Fertility and gonadal function in female survivors after treatment of early unfavorable Hodgkin lymphoma (HL) within the German Hodgkin Study Group HD14 trial.

BACKGROUND: In the HD14 trial, 2×BEACOPPescalated+2×ABVD (2+2) has improved the primary outcome. Compared with 4×ABVD, this benefit might be compromised by more infertility in women. Therefore, we analyzed gonadal function and fertility. PATIENTS AND METHODS: Women≤45 years in ongoing remission at least 1 year after therapy were included. Hormone parameters, menopausal symptoms, measures to preserve fertility, menstrual cycle, pregnancies, and offspring were evaluated. RESULTS: Three hundred and thirty one of 579 women addressed participated (57.2%) and 263 per-protocol treated patients qualified (A=ABVD: 137, B=2+2: 126, mean time after therapy 42 and 43 months, respectively). Regular menstrual cycle after treatment (A: 87%, B: 83%) and time to recovery (≤12 months) were not different. Follicle-stimulating hormone and anti-Muellerian hormone were significantly better in arm A. However, pregnancies after therapy favored arm B (A: 15%, B: 26%, P=0.043) and motherhood rates were equivalent to the German normal population. Multivariate analysis revealed prophylactic use of gonadotropin-releasing hormone (GnRH) analogues as highly significant prognostic factor for preservation of fertility (odds ratio=12.87, P=0.001). Severe menopausal symptoms were frequent in women≥30 years (A: 21%, B: 25%). CONCLUSIONS: Hormonal levels after 2+2 indicate a reduced ovarian reserve. However, 2+2 in combination with GnRH analogues does not compromise fertility within the evaluated observation time.

Large mediastinal tumor mass as a prognostic factor in Hodgkin's lymphoma. Is the definition on the basis of a chest radiograph in the era of CT obsolete?

PURPOSE: The risk factor "large mediastinal tumor mass" is an internationally accepted unfavorable prognostic factor in the staging of Hodgkin's lymphoma (HL). The definition of this risk factor varies considerably between large cooperative study groups. The purpose of the present analysis was to determine to which degree data obtained from chest radiograph (CRX) give the same results as those from CT scans (CT). METHODS: A total of 145 de novo HL patients in early unfavorable and advanced stages were included in this study. A total of 94 patients had a large mediastinal tumor mass according to the guidelines of the German Hodgkin Study Group (GHSG), while 51 had mediastinal lymph node involvement only. The size of mediastinal involvement and the thoracic diameter were measured on CRX and CT. Agreement between CRX and CT was determined by sensitivity and specificity analysis as well as descriptive statistics and correlations. RESULTS: The correlation of the diameters on CRX with those of CT was 0.95 for the tumor size and 0.77 for the thoracic diameter. The diagnostic decision-large mediastinal mass or not-correlated with 0.81 between CRX and CT and was identical in 90.3% of cases. The sensitivity was 0.87 and the specificity 0.96 for CRX, which is considered the current standard. CONCLUSION: The results show that there is a high agreement between the measurements of CRX and CT. Diagnosis of a large mediastinal mass disagreed in 10% of patients. Since the correct diagnosis of this risk factor is decisive for the adequate multimodal treatment choice, CRX should not be omitted.

A comparison of rh-TSH and thyroid hormone withdrawal in patients with differentiated thyroid cancer: preliminary evidence for an influence of age on the subjective well-being in hypothyroidism.

