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Buoyancy and balance are important parameters for static or slow moving low-metabolic aquatic organisms. The extant coelacanths, a single genus (Latimeria) consisting of two species living at moderate depths (100 - 400 m) in the Western Indian Ocean and off Indonesia and representing an ancient group of lobe finned fishes dating back to the early Devonian (410 Myr), have among the lowest metabolic rates of any living vertebrate, and thus would be predicted to expend precious little energy to maintain buoyancy and balance. Previous observations on living coelacanths support the hypothesis that the coelcanth is neutrally buoyant and is in close to perfect hydrostatic balance in any body posture. Likewise, point-by-point measurements of tissue composition have shown a generally high lipid content of coelacanth tissue supporting neutral buoyancy without a gas filled bladder as found in other sarcopterygians (lungs) and in many actinopterygians (swim bladder). However, precise measurements of buoyancy and hydrostatic balance at different depths have never been made in the coelacanth. Here we show using non-invasive imaging that buoyancy of the coelacanth closely matches its depth distribution and a close-to-perfect balance can be used by the animal to change body posture with little effort. We found that the lipid filled "fatty organ" of the coelacanth is well adapted to support neutral buoyancy and simple maneuvers of fins can cause a considerable shift in torque around the pitch axis. This allows the coelacanth to assume and remain in any body posture like horizontal orientation, headstand or tail stand with little physical effort. Our results demonstrate a close match between tissue composition in the extant coelacanth, depth range and behavior (e.g. effortless vertical drift hunting with the electrosensitive rostral organ in close contact with the substrate). We anticipate our non-invasive technique of mapping tissue components to be a starting point for more sophisticated models of buoyancy and hydrostatic balance in aquatic vertebrates in general. Specifically, we suggest the technique can be used on the few late term and juvenile coelacanth specimens in existence to predict the most likely habitat depth of the juvenile life stage which is currently unknown.

"This is the peer reviewed version of the following article: Torquato, F., & Møller, P. R. (2022). Physical–biological interactions underlying the connectivity patterns of coral-dependent fishes around the Arabian Peninsula. Journal of Biogeography, 49 ,483–496., which has been published in final form at https://doi.org/10.1111/jbi.14318 .This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited." Aim: Distribution patterns of lineages alone do not explain the processes underlying phylogenetic differentiation in fishes observed around the Arabian Peninsula, whose hypotheses traditionally rely on (i) Pleistocene vicariance events, (ii) successive bottlenecks, (iii) recent founder effects (iv) and large spatial gradients in physical conditions. In this study, we test the hypothesis that phylogeographical patterns of coral- dependent fish species inhabiting the peninsula may be driven by a combination of ocean circulation, larval behaviour and seascape features.Location: Arabian Peninsula.Taxa: Coral reef fish.Methods: A biophysical modelling system that relies on stochastic Lagrangian frame-work and Individual-Based Model was used to simulate larval dispersal through three putative barriers, by tracking three-dimensional movements of virtual particles in ocean circulation scenarios. We explored the range of dispersal capabilities across reef fish species by creating 72 hypothetical strategies, each representing a unique combination of five biological traits, namely pelagic larval duration, spawning periodicity, mortality rate, reproductive output and vertical migration.Results: The strength of the barriers was highly variable as a function of all biological traits (except reproductive output) and indicated high asymmetry of connectivity, and hence gene flow, between adjacent areas. In addition, direction and distance travelled by the virtual larvae varied according to both the geographical position of releasing site and biannual monsoonal winds. On average, larvae released during the summer exhibited a higher potential for dispersal than larvae released during the winter.Main conclusions: Our biophysical models showed that in the Arabian Peninsula, the combination of hydrodynamic, seascape features and larval traits likely affects the distribution of genetic lineages due to the interruption, reduction or asymmetry of larval movements through the putative barriers.

European plaice (Pleuronectes platessa) is a key species in commercial fisheries in the North Sea, Skagerrak, Kattegat, and Baltic Sea. The reformed European Union Common Fisheries Policy includes the possibility of exemptions from the landing obligation for “species for which scientific evidence demonstrates high survival rates”. Discard survival from set-net fisheries is poorly studied. Trials were conducted on two commercial fishing vessels over seven trips from November to February 2017–2018 in the Baltic Sea. The nylon trammel nets had a nominal bar size for the inner/outer wall of 75/350 mm and 85/400 mm. Soaking time was 23–47 h, water depth 7–18 m, and deck temperature was −0.1–6.0 °C. Following commercial practice, the trammel nets were hauled back onto the vessel, after which netting and fish passed through a net hauler onto a steel sorting table where the entire fish catch were manually untangled by the fishers and plaice collected by scientists. We used a storage system for housing the captured fish inside fishing harbours during observations. Catch-damage-index (CDI) and Reflex Action Mortality Predictor (RAMP) scores were used to assess fish condition immediately after capture and at the end of observation periods. All plaice below 40 cm were sampled with a total number of 118 individuals from 13 fleets (several nets joined together). The fish were assessed for short-term survival for 4–10 days with full survival (100%). The majority of fish exhibited no reflex impairments. Minor bruises, fraying, and net marks were frequently observed on captured fish. The overall condition of the fish did not change during observation periods.

