Relationship between the audiogram and the duration of the tone measuring the threshold

Summary In addition to the data on intensity-duration curves of the threshold tones, the threshold audiograms are constructed for the different durations of the threshold measuring tone. The durations 0.5; 2; 5; 20; 100 and 850 msec and frequencies 200, 500, 1000, 2000, 3000, and 5000 cps were used. Even when the duration of the testing tone is so short that this tone becomes a noise, the pattern of an audiogram in cases of normal hearing has some resemblance to the typical audiogram. But the great remoteness of the point for 1000 cps from the minimum zone draws attention. As the duration of the testing becomes longer, the audiogram of a person with normal hearing is gradually transforrned from a V-shaped curve with a sharp minimum into a typical curve with an elongated minimum zone, and the point for 1000 cps shifts from the left ascending branch of the audiogram to the center of the minimum zone. Several audiograms are obtained for 2 patients with a partial hearing loss, resulting from growing age, and 1 patient with a severe hearing loss of traumatic origin. Peculiar changes in these audiogram could be clearly seen at the least durations of the testing tone used. The diminishing of absolute threshold, when the tone duration is prolonged from 100 to 850 msec, is less for the listeners with impaired hearing.(Presented by Academician V. N. Chernigovskii) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 54, No. 10, pp. 21–26, October 1962.     

Adequate function of the cell: Interactions between the needs of the cell and the needs of the organism

The continuous maintenance of cell adequate function (cellular stress) is considered to be the main feature which characterizes the activity of a live cell. In accordance with the concept of cellular stress, the transition of the cell to the state of adequate funcitoning represents a dual commitment. The cell must function adequately to respond to the demands of the organism and to provide for its own needs. Thus, it is proposed that two systems exist for the regulation of the adequate function of the cell: one enabling the cell to respond to the demands of the organism, and the other providing for the needs of the cell itself. The hormonal system of the organism represents the first of these mechanisms, and I believe that another system exists for regulation of intracellular needs. Adequate function of the cell is determined by the regulative, controlling and defense mechanisms. The balance between the needs of the cell and of the organism should be a concern of physician, since it provides for the optimal function and health of the organism as a whole.     

Beyond the genome to the proteome

The sequence of the human genome has been decoded and a post-genome era is now beginning. This is the start of the protein/peptide era. Working in the fundamental research division of a pharmaceutical company and being engaged in studies on the research and development of new drugs based upon genomic information, it was clear to me that genomic information was useful, significant and indispensable in driving forward to new drug discovery. However, it is also true that we need more than that. I have faced multiple barriers in pursuing genomic information alone. There are numerous dead-end stories in genome-based new drug discovery and in many cases, those hurdles are very hard to get over. What approach can be a breakthrough of this bottleneck? I believe that one answer is research into proteins. The proteome describes all the proteins within an organism. The proteome analysis research field promises a bright future for the discovery of new drugs, diagnosis and therapeutics. I believe the mass spectrometer(MS) will be a key instrument in this research. The contribution of mass spectrometry was recently recognized in the Nobel Prize for Chemistry 2002, for 'the discovery of Soft Laser Desorption/Ionization' awarded to Mr. Koichi Tanaka. There is no doubt that the MS will play an essential role in accelerating proteome analysis. However, the present proteome analysis technology has not yet reached a sufficient scientific level. Further improvements of both hardware and software are necessary. For the hardware, improvements in sensitivity, accuracy and high-throughput, in addition to equipment for ultra-micro analysis applied to the analysis of the proteome should be addressed. Regarding software, we need to develop new chemistries for proteome analyses and propose original, user-friendly proteome analysis methods. In this review, starting with a briefing on genome-based drug discovery, I will discuss a new concept for proteome analysis based on mass spectrometry and new methodologies. This 'next generation' platform may provide a solution for the development of an integrated system that will contribute to our understanding of clinical information/bioinformatics, therapeutics, diagnosis and even drug discovery.     

