acoustically compromised conditions? The support through top-down knowledge is inevitable but can we identify brain measures of this matching process between degraded auditory input and possible meaning? To answer these questions, the present study investigated the modulation of the induced gamma-band activity (GBA) in the auditory domain in response to degraded speech. During an EEG experiment subjects first listened to digitally degraded unintelligible speech signals (derived from German nouns). In an exposure sequence, half of the nouns were presented in a non-degraded intelligible format and memorized, while in the crucial test sequence subjects listened to all degraded speech signals again and were asked to identify the words. The induced GBA (40-Hz range) showed an increase at left temporal electrode sites around 350 ms only for words correctly identified in the test sequence. No differences in induced GBA were evident in the baseline sequence; neither did the evoked brain potentials yield any comparable effect. We conclude that the observed enhancement in induced gamma-band activity reflects a matching process of top-down lexical memory traces with degraded sensory input to form a comprehendible speech percept. The findings are highly corroborant to analogous studies in the visual system. They lend further plausibility to a left-lateralized fronto-temporal network enabling lexically guided speech perception, and they demonstrate the complementary role of time-sensitive brain analyses in discerning the functional neuroanatomy of speech.

Analysis of resonance chemotherapy in leukemia treatment via multi-staged population balance models.

An age-structured population balance model that explicitly models cell cycle phases is developed to investigate the effects of cell cycle specific (CCS) drugs. In particular, the benefits of timing CCS drug treatments in resonance chemotherapy are predicted and measured directly in vitro before evaluating likely in vivo scenarios. The phase transition rates are measured in vitro for the HL60 leukemia cell line and are used to predict the transient phase dynamics after exposure to the S phase specific drug, camptothecin. The phase oscillations predicted by the model are observed experimentally and the timing of a second camptothecin pulse is shown to significantly alter the overall treatment effectiveness. To explore the feasibility of designing resonance chemotherapeutic treatments to preferentially eliminate one cell type over another, Jurkat and HL60 leukemia cells are exposed to the same dual-pulse camptothecin treatment regimen. With the model framework validated for simplified cases, the model is used to extrapolate the effectiveness of resonance chemotherapy considering in vivo effects such as quiescence, drug metabolism, drug properties, and transport considerations that were not included in the in vitro experiments. While resonance chemotherapy is intuitive and looks promising in vitro, when in vivo considerations are included in the model, the phenomenon is dampened and the window of applicability becomes narrower.

[Incidence of autonomy and immune hyperthyroidism before and following preventive use of iodized salt in the Berlin-Brandenburg area]. / Inzidenz von Autonomie und Immunhyperthyreose vor und nach Jodsalzprophylaxe in der Region Berlin-Brandenburg.

The incidence of hyperthyroidism was observed in the area of Berlin (1.2 million inhabitants) and in a rural district in the geographical region of the "Mark Brandenburg" (48.115 inhabitants) during the period from 1975 und 1989. This area is characterized with a iodine deficiency grade II (WHO). In 1985 an iodine salt supplementation was introduced by law. The period before iodine salt supplementation 1975-1985 was compared to the period after iodine prophylaxis: there was an increase in hyperthyroidism in the Berlin-area by the ratio 1:3.1 and 1:2.8 (1975-83 compared to 1988 and 1989), in the rural district by 1:1.7 (1980-1985 compared to 1986/87). The ratio autonomy (non immunogenic form) to immunogenic etiology was 1:12 (1977-83), and changed to 1:1.45 in 1988 and 1:16.3 in 1989 after iodine supplementation. The sex ratio male:female was 1:10 before, and 1:6.8 after prophylaxis for hyperthyroidism in total, in autonomy the ratio was observed as 1:12 before and 1:7.7 (1988), 1:4.7 (1989) after supplementation, in immunogenic hyperthyroidism 1:10 unchanged in the early and late period of observation. The increase of hyperthyroidism after iodine prophylaxis correlated well with the consumption of thyrostatic drug Thiamazol (Methimazol) for the whole country. The defined daily dose (DDD)/1000 inhabitants/day increased during the observation time from 0.5 (1984), 0.55 (1985), 0.66 (1986), to 1.47 (1987), 1.26 (1988) and 0.81 (1989). The results are compared and discussed with reports from USA, Iceland, Great Britain, Denmark, Italy and Tasmania. During the period of seven years (1980-87) in the rural district a seasonal dependence of onset in hyperthyroidism was observed in spring time between May and June only in immunogenic hyperthyroidism, despite in thyroidal autonomy the disease began throughout the year without a seasonal peak.

