Radioimmunoassay of Human Serum Thyrotrophin

The double antibody radioimmunoassay of serum thyroid-stimulating hormone (TSH) allows measurement of circulating levels of the hormone in most normal subjects. The serum TSH level in normal subjects is 1·6 ± 0·8μU/ml. Patients with non-toxic goitre and acromegaly have normal TSH levels. Values are always raised in hypothyroid patients (with primary thyroid disease) and are significantly lowered in those with hyperthyroidism. Of the many stimuli used in an attempt to raise TSH levels in normal adult subjects only three—synthetic thyrotrophin-releasing hormone, ethinyloestradiol, and carbimazole plus iodides—have been effective. The major clinical application of the TSH immunoassay lies in the diagnosis of minor degrees of hypothyroidism. An impaired response of serum TSH to synthetic thyrotrophin-releasing hormone should also help in the diagnosis of hypopituitarism affecting TSH production.     

distAngsd: Fast and Accurate Inference of Genetic Distances for Next-Generation Sequencing Data

Commonly used methods for inferring phylogenies were designed before the emergence of high-throughput sequencing and can generally not accommodate the challenges associated with noisy, diploid sequencing data. In many applications, diploid genomes are still treated as haploid through the use of ambiguity characters; while the uncertainty in genotype calling—arising as a consequence of the sequencing technology—is ignored. In order to address this problem, we describe two new probabilistic approaches for estimating genetic distances: distAngsd-geno and distAngsd-nuc, both implemented in a software suite named distAngsd. These methods are specifically designed for next-generation sequencing data, utilize the full information from the data, and take uncertainty in genotype calling into account. Through extensive simulations, we show that these new methods are markedly more accurate and have more stable statistical behaviors than other currently available methods for estimating genetic distances—even for very low depth data with high error rates.     

NON-TOXIC GOITER TREATMENT WITH I-TRIIODOTHYRONINE AND I-THYROXINE

Twenty-one patients with goiters—four diffuse and 17 nodular—were treated with I-triiodothyronine and I-thyroxine in doses to tolerance. The four diffuse goiters were barely palpable at the end of the treatment. The average dose of I-triiodothyronine required was 100 mcg. per day. The average dose of I-thyroxine was 0.3 mg. per day. Of the 17 multinodular goiters, 11 showed at least a 50 per cent reduction in size. The average dose of I-triiodothyronine used was 125 mcg. In six cases the gland did not change in size; in three of the six the lesion was diagnosed, at operation, as microfollicular and macrofollicular colloid goiter.Hypermetabolic symptoms may occur when doses of 100 mcg. or more of I-triiodothyronine are used.Results indicated that suppressive therapy with thyroid hormone to tolerance is effective in diffuse goiters. It is only partially effective in the treatment of multinodular goiters. In the cases in which operation was done, no change in the basic histological goiter structure was observed.     

Evolving the neuroendocrine physiology of human and primate cooperation and collective action

While many hormones play vital roles in facilitating or reinforcing cooperative behaviour, the neurohormones underlying competitive and cooperative behaviours are largely conserved across all mammals. This raises the question of how endocrine mechanisms have been shaped by selection to produce different levels of cooperation in different species. Multiple components of endocrine physiology—from baseline hormone concentrations, to binding proteins, to the receptor sensitivity and specificity—can evolve independently and be impacted by current socio-ecological conditions or individual status, thus potentially generating a wide range of variation within and between species. Here, we highlight several neurohormones and variation in hormone receptor genes associated with cooperation, focusing on the role of oxytocin and testosterone in contexts ranging from parenting and pair-bonding to reciprocity and territorial defence. While the studies reviewed herein describe the current state of the literature with regard to hormonal modulators of cooperation and collective action, there is still a paucity of research on hormonal mechanisms that help facilitate large-scale collective action. We end by discussing several potential areas for future research.     