Short-term tests and the myth of the non-clastogenic mutagen

I suggest that there are several good reasons for retainingmammalian cell mutation assays in a basic test package for genotoxicityand that the possible existence of a non-clastogenic mammalianmutagen is not one of them. I put forward a number of propositions,not necessarily original, concerning in vitro assays, includingtheir need for repetition, the inappropriateness of rodent carcinogenicityas a reference point for validation, the need for assays tocorroborate rather than complement each other, the need forongoing validation and development, and the need for as completean in vitro package as possible in order to avoid unnecessaryanimal experimentation.     

Anatomical evidence for the epididymis as the prime mover in the evolution of the scrotum

Extensive investigation of the sensitivity of the descended testis to abdominal temperature, and of its thermo-regulation by the scrotum, has so far failed to explain the adaptive significance of the scrotal state. The present viewpoint, derived primarily from comparative anatomical and from experimental studies, suggests a different line of reasoning – that descent into a scrotum has been influenced primarily by the need for migration of the cauda epididymidis to this cooler location; testicular descent is seen as a merely mechanistic event which enables the cauda epididymidis to project from the body, but has no significance for the biological function of the testis as such. The possibility that some advantage derived by the sperm-storage region of the epididymis has been a prime determinant in the evolution of the scrotum is suggested by at least three anatomical features. This is indicated firstly by the relationship of testis and cauda epididymidis to each other in cryptorchid and in scrotal species. In natural cryptorchids (e.g., many insectivores and hystricomorph rodents) which express the transitional stage in testicular descent, the cauda generally precedes the testis within the cremasteric sac, thereby lying closest to the integument. In the scrotum, the disposition of the cauda epididymidis ensures that it occupies the coolest site there also. A second consideration concerns the curious course traced by the Wolffian duct in cryptorchid and scrotal mammals; for its diversionary route along and beyond the border of the testis would seem illogical and unnecessary were descent into a scrotum related solely to the function of the testis. This U-shaped disposition of the duct, which retraces its course from the acute flexure of the cauda, is seen here as a device which permits the cauda epididymidis to occupy a cooler site, whether this be subintegumental or scrotal. Thirdly, although evidenced to different degrees and not in all species, a variety of scrotal features, e.g., a circumscribed hormonally-determined baldness, exaggerated dartos responsitivity and, occasionally, black pigmentation of the peri-caudal surface, as well as the presence of a fat pad between cauda and testis, each appear to favor controlled cooling of the caudal epididymidis. In no animal, by contrast, does the form of the scrotum and the disposition of its content seem designed for preferential cooling of the testis. These considerations do not explain the adaptive significance of the scrotum or the reasons for its variable occurrence among mammals. However, with a few exceptions found particularly amongst marine mammals, a scrotum characterizes polygynous species in which a dominant male achieves all or most of the fertile matings in a large group, and also those known to engage in multiple ejaculatory coitus with one female. Conversely, our limited knowledge of their habits notwithstanding, the frequency of sexual interaction for the males of most ascrotal species would appear to be relatively low. In light of its suggested relationship to the function of the cauda epididymidis, the possibility is raised that the scrotal state may be linked to the sexual capacity of the male, in particular the ability to produce fertile ejaculates repeatedly within a limited period of time.     

Studies on the influence of the structural modifications in the tracer on the immunoassay of progesterone

