Sensory perception: supernormal hearing in the blind?

A recent experimental study suggests that blind individuals may compensate for their lack of vision with better-than-normal hearing. This provides support for a view dating back to 18th century philosophers, but the data raise as many problems as they solve.     

Worms and malaria: blind men feeling the elephant?

For thousands of years the deadliest human parasite, Plasmodium falciparum, has been evolving in populations also infected by the most prevalent parasites, worms. This is likely to have shaped the genome of all 3 protagonists--man, worms and malaria. Observational studies in Thailand have shown that although P. falciparum malaria incidence increased two-fold in helminth-infected patients, there was a 64% reduction of cerebral malaria and an 84% reduction of acute renal failure in helminth-infected patients relative to those without helminths. In addition, it was suggested that mixed infections, anaemia and gametocyte carriage were more frequent in helminth-infected patients. On the contrary, fever was lower in helminth-infected patients. The present hypotheses, their implications and the limitations of the results described and of those from studies in Africa are discussed.     

On the origin of SARS-CoV-2——The blind watchmaker argument

正In the comparison with SARS-CoVof 2003, SARS-CoV-2 is extremely well adapted to the human populations and its adaptive shift from the animal host to humans must have been even more extensive. By the blind watchmaker argument, such an adaptive shift can only happen prior to the onset of the current pandemic and with the aid of step-by-step selection.     

Photic stimulation of the suprachiasmatic nucleus via the non-visual optic system. A gene expression study in the blind Crx −/− mouse

The visual system of vertebrates consists of an image-forming and a non-image-forming optic system; the image-forming optic system involves the classic photoreceptors, the rods and cones, whereas the non-image-forming optic system involves the melanopsin-containing retinal ganglion cells. Both optic systems make direct neuroanatomical connections to the suprachiasmatic nucleus (SCN) in the hypothalamus in which the biological clock of vertebrates is located. The rhythmic output from SCN neurons is entrained by light via the retina and the retinohypothalamic tract. The response of exposure to light during the subjective night is an immediate expression of several early response genes in the SCN. We show, by quantitative real-time polymerase chain reaction, that the amount of melanopsin mRNA in the retinal ganglion cells is preserved in the blind Crx ^?/? mouse with degenerated classic photoreceptors. At zeitgeber time 16, the Crx ^?/? and wild-type mice were exposed to 1 h of light. This resulted in a strong up-regulation of the immediate early genes Nr4a1, Erg, and Rrad in the SCN of both genotypes. Light stimulation during the subjective night resulted in a strong up-regulation of c-fos in both genotypes with a significantly higher up-regulation in the blind Crx ^?/? mouse. Expression of Grp and Vip, the genes for two classic peptides located in the SCN, was not influenced by light stimulation. The data strongly indicate the involvement of the melanopsin-based non-visual optic system in the regulation of immediate early genes in the SCN.     

Acetylcholine nicotinic receptors: finding the putative binding site of allosteric modulators using the “blind docking” approach

Allosteric potentiation of acetylcholine nicotinic receptors is considered to be one of the most promising approaches for the treatment of Alzheimer’s disease. However, the exact localization of the allosteric binding site and the potentiation mechanism at the molecular level are presently unknown. We have performed the “blind docking” of three known allosteric modulators (galanthamine, codeine and eserine) with the Acetylcholine Binding Protein and models of human α7, α3β4 and α4β2 nicotinic receptors, created by homology modeling. Three putative binding sites were identified in the channel pore, each one showing different affinities for the ligands. One of these sites is localized opposite to the agonist binding site and is probably implicated in the potentiation process. On the basis of these results, a possible mechanism for nicotinic acetylcholine receptor (nAChRs) activation is proposed. The present findings may represent an important advance for understanding the allosteric modulation mechanism of nAChRs. Electronic supplementary material Supplementary material is available for this article at     

Transmembrane helix 6 observed at the interface of β2AR homodimers in blind docking studies

