Natural disturbance regimes as a guide for sustainable forest management in Europe.

In Europe, forest management has controlled forest dynamics to sustain commodity production over multiple centuries. Yet over-regulation for growth and yield diminishes resilience to environmental stress as well as threatens biodiversity, leading to increasing forest susceptibility to an array of disturbances. These trends have stimulated interest in alternative management systems, including natural dynamics silviculture (NDS). NDS aims to emulate natural disturbance dynamics at stand and landscape scales through silvicultural manipulations of forest structure and landscape patterns. We adapted a "Comparability Index" (CI) to assess convergence/divergence between natural disturbances and forest management effects. We extended the original CI concept based on disturbance size and frequency by adding the residual structure of canopy trees after a disturbance as a third dimension. We populated the model by compiling data on natural disturbance dynamics and management from 13 countries in Europe, covering four major forest types (i.e., spruce, beech, oak, and pine-dominated forests). We found that natural disturbances are highly variable in size, frequency, and residual structure, but European forest management fails to encompass this complexity. Silviculture in Europe is skewed toward even-aged systems, used predominately (72.9% of management) across the countries assessed. The residual structure proved crucial in the comparison of natural disturbances and silvicultural systems. CI indicated the highest congruence between uneven-aged silvicultural systems and key natural disturbance attributes. Even so, uneven-aged practices emulated only a portion of the complexity associated with natural disturbance effects. The remaining silvicultural systems perform poorly in terms of retention compared to tree survivorship after natural disturbances. We suggest that NDS can enrich Europe's portfolio of management systems, for example where wood production is not the primary objective. NDS is especially relevant to forests managed for habitat quality, risk reduction, and a variety of ecosystem services. We suggest a holistic approach integrating NDS with more conventional practices.

Preclinical Antitumor Efficacy of BAY 1129980-a Novel Auristatin-Based Anti-C4.4A (LYPD3) Antibody-Drug Conjugate for the Treatment of Non-Small Cell Lung Cancer.

C4.4A (LYPD3) has been identified as a cancer- and metastasis-associated internalizing cell surface protein that is expressed in non-small cell lung cancer (NSCLC), with particularly high prevalence in the squamous cell carcinoma (SCC) subtype. With the exception of skin keratinocytes and esophageal endothelial cells, C4.4A expression is scarce in normal tissues, presenting an opportunity to selectively treat cancers with a C4.4A-directed antibody-drug conjugate (ADC). We have generated BAY 1129980 (C4.4A-ADC), an ADC consisting of a fully human C4.4A-targeting mAb conjugated to a novel, highly potent derivative of the microtubule-disrupting cytotoxic drug auristatin via a noncleavable alkyl hydrazide linker. In vitro, C4.4A-ADC demonstrated potent antiproliferative efficacy in cell lines endogenously expressing C4.4A and inhibited proliferation of C4.4A-transfected A549 lung cancer cells showing selectivity compared with a nontargeted control ADC. In vivo, C4.4A-ADC was efficacious in human NSCLC cell line (NCI-H292 and NCI-H322) and patient-derived xenograft (PDX) models (Lu7064, Lu7126, Lu7433, and Lu7466). C4.4A expression level correlated with in vivo efficacy, the most responsive being the models with C4.4A expression in over 50% of the cells. In the NCI-H292 NSCLC model, C4.4A-ADC demonstrated equal or superior efficacy compared to cisplatin, paclitaxel, and vinorelbine. Furthermore, an additive antitumor efficacy in combination with cisplatin was observed. Finally, a repeated dosing with C4.4A-ADC was well tolerated without changing the sensitivity to the treatment. Taken together, C4.4A-ADC is a promising therapeutic candidate for the treatment of NSCLC and other cancers expressing C4.4A. A phase I study (NCT02134197) with the C4.4A-ADC BAY 1129980 is currently ongoing. Mol Cancer Ther; 16(5); 893-904. ©2017 AACR.

Impact of three hours of discotheque music on pure-tone thresholds and distortion product otoacoustic emissions.