Two specimens from the Koko Seamount (Koko Guyot), in the Hawaiian-Emperor seamount chain, Central North Pacific, caught in 2009 and 2010 are here described as a new species, Bidenichthys okamotoi. The taxonomy of the species in the genera Bidenichthys Barnard, 1934, and Fiordichthys Paulin, 1995, has been confusing due to the lost type of B. consorbrinus (Hutton, 1876) and the rarity of some of the species. Following the synonymization of Fiordichthys Paulin, 1995, with Bidenichthys by Møller and Nielsen 2015 and of Bidenichthys beeblebroxi Paulin, 1995, with Bidenichthys consobrinus Hutton, 1876, the genus Bidenichthys now comprises five species: B. capensis, B. consobrinus, B. okamotoi, B. paxtoni and B. slartibartfasti. Bidenichthys okamotoi differs from its congeners in, e.g., the fewer precaudal vertebrae (12 vs. 13), more palatine teeth rows (4–6 vs. 2–3), shorter pelvic fins (12.1–13.4% vs. 14.4–21.0% SL), max size (187 vs. 147 mm SL) and the shape of the sulcus of the otolith. We here present an updated diagnosis of the genus. A computed tomography (CT) scan of the holotype of B. okamotoi provides for additional anatomical details. The disjunctive occurrence of Bidenichthys okamotoi on the Emperor Seamount chain about 7500 km from the nearest congeneric taxon in New Zealand is discussed. The fossil otolith-based record of the genus Bidenichthys and its systematic implications is briefly discussed.

This chapter reviews the historical perspective of brainstem auditory-evoked potentials (BAEPs) recordings and its intraoperative use. It describes the neurophysiologic basis for the generation of far-field BAEP and methods for monitoring the neural conduction in the auditory pathways using BAEPs and evoked potentials recorded directly from the VIIIth nerve. Monitoring BAEPs is beneficial in operations of large acoustic tumors, posterior fossa procedures, procedures that can compress the brainstem, and other related procedures. BAEPs have improved the outcomes in these complex procedures by giving the surgical team information on the functional status of the auditory pathway from the cochlea through the brainstem.

Antisense oligonucleotides that are dependent on RNase H for cleavage and subsequent degradation of complementary RNA are being developed as therapeutics. Besides the intended RNA target, such oligonucleotides may also cause degradation of unintended RNA off-targets by binding to partially complementary target sites. Here, we characterized the global effects on the mouse liver transcriptome of four oligonucleotides designed as gapmers, two targeting Apob and two targeting Pcsk9, all in different regions on their respective intended targets. This study design allowed separation of intended- and off-target effects on the transcriptome for each gapmer. Next, we used sequence analysis to identify possible partially complementary binding sites among the potential off-targets, and validated these by measurements of melting temperature and RNase H-cleavage rates. Generally, our observations were as expected in that fewer mismatches or bulges in the gapmer/transcript duplexes resulted in a higher chance of those duplexes being effective substrates for RNase H. Follow-up experiments in mice and cells show, that off-target effects can be mitigated by ensuring that gapmers have minimal sequence complementarity to any RNA besides the intended target, and that they do not have exaggerated binding affinity to the intended target.

The introduction of non-bridging phosphorothioate (PS) linkages in oligonucleotides has been instrumental for the development of RNA therapeutics and antisense oligonucleotides. This modification offers significantly increased metabolic stability as well as improved pharmacokinetic properties. However, due to the chiral nature of the phosphorothioate, every PS group doubles the amount of possible stereoisomers. Thus PS oligonucleotides are generally obtained as an inseparable mixture of a multitude of diastereoisomeric compounds. Herein, we describe the introduction of non-chiral 3′ thiophosphate linkages into antisense oligonucleotides and report their in vitro as well as in vivo activity. The obtained results are carefully investigated for the individual parameters contributing to antisense activity of 3′ and 5′ thiophosphate modified oligonucleotides (target binding, RNase H recruitment, nuclease stability). We conclude that nuclease stability is the major challenge for this approach. These results highlight the importance of selecting meaningful in vitro experiments particularly when examining hitherto unexplored chemical modifications.

Over the past 20 years, the field of RNA-targeted therapeutics has advanced based on discoveries of modified oligonucleotide chemistries, and an ever-increasing understanding of how to apply cellular assays to identify oligonucleotides with improved pharmacological properties in vivo. Locked nucleic acid (LNA), which exhibits high binding affinity and potency, is widely used for this purpose. Our understanding of RNA biology has also expanded tremendously, resulting in new approaches to engage RNA as a therapeutic target. Recent observations indicate that each oligonucleotide is a unique entity, and small structural differences between oligonucleotides can often lead to substantial differences in their pharmacological properties. Here, we outline new principles for drug discovery exploiting oligonucleotide diversity to identify rare molecules with unique pharmacological properties.