Dynamics of thyroid diseases and thyroid‐axis gland masses

Thyroid disorders are common and often require lifelong hormone replacement. Treating thyroid disorders involves a fascinating and troublesome delay, in which it takes many weeks for serum thyroid‐stimulating hormone (TSH) concentration to normalize after thyroid hormones return to normal. This delay challenges attempts to stabilize thyroid hormones in millions of patients. Despite its importance, the physiological mechanism for the delay is unclear. Here, we present data on hormone delays from Israeli medical records spanning 46 million life‐years and develop a mathematical model for dynamic compensation in the thyroid axis, which explains the delays. The delays are due to a feedback mechanism in which peripheral thyroid hormones and TSH control the growth of the thyroid and pituitary glands; enlarged or atrophied glands take many weeks to recover upon treatment due to the slow turnover of the tissues. The model explains why thyroid disorders such as Hashimoto''s thyroiditis and Graves'' disease have both subclinical and clinical states and explains the complex inverse relation between TSH and thyroid hormones. The present model may guide approaches to dynamically adjust the treatment of thyroid disorders.     

Bioassay of Thyroid Stimulating Hormone Using the Goldfish

A new method for the bioassay of thyroid stimulating hormone using goldfish is described. The technique can detect thyroid stimulating substances in euthyroid unconcentrated plasma. Early results show that the method compares well with other techniques. Some evidence has been obtained which suggests that in primary myxoedema there may be some impairment of the thyropituitary “servo-mechanism” in older patients.     

Hypothalamic and rate feedback in the thyroid hormone regulation system: An hypothesis

Several alternative models of the system regulating the plasma concentration of thyroid hormones are presented and investigated from the point of view of certain optimal system performance indices. The models differ from each other in the number and types of feed-back pathways. Various combinations of thyroid hormone feedback actions at pituitary and/or hypothalamic chemoreceptor sites, having proportional and/or rate characteristics, are considered in terms of minimum energy consumption and minimum sensitivity to the maximum number of model parameters likely to vary. It is concluded that the model which includes proportional inhibitory feedback of thyroid hormone at the hypothalamic level and rate feedback of thyroid hormone at the level of the pituitary provides the best performance.     

Personalized brain stimulation for effective neurointervention across participants

Accumulating evidence from human-based research has highlighted that the prevalent one-size-fits-all approach for neural and behavioral interventions is inefficient. This approach can benefit one individual, but be ineffective or even detrimental for another. Studying the efficacy of the large range of different parameters for different individuals is costly, time-consuming and requires a large sample size that makes such research impractical and hinders effective interventions. Here an active machine learning technique is presented across participants—personalized Bayesian optimization (pBO)—that searches available parameter combinations to optimize an intervention as a function of an individual’s ability. This novel technique was utilized to identify transcranial alternating current stimulation (tACS) frequency and current strength combinations most likely to improve arithmetic performance, based on a subject’s baseline arithmetic abilities. The pBO was performed across all subjects tested, building a model of subject performance, capable of recommending parameters for future subjects based on their baseline arithmetic ability. pBO successfully searches, learns, and recommends parameters for an effective neurointervention as supported by behavioral, simulation, and neural data. The application of pBO in human-based research opens up new avenues for personalized and more effective interventions, as well as discoveries of protocols for treatment and translation to other clinical and non-clinical domains.     

Scale Invariance Properties of Intracerebral EEG Improve Seizure Prediction in Mesial Temporal Lobe Epilepsy

Although treatment for epilepsy is available and effective for nearly 70 percent of patients, many remain in need of new therapeutic approaches. Predicting the impending seizures in these patients could significantly enhance their quality of life if the prediction performance is clinically practical. In this study, we investigate the improvement of the performance of a seizure prediction algorithm in 17 patients with mesial temporal lobe epilepsy by means of a novel measure. Scale-free dynamics of the intracerebral EEG are quantified through robust estimates of the scaling exponents—the first cumulants—derived from a wavelet leader and bootstrap based multifractal analysis. The cumulants are investigated for the discriminability between preictal and interictal epochs. The performance of our recently published patient-specific seizure prediction algorithm is then out-of-sample tested on long-lasting data using combinations of cumulants and state similarity measures previously introduced. By using the first cumulant in combination with state similarity measures, up to 13 of 17 patients had seizures predicted above chance with clinically practical levels of sensitivity (80.5%) and specificity (25.1% of total time under warning) for prediction horizons above 25 min. These results indicate that the scale-free dynamics of the preictal state are different from those of the interictal state. Quantifiers of these dynamics may carry a predictive power that can be used to improve seizure prediction performance.     