The main objective of the present study was to examine the influence of different bridges in radioiodinated tracers on the assay performance of progesterone using antibodies. Three homologous and two heterologous immunoassay systems for the measurement of progesterone in human serum are described. Using an antiserum raised against progesterone-11alpha-hemisuccinate-bovine serum albumin (BSA), assays with homologous radioligands, namely progesterone-11alpha-hemisuccinate-125I-tyrosine methyl ester (TME) and progesterone-11alpha-hemisuccinate-125I-histamine, heterologous bridge radioligand, namely progesterone-11alpha-hemiphthalate-125I-TME, and a heterologous site radioligand namely progesterone-3-(O-carboxymethyl) oxime (CMO)-125I-histamine were optimized. A homologous assay system, using antiserum raised against progesterone-3-carboxymethyl oxime-BSA and progesterone-3-CMO-125I-histamine as the radioligand was also optimized to develop a radio-immunoassay (RIA) for serum progesterone. Amongst the two homologous radioligands, viz., progesterone-11alpha-hemisuccinate-125I-histamine and the corresponding TME conjugate tracer, the former yielded a standard curve with a higher slope (-0.6) as compared to the latter (-0.5). The heterologous bridge system with progesterone-11alpha-hemiphthalate-125I-TME resulted in a more sensitive assay (slope of -0.8) than the homologous tracers, whilst the heterologous site radioligand, viz., progesterone-3-CMO-125I-histamine gave the most sensitive assay (slope of -1.2). The homologous assay with antiserum against progesterone-3-CMO-BSA and progesterone-3-CMO-125I-histamine tracer gave a standard curve having a slope of -0.97. The two antibodies developed against progesterone, viz., progesterone-11alpha-hemisuccinate-BSA and progesterone-3-CMO-BSA were characterized for their titre, sensitivity, and specificity. Considering the slope, sensitivity, cross-reactivity, and the quality of tracer, the assay system using antiserum against progesterone-11alpha-hemisuccinate-BSA and progesterone-3-CMO-125I-histamine was found to be suitable for the development of RIA for serum progesterone. The bridges used in an immunogen for production of antibodies, as well as in the preparation of tracer, have a great influence on the assay characteristics.     

Counterpointing the functional role of the forebrain and of the brainstem in the control of the sleep-waking system

This paper reviews the lifetime contributions of the author to the field of sleep-wakefulness (S-W), reinterprets results of the early studies, and suggests new conclusions and perspectives. Long-term cats with mesencephalic transection show behavioral/polygraphic rapid eye movement sleep (REMS), including the typical oculo-pupillary behavior, even when the section is performed in kittens prior to S-W maturation. REMS can be induced as a reflex. Typical non-rapid eye movement S (NREMS) is absent and full W/arousal is present only after a precollicular section. The isolated forebrain (IF) rostral to the transection exhibits all features of W/arousal and NREMS [with electroencephalographic (EEG) spindles and delta waves], arousal to olfactory stimuli, and including the appropriate oculo-pupillary behaviors. These features also mature normally after neonatal transection. REMS is absent from the IF. After deprivation there is NREMS pressure and rebound in the IF, but the decerebrate cat only shows pressure for REMS. Most IF reactions to pharmacologic agents are within expectations, except for the tolerance/withdrawal effects of long-term morphine use which are absent. In contrast, these effects are supported by the brainstem (i.e. seen in the decerebrate cat). In cats with ablation of the telencephalon, or diencephalic cats, delta waves are absent in the thalamus. EEG thalamic spindle waves are seen triggering S for only 4-5 days after ablation. Therefore, true NREMS is absent in chronic diencephalic cats although pre- and postsomniac behaviors persist. These animals are hyperactive and show a pronounced, permanent insomnia; however, a low dose of barbiturate triggers a dramatic REMS/atypical NREMS rebound. Cats without the thalamus (athalamic cats), initially show a dissociation between behavioral hyperactivity/insomnia and the neocortical EEG, which for 15-20 days exhibits only delta and slower oscillations. Fast, low-voltage W rhythms appear later on, first during REMS, but spindle waves and S postures are absent from the start, such that these cats also display only atypical NREMS. Athalamic cats also show barbiturate-sensitive insomnia. Cats with ablation of the frontal cortices or the caudate nuclei remain permanently hyperactive. They also show a mild, but significant hyposomnia, which is permanent in afrontal cats, but lasts for about a month in acaudates. The polygraphic/behavioral features of their S-W states remain normal. We conclude and propose that: (a) the control of the S-W system is highly complex and distributed, but is organized hierarchically in a well-defined rostro-caudal manner; the rostral-most or highest level (telencephalon), is the most functionally complex/adaptative and regulates the lower levels; the diencephalic/basal forebrain, or middle level, has a pivotal role in inducing switching between S and W and in coordinating the lowest (brainstem) and highest levels; (b) W can occur independently in both the forebrain and brainstem, but true NREMS- and REMS-generating mechanisms exist exclusively in the forebrain and brainstem, respectively; (c) forebrain and brainstem S-W processes can operate independently from each other and are preprogrammed at birth; this helps understanding normal and abnormal polygraphic/behavioral dissociations in humans and normal dissociations/splitting in aquatic mammals; (d) NREMS homeostasis is present in the IF, but only REMS pressure after deprivation persists in the decerebrate cat; (e) the thalamus engages in both NREMS and W; (f) insomnia in diencephalic cats is the result of an imbalance between antagonistic W- and S-promoting cellular groups in the ventral brain (normally modulated by the telencephalon); (g) the EEG waves, which are signature for each S-W state, appear to truly drive the concomitant behaviors, e.g. a hypothetical human IF could alternate between behavioral NREMS and W/arousal/awareness; (h) a role for REMS is to keep the individual sleeping at the end of the self-limiting NREMS periods. The need for accelerating research on telencephaling NREMS periods. The need for accelerating research on telencephalic S-W processes and downstream control of the lower S-W system levels is emphasized.     

