Ketonaemia in Uncontrolled Diabetes Mellitus

Blood ketone bodies, serum insulin levels, and plasma free fatty acids were examined in a series of patients with “non-ketotic diabetic coma” and compared with the findings in ketoacidotic subjects. Serum insulin levels in six “non ketotic” patients ranged between 1 and 25 μu./ml. and were not significantly different from levels reported in patients with ketoacidosis. In addition, plasma free fatty acids were shown to be unrelated to the degree of ketonaemia. The investigation shows that neither the levels of serum insulin nor those of free fatty acids can explain the absence of hyperketonaemia in some cases.     

Control of Basal Insulin Secretion,with Special Reference to the Diagnosis of Insulinomas

Estimation of plasma glucose and immunoreactive insulin concentrations in normal subjects after an overnight fast showed that subjects with high basal plasma glucose levels tended to have high plasma insulin concentrations. A similar correlation between glucose and insulin levels was seen in patients with obesity and various endocrine disorders. The suppression of plasma insulin levels associated with hypoglycaemia was used to derive an “amended insulin-glucose ratio,” which appeared to be a good discriminant for the diagnosis of insulinomas. In normal subjects the ratio was less than 30 μU insulin/mg glucose, in obese subjects less than 50 μU/mg, and most of the patients with insulinomas had values over 200 μU/mg.     

Tyrosinosis: a new variant

Abnormalities of tyrosine metabolism are discussed under four headings: (1) accumulation of tyrosine and its metabolites secondary to severe liver damage, vitamin C deficiency, etc.; (2) transient neonatal tyrosinemia; (3) hereditary tyrosinosis with hepatorenal dysfunction where elevation of tyrosine and methionine levels in the plasma may be a secondary manifestation of an unknown disease process; and (4) “essential tyrosinemia” or tyrosinosis without hepatorenal dysfunction which may represent a kkrimary fault in the metabolism of tyrosine.A new case of tyrosinosis without hepatorenal dysfunction in a 13-year-old mentally retarded girl is reported. Clinical findings, laboratory investigations and results of dietary management and normalization of the plasma tyrosine level and of urinary metabolites are presented and compared with the features of three similar cases in the liteature. It is suggested that these cases represent “essential tyrosinemia” where there is a primary genetic defect in tyrosine metabolism.     

Thalassaemia in the British

Different forms of thalassaemia or related disorders were found in 116 people of apparently pure British stock. Among them were one family with a child homozygous for β-thalassaemia and eight heterozygous relatives, 16 families with 83 persons heterozygous for β-thalassaemia, two families with three persons with Hb H disease and three heterozygous for α-thalassaemia 1, one family with a child apparently homozygous for the “silent β-thalassaemia gene,” one family with six members heterozygous for a form of β-thalassaemia intermedia, and three families with 11 members heterozygous for different types of hereditary persistence of fetal haemoglobin. The clinical, haematological, and haemoglobin biosynthetic findings in these persons were similar to those of patients with thalassaemia from other racial groups. The heterozygous state for β-thalassaemia is overlooked in British patients, particularly during pregnancy, because it is not considered in the differential diagnosis of refractory anaemia. In many cases this leads to much unnecessary investigation and potentially harmful treatment.There seem to be several varieties of hereditary persistence of fetal haemoglobin production among British people. These conditions, while not causing anaemia, may cause difficulties during examination of maternal blood for fetal cells and may, if inherited with a β-thalassaemia gene, produce an unusually high level of Hb F in a person heterozygous for β-thalassaemia.     

Onset,Early Stages,and Prognosis of Rheumatoid Arthritis: A Clinical Study of 100 Patients with 11-year Follow-up

One hundred patients with “definite” or “classical” rheumatoid arthritis were followed in a hospital clinic from within one year of the onset of the arthritis. The average interval between onset and first attendance was 3·7 months. Onset was commoner in the winter, transient prodromal symptoms being noted in 23, with possible precipitating factors in 14. The serum rheumatoid factor test was positive at some time in 88.The patients were reassessed between eight and 14 years later. Seventeen died during this period, five possibly as a result of the disease or its treatment.The remaining patients had improved as a whole in terms of the blood sedimentation rate, haemoglobin, titre of the rheumatoid factor test, and status of the disease, but there was an overall deterioration in functional capacity. Both the rheumatoid factor titre and the functional capacity at an earlier review could be directly correlated with the outcome, but other factors were not found to influence the ultimate prognosis.     