ON RHODOPSIN IN SOLUTION

1. The properties of rhodopsin in solution have been examined in preparations from marine fishes, frogs, and mammals. 2. The bleaching of neutral rhodopsin in solution includes a photic and at least three thermal ("dark") processes. Thermal reactions account for approximately half the total fall in extinction at 500 mµ. 3. Bleaching has been investigated at various pH''s from 3.9 to about 11. With increase in pH the velocity of the thermal components increases rapidly. Though the spectrum of rhodopsin itself is scarcely affected by change in pH, the spectra of all product-mixtures following irradiation are highly pH-labile. 4. The spectrum of pure rhodopsin—or of the rhodopsin chromophore—is fixed within narrow limits. The extinction at 400 mµ lies between 0.20 to 0.32 of that at the maximum. 5. Within the limitations of available data, the spectrum of pure rhodopsin corresponds in form and position with the spectral sensitivity of human rod vision, computed at the retinal surface. 6. The nature of bleaching of rhodopsin in solution, its kinetics, and its significance in the retinal cycle are discussed.     

The effect of indomethacin on the response of thyroid tissue to thyrotropin

Indomethacin, in concentrations up to 400 μM, fails to alter the stimulation by thyrotropin in various thyroid preparations of [1-¹⁴C]glucose oxidation, hormone and iodine secretion, and adenylate cyclase activity. It is concluded that prostaglandin synthesis is not an obligatory step in the activation of these thyroid functions by thyrotropin.     

Cell Lineages and the Logic of Proliferative Control

It is widely accepted that the growth and regeneration of tissues and organs is tightly controlled. Although experimental studies are beginning to reveal molecular mechanisms underlying such control, there is still very little known about the control strategies themselves. Here, we consider how secreted negative feedback factors (“chalones”) may be used to control the output of multistage cell lineages, as exemplified by the actions of GDF11 and activin in a self-renewing neural tissue, the mammalian olfactory epithelium (OE). We begin by specifying performance objectives—what, precisely, is being controlled, and to what degree—and go on to calculate how well different types of feedback configurations, feedback sensitivities, and tissue architectures achieve control. Ultimately, we show that many features of the OE—the number of feedback loops, the cellular processes targeted by feedback, even the location of progenitor cells within the tissue—fit with expectations for the best possible control. In so doing, we also show that certain distinctions that are commonly drawn among cells and molecules—such as whether a cell is a stem cell or transit-amplifying cell, or whether a molecule is a growth inhibitor or stimulator—may be the consequences of control, and not a reflection of intrinsic differences in cellular or molecular character.     

THERAPY OF PARKINSON'S DISEASE

The most disabling form of Parkinsonism is that occurring after encephalitis. It may occur in persons of any age. The results of surgical treatment, which has been used for the most part only for seriously handicapped patients, have been discouraging in general, although in a few isolated circumstances operation has been of dramatic benefit.The solanaceous alkaloids—atropine, stramonium and hyoscine—either in pure forms or in mixed extracts or tinctures — are the best established drugs at present for the treatment of the postencephalitic forms of Parkinsonism. They have not proven too helpful for patients in the older age group with paralysis agitans. The antihistaminic compounds, particularly Benadryl,® have been a very valuable addition. They are of greatest value for patients in the older age group. The newer synthetic compounds, Artane® and Panparnit,® are also valuable additions. Amphetamine and the related and subsequently produced agents in this group are very helpful for patients showing undue fatigue and lethargy. Tolserol® is proving helpful, particularly for patients with painful spasms of rigid muscles.     