The aim of this study was to investigate whether distortion product otoacoustic emissions (DPOAEs) are a suitable means for detecting changes in outer hair cell (OHC) functionality due to exposure to three hours of discotheque music and whether efferent reflex strength of the medial olivocochlear bundle is able to predict the ear's susceptibility to high-level noise. High-resolution DPOAEs (Δf(2)=47 Hz) were recorded between 3.5 and 4.5 kHz at close-to-threshold primary tone levels. For comparison, high-resolution pure-tone audiometry was conducted in the same frequency range. Efferent reflex strength was measured by means of DPOAEs at a specific frequency with and without contralateral acoustic stimulation. A significant deterioration of more than 10 dB was found for pure-tone thresholds and DPOAE levels indicating that three hours of high-level noise exert a considerable influence on hearing capability and OHC functionality. A significant correlation between shifts in pure-tone threshold and shifts in DPOAE level occurred when removing data with differing calibration across measurements. There was no clear correlation between efferent reflex strength and shifts in pure-tone threshold or shifts in DPOAE level suggesting that the applied measures of efferent reflex strength may not be suitable for quantifying individual vulnerability to noise.

Laterality of auditory startle responses in humans.

OBJECTIVE: To examine whether the auditory startle reaction in humans is a symmetrical or asymmetrical bilateral brainstem reflex in response to an unexpected loud stimulus. METHODS: We investigated physiological side-to-side differences of auditory startle responses (ASRs) in 28 healthy adult subjects. ASRs were elicited by randomly presented auditory stimuli. Reflex electromyographic activity was simultaneously recorded from masseter, orbicularis oculi, sternocleidomastoid and biceps brachii muscles bilaterally. RESULTS: ASR area-under-the-curve was significantly larger on the side contralateral to hand dominance in sternocleidomastoid, and tended to be larger on the dominant side in biceps brachii. In contrast, in orbicularis oculi, ASR area was significantly larger on the right vs. left side, irrespective of handedness. There was no significant side-to-side difference of ASR probability and ASR latency in any muscle. CONCLUSIONS: The present data expand our knowledge on physiological variables influencing ASRs and provide evidence of laterality of ASRs in sternocleidomastoid and biceps brachii, being associated with hand dominance, and in orbicularis oculi, irrespective of handedness. SIGNIFICANCE: Normal limits of side-to-side differences offer an additional parameter to be taken into account in studies of patients presenting with asymmetric symptoms.

Auditory startle reaction in primary blepharospasm.

Primary dystonia is associated with abnormal brainstem function, as shown by abnormalities of the blink reflex in blepharospasm (BSP) and of the auditory startle reaction in cervical dystonia. We examined the auditory startle reaction--a brainstem reflex elicited by an unexpected loud stimulus--in patients with primary BSP to expand knowledge on brainstem pathophysiology in primary focal dystonia. Thirteen patients with primary BSP were included and 13 age- and sex-matched healthy volunteers served as controls. Auditory startle responses (ASRs) were elicited by binaural high-intensity auditory stimuli, and reflex electromyographic activity was recorded simultaneously with surface electrodes bilaterally from masseter, orbicularis oculi, sternocleidomastoid, and biceps brachii muscles. Patients with BSP showed higher ASR probabilities (masseter, sternocleidomastoid, biceps brachii), shorter ASR onset latencies (masseter, orbicularis oculi, sternocleidomastoid), and larger ASR area-under-the-curve (masseter, sternocleidomastoid) as compared with normal controls. Habituation of ASRs did not differ significantly between patients and controls. These results corroborate previous findings of increased brainstem excitability in primary BSP but point to a different pattern of brainstem dysfunction compared to cervical dystonia, indicating that different pathophysiological mechanisms are involved in the two types of focal dystonia.

Distortion product otoacoustic emissions for hearing threshold estimation and differentiation between middle-ear and cochlear disorders in neonates.

Our aim in the present study was to apply extrapolated DPOAE I/O-functions [J. Acoust. Soc. Am. 111, 1810-1818 (2002); 113, 3275-3284 (2003)] in neonates in order to investigate their ability to estimate hearing thresholds and to differentiate between middle-ear and cochlear disorders. DPOAEs were measured in neonates after birth (mean age = 3.2 days) and 4 weeks later (follow-up) at 11 test frequencies between f2 = 1.5 and 8 kHz and compared to that found in normal hearing subjects and cochlear hearing loss patients. On average, in a single ear hearing threshold estimation was possible at about 2/3 of the test frequencies. A sufficient test performance of the approach is therefore suggested. Thresholds were higher at the first measurement compared to that found at the follow-up measurement. Since thresholds varied with frequency, transitory middle ear dysfunction due to amniotic fluid instead of cochlear immaturity is suggested to be the cause for the change in thresholds. DPOAE behavior in the neonate ears differed from that found in the cochlear hearing loss ears. From a simple model it was concluded that the difference between the estimated DPOAE threshold and the DPOAE detection threshold is able to differentiate between sound conductive and cochlear hearing loss.