U-Shaped Relation between Plasma Oxytocin Levels and Behavior in the Trust Game

Trust underpins much of social and economic exchanges across human societies. In experimental economics, the Trust Game has served as the workhorse for the study of trust in a controlled incentivized setting. Recent evidence using intranasal drug administration, aka ‘sniffing’, suggests that oxytocin (OT) can function as a social hormone facilitating trust and other affiliative behaviors. Here we hypothesized that baseline plasma OT is a biomarker that partially predicts the degree of trust and trustworthiness observed in the trust game. Using a large sample of 1,158 participants, we observed a significant U-shaped relationship between plasma OT with the level of trust, and marginally with the level of trustworthiness, especially among males. Specifically, subjects with more extreme levels of plasma OT were more likely to be trusting as well as trustworthy than those with moderate levels of plasma OT. Our results contribute to a deeper understanding of the biological basis of human trust and underscore the usefulness of peripheral plasma OT measures in characterizing human social behavior. “You must trust and believe in people or life becomes impossible.” Anton Chekhov.     

Circulating Docosahexaenoic Acid Levels Are Associated with Fetal Insulin Sensitivity

Background

Arachidonic acid (AA; C20∶4 n-6) and docosahexaenoic acid (DHA; C22∶6 n-3) are important long-chain polyunsaturated fatty acids (LC-PUFA) in maintaining pancreatic beta-cell structure and function. Newborns of gestational diabetic mothers are more susceptible to the development of type 2 diabetes in adulthood. It is not known whether low circulating AA or DHA is involved in perinatally “programming” this susceptibility. This study aimed to assess whether circulating concentrations of AA, DHA and other fatty acids are associated with fetal insulin sensitivity or beta-cell function, and whether low circulating concentrations of AA or DHA are involved in compromised fetal insulin sensitivity in gestational diabetic pregnancies.

Methods and Principal Findings

In a prospective singleton pregnancy cohort, maternal (32-35 weeks gestation) and cord plasma fatty acids were assessed in relation to surrogate indicators of fetal insulin sensitivity (cord plasma glucose-to-insulin ratio, proinsulin concentration) and beta-cell function (proinsulin-to-insulin ratio) in 108 mother-newborn pairs. Cord plasma DHA levels (in percentage of total fatty acids) were lower comparing newborns of gestational diabetic (n = 24) vs. non-diabetic pregnancies (2.9% vs. 3.5%, P = 0.01). Adjusting for gestational age at blood sampling, lower cord plasma DHA levels were associated with lower fetal insulin sensitivity (lower glucose-to-insulin ratio, r = 0.20, P = 0.036; higher proinsulin concentration, r = −0.37, P <0.0001). The associations remained after adjustment for maternal and newborn characteristics. Cord plasma saturated fatty acids C18∶0 and C20∶0 were negatively correlated with fetal insulin sensitivity, but their levels were not different between gestational diabetic and non-diabetic pregnancies. Cord plasma AA levels were not correlated with fetal insulin sensitivity.

Conclusion

Low circulating DHA levels are associated with compromised fetal insulin sensitivity, and may be involved in perinatally “programming” the susceptibility to type 2 diabetes in the offspring of gestational diabetic mothers.     

Effect of Different Levels of Pressure Relieving Air-Mattress Firmness on Cough Strength

Cough is an important host-defense mechanism. The elderly and patients who are severely ill cannot cough effectively when lying in the supine position. Furthermore, pressure relieving air-mattresses are recommended for preventing the development of pressure ulcers. In this study, we clarified whether or not the cough peak flow (CPF), an index of cough strength, is affected by different firmness levels of a pressure relieving air-mattress in healthy volunteers in the supine position. Fifty-two healthy young men participated. All the measurements were carried out on each participant in the supine position on a pressure relieving air-mattress. The participants were assessed at two firmness levels, a “hard” and “soft” mode. The CPF, forced vital capacity (FVC), maximal expiratory pressure (PEmax), and maximal inspiratory pressure (PImax) were determined for each mode. The sinking distance of the body into the mattress was measured without any activity and the difference between the sinking distances of the two firmness levels was determined. The CPF, FVC, PEmax, and PImax were determined for each mode. The sinking distance of the body into the mattress was measured and the difference between the sinking distances of the two firmness levels was determined. The CPF, FVC, PEmax and PImax values of the participants coughing on the mattress were significantly lower when the mattress was in “soft” than in “hard” mode. The differences between the sinking distances of the mattress in “soft” and “hard” modes were larger for the anterior superior iliac spine. A harder mattress may lead to increased CPF in healthy young men lying in the supine position, and increased CPF may be important for host defense.     

Prospective Antiretroviral Treatment of Asymptomatic,HIV-1 Infected Controllers

The study of HIV-infected “controllers” who are able to maintain low levels of plasma HIV RNA in the absence of antiretroviral therapy (ART) may provide insights for HIV cure and vaccine strategies. Despite maintaining very low levels of plasma viremia, controllers have elevated immune activation and accelerated atherosclerosis. However, the degree to which low-level replication contributes to these phenomena is not known. Sixteen asymptomatic controllers were prospectively treated with ART for 24 weeks. Controllers had a statistically significant decrease in ultrasensitive plasma and rectal HIV RNA levels with ART. Markers of T cell activation/dysfunction in blood and gut mucosa also decreased substantially with ART. Similar reductions were observed in the subset of “elite” controllers with pre-ART plasma HIV RNA levels below conventional assays (<40 copies/mL). These data confirm that HIV replication persists in controllers and contributes to a chronic inflammatory state. ART should be considered for these individuals (ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01025427","term_id":"NCT01025427"}}NCT01025427).     