Roentgen Examination of Soft Tissues of the Pelvis

With meticulous preparation of the patient and with careful technique, the soft tissues of the pelvis are identifiable in most cases. Search should be made for the traces of abnormal pelvic structures on plain-film studies. Once the normal is recognized, any variations are easily identified. The fundamental differences between various radiologic densities—air, fat, fluid, muscle, calcium, bone and metal—should be observed. Special procedures can be used to enhance the contrasts after adequate evaluation of the simplest and, on many occasions, the invaluable, plain-film study of the soft tissues of the pelvis.     

Qualitative and Quantitative Protein Complex Prediction Through Proteome-Wide Simulations

Despite recent progress in proteomics most protein complexes are still unknown. Identification of these complexes will help us understand cellular regulatory mechanisms and support development of new drugs. Therefore it is really important to establish detailed information about the composition and the abundance of protein complexes but existing algorithms can only give qualitative predictions. Herein, we propose a new approach based on stochastic simulations of protein complex formation that integrates multi-source data—such as protein abundances, domain-domain interactions and functional annotations—to predict alternative forms of protein complexes together with their abundances. This method, called SiComPre (Simulation based Complex Prediction), achieves better qualitative prediction of yeast and human protein complexes than existing methods and is the first to predict protein complex abundances. Furthermore, we show that SiComPre can be used to predict complexome changes upon drug treatment with the example of bortezomib. SiComPre is the first method to produce quantitative predictions on the abundance of molecular complexes while performing the best qualitative predictions. With new data on tissue specific protein complexes becoming available SiComPre will be able to predict qualitative and quantitative differences in the complexome in various tissue types and under various conditions.     

Effects of cryoprotectants in combination on the survival of frozen sugarcane cells

Cryoprotection of suspension cultures of sugarcane cells (Saccharum sp.) during freezing to various temperatures was tested using glucose, dimethylsulfoxide, and ethylene glycol at various concentrations, alone and in combinations. Viability of the thawed cells was assessed by triphenyltetrazolium chloride reduction, cell growth, and microscopic examination. Enhanced cryoprotection—as much as a doubling in viability value—was achieved by employing glucose and dimethylsulfoxide in mixtures, as compared with the lesser cryoprotective effect of either compound alone, at 1.9 molar total concentration in all cases; the mixture was most effective at a concentration of about 1.9 molar, with a molar ratio of the two components of about 1:3, respectively. Much of the increase in viability value arose from a decrease in toxic effect that came about through mixing the cryoprotective agents. Binary mixtures containing ethylene glycol and either glucose or dimethylsulfoxide were less effective and more toxic than comparable glucose-dimethylsulfoxide mixtures. Use of the optimized latter mixture allowed freezing of these tropical cells to −23 C with little decrease in survival, or to −40 C, still with the capability for delayed growth.     

Historical and Current Perspective in the Use of Thyroid Extracts for the Treatment of Hypothyroidism

Objective: To describe the history, refinements, implementation, physiology, and clinical outcomes achieved over the past several centuries of thyroid hormone replacement strategies.Methods: A Medline search was initiated using the following search terms: bioidentical thyroid hormone, thyroid hormone extract, combination thyroxine (T4) and tri-iodothyronine (T3) therapy, homeopathic thyroid hormone therapy, and thyroid hormone replacement. Pertinent articles of interest were identified by title (and where available abstract) for further review. Additional references were identified during a review of the identified literature.Results: A rich history of physician intervention in thyroid dysfunction was identified dating back more than 2 millennia. Although not precisely documented, thyroid ingestion from animal sources had been used for centuries but was finally scientifically described and documented in Europe over 130 years ago. Since the reports by Bettencourt and Murray, there has been a continuous documentation of outcomes, refinement of hormone preparation production, and updating of recommendations for the most effective and safe use of these hormones for relieving the symptoms of hypothyroidism. As the thyroid extract preparations contain both levothyroxine (LT4) and liothyronine (LT3), current guidelines do not endorse their use as controlled studies do not clearly document enhanced objective outcomes compared with LT4 monotherapy. Among current issues cited, the optimum ratio of LT4 to LT3 has yet to be determined, and the U.S. Food and Drug Administration (FDA) does not appear to be monitoring the thyroid hormone ratios or content in extract preparations on the market. Taken together, these limitations are important detriments to the use of thyroid extract products.Conclusion: The evolution of thyroid hormone therapies has been significant over the extended period of time they have been in use to treat hypothyroidism. Although numerous websites continue to advocate the use of thyroid hormone extracts as a superior therapy for hypothyroidism, none of the most recent guidelines of major endocrine societies recommend thyroid extract use for hypothyroidism.Abbreviations: AACE = American Association of Clinical Endocrinologists ATA = American Thyroid Association BMR = basal metabolic rate FDA = Food and Drug Administration FT4 = free thyroxine 131-I = radioactive iodine 131 LT3 = liothyronine LT4= levothyroxine NDA = new drug application PBI = proteinbound iodine T3 = triiodothyronine T4 = thyroxine TSH = thyroid-stimulating hormone TT3 = total triiodothyronine USP = U.S. Pharmacopeia     