We aimed to investigate the subjective well-being in patients with differentiated thyroid cancer after hormone withdrawal. Since this might be confounded by psycho-oncological processes unrelated to hypothyroidism we intended to minimize such factors by only including patients with a history of uneventful follow-up examinations for several years. We investigated 67 patients applying the General Health Questionnaire (GHQ-12) at 3 time points t1, t2, and t3. The time point t2 represented an intensified follow-up examination 5 years after thyroidectomy, which was performed either on hormone withdrawal (49 patients) or using rh-TSH (18 patients). The time points t1 and t3 took place during follow-up examinations 6 months before and after t2 in a euthyroid state. Additionally, we assessed the impact of age, gender, family status, and education on the GHQ-12 score at all 3 time points. Within the hormone withdrawal group the analyses demonstrated a significant difference between t1 and t2 as well as t3 and t2. Additionally, there was a significant negative correlation of age with GHQ-12 sum scores at t2, but not at t1 or t3. Subgroup analyses at t2 indicated that the subjective well-being in younger patients was more impaired compared to elderly patients. The between-group analysis showed no significant differences. However, concerning the age effect there was a significant difference between the subgroup of young hypothyroid patients and the total rh-TSH group at t2. We demonstrated preliminary evidence for an influence of age on the subjective well-being in hypothyroidism suggesting that younger subjects are subjectively more impaired by hypothyroidism than elderly ones.

Evaluation of body fat composition after linagliptin treatment in a rat model of diet-induced obesity: a magnetic resonance spectroscopy study in comparison with sibutramine.

The effects of linagliptin on fat content in diet-induced obese rats were compared with those of the appetite suppressant sibutramine. Female Wistar rats fed a high-fat diet (HFD) for 3 months received vehicle, linagliptin (10 mg/kg) or sibutramine (5 mg/kg) treatment orally, once daily for 6 additional weeks, while continuing the HFD. Magnetic resonance spectroscopy analysis of fat content was performed at baseline and at the end of the 6-week treatment period. Linagliptin treatment profoundly reduced hepatic fat compared with vehicle, with an effect comparable to that of sibutramine. The vehicle-corrected mean change (95% CI) from baseline in hepatic fat and intramyocellular lipid was -59.0% (-104.3%, -13.6%; p = 0.015) and -62.1% (-131.6%, 7.4%; p = 0.073), respectively, for linagliptin compared with -54.3% (-101.5%, -7.1%; p = 0.027) and -72.4% (-142.4%, -2.4%; p = 0.044), respectively, for sibutramine.

Is It Okay to Use Compressed NU-6 Files for Clinical Word Recognition Testing?

PURPOSE: The purpose of this study was to evaluate the impact of file compression on clinically measured word recognition scores obtained using the Northwestern University Test Number Six (NU-6; Auditec recording) materials. METHOD: Participants were 86 adults (N = 170 ears; M age = 65.5). The 25 most difficult words from each of four NU-6 test lists were used to measure word recognition. Two lists were compressed using a freely available Advanced Audio Coding compression algorithm and two were not. Word recognition was measured in each ear using one compressed file and one uncompressed file. Percent correct scores were calculated in each test condition and log transformed for analyses. Clinically meaningful differences between uncompressed and compressed scores were examined using 95% critical difference ranges. The effects of file compression on word recognition scores were examined in the context of multiple potential confounding effects, including age and degree of hearing loss, using linear mixed-effects models (LMMs). RESULTS: Differences between compressed and uncompressed scores in a given ear exceeded the 95% critical difference range in about 7% of cases, approximating the 5% of expected cases occurring due to chance. Likewise, LMM results revealed no significant effect of file compression on clinically measured NU-6 word recognition scores and no significant interactions between compression effects and age or degree of hearing loss. CONCLUSIONS: While the original uncompressed audio files are clearly the most appropriate stimuli for clinical purposes, our study results suggest that file compression, even at an aggressive 64 kilobits per second, does not have a statistically significant, or clinically meaningful, effect on word recognition scores when measured using these Auditec materials.

Reversal of imbalance between kynurenic acid and 3-hydroxykynurenine by antipsychotics in medication-naïve and medication-free schizophrenic patients.