Evaluation of test-weighing for the assessment of milk volume intake of formula-fed infants and its application to breast-fed infants.

Test-weighing (TW) was evaluated in formula-fed (FF) infants by comparison with direct measurement (DM) of formula intake during a 24 h period at 1, 2, 4 and 6 mo of age. Formula intakes estimated by TW ranged from 87 to 93% of those determined by DM over the 6-mo period. During the study period the number of feedings per day decreased but were not significantly different for FF and BF infants. Volume of intake per feeding by FF infants increased significantly during the 6-mo period whereas milk intakes of BF infants were not different at the four ages studied. These data indicated that when the number of daily feedings decreased with age, FF infants increased their volume of intake per feeding whereas BF infants did not adjust their intakes. Mean volume of milk intake at 4 and 6 mo, estimated by TW, was significantly greater in FF infants compared to breast-fed (BF) infants matched for age and size. Data from this study indicated clearly that when milk intakes of BF infants are compared to those of FF infants, both groups of infants should be test-weighed.

PIP: Test-weighing (TW) was evaluated in formula-fed (FF) infants from a University community in Indiana by comparison with direct measurement (DM) of formula intake during a 24 hour period at 1, 2, 4, and 6 months of age. Formula intakes estimated by TW ranged from 87 to 93% of those determined by DM over the 6-month period. During the study period the number of feedings per day decreased but were not significantly different for FF and BF infants. Volume of intake per feeding by FF infants increased significantly during the 6-month period whereas milk intakes of BF infants were not different at the 4 ages studied. These data indicate that when the number of daily feedings decreased with age, FF infants increased their volume of intake per feeding whereas BF infants did not adjust their intakes. Mean volume of milk intake at 4 and 6 months, estimated by TW, was significantly greater in FF infants compared to BF infants matched for age and size. Data from this study indicate clearly that when milk intakes of BF infants are compared to those of FF infants, both groups of infants should be test-weighed.

Effects of vitamin B6 intake on nutriture and growth of young infants.

Vitamin B6 is critical to normal development; however, the requirement for adequate nutriture of the human infant is based on limited experimental data. In this study vitamin B6 intakes of breast-fed (BF) and formula-fed (FF), healthy, term infants were related to levels of pyridoxal phosphate (PLP) in their plasma at 1, 2, 4, and 6 mo of age. Mothers of BF infants were supplemented with either 2.5 or 15.0 mg pyridoxine . hydrochloride (PN . HCl)/d. Growth was similar for FF and BF infants and was within normal ranges over the 6 mo period. Plasma PLP in cord blood was similar in BF and FF infants; however, at 1-5 d of age and at each subsequent age studied, levels of plasma PLP were significantly higher in FF infants than in BF. Lowest PLP values were for BF infants of mothers who received 2.5 mg PN . HCl/d. Mean plasma PLP decreased with age and was not correlated to vitamin B6 intakes except at 1 mo of age. At this age, vitamin B6 intake of BF infants whose mothers received 2.5 mg PN . HCl/d was only 0.1 mg B6/d. The consequences of this are uncertain; however, plasma PLP levels of the infants were low and reflected their intakes of vitamin B6.

Evaluating drug effectiveness in an office setting for children with attention deficit disorders.