Saccade-related activity in the primate superior colliculus depends on the presence of local landmarks at the saccade endpoint

Saccade-related discharge in the superior colliculus is greater for saccades made to a spot of light than for saccades in complete darkness. However, it is unclear whether this enhancement is due to the discontinuity of the spot or due to its being a new object of fixation. In these experiments, we examined the saccade-related activity of intermediate-layer neurons in the primate superior colliculus during delayed saccades to the center or corner of a large, bright square, as well as for visual and memory-guided movements to small spots in isolation. The saccade-related discharge for movements made to a local visual landmark present at the time of the saccade, be it a corner of a square or a small spot, was higher than that for saccades made to the center of a square that contained no local visual landmarks within. Moreover, discharge for movements to the center of a square were very similar to that for saccades to blank, dark space. Saccade velocity was similarly dependent on the presence of such a landmark, though less dramatically. The endpoints of saccades directed toward a square's corner were slightly displaced toward the center of the square. Across all neurons, discharge and velocity for saccades to the center of a square increased as the square size was decreased, but were never greater than those for saccades to a small spot of light. These results suggest that both saccade-related discharge in the superior colliculus and saccade metrics are enhanced for movements directed to parts of the visual scene with high contrast, while shifting fixation to a new object is not itself sufficient to elevate discharge and metrics above those of saccades to blank space.     

Novel assays to assess the functional capacity of the classical, the alternative and the lectin pathways of the complement system

Deficiencies in many of the complement proteins and their regulatory molecules have been described and a variety of diseases, such as recurrent infections, systemic lupus erythematosus (SLE) and renal diseases, may be linked to deficiency in the complement system. Screening for complement defects is therefore of great importance. In this study, we present novel improved enzyme-linked immunosorbent assays for the functional assessment of the three individual pathways of the complement system. The method is applicable at high serum concentrations and we demonstrate that it minimizes both false negative as well as false positive results. In particular, for the functional mannose-binding lectin activity it represents an improvement on the existing assays. In this respect, the present assays represent novel improved diagnostic protocols for patients with suspected immunodeficiencies related to the complement system.     

Removing the heart from the brain: Compensation for the pulse artifact in the photon migration signal

Various factors, including variations in the concentration of hemoglobin, determine changes in the transparency of living tissue to near-infrared light. Hence, optical measures have been proposed as a noninvasive method for investigating regional changes in brain activity. However, the amount of near-infrared light traversing a region of the head is also influenced by the periodic changes in blood pressure that occur during the cardiac cycle (pulse). These large changes may obscure smaller, localized events associated with brain activity. We developed a least-squares regression algorithm for compensating for the artifact introduced by the pulse. This procedure takes into account beat-to-beat variability in heart rate and differences in the shape of the pulse among subjects and among recording conditions.     