Background: THe natural clinical and immunological courses following HIV seroconversion with CXCR4-tropic or dual-mixed (X4/DM) viruses are controversial. We compared spontaneous immunological outcome in patients harbouring an X4/DM virus at the time of seroconversion with those harbouring a CCR5-tropic (R5) virus. Methods: Data were included from patients participating in CASCADE, a large cohort collaboration of HIV seroconverters, with ≥ 2 years of follow-up since seroconversion. The HIV envelope gene was sequenced from frozen plasma samples collected at enrolment, and HIV tropismwas determined using Geno 2Pheno (false-positive rate 10%). The spontaneous CD4 T cell evolution was compared by modelling CD4 kinetics using linear mixed-effects models with random intercept and random slope. Results: A total of 1387 patients were eligible. Median time between seroconversion and enrolment was 1month (range 0-3). At enrolment, 202 of 1387 (15%) harboured an X4/DM-tropic virus. CD4 decrease slopes were not significantly different according to HIV-1 tropism during the first 30months after seroconversion. No marked change in these results was found after adjusting for age, year of seroconversion and baseline HIV viral load. Time to antiretroviral treatment initiation was not statistically different between patients harbouring an R5 (20.76months) and those harbouring an X4/DM-tropic virus (22.86months, logrank test P"0.32). Conclusions: In this large cohort collaboration, 15% of the patients harboured an X4/DM virus close to HIV seroconversion. Patients harbouring X4/DM-tropic viruses close to seroconversion did not have an increased risk of disease progression, estimated by the decline in CD4 T cell count or time to combined ART initiation.

Antisense oligonucleotides that recruit RNase H and thereby cleave complementary messenger RNAs are being developed as therapeutics. Dose-dependent hepatic changes associated with hepatocyte necrosis and increases in serum alanine-aminotransferase levels have been observed after treatment with certain oligonucleotides. Although general mechanisms for drug-induced hepatic injury are known, the characteristics of oligonucleotides that determine their hepatotoxic potential are not well understood. Here, we present a comprehensive analysis of the hepatotoxic potential of locked nucleic acid-modified oligonucleotides in mice. We developed a random forests classifier, in which oligonucleotides are regarded as being composed of dinucleotide units, which distinguished between 206 oligonucleotides with high and low hepatotoxic potential with 80% accuracy as estimated by out-of-bag validation. In a validation set, 17 out of 23 oligonucleotides were correctly predicted (74% accuracy). In isolation, some dinucleotide units increase, and others decrease, the hepatotoxic potential of the oligonucleotides within which they are found. However, a complex interplay between all parts of an oligonucleotide can influence the hepatotoxic potential. Using the classifier, we demonstrate how an oligonucleotide with otherwise high hepatotoxic potential can be efficiently redesigned to abate hepatotoxic potential. These insights establish analysis of sequence and modification patterns as a powerful tool in the preclinical discovery process for oligonucleotide-based medicines.

Tinnitus is not a single disease but a group of different diseases with different pathologies and therefore different treatments. Regarding tinnitus as a single disease is hampering progress in understanding of the pathophysiology of tinnitus and perhaps, more importantly, it is a serious obstacle in development of effective treatments for tinnitus. Subjective tinnitus is a phantom sound that takes many different forms and has similarities with chronic neuropathic pain. The pathology may be in the cochlea, in the auditory nerve, or, most commonly, in the brain. Like chronic neuropathic pain tinnitus is not life threatening but influences many normal functions such as sleep and the ability to concentrate on work. Some forms of chronic tinnitus have two components, a (phantom) sound and a component that may best be described as suffering or distress. The pathology of these two components may be different and the treatment that is most effective may be different for these two components. The most common form of treatment of tinnitus is pharmacological agents and behavioral treatment combined with sound therapy. Less common treatments are hypnosis and acupuncture. Various forms of neuromodulation are becoming in use in an attempt to reverse maladaptive plastic changes in the brain.

Hemifacial spasm can be cured by microvascular decompression (MVD) operations of the root exit zone of the facial nerve. This fact was the basis for the (“ephaptic”) hypothesis stating that the anatomical location of the pathology that generates the signs of HFS, spasm in the mimic muscle on one side of the face and synkinesis, was the root exit zone of the facial nerve. However, later intracranial recording from the facial nerve provided strong experimental support of a different hypothesis about the pathology of HFS, namely, that the anatomical location of the pathology is the facial motonucleus.

Disabling positional vertigo (DPV) and some forms of tinnitus can be treated successfully with microvascular decompression (MVD) of the root of the auditory-vestibular nerve. These two diseases have many different forms and the operation is more complex than MVD for trigeminal neuralgia or hemifacial spasm. Success of DPV depends on correct selection of candidates for the treatments. In a study of 41 patients operated upon for severe DPV, 73.2 % were totally free of DPV symptoms or experienced significant improvements that allowed them to return to nearly normal life, 4.9 % had minor relief of symptoms, and 22 % had no noticeable improvement. Other studies have shown that treatment with medications of the benzodiazepine family such as Valium is effective in some individuals who have DPV symptoms.