The association between the pro-inflammatory state of schizophrenia and increased tryptophan degradation into kynurenine has been reported. However, the relationship between metabolites from subdivisions of the kynurenine pathway, kynurenic acid and 3-hydroxykynurenine, remains unknown. The present study tested the relationship between these kynurenine metabolites in the plasma of medication-naïve (n=35) or medication-free (n=18) patients with schizophrenia at admission and following 6-week antipsychotic treatment compared to healthy controls (n=48). The plasma concentrations of kynurenic acid (nmol/l) were lower (difference=-8.44 (-13.22 to -3.65); p=0.001) and of 3-hydroxykynurenine (nmol/l) were higher (difference=11.24 (8.11-14.37); p<0.001) in the patients compared with the healthy controls. The kynurenic acid/kynurenine (difference=-2.75 (-5.115 to -0.336); p=0.026) and kynurenic acid/3-hydroxykynurenine (difference=-1.08 (-1.431 to -0.729); p<0.001) ratios were also lower in the patients. After the 6-week treatment, the patients' plasma kynurenic acid levels (difference=3.85 (-0.23 to 7.94); p=0.064) showed a trend towards an increase, whereas plasma 3-hydroxykynurenine levels (difference=22.41 (19.76-25.07); p<0.001) decreased. As a consequence, the kynurenic acid/3-hydroxykynurenine ratio (difference=-4.41 (-5.51 to -3.3); p<0.001) increased. Higher initial plasma kynurenic acid levels on admission or increased kynurenic acid/kynurenine ratio after treatment were associated with reduction of clinical symptoms scores upon discharge although higher kynurenic acid/kynurenine on admission may induce higher positive symptoms score. In contrast, higher 3-hydroxykynurenine is associated with lower positive symptoms score. These results indicate that there is an imbalance in the kynurenine pathway in schizophrenia. The 6-week antipsychotic treatment may partially reverse the imbalance in kynurenine metabolism and that in turn induces clinical response.

In vivo imaging neurotransmitter function. The rat 6-hydroxydopamine model and its relevance for human Parkinson's disease.

This article gives an overview of those small animal imaging studies which have been conducted on neurotransmitter function in the rat 6-hydoxydopamine (6-OHDA) model of Parkinson's disease, and discusses findings with respect to the outcome of clinical studies on Parkinsonian patients.

Clinical evaluation of a new hearing aid anti-cardioid directivity pattern.

OBJECTIVE: The purpose of this research was to evaluate a new directional hearing aid algorithm which automatically adapts to an anti-cardioid pattern in background noise when a speech signal originates from behind the hearing aid user. DESIGN: Using the hearing-in-noise-test (HINT) in the soundfield, with the sentences delivered adaptively from the back (180°) and the standard HINT competing noise from the front (0°; 72 dB SPL), the participants were tested for three different hearing aid conditions: omnidirectional, conventional adaptive directional, and adaptive directional with the anti-cardioid algorithm enabled. STUDY SAMPLE: Adults (n = 21) with bilaterally symmetrical downward sloping sensorineural hearing loss; experienced hearing aid users and aided bilaterally for experimental testing. RESULTS: Results revealed a significant effect for the hearing aid microphone setting (p < .0001), with a HINT mean RTS of 4.2 dB for conventional adaptive directional, -0.1 dB for omnidirectional, and -5.7 dB when the anti-cardioid algorithm was active. This was a large effect size (Cohen's f2). CONCLUSION: The findings suggest that the signal classification system steered the algorithm correctly, and that when implemented, the anti-cardioid polar pattern resulted in an improvement in speech recognition in background noise for this listening situation.

No protection of the ovarian follicle pool with the use of GnRH-analogues or oral contraceptives in young women treated with escalated BEACOPP for advanced-stage Hodgkin lymphoma. Final results of a phase II trial from the German Hodgkin Study Group.