Stimulant medications have been demonstrated to be useful in treating groups of children with attention deficit disorders, but placebo effects and situational differences in behavior in individual cases need to be followed and assessed. A simple procedure for systematically assessing these factors in the individual child in the office setting is described and illustrated. The procedure provides an objective means of determining the drug and placebo effects on the reported problem behavior and the differences between parent and teacher perceptions of the behavior.

Digital plethysmography for assessing erythrityl tetranitrate bioavailability.

The bioavailability or oral, sublingual, and chewable tablets or erythrityl tetranitrate (ETN) was evaluated in 15 normal men. In a randomized, complete crossover investigation with nitroglycerin and placebo controls, drug-induced changes in the diastolic amplitude response intensity were measured with a digital plethysmogram. Values for area under the response intensity curve (AUC), maximum response intensity (Imax), and time lapse from dosing to peak response (tmax) were obtained by computer processing and converted to intensity values and AUC segments for specific time intervals. Sublingual nitroglycerin induced a response (p less than 0.05) from placebo within the first hour. Although somewhat slower in reaching peak intensity, all forms of ETN induced significant responses over placebo (p less than 0.05) for 2 hr, with oral (swallowed) ETN different 6 hr. Our results indicate that all the ETN dosage forms were bioavailable, with the longest duration of effect by the oral form.

Respiratory distress associated with elective repeat cesarean section. A two-year experience in one medical community.

One hundred and forty-five elective repeat cesarean sections performed in one large medical community during a two-year period were studied. Ninety-nine of the patients had no prenatal test for determination of pulmonary or fetal maturity; 18 patients had an amniocentesis for L/S ratio. Only two infants were thought to be delivered prematurely, at 37 weeks gestational age. One of these infants had no respiratory distress. The other infant was delivered before the EDC by menstrual dates because a single ultrasound measurement performed one week before delivery suggested a "term fetus", and this infant had severe hyaline membrane disease. Six other infants had mild respiratory distress compatible with transient tachypnea or aspiration. In this medical community, one must question whether the risk of routine amniocentesis for L/S ratio before every elective repeat cesarean section might outweigh the potential benefits of the procedure.

Determination of serum bilirubin by skin reflectance: effect of pigmentation.

A noninvasive optical technique by which serum bilrubin can be estimated from skin spectral reflectance measurements has been further investigated. The original work on 30 healthy, full-term white infants and an independent study on 14 white and 30 black infants demonstrate that the method has potential not only for clinical use, but also for the study of the transport of bilrubin to, from and within the skin. The objectives of the present study are to evaluate the method on a larger sample population with special attention to natural skin pigmentation effects and the development of a physical model of the tissue to explain the relationship between serum bilrubin concentration and skin reflectance. Reflectance spectra (380-800 nm) and concurrent serum bilirubin measurements were taken on a sample population of 58 white and 45 full-term black infants (1-3 days of age). Multiple linear regression analysis, comprised of six wavelengths gave a correlation coefficient, r = 0.831 for the white infant group. For the black infant group, a five wavelength analysis provided r = 0.877 with the standard error of estimate being +/- 1.46 mg/100 ml for both groups. The model for establishing a physical basis for the relationship shows that a transformed, normalized Kubelka-Monk function xi (460, 510, 420) is linearly related to serum bilrubin concentration. This function is determined from the spectral reflectance values at three wavelengths, 420, 460, and 510 nm. The wavelength combination is such that effects due to hemoglobin and melanin pigments are minimized. Regression analysis showed that r = 0.778 and r = 0.865 for the white and black infant groups, respectively, with standard error of estimates being +/- 1.4 mg/100 ml for both groups. Routine determinations of total serum bilrubin by laboratory methods have standard errors of estimate ranging from +/- 1 to 1.5 mg/100 ml. Thus, the method herein described shows that the relationship between skin reflectance and serum bilrubin in full-term infants is close to the acceptable limits for clinical use. Furthermore, this work shows that skin pigmentation does not obscure this relationship.