Object Tinnitus is a prevalent symptom, with clinical, pathophysiological, and treatment features analogous to pain. Noninvasive transcranial magnetic stimulation (TMS) and intracranial auditory cortex stimulation (ACS) via implanted electrodes into the primary or overlying the secondary auditory cortex have been developed to treat severe cases of intractable tinnitus. Methods A series of 43 patients who benefited transiently from 2 separate placebo-controlled TMS sessions underwent implantation of auditory cortex electrodes. Targeting was based on blood oxygen level–dependent activation evoked by tinnitus-matched sound, using functional MR imaging–guided neuronavigation. Results Thirty-seven percent of the patients responded to ACS with tonic stimulation. Of the 63% who were nonresponders, half benefited from burst stimulation. In total, 33% remained unaffected by the ACS. The average tinnitus reduction was 53% for the entire group. Burst stimulation was capable of suppressing tinnitus in more patients and was better than tonic stimulation, especially for noise-like tinnitus. For pure tone tinnitus, there were no differences between the 2 stimulation designs. The average pure tone tinnitus improvement was 71% versus 37% for noise-like tinnitus and 29% for a combination of both pure tone and noise-like tinnitus. Transcranial magnetic stimulation did not predict response to ACS, but in ACS responders, a correlation (r = 0.38) between the amount of TMS and ACS existed. A patient's sex, age, or tinnitus duration did not influence treatment outcome. Conclusions Intracranial ACS might become a valuable treatment option for severe intractable tinnitus. Better understanding of the pathophysiological mechanisms of tinnitus, predictive functional imaging tests, new stimulation designs, and other stimulation targets are needed to improve ACS results.

OBJECTIVE: We report on vascular compression syndrome of the 12th cranial nerve (hypoglossal), an occurrence not previously reported, and demonstrate, through corresponding objective electrophysiological evidence, that microvascular decompression of the hypoglossal nerve root can cure hemilingual spasm. CLINICAL PRESENTATION: A 52-year-old man had lower face muscle twitching and tongue spasms, which worsened with talking, chewing, or emotional stress. Carbamazepine offered only temporary relief, and relief from injections of botulinum toxin was insignificant. He was referred for surgical treatment. High-resolution magnetic resonance imaging of his posterior fossa contents revealed no obvious evidence of any compressive vessel along the facial nerve, but a compressive vessel along the hypoglossal nerve was apparent. INTERVENTION: The presence of preoperative tongue spasms encouraged interoperative monitoring of tongue motor responses. The facial nerve exit zone was explored, but microsurgical inspection of the seventh/eighth cranial nerve complex did not reveal any compressive vessel. However, at the anterolateral aspect of the medulla oblongata, the hypoglossal nerve was clearly compressed and distorted laterally by a large tortuous vertebral artery. When the artery was mobilized away from the nerve, the abnormal late electromyographic response to transcranial electrical stimulation disappeared; immediately after shredded Teflon was interpositioned between the artery and the nerve, the abnormal spontaneous tongue fasciculation also disappeared. The patient has remained spasm free 6 months after surgery. CONCLUSION: Hemilingual spasm may be caused by vascular contact/compression along cranial nerve XII at the lower brainstem and belong to the same family of cranial nerve hyperactivity disorders as hemifacial spasm.

The aim of this paper is to review the effects of activation of neural plasticity and present hypotheses using a systems approach about how activation of neural plasticity can cause symptoms and signs of disease (plasticity diseases).Literature review.It is hypothesized that a program that is initiated by internal or external events controls plastic changes in specific structures of the CNS. Not all structures that have abnormal activity are pathologic but some behave pathological because they receive abnormal input from pathologic structures. The changes in function may remain after the events that elicited the expression of neural plasticity no longer exist.Activation of neural plasticity can have beneficial effects and it can cause symptoms and signs of disease. Activation of neural plasticity can help to adapt to changing demands and it is necessary for normal childhood development of the central nervous system. Plastic changes can cause signs and symptoms of disease by abnormal neural activity in pathologic structures and in structures that receive input from pathologic structures. It is hypothesized that a program controls the plastic changes and that failure in activation of neural plasticity can cause developmental disorders such as autism.

Experimental infection with Chlamydia trachomatis, immunotype K, was carried out in six grivet monkeys. Three routes of infection were used: (A) into the uterine cavity through the cervical canal: (B) into the uterine cavity, but after ligature of the tubal isthmus, followed by curettement of the endometrium: (C) into the cervical epithelium. Two monkeys were used for each type of experiment. All monkeys inoculated by routes (A) and (C) developed marked signs of inflammation in the Fallopian tubes. Characteristically, the tubes were reddened and swollen. Exudate appeared in the abdominal ostia and in the cul-de-sac. In three of the four monkeys studied, a yellowish discharge was seen in the posterior vaginal fornix. An exudate composed mostly of lymphocytes and clusters of desquamated cells was found in the lumen of the tubes. The epithelium was injured in some areas and there were adhesions between the mucosal folds. In two of the monkeys, tubal occlusion was present two months after the inoculation. With one exception, all monkeys presented a significant rise in antibodies to C. trachomatis. In the two monkeys inoculated by route (B), no signs of inflammation in the upper genital tract were seen, but one of the animals died day 14 post inoculation;autopsy showed peritonitis and perihepatitis. One monkey was inoculated with non-infected yolk sac specimen by route (A) and another by route (B). Practically no inflammatory changes in the genital organs or elsewhere could be detected in these monkeys. The results indicate that C. trachomatis can cause salpingitis in female grivet monkeys by canalicular spread from the lower genital tract. The histological findings and the infection route in this experimentally induced salpingitis in the grivet monkeys closely resemble those ascribed to «gonococcal« salpingitis in man.