BACKGROUND: The reduction of treatment-related toxic effects is the main goal in the current trials of the German Hodgkin Study Group (GHSG). In this regard, the protection of the ovarian reserve in young women is very important. Therefore, the GHSG investigated the use of gonadotropin-releasing hormone-analogues (GnRH-a) and oral contraceptives (OC) in young women with advanced-stage Hodgkin lymphoma (HL). PATIENTS AND METHODS: Women (18-40 years) were randomly assigned either to receive daily OC or monthly GnRH-a during escalated combination therapy with bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc). Hormonal levels were determined at baseline, during therapy, and at follow-up. RESULTS: The study was closed prematurely after an interim analysis of 12 patients in arm A (OC) and 11 in arm B (GnRH-a), 9 and 10 are assessable for the primary end point. Women's median age was 25 years in both arms. The anti-Mullerian hormone level after at least 12 months was reduced in all patients. For the entire study cohort, the respective ovarian follicle preservation rate was 0% (95% confidence interval 0% to 12%). CONCLUSION: We observed no protection of the ovarian reserve with hormonal co-treatment during BEACOPPesc. This result supports efforts of ongoing trials to reduce chemotherapy intensity and toxicity. Alternative strategies for the protection of fertility must be offered to young female HL patients before the start of BEACOPPesc therapy.

In vivo requirement of the alpha-syntrophin PDZ domain for the sarcolemmal localization of nNOS and aquaporin-4.

alpha-Syntrophin is a scaffolding adapter protein expressed primarily on the sarcolemma of skeletal muscle. The COOH-terminal half of alpha-syntrophin binds to dystrophin and related proteins, leaving the PSD-95, discs-large, ZO-1 (PDZ) domain free to recruit other proteins to the dystrophin complex. We investigated the function of the PDZ domain of alpha-syntrophin in vivo by generating transgenic mouse lines expressing full-length alpha-syntrophin or a mutated alpha-syntrophin lacking the PDZ domain (Delta PDZ). The Delta PDZ alpha-syntrophin displaced endogenous alpha- and beta 1-syntrophin from the sarcolemma and resulted in sarcolemma containing little or no syntrophin PDZ domain. As a consequence, neuronal nitric oxide synthase (nNOS) and aquaporin-4 were absent from the sarcolemma. However, the sarcolemmal expression and distribution of muscle sodium channels, which bind the alpha-syntrophin PDZ domain in vitro, were not altered. Both transgenic mouse lines were bred with an alpha-syntrophin-null mouse which lacks sarcolemmal nNOS and aquaporin-4. The full-length alpha-syntrophin, not the Delta PDZ form, reestablished nNOS and aquaporin-4 at the sarcolemma of these mice. Genetic crosses with the mdx mouse showed that neither transgenic syntrophin could associate with the sarcolemma in the absence of dystrophin. Together, these data show that the sarcolemmal localization of nNOS and aquaporin-4 in vivo depends on the presence of a dystrophin-bound alpha-syntrophin PDZ domain.

The effect of various protein fractions on Z- and M-line reconstitution.

Extraction of thin, glycerinated bundles of rabbit psoas muscle with a low ionic strength solvent results in removal first of M lines and then of Z lines. When these extracted myofibrillar bundles are allowed to interact, at adjusted ionic conditions, with the dilute myofibrillar extract or with the fractions obtained at 40% ammonium sulfate saturation from either the myofibrillar extract or from the Bailey extract of natural actomyosin, reconstitution of Z lines occurs. The ammonium sulfate fraction from the Bailey extract of natural actomyosin restores the tetragonal lattice structure of the Z line. Other structural features such as I-band tufts or cross-bridges, M lines and H-zone binding also occur with some of the proteins used for recombination. Although it has not yet been possible to identify exactly the protein(s) constituting the Z line, it appears unlikely that tropomyosin or troponin alone is the major protein of the Z line. A more likely candidate is alpha-actinin or a combination of alpha-actinin with another protein(s). In addition, this study demonstrates that basic morphological differences exist between cross-sections through the Z-line lattice and cross-sections through tropomyosin crystals.

Hawks select odd prey.