Peptide– and protein–protein dockings were carried out on β₂-adrenergic receptor (β₂AR) to confirm the presence of transmembrane helix 6 (TM6) at the interface region between two β₂AR monomers, thereby its possible role in dimerization as suggested in numerous experimental and computational studies. Initially, a portion of TM6 was modeled as a peptide consisting of 23 residues and blindly docked to β₂AR monomer using a rigid body approach. Interestingly, all highest score conformations preferred to be near TM5 and TM6 regions of the receptor. Furthermore, longer peptides generated from a whole TM region were blindly docked to β₂AR using the same rigid body approach. This yielded a total of seven docked peptides, each derived from one TM helix. Most interestingly, for each peptide, TM6 was among the most preferred binding site region in the receptor. Besides the peptide dockings, two β₂AR monomers were blindly docked to each other using a full rigid-body search of docking orientations, which yielded a total of 16,000 dimer conformations. Each dimer was then filtered according to a fitness value based on the membrane topology. Among 149 complexes that met the topology requirements, 102 conformers were composed of two monomers oriented in opposite directions, whereas in the remaining 47, the monomers were arranged in parallel. Lastly, all 149 conformers were clustered based on a root mean-squared distance value of 6 Å. In agreement with the peptide results, the clustering yielded the largest population of conformers with the highest Z-score value having TM6 at the interface region.     

Pattern discrimination by the honeybee (Apis mellifera ) is colour blind for radial / tangential cues

Bees were trained to discriminate between two patterns, one of which was associated with a reward, in a Y-choice apparatus with the targets presented vertically at a distance at an angular subtense of 50°. Previous work with this apparatus has found discrimination between two patterns of coloured gratings or radial sectors that are fixed in different orientations during the training. When there was contrast to the blue receptors alone, gratings of period 6° were resolved, and 4° when there was contrast to the green receptors. In the present work, bees discriminate between a pattern containing tangentially arranged edges and one containing radially arranged edges, both with no average edge orientation. The targets were rotated every 5 min to make the locations of areas useless as cues. The edges remained consistently radial or tangential and were therefore the only cues. Tests with patterns of selected colours and various levels of grey show that for each colour there is a level of grey at which discrimination fails. Discrimination is therefore colour-blind. The same patterns were made with combinations of coloured papers that give no contrast to the green receptors or alternatively to the blue receptors. The bees discriminate only if the edges between colours present a contrast to the green receptors. The system that discriminates generalized radial and tangential cues is therefore colour blind because the inputs are restricted to the green receptors, not because receptor outputs are added together. The same result was obtained with a very coarse pattern of period 20°. Accepted: 10 January 1999     

Seismic communication signals in the blind mole-rat (Spalax ehrenbergi ): electrophysiological and behavioral evidence for their processing by the auditory system

Based on morphological and behavioral findings we suggest that the seismic vibratory signals that blind mole-rats (Spalax ehrenbergi) use for intraspecific communication are picked up from the substrate by bone conduction and processed by the auditory system. An alternative hypothesis, raised by others, suggest that these signals are processed by the somatosensory system. We show here that brain stem and middle latency responses evoked by vibrations are similar to those evoked by high-intensity airborne clicks but are larger in their amplitudes, especially when the lower jaw is in close contact with the vibrating substrate. Bilateral deafening of the mole-rat or high-intensity masking noise almost completely eliminated these responses. Deafening also gradually reduced head-drumming behavior until its complete elimination about 4–6 weeks after surgery. Successive vibrations, at a rate of 0.5 vibrations/s, elicited prominent responses. At rates higher than 2 vibrations/s the amplitude of the brain stem response did not change, yet the middle latency response disappeared almost completely. It is concluded that the seismic signals that mole rats use for long distance communication are indeed processed primarily by the auditory system. Accepted: 11 May 1998     

Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial

Objective To evaluate the effect of the oral synthetic δ-9-tetrahydrocannabinol dronabinol on central neuropathic pain in patients with multiple sclerosis.Design Randomised double blind placebo controlled crossover trial.Setting Outpatient clinic, University Hospital of Aarhus, Denmark.Participants 24 patients aged between 23 and 55 years with multiple sclerosis and central pain.Intervention Orally administered dronabinol at a maximum dose of 10 mg daily or corresponding placebo for three weeks (15-21 days), separated by a three week washout period.Main outcome measure Median spontaneous pain intensity (numerical rating scale) in the last week of treatment.Results Median spontaneous pain intensity was significantly lower during dronabinol treatment than during placebo treatment (4.0 (25th to 75th centiles 2.3 to 6.0) v 5.0 (4.0 to 6.4), P = 0.02), and median pain relief score (numerical rating scale) was higher (3.0 (0 to 6.7) v> 0 (0 to 2.3), P = 0.035). The number needed to treat for 50% pain relief was 3.5 (95% confidence interval 1.9 to 24.8). On the SF-36 quality of life scale, the two items bodily pain and mental health indicated benefits from active treatment compared with placebo. The number of patients with adverse events was higher during active treatment, especially in the first week of treatment. The functional ability of the multiple sclerosis patients did not change.Conclusions Dronabinol has a modest but clinically relevant analgesic effect on central pain in patients with multiple sclerosis. Adverse events, including dizziness, were more frequent with dronabinol than with placebo during the first week of treatment.     

Do blind cavefish have behavioral specializations for active flow-sensing?

Blind cavefish use a form of active sensing in which burst-coast swimming motions generate flow signals detected by the lateral line. To determine if blind cavefish have evolved behavioral specializations for active flow-sensing, including the ability to regulate flow signal production through lateral line feedback, the swimming kinematics of blind and sighted morphs of Astyanax were compared before and after 24?h of familiarization with a novel, dark environment and with and without lateral line functionality. Although both morphs showed little difference in the vast majority of kinematic parameters measured, blind morphs differed significantly from sighted morphs in having a much higher incidence of swim cycle sequences devoid of sharp turns. Both lateral line deprivation and familiarization with the arena led to significant declines in this number for blind, but not sighted morphs. These findings suggest that swimming kinematics are largely conserved, but that blind morphs have nevertheless evolved enhanced abilities to use lateral line feedback when linking swim cycles into continuous, straight trajectories for exploratory purposes. This behavioral specialization can best be understood in terms of the intermittent and short-range limitations of active flow-sensing and the challenges they pose for spatial orientation and navigation.     

Flying blind,or just flying under the radar? The underappreciated power of de novo methods of mass spectrometric peptide identification

Mass spectrometry‐based proteomics is a popular and powerful method for precise and highly multiplexed protein identification. The most common method of analyzing untargeted proteomics data is called database searching, where the database is simply a collection of protein sequences from the target organism, derived from genome sequencing. Experimental peptide tandem mass spectra are compared to simplified models of theoretical spectra calculated from the translated genomic sequences. However, in several interesting application areas, such as forensics, archaeology, venomics, and others, a genome sequence may not be available, or the correct genome sequence to use is not known. In these cases, de novo peptide identification can play an important role. De novo methods infer peptide sequence directly from the tandem mass spectrum without reference to a sequence database, usually using graph‐based or machine learning algorithms. In this review, we provide a basic overview of de novo peptide identification methods and applications, briefly covering de novo algorithms and tools, and focusing in more depth on recent applications from venomics, metaproteomics, forensics, and characterization of antibody drugs.     

Does HIV status influence the outcome of patients admitted to a surgical intensive care unit? A prospective double blind study.

OBJECTIVES: (a) To assess the impact of HIV status (HIV negative, HIV positive, AIDS) on the outcome of patients admitted to intensive care units for diseases unrelated to HIV; (b) to decide whether a positive test result for HIV should be a criterion for excluding patients from intensive care for diseases unrelated to HIV. DESIGN: A prospective double blind study of all admissions over six months. HIV status was determined in all patients by enzyme linked immunosorbent assay (ELISA), immunofluorescence assay, western blotting, and flow cytometry. The ethics committee considered the clinical implications of the study important enough to waive patients'' right to informed consent. Staff and patients were blinded to HIV results. On discharge patients could be advised of their HIV status if they wished. SETTING: A 16 bed surgical intensive care unit. SUBJECTS: All 267 men and 135 women admitted to the unit during the study period. INTERVENTIONS: None. MAIN OUTCOME MEASURES: APACHE II score (acute physiological, age, and chronic health evaluation), organ failure, septic shock, durations of intensive care unit and hospital stay, and intensive care unit and hospital mortality. RESULTS: No patient had AIDS. 52 patients were tested positive for HIV and 350 patients were tested negative. The two groups were similar in sex distribution but differed significantly in age, incidence of organ failure (37 (71%) v 171 (49%) patients), and incidence of septic shock (20 (38%) v 54 (15%)). After adjustment for age there were no differences in intensive care unit or hospital mortality or in the durations of stay in the intensive care unit or hospital. CONCLUSIONS: Morbidity was higher in HIV positive patients but there was no difference in mortality. In this patient population a positive HIV test result should not be a criterion for excluding a patient from intensive care.     