Overstimulation is known to activate neural plasticity in the auditory nervous system causing changes in function and re-organization. It has been shown earlier that overstimulation using high-intensity noise or tones can induce signs of tinnitus. Here we show in studies in rats that overstimulation causes changes in the way place cells of the hippocampus respond as rats search for rewards in a spatial maze. In familiar environments, a subset of hippocampal pyramidal neurons, known as place cells, respond when the animal moves through specific locations but are relatively silent in others. This place-field activity (i.e. location-specific firing) is stable in a fixed environment. The present study shows that activation of neural plasticity through overstimulation by sound can alter the response of these place cells. Rats implanted with chronic drivable dorsal hippocampal tetrodes (four microelectrodes) were assessed for stable single-unit place-field responses that were extracted from multiunit responses using NeuroExplorer computer spike-sorting software. Rats then underwent either 30 min exposure to a 4 kHz tone at 104 dB SPL or a control period in the same sound chamber. The place-field activity was significantly altered after sound exposure showing that plastic changes induced by overstimulation are not limited to the auditory nervous system but extend to other parts of the CNS, in this case to the hippocampus, a brain region often studied in the context of plasticity.

The brain’s ability to change its organization and function is necessary for normal development of the nervous system and it makes it possible to adapt to changing demands but it can also cause disorders when going awry. This property, known as neural plasticity, is only evident when induced, very much like genes. Plastic changes may be programmed and providing a “midcourse correction” during childhood development. If that is not executed in the normal way severe developmental disorders such as autism may results. Normal development of functions and anatomical organization of the brain and the spinal cord depend on appropriate sensory stimulation and motor activations. So-called enriched sensory environments have been shown to be beneficial for cognitive development and enriched acoustic environment may even slow the progression of age-related hearing loss. It is possible that the beneficial effect of physical exercise is achieved through activation of neural plasticity. The beneficial effect of training after trauma to the brain or spinal cord is mainly achieved through shifting functions from damaged brain area to other parts of the central nervous system and adapting these parts to take over the functions that are lost. This is accomplished through activation of neural plasticity. Plastic changes can also be harmful and cause symptoms and signs of disorders such as some forms of chronic pain (central neuropathic pain) and severe tinnitus. We will call such disorders “plasticity disorders”.

Introduction: Some forms of tinnitus are considered to be auditory phantom phenomena related to reorganization and hyperactivity of the auditory central nervous system. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive tool capable of modulating human brain activity, using single pulse or burst stimuli. Burst rTMS has only been performed in the theta range, and has not been used clinically. The authors analyze whether burst TMS at theta (5 Hz), alpha (10 Hz) and beta (20 Hz) frequencies can temporarily suppress narrow band noise/white noise tinnitus, which has been demonstrated to be intractable to tonic stimulation. Methods: rTMS is performed both in tonic and burst mode in 46 patients contralateral to the tinnitus side, at 5, 10 and 20 Hz. Fourteen placebo negative rTMS responders are further analyzed. Results: In 5 patients, maximal tinnitus suppression is obtained with theta, in 2 with alpha and in 7 with beta burst stimulation. Burst rTMS suppresses narrow band/white tinnitus much better than tonic rTMS t(13)=6.4, p

The only FDA approved treatment for ischemic strokes is tissue plasminogen activator (tPA). The benefit of treatment with tPA is limited and it has to be administrated within a short time window; furthermore, the side effects are serious including increased risk of subsequent hemorrhagic transformation. This review discusses minocycline’s role in neuroprotection, and it discusses the results of five published clinical trials regarding the use of administration of minocycline for treatment of acute stroke. The studies find that the benefit of tPA treatment alone is limited and has serious side effects. While many new agents have been studied to ameliorate this, minocycline, a tetracycline antibiotic, seems the most promising. Some investigators have suggested that administration of minocycline may be suitable as a general treatment of patients with acute stroke that is safe and can be used in both ischemic and hemorrhagic strokes as a single treatment that may provide benefits in reducing the deficits from ischemic stokes with little side effects.