On the maturation rate of the neutrophil

Fifty-three maturing bone marrow cells of the granulocyte cell series stained with Giemsa stain and magnified 1,000 times were scanned by a "computerized microscope" consisting of a LSI-11/23 microprocessor and a black-and-white video camera attached to a "frame grabber ." Each sampled cell was digitized into 70 X 70 pixels, each pixel representing 0.04 micron of the real image. The pixel gray values ranged between 0 and 255. Zero stood for white, 255 represented black, while the numbers in between stood for the various shades of gray. The cells represented six different stages of granulocytic maturation: myeloblast, promyelocyte, myelocyte, metamyelocyte , band form, and polymorphonuclear granulocyte. A discriminant analysis program selected 19 features best distinguishing between the six different cell types and computed five canonical discriminant functions defining a Space in which maturation was studied. In the Space, distance between two cells serves as a measure of similarity. The closer two cells are, the more similar they are and vice versa. This measure was applied here to express the degree of similarity between the neutrophil maturation classes, and since they represent states in the neutrophil life history, it is applicable also as a yardstick for the quantitation of differentiation. In the Space, the life history of a cell is represented by a trajectory originating in the myeloblast and terminating in the granulocyte state. Displacement along the trajectory represents cell maturation that is expressed relatively to the least differentiated state of the myeloblast. The further a cell from this state the more mature it is. The same yardstick also serves for differentiation rate estimates represented in the Space by displacement velocities that are derived from the known "transit times" of a cell in each state. The methodology is also applied for cell production estimates. Unlike other "computerized microscopes" serving for cell classification, the instrument described in this study is primarily a cell-comparator providing a precise measure of similarity between any two cells.     

Electroanatomical maps of the heart in the athletes

The CARTO system is a new, non fluoroscopic method for mapping designed of associating a specific intracardiac electrocardiogram with the endocardial location from which it has been recorded. Thus for the first time, the CARTO system allows precise correlation of electrophysiological information with cardiac anatomy. It acquires, through a special catheter, and then displays on its computer screen, the precise three-dimensional electro-anatomical maps of the different cardiac chambers. The maps are constructed by integrating information from recorded intracardiac electro-grams with knowledge of their precise anatomic location within the heart. The method is based on the ability to connect a new locatable catheter with a system for endocardial navigation and mapping.     

The Beauty of the Network in the Brain and the Origin of the Mind in the Control of Behavior

Behavior is not adequately described as a stimulus-response process. It is initiated by the animal and is generated because of its expected outcome in the future. The outcome can be good or bad for the animal. The brain is in charge of the selection process. This is the basic function of the brain. Taking Drosophila as a study case, this paper discusses initiating activity, several examples of outcome expectations, trying out (the internal search for a suitable behavior), chaining of actions, and the functional roles of chance in action selection. It takes mental processes and states such as goals, intentions, feelings, memories, cognition, and attention as higher levels of behavioral control that have their origin in biological evolution.     

The third time is the charm--anastomosis between the celiac trunk and the left colic artery

An atypical case of abdominal vasculature, found in a 58-year-old woman is presented. The multidetector computed tomography angiogram revealed a large tortuous anastomotic vessel between the stem of the celiac trunk and the left colic artery, supplying branches for the left colon and pancreatic body and tail. We propose a simple embryological explanation for the development of this aberrant artery--the longitudinal ventral anastomosis, which connects the precursors of principal visceral arteries in a loop-like manner, loses its direct communication with the superior mesenteric artery but maintains its continuity above and below this level. This variation could pose a problem for radiological interpretation and affect surgical approaches to the aorta, left colon, and the pancreas.     

Cryptic resolution sites in the vector plasmid lead to the heterogeneities in the rAAV vectors

Recombinant adeno-associated virus (rAAV) vectors carry a cassette of interest retaining only the inverted terminal repeats (ITRs) from the wild-type virus. Conventional rAAV production primarily uses a vector plasmid as well as helper genes essential for AAV replication and packaging. Nevertheless, plasmid backbone related contaminants have been a major source of vector heterogeneity. The mechanism driving the contamination phenomenon has yet to be elucidated. Here we identified cryptic resolution sites in the plasmid backbone as a key source for producing snapback genomes, which leads to the increase of vector genome heterogeneity in encapsidated virions. By using a single ITR plasmid as a model molecule and mapping subgenomic particles, we found that there exist a few typical DNA break hotspots in the vector DNA plasmid backbone, for example, on the ampicillin DNA element, called aberrant rescue sites. DNA around these specific breakage sites may assume some typical secondary structures. Similar to normal AAV vectors, plasmid DNA with a single ITR was able to rescue and replicate efficiently. These subgenomic DNA species significantly compete for trans factors required for rAAV rescue, replication, and packaging. The replication of single ITR contaminants during AAV production is independent of size. Packaging of these species is greatly affected by its size. A single ITR and a cryptic resolution site in the plasmid work synergistically, likely causing a source of plasmid backbone contamination.     