How blind is double-blind? A study of fish oil versus placebo

The distinctive aftertaste associated with fish oil preparations used in clinical trials of omega-3 fatty acids may weaken the double-blind. This double-blind pilot study was designed to examine whether normal subjects could correctly 'guess' if they were receiving capsules containing concentrated fish oil or capsules of pure olive oil. The informed consent was designed to give subjects ambiguous expectations about what oil they might be receiving to examine whether this would influence their guess. Despite a marked difference in taste experience, there was no significant difference in correct guesses between the two groups. The results suggest that altering subjects' expectations could further improve the validity of the double-blind.     

A double blind,randomized, placebo controlled study of the efficacy and safety of 5-Loxin<Superscript>®</Superscript>for treatment of osteoarthritis of the knee

Introduction

5-Loxin^® is a novel Boswellia serrata extract enriched with 30% 3-O-acetyl-11-keto-beta-boswellic acid (AKBA), which exhibits potential anti-inflammatory properties by inhibiting the 5-lipoxygenase enzyme. A 90-day, double-blind, randomized, placebo-controlled study was conducted to evaluate the efficacy and safety of 5-Loxin^® in the treatment of osteoarthritis (OA) of the knee.

Methods

Seventy-five OA patients were included in the study. The patients received either 100 mg (n = 25) or 250 mg (n = 25) of 5-Loxin^® daily or a placebo (n = 25) for 90 days. Each patient was evaluated for pain and physical functions by using the standard tools (visual analog scale, Lequesne''s Functional Index, and Western Ontario and McMaster Universities Osteoarthritis Index) at the baseline (day 0), and at days 7, 30, 60 and 90. Additionally, the cartilage degrading enzyme matrix metalloproteinase-3 was also evaluated in synovial fluid from OA patients. Measurement of a battery of biochemical parameters in serum and haematological parameters, and urine analysis were performed to evaluate the safety of 5-Loxin^® in OA patients.

Results

Seventy patients completed the study. At the end of the study, both doses of 5-Loxin^® conferred clinically and statistically significant improvements in pain scores and physical function scores in OA patients. Interestingly, significant improvements in pain score and functional ability were recorded in the treatment group supplemented with 250 mg 5-Loxin^® as early as 7 days after the start of treatment. Corroborating the improvements in pain scores in treatment groups, we also noted significant reduction in synovial fluid matrix metalloproteinase-3. In comparison with placebo, the safety parameters were almost unchanged in the treatment groups.

Conclusion

5-Loxin^® reduces pain and improves physical functioning significantly in OA patients; and it is safe for human consumption. 5-Loxin^® may exert its beneficial effects by controlling inflammatory responses through reducing proinflammatory modulators, and it may improve joint health by reducing the enzymatic degradation of cartilage in OA patients.

Trail Registration

(Clinical trial registration number: ISRCTN05212803.)     

Can cognitive enhancers reduce the risk of falls in older people with Mild Cognitive Impairment? A protocol for a randomised controlled double blind trial

Background  

Older adults with cognitive problems have a higher risk of falls, at least twice that of cognitively normal older adults. The consequences of falls in this population are very serious: fallers with cognitive problems suffer more injuries due to falls and are approximately five times more likely to be admitted to institutional care. Although the mechanisms of increased fall risk in cognitively impaired people are not completely understood, it is known that impaired cognitive abilities can reduce attentional resource allocation while walking. Since cognitive enhancers, such as cholinesterase inhibitors, improve attention and executive function, we hypothesise that cognitive enhancers may reduce fall risk in elderly people in the early stages of cognitive decline by improving their gait and balance performance due to an enhancement in attention and executive function.