Danbo is a semi-hard, matured Danish cheese made from cow's milk, buffalo's milk, or their mixture. It is one of the most commonly consumed cheeses in Denmark. Due to the proclaimed health benefits of eating a low salt (NaCl) diet, WHO recommends consuming less than 5g salt/day. The fact that higher fat varieties of Danbo contain 1.8% salt, it is of public concern to reduce the salt content of the cheese. However this reduction might have an effect on the taste, texture, and microbial flora development of the cheese and it is therefore important to study how technologies, ingredients, and new cultures can work as alternatives for salt and how these parameters relate in low-salt cheese production. High-resolution NMR spectroscopy-based metabolomics is emerging as a powerful approach in agricultural and food science. However, this methodology has certain limitations for semi-solid foods such as cheese. To overcome these limitations, high-resolution magic-angle spinning (HRMAS) NMR spectroscopy could be an appealing technique, as the analysis is performed directly on the sample (semi-solid foods) without any prior extraction. The aim of the present study was to elucidate the potential use of proton HRMAS NMR spectroscopy for metabolite profiling of Danbo (30+) cheese and to investigate the effects of different rennet and starter culture combinations and extent of brine-salting period. Furthermore, the HRMAS NMR analysis was combined with sensory profiling in order to elucidate possible relations between the cheese metabolite profile and its sensory attributes.

Throughout much of the Quaternary Period, inhospitable environmental conditions above the Arctic Circle have been a formidable barrier separating most marine organisms in the North Atlantic from those in the North Pacific1,2. Rapid warming has begun to lift this barrier3, potentially facilitating the interchange of marine biota between the two seas4. Here, we forecast the potential northward progression of 515 fish species following climate change, and report the rate of potential species interchange between the Atlantic and the Pacific via the Northwest Passage and the Northeast Passage. For this, we projected niche-based models under climate change scenarios and simulated the spread of species through the passages when climatic conditions became suitable. Results reveal a complex range of responses during this century, and accelerated interchange after 2050. By 2100 up to 41 species could enter the Pacific and 44 species could enter the Atlantic, via one or both passages. Consistent with historical and recent biodiversity interchanges5,6, this exchange of fish species may trigger changes for biodiversity and food webs in the North Atlantic and North Pacific, with ecological and economic consequences to ecosystems that at present contribute 39% to global marine fish landings.

Background. Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited disease, characterized by a wide variety of clinical manifestations, including epistaxis, gastrointestinal (GI) bleeding, pulmonary arteriovenous malformations (PAVMs) and neurological symptoms. HHT is a genetically heterogeneous disorder involving at least two loci; HHT1 mapping to chromosome 9q34.1 (ENG) and HHT2 mapping to chromosome 12q31 (ALK-1). Objective. To evaluate and describe the diversity of clinical manifestations in a Danish population of HHT patients with known HHT1 or HHT2 subtype. Design. Prospective clinical examination with genetic evaluation and follow-up. Setting. Investigation centre was Odense University Hospital. All HHT patients in the County of Fyn were included. Methods. HHT family members were invited to a clinical examination including registration of HHT manifestations, screening for PAVM and neurological evaluation. Blood tests were performed for analysis of disease-causing mutation, and clinical manifestations in the HHT subtypes were compared. The survival of the patients was studied in the follow-up period. Results. Included in the study were 73 HHT patients representing 18 families. In 14 of the families we identified a disease-causing mutation. Thirty-nine patients (from 10 families) had HHT1 and 16 HHT patients from four families had HHT2. Conclusion. Amongst patients with HHT1 genotype the prevalence of PAVM was higher than amongst HHT patients with HHT2 genotype. HHT1 patients had experienced more severe GI bleeding than HHT2 patients. There was no significant difference in severity of epistaxis or age at debut. Finally the mortality over a 90-month observation period was not significantly increased.

To test the hypothesis that some of the abnormal sensory perceptions that characterize autism may be explained by an abnormal activation of non-classical (extra-lemniscal) sensory pathways.Twenty-one individuals, 18--45 years of age who were diagnosed with autism participated in the study. Sounds (clicks presented at a rate of 40 per second and 65 dB above the normal threshold) were applied through earphones. Electrical stimulation (100 microS rectangular impulses at a rate of 4 per second) was applied through electrodes placed on the skin over the median nerve at the wrist. The participants were asked to match the loudness of the sound with and without the electrical stimulation applied to the median nerve.Electrical stimulation of the median nerve at the wrist in individuals with autism could change the perception of loudness of sounds presented to one ear through an earphone showing a statistically significant abnormal sensory cross-modal interaction.We interpreted our results to support the hypothesis that some individuals with autism have an abnormal cross-modal interaction between the auditory and the somatosensory systems. Cross-modal interaction between senses such as hearing and the somatosensory system does not occur normally in adults. As only the non-classical (extralemniscal) ascending auditory pathways receive somatosensory input, the presence of cross-modal interaction in autistic individuals is a sign that autism is associated with abnormal involvement of the non-classical auditory pathways, implying that sensory information is processed by different populations of neurons than in non-autistic individuals.