Hawks were offered one color of mouse for ten consecutive captures and then a choice between that and another color. The birds usually selected the odd, or unusual, color. This behavior is probably adaptive because odd prey in nature would be unfit.

Ocular hazard from picosecond pulses of Nd: YAG laser radiation.

Seven rhesus monkeys (14 eyes) were exposed to 1064-nanometer radiation in single pulses of 25 to 35 picoseconds fromn a mode-locked Nd: YA G laser. Threshold injury resulted from single pulses with a mnean energy of 13 +/- 3 mnicrojoules. Electron microscopy of the retina revealed that damnage was highly localized in the photoreceptor and pigmented epithelial cells at the oluter retina. Membrane disruption, distorted outer segmtzents, and abnormnal melanin granules resembling fetal premelanosomnies were observed.

Neural traffic as voxel-based measure of cerebral functional connectivity in fMRI.

To access functional connectivity by in vivo brain imaging voxel-by-voxel, we developed a novel approach named neural traffic (NT). NT depicts the intensity of functional connectivity on a voxel-by-voxel basis in the whole brain. Functional magnetic resonance imaging (fMRI) experiments were carried out on eight individuals during either hearing or viewing words. The blood oxygen level dependant (BOLD) signal was taken as measure of neural activity. For each voxel, functional connectivity with all other brain voxels was determined by calculating Pearson correlation coefficients at two connectivity thresholds (r=0.35 and 0.65). Then, NT images were derived by counting the number of suprathreshold connections for each individual voxel. Calculations based on random networks indicate that statistically reliable NT images can be derived in individuals. With regard to group analysis, at r=0.35 NT images are similar though not identical with the first component of principal component analysis (PCA), displaying a widespread but not ubiquitous pattern of functionally connected cortical areas. At r=0.65, NT group images display functional connectivity confined to circumscribed cortical regions which reach beyond the corresponding primary sensory areas, their known associated areas and the default network. In conclusion, NT goes beyond the approach of correlating the BOLD signal with the external stimulus-presentation time course by computing linear functional connectivity between all brain voxels based on any BOLD time course. First results demonstrate that the NT approach is likely - on an individual base - to reveal novel cortical and subcortical connectivities involved in stimulus processing.

Statistically derived factors of varied importance to audiologists when making a hearing aid brand preference decision.

PURPOSE: To determine the amount of importance audiologists place on various items related to their selection of a preferred hearing aid brand manufacturer. RESEARCH DESIGN: Three hundred forty-three hearing aid-dispensing audiologists rated a total of 32 randomized items by survey methodology. RESULTS: Principle component analysis identified seven orthogonal statistical factors of importance. In rank order, these factors were Aptitude of the Brand, Image, Cost, Sales and Speed of Delivery, Exposure, Colleague Recommendations, and Contracts and Incentives. While it was hypothesized that differences among audiologists in the importance ratings of these factors would dictate their preference for a given brand, that was not our finding. Specifically, mean ratings for the six most important factors did not differ among audiologists preferring different brands. A statistically significant difference among audiologists preferring different brands was present, however, for one factor: Contracts and Incentives. Its assigned importance, though, was always lower than that for the other six factors. CONCLUSIONS: Although most audiologists have a preferred hearing aid brand, differences in the perceived importance of common factors attributed to brands do not largely determine preference for a particular brand.

Neural correlates of subliminal and supraliminal letter processing--an event-related fMRI study.

One problem of interpreting research on subconscious processing is the possibility that participants are weakly conscious of the stimuli. Here, we compared the fMRI BOLD response in healthy adults to clearly visible single letters (supraliminal presentation) with the response to letters presented in the absence of any behavioural evidence of visibility (subliminal presentation). No letter catch trials served as a control condition. Forced-choice responses did not differ from chance when letter-to-background contrast was low, whereas they were almost 100% correct when contrast was high. A comparison of fMRI BOLD signals for supraliminal and subliminal letters with the control trials revealed a signal increase in left BA 37 (fusiform gyrus). Comparison of supraliminal with subliminal letters showed a significant increase in the right inferior frontal gyrus (BA 44, partly extending to BA 9 and BA 45, as well as BA 46). Finally, a comparison of subliminal with supraliminal letters showed increases in the left middle temporal gyrus (BA 21) and the right extrastriate cortex (BA 19).