Evidence for a bipolar change in distortion product otoacoustic emissions during contralateral acoustic stimulation in humans.

The aim of this study was to investigate the activity of the medial olivocochlear (MOC) efferents during contralateral (CAS) and ipsilateral acoustic stimulation (IAS) by recording distortion product otoacoustic emission (DPOAE) suppression and DPOAE adaptation in humans. The main question was: do large bipolar changes in DPOAE level (transition from enhancement to suppression) also occur in humans when changing the primary tone level within a small range as described by Maison and Liberman for guinea pigs [J. Neurosci. 20, 4701-4707 (2000)]? In the present study, large bipolar changes in DPOAE level (14 dB on average across subjects) were found during CAS predominantly at frequencies where dips in the DPOAE fine structure occurred. Thus, effects of the second DPOAE source might be responsible for the observed bipolar effect. In contrast, comparable effects were not found during IAS as was reported in guinea pigs. Reproducibility of CAS DPOAEs was better than that for IAS DPOAEs. Thus, contralateral DPOAE suppression is suggested to be superior to ipsilateral DPOAE adaptation with regard to measuring the MOC reflex strength and for evaluating the vulnerability of the cochlea to acoustic overexposure in a clinical context.

Frataxin deficiency in pancreatic islets causes diabetes due to loss of beta cell mass.

Diabetes is caused by an absolute (type 1) or relative (type 2) deficiency of insulin-producing beta cells. We have disrupted expression of the mitochondrial protein frataxin selectively in pancreatic beta cells. Mice were born healthy but subsequently developed impaired glucose tolerance progressing to overt diabetes mellitus. These observations were explained by impairment of insulin secretion due to a loss of beta cell mass in knockout animals. This phenotype was preceded by elevated levels of reactive oxygen species in knockout islets, an increased frequency of apoptosis, and a decreased number of proliferating beta cells. Hence, disruption of the frataxin gene in pancreatic beta cells causes diabetes following cellular growth arrest and apoptosis, paralleled by an increase in reactive oxygen species in islets. These observations might provide insight into the deterioration of beta cell function observed in different subtypes of diabetes in humans.

Exaggerated auditory startle responses in multiple system atrophy: a comparative study of parkinson and cerebellar subtypes.

OBJECTIVE: Auditory startle responses (ASRs) have recently been reported to be exaggerated in cranial and peripheral nerve supplied muscles of patients with multiple system atrophy (MSA). ASRs displayed increased probability, amplitude and duration, shorter onset latency, and reduced habituation in comparison with healthy subjects. In order to investigate whether certain ASR features may differentiate MSA subtypes, the authors studied ASRs in 21 MSA patients (olivopontocerebellar type, MSA-C: n = 8, striatonigral type, MSA-P: n = 13), and 17 age-matched normal controls. METHODS: ASRs were elicited by binaural high-intensity auditory stimuli which differed randomly in tonal frequency and intensity (250 Hz, 90 db; 500 Hz, 105 db; 750 Hz, 105 db; 1000 Hz, 110 db normal hearing level), presented through tubal insert phones. Reflex electromyographic activity was simultaneously recorded with surface electrodes from masseter, orbicularis oculi, sternocleidomastoid, biceps brachii, abductor pollicis brevis, rectus femoris, tibialis anterior, and soleus muscles. RESULTS: Eighteen MSA patients (86%) had exaggerated ASRs as compared to normal subjects. At group level, indices of ASR disinhibition including increased ASR probability (in extremity muscles), shortened onset latency, and enlarged response magnitude were significantly more marked in MSA-P as compared to MSA-C patients. ASR probability showed habituation in normal subjects, less in MSA-P. and none in MSA-C patients. Three MSA-patients had no ASRs except in orbicularis oculi muscle. CONCLUSIONS: Although absent ASRs may occur in some MSA patients, most of them exhibit exaggerated ASRs. This finding may reflect disinhibition of lower brainstem nuclei due to the degenerative disorder. ASRs were significantly more disinhibited in MSA-P versus MSA-C. suggesting involvement of different neural structures in the two MSA-subtypes.