Some Formal Approaches to the Analysis of Kinetic Data in Terms of Linear Compartmental Systems

A formal approach to the routine analysis of kinetic data in terms of linear compartmental systems is presented. The methods of analysis are general in that they include much of the theory in common use, such as direct solution of differential equations, integral equations, transfer functions, fitting of data to sums of exponentials, matrix solutions, etc. The key to the formalism presented lies in the fact that a basic operational unit—called “compartment”—has been defined, in terms of which physical and mathematical models as well as input and output functions can be expressed. Additional features for calculating linear combinations of functions and for setting linear dependence relations between parameters add to the versatility of this method. The actual computations for the values of model parameters to yield a least squares fit of the data are performed on a digital computer. A general computer program was developed that permits the routine fitting of data and the evolution of models.     

A survey of bacterial insertion sequences using IScan

Bacterial insertion sequences (ISs) are the simplest kinds of bacterial mobile DNA. Evolutionary studies need consistent IS annotation across many different genomes. We have developed an open-source software package, IScan, to identify bacterial ISs and their sequence elements—inverted and target direct repeats—in multiple genomes using multiple flexible search parameters. We applied IScan to 438 completely sequenced bacterial genomes and 20 IS families. The resulting data show that ISs within a genome are extremely similar, with a mean synonymous divergence of K_s = 0.033. Our analysis substantially extends previously available information, and suggests that most ISs have entered bacterial genomes recently. By implication, their population persistence may depend on horizontal transfer. We also used IScan's ability to analyze the statistical significance of sequence similarity among many IS inverted repeats. Although the inverted repeats of insertion sequences are evolutionarily highly flexible parts of ISs, we show that this ability can be used to enrich a dataset for ISs that are likely to be functional. Applied to the thousands of genomes that will soon be available, IScan could be used for many purposes, such as mapping the evolutionary history and horizontal transfer patterns of different ISs.     

Selection of primers for optimal taxonomic classification of environmental 16S rRNA gene sequences

Microbial community profiling using 16S rRNA gene sequences requires accurate taxonomy assignments. ‘Universal'' primers target conserved sequences and amplify sequences from many taxa, but they provide variable coverage of different environments, and regions of the rRNA gene differ in taxonomic informativeness—especially when high-throughput short-read sequencing technologies (for example, 454 and Illumina) are used. We introduce a new evaluation procedure that provides an improved measure of expected taxonomic precision when classifying environmental sequence reads from a given primer. Applying this measure to thousands of combinations of primers and read lengths, simulating single-ended and paired-end sequencing, reveals that these choices greatly affect taxonomic informativeness. The most informative sequence region may differ by environment, partly due to variable coverage of different environments in reference databases. Using our Rtax method of classifying paired-end reads, we found that paired-end sequencing provides substantial benefit in some environments including human gut, but not in others. Optimal primer choice for short reads totaling 96 nt provides 82–100% of the confident genus classifications available from longer reads.