User preference and reliability of bilateral hearing aid gain adjustments.

The purpose of the current study was to evaluate the consistency and reliability of user adjustments to hearing aid gain and the resulting effects on speech understanding. Sixteen bilaterally aided individuals with hearing loss adjusted their hearing aid gain to optimize listening comfort and speech clarity while listening to speech in quiet and noisy backgrounds. Following these adjustments, participants readjusted their aids to optimize clarity and comfort while listening to speech in quiet. These final gain settings were recorded and compared to those provided by NAL-NL1 prescriptive targets. In addition, speech understanding was tested with the hearing aids set at target and user gain settings. Performance differences between the gain settings were then assessed. Study results revealed that although some listeners preferred more or less gain than prescribed, on average, user and prescribed gain settings were similar in both ears. Some individuals, however, made gain adjustments between ears resulting in "gain mismatches." These "mismatches" were often inconsistent across trials suggesting that these adjustments were unreliable. Speech testing results, however, showed no significant difference across the different gain settings suggesting that the gain deviations introduced in this study were not large enough to significantly affect speech understanding.

Using trainable hearing aids to examine real-world preferred gain.

BACKGROUND: While there have been many studies of real-world preferred hearing aid gain, few data are available from participants using hearing aids with today's special features activated. Moreover, only limited data have been collected regarding preferred gain for individuals using trainable hearing aids. PURPOSE: To determine whether real-world preferred hearing aid gain with trainable modern hearing aids is in agreement with previous work in this area, and to determine whether the starting programmed gain setting influences preferred gain outcome. RESEARCH DESIGN: An experimental crossover study. Participants were randomly assigned to one of two treatment groups. Following initial treatment, each subject crossed to the opposite group and experienced that treatment. STUDY SAMPLE: Twenty-two adults with downward sloping sensorineural hearing loss served as participants (mean age 64.5; 16 males, 6 females). All were experienced users of bilateral amplification. INTERVENTION: Using a crossover design, participants were fitted to two different prescriptive gain conditions: VC (volume control) start-up 6 dB above NAL-NL1 (National Acoustic Laboratories-Non-linear 1) target or VC start-up 6 dB below NAL-NL1 target. The hearing aids were used in a 10 to 14 day field trial for each condition, and using the VC, the participants could "train" the overall hearing aid gain to their preferred level. During the field trial, daily hearing aid use was logged, as well as the listening situations experienced by the listeners based on the hearing instrument's acoustic scene analysis. The participants completed a questionnaire at the start and end of each field trial in which they rated loudness perceptions and their satisfaction with aided loudness levels. RESULTS: Because several participants potentially experienced floor or ceiling effects for the range of trainable gain, the majority of the statistical analysis was conducted using 12 of the 22 participants. For both VC-start conditions, the trained preferred gain differed significantly from the NAL-NL1 prescriptive targets. More importantly, the initial start-up gain significantly influenced the trained gain; the mean preferred gain for the +6 dB start condition was approximately 9 dB higher than the preferred gain for the -6 dB start condition, and this difference was statistically significant (p < .001). Partial eta squared (n2) = 0.919, which is a large effect size. Deviation from the NAL-NL1 target was not significantly influenced by the time spent in different listening environments, amount of hearing aid use during the trial period, or amount of hearing loss. Questionnaire data showed more appropriate ratings for loudness and higher satisfaction with loudness for the 6 dB below target VC-start condition. CONCLUSIONS: When trainable hearing aids are used, the initial programmed gain of hearing instruments can influence preferred gain in the real world.