OBJECTIVE The functional anatomy (i.e., tonotopy) of the human cochlear nerve is unknown. A better understanding of the tonotopy of the central nervous system segment of the cochlear nerve and of the pathophysiology of tinnitus might help to ameliorate the disappointing results obtained with microvascular decompressions in patients with tinnitus. METHODS We assume that vascular compression of the cochlear nerve can induce a frequency-specific form of hearing loss and that when the nerve is successfully decompressed, this hearing loss can recuperate. Thirty-one patients underwent a microvascular decompression of the vestibulocochlear nerve for vertigo or tinnitus. Preoperative audiograms were subtracted from postoperative audiograms, regardless of the surgical result with regard to the tinnitus and vertigo, because the hearing improvement could be the only sign of the vascular compression. The frequency of maximal improvement was then correlated to the site of vascular compression. A tonotopy of the cochlear nerve was thus obtained. RESULTS A total of 18 correlations can be made between the site of compression and postoperative maximal hearing improvement frequency when 5-dB hearing improvement is used as threshold, 13 when 10-dB improvement is used as threshold. A clear distribution can be seen, with clustering of low frequencies at the posterior and inferior side of the cochlear nerve, close to the brainstem, and close to the root exit zone of the facial nerve. High frequencies are distributed closer to the internal acoustic meatus and more superiorly along the posterior aspect of the cochlear nerve. CONCLUSION The tonotopic organization of the cisternal segment of the cochlear nerve has an oblique rotatory structure as a result of the rotatory course of the cochlear nerve in the posterior fossa. Knowledge of this tonotopic organization of the auditory nerve in its cisternal course might benefit surgeons who perform microvascular decompression operations for the vestibulocochlear compression syndrome, especially in the treatment of unilateral severe tinnitus.

Consider a risk Y-1 (x) depending on an observable covariate x which is the outcome of a random variable A with a known distribution, and consider a premium p(x) of the form p(x) = EY1 (x) + etap(1) (x). The corresponding adjustment coefficient gamma is the solution of E exp{gamma[Y-1(A) - p(A)]} = 1, and we characterize the rule for the loading premium p(1)((.)) which maximizes gamma subject to the constraint Ep(1) (A) = 1. In a life insurance study, the optimal p(1)(*)((.)) is compared to other premium principles like the expected value, the variance and the standard deviation principles as well as the practically important rules based on safe mortality rates (i.e., using the first order basis rather than the third order one). The life insurance model incorporates premium reserves, discounting, and interest return on the premium reserve but not on the free reserve. Bonus is not included either. (C) 2003 Published by Elsevier Science B.V.

Auditory information ascends through the brainstem to the cerebral cortices in two parallel pathways, known as the classical and the non-classical ascending auditory pathways. The importance of the non-classical auditory pathway for hearing in humans is unknown but its subcortical connection to limbic structures may be important in tinnitus. In this study we show evidence that non-classical pathways are involved in loudness perception in young individuals but not in adults. We used the fact that some neurons in the non-classical auditory pathways receive somatosensory input and we determined the effect on loudness perception of monaural sounds from electrical stimulation of the median nerve at the wrist. Stimulation of the somatosensory system had the greatest effect on loudness perception in the youngest children that we studied (7-8 years) and the effect was minimal for individuals above 20 years of age. The effect was an increase in loudness in 20 of the 40 individuals we studied and a decrease in 4 individuals; 16 experienced no noticeable change in loudness during somatosensory stimulation.

IntroductionBoth 1st and 2nd generation of antipsychotics are associated with prolonged QTc interval. Prolonged QTc can lead to ventricular tachycardia and Torsade's de pointes, ultimatime resulting to cardiac arrest and sudden death. Prolonged QTc interval due to increased DDD has not yet been investigated.ObjectiveTo investigate whether increased DDD of antipsychotics, causes further prolonged QTc, by patients diagnosed with schizophrenia.AimsTo learn more about antipsychotics impact on the QTc interval in patients diagnosed with schizophrenia.MethodsAn observational study of unselected patients diagnosed with schizophrenia. Enrolled from January 2013 through March 2015 with follow-up until June 2015 in the region of central Denmark. Data was collected from ECG records and patient journals.ResultECGs were available in 58 patients. We observed no relation between increased DDD of antipsychotics and prolonged QTc. There were no differences in average QTc interval for the whole sample of patients receiving different DDD of antipsychotics.ConclusionWe do not recommend increased attention to patients treated with higher DDD of antipsychotics.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Plastic changes play an important role in the recovery of motor and sensory functions after ischemic strokes and other forms of injury to the central nervous system. The deficits from ischemia may be exacerbated by immune reactions from the decay products of cells that have died as a result of the ischemia. Recovery from deficits after strokes is mainly achieved through activation of neural plasticity. Recent studies have shown that enhancing activation of neuroplasticity through vagus nerve stimulation (VNS) has a beneficial effect on recovery. It has been also shown that suppression of the immune reaction through administration of minocycline can improve recovery from deficits significantly. The role of the vagus nerve in controlling the immune system suggests that VNS may also be beneficial in reducing injuries to the brain caused by harmful immune reactions.

The exponential tail decay of the steady-state vector is considered for M/G/1-type processes with light-tailed increments. Regeneration and exponential change of measure are applied as are Markov additive processes.