Ectopic thyroid follicles in the submucosa of the duodenum

Summary Ectopic microscopic thyroid follicles were encountered fortuitously in the submucosa of the duodenum in a 63-year-old man undergoing pancreaticoduodenectomy for pancreatic carcinoma. The follicles, filled with a colloid-like substance, were intermingled with Brunner's glands of the duodenum. There were no signs or symptoms of a thyroid tumour. The epithelial cells and colloid-like substance were both immunoreactive for thyroglobulin but no cells stained for calcitonin. The possibility of a metastatic origin for the follicles from an occult thyroid carcinoma was excluded by the clinical and histopathological findings. These ectopic thyroid follicles cannot be explained by developmental inclusions or metastasis and may be metaplastic in nature.     

Inhibition of the immediate allergic reaction in the nose by the beta-2 adrenostimulant fenoterol

Sympathomimetic agents inhibit antigen-induced release of histamine in animal experiments and in in vitro studies of human tissue, but the significance of this effect for treatment of allergic airway diseases has not been established. It was the aim of our study to investigate the protective effect of the beta-2 adrenostimulant fenoterol on allergen-induced nasal symptoms and to relate the efficacy to dose and time. In a double-blind crossover design 16 patients with hay fever were challenged with grass pollen extract in the nose after pretreatment with intranasal placebo and fenoterol in different doses, delivered as a micronized powder from a pressurized canister and as a watery solution from a pump spray. Sneezing was recorded, and rhinorrhea and changes in nasal airway resistance were measured for 15 min after the provocation. Fenoterol, micronized powder as well as solution, had a marked inhibitory effect on all three nasal symptoms (p < 0.05) in doses ordinarily used for inhalation in the treatment of branchial asthma. The effect lasted for more than 4 hr. Our study has suggested that topical application of beta-2 adrenostimulants has a mast cell stabilizing effect in the airways and that these drugs may be of value for treatment of allergic rhinitis.     

Outlining the prostate boundary using the harmonics method

In a computerised ultrasound image guidance for automated prostatectomy system, it is necessary to identify a smooth, continuous contour for the prostate (boundary) from the ultrasound image. The radial bas-relief (RBR) method, which has been reported previously, can extract a skeletonised image from an ultrasound image automatically. After this process the prostate boundary is clearly revealed. However, analysis of the image is far from complete, as there are many spurious branches that create too much ambiguity for the system to define the actual boundary. There are also sections missing from the prostate boundary. Therefore further post-processing is required to describe and define the prostate boundary. In the paper, the harmonics method is used to describe the prostate boundary. The harmonics method uses Fourier information for noise removal and encodes a smooth boundary. The results of using the harmonics method after application of the RBR method on ultrasound images are presented. Factors that affect the performance are also highlighted and discussed.     

Migraine--a burden for the individual and the society

According to World Health Organization migraine is ranked among the first 20 disorders in the world that cause significant disability. The economic burden due to migraine is significant; direct costs include visits to general practitioner and emergency department, costs of hospitalization and pharmacotherapy. Indirect costs comprise 2/3 of total costs and include absenteeism from work and costs due to reduced productivity. Reasons for the high economic burden are primarily insufficient diagnosing of migraine, the lack of information in the general population, underdevelopment of healthcare system and non-existence of plans and programms for a systematic approach in the management of headaches. Triptans as a specific and very efficient therapy for migraine are available on the market; studies have shown a high benefit-to-cost ratio when triptans were introduced as an acute therapy of migraine attacks. More attention should be paid to better diagnosis and treatment of headaches, especially migraine. We propose the main aspects for improvement of healthcare for patients with headaches.