We consider the waiting time (delay) W in a FCFS c-server queue with arrivals which are either renewal or governed by Neuts' Markovian arrival process, and (possibly heterogeneous) service time distributions of general phase-type Fi, with mi phases for the ith server. The distribution of W is then again phase-type, with m1⋅⋅⋅mc phases for the general heterogeneous renewal case and ${\pmatrix{{m+c-1}\\{c}}}$ phases for the homogeneous case FieF, miem. We derive the phase-type representation in a form which is explicit up to the solution of a matrix fixed point problem; the key new ingredient is a careful study of the not-all-busy period where some or all servers are idle. Numerical examples are presented as well.

Objectives To estimate the incidence of human parvovirus B19 among pregnant women before and during an epidemic, to elucidate possible sociodemographic and medical risk factors during pregnancy and to estimate the association between parvovirus B19 infection and negative pregnancy outcome. Design Prospective study among pregnant women followed from their first antenatal visit before 24 full weeks of gestation until delivery. Setting Department of Obstetrics and Gynaecology, Odense University Hospital, Denmark, November 1992 to February 1994. Methods 3596 pregnant women were invited to participate. The women were examined at first antenatal visit in the period from November 1992 to February 1994 and at delivery. The last delivery was in August 1994 and samples were thus collected before and during a large parvovirus B19 epidemic in Denmark January to September 1994. A blood sample for parvovirus B19 serology was taken at enrolment and from the umbilical cord at delivery. Three questionnaires were completed during 2nd and 3rd trimesters and a registration form at delivery. In total, 3174 (87.6%) were enrolled and 79.5% completed the study. Results The prevalence of B19 IgG seropositivity at the first antenatal visit before 24 full weeks of gestation was 66%. The cumulative prevalence proportion of acute parvovirus B19 infection during pregnancy among IgG negative women was found to be 10.3% (IgM seropositivity and/or IgG sero-conversion). The IgG seroconversion incidence increased significantly from 1.0% to 13.5% among 932 seronegative pregnant women before and during the epidemic, respectively (P < 0.001). Independent risk factors related to increased risk of B19 infection during pregnancy, adjusted for other sociodemographic and medical factors, were: children at home (adjusted OR 2.1, 95% CI 1.3–3.2); serious medical disease (adjusted OR 3.0, 95% CI 1.0–8.5); and a stressful job (adjusted OR 1.8, 95% CI 1.0–3.3). Parvovirus B19 IgM seropositivity was associated with events of late spontaneous abortions and stillbirths (crude OR 9.9; 95% CI 3.3–29.4). Conclusion Before and during an epidemic of acute B19 infection incidences were measured among pregnant women to be 1.0% and 13.5%, respectively. Three factors, significantly increasing the risk of acute B19, were identified as: having children at home; suffering from serious medical diseases; and having a stressful job. IgM positivity for parvovirus B19 was associated with negative outcome of pregnancy.

Bivariate regenerative Markov modulated queueing processes \{I_n,L_n\} are described. \{I_n\} is the phase process, and \{L_n\} is the level process. Increments in the level process have subexponential distributions. A general boundary behavior at the level 0 is allowed. The asymptotic tail of the cycle maximum, M_{C^{\mathrm{reg}}}, during a regenerative cycle, C^{\mathrm{reg}}, and the asymptotic tail of the stationary random variable L_\infty, respectively, of the level process are given and shown to be subexponential with L_{\infty} having the heavier tail.

The development of the microvascular decompression (MVD) operation is reviewed. It is stressed that a few innovative neurosurgeons discovered the role of vascular compression of cranial nerves V and VII in trigeminal neuralgia (TGN) and hemifacial spasm (HFS) and developed an operation, later to be known as the MVD operation. While the understanding of the pathophysiology of these disorders has improved, the surgical procedure has undergone little change since Gardner described the operation about 1960.

Although Mycoplasma genitalium was described 20 years ago, the knowledge concerning it is still limited. The publications in the area are surprisingly few in number, especially considering that the pathogen is rather common and has been connected with a number of different urogenital diseases. The PCR technique has made it possible to perform investigations on a large scale, which might elucidate the pathogenic role of M. genitalium in the urogenital tract. However, it seems well established that M. genitalium causes non-gonococcal urethritis (NGU). The mycoplasma behaves almost identically to Chlamydia trachomatis with respect to routes of infection and inflammatory response, but no further relationship between the two organisms seems obvious. M. genitalium is believed to produce urethritis with almost the same frequency as C. trachomatis. In the female genital tract, M. genitalium is strongly incriminated as a primary cause of cervicitis, endometritis and salpingitis, the latter complicated by tubal damage. The role of the organisms in epididymitis, prostatitis and neonatal infections is unclear. In the case of urethritis and upper genital tract infections in the female, it is recommended to test for M. genitalium using molecular biological assays and in the event of a positive result institute antimicrobial therapy.

Intraoperative prolongation of the latency and decrement of the amplitude of peak V of brainstem auditory evoked potentials (BAEP) were studied in 38 microvascular decompression operations in which prolongation of the latency of peak V exceeded 1.0 msec. Postoperative hearing tests of all patients were compared with their preoperative hearing tests. Postoperative hearing loss was unrelated to the maximum prolongation of latency, but the amplitude decreased to lower values in patients with postoperative hearing loss compared to patients whose postoperative hearing was unchanged (P