Variability of NPH Insulin Preparations

In 1968-69 certain juvenile diabetics receiving NPH insulin began having pre-breakfast glucosuria and mid-morning hypoglycemic reactions. A mail survey of our clinic population and a study done at the Quebec camp for diabetic children in 1969 revealed that certain lot numbers were associated with poor control and that a change to new lot numbers or alternate insulin preparations resulted in better control. “Suspect” insulin preparations and non-suspect insulins were given to newly diagnosed diabetics, and plasma insulin and glucose levels were measured over a 24-hour period. The data confirmed that the “suspect” insulins were causing early hypoglycemia and failing to control hyperglycemia during the latter hours of the 24-hour period. The lower glucose levels were associated with higher plasma insulin levels. The “suspect” insulins were further found to have elevated levels of free insulin in the supernatant fluid.The requirements for quality control of modified insulin preparations are reviewed and suggestions are offered for their improvement.     

The Sickle-cell and Altitude

High altitude seemed to be responsible for seven recent cases of sickling crisis. People with sickle-cell trait are at risk if they fly in unpressurized aircraft, which are used for many local air services. Those with sickle-cell haemoglobin C disease should avoid air travel even in pressurized aircraft. Possibly as a result of “autosplenectomy,” patients with sickle-cell anaemia seem to be able to fly in pressurized aircraft with little risk. All passengers and aircrew who might have some form of sickle-cell disease should be screened before flight.     

A Fundamental Trade-off in Covalent Switching and Its Circumvention by Enzyme Bifunctionality in Glucose Homeostasis

Covalent modification provides a mechanism for modulating molecular state and regulating physiology. A cycle of competing enzymes that add and remove a single modification can act as a molecular switch between “on” and “off” and has been widely studied as a core motif in systems biology. Here, we exploit the recently developed “linear framework” for time scale separation to determine the general principles of such switches. These methods are not limited to Michaelis-Menten assumptions, and our conclusions hold for enzymes whose mechanisms may be arbitrarily complicated. We show that switching efficiency improves with increasing irreversibility of the enzymes and that the on/off transition occurs when the ratio of enzyme levels reaches a value that depends only on the rate constants. Fluctuations in enzyme levels, which habitually occur due to cellular heterogeneity, can cause flipping back and forth between on and off, leading to incoherent mosaic behavior in tissues, that worsens as switching becomes sharper. This trade-off can be circumvented if enzyme levels are correlated. In particular, if the competing catalytic domains are on the same protein but do not influence each other, the resulting bifunctional enzyme can switch sharply while remaining coherent. In the mammalian liver, the switch between glycolysis and gluconeogenesis is regulated by the bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2). We suggest that bifunctionality of PFK-2/FBPase-2 complements the metabolic zonation of the liver by ensuring coherent switching in response to insulin and glucagon.     

Comparison of tests for glycated haemoglobin and fasting and two hour plasma glucose concentrations as diagnostic methods for diabetes.

OBJECTIVE--To compare the ability of tests measuring two hour plasma glucose, fasting plasma glucose, and glycated haemoglobin concentrations in predicting the specific microvascular complications of non-insulin dependent diabetes mellitus. DESIGN--Cross sectional and longitudinal analysis of the relation between complications and concomitant results of the three tests. SETTING--Gila River Indian Community, Arizona. SUBJECTS--Pima Indians (cross sectional, n = 960), aged 25 years or above who were not receiving insulin or oral hypoglycaemic treatment at the baseline examination. MAIN OUTCOME MEASURES--Development of retinopathy and nephropathy. RESULTS--Cross sectionally, frequency distributions of logarithms of the three sets of results were bimodal, with the prevalence of retinopathy and nephropathy being, respectively, 12.0-26.7 and 3.9-4.2 times as high above as below cut off points which minimised overlap (two hour plasma glucose concentration 12.6 mmol/l; fasting plasma glucose concentration 9.3 mmol/l; glycated haemoglobin (HbA1c) concentration 7.8%). Longitudinally, each of the three measures of glycaemia significantly predicted the development of retinopathy (P < 0.0001) and nephropathy (P < 0.05). Receiver operating characteristic curves showed that two hour plasma glucose concentration was superior to fasting plasma glucose concentration (P < 0.05) for prevalent cases of retinopathy, but otherwise no variable had a significant advantage for detecting incident or prevalent cases of either complication. CONCLUSIONS--These findings suggest that determination of glycated haemoglobin or fasting plasma glucose concentrations alone may be acceptable alternatives to measuring glucose concentration two hours after challenge with 75 g glucose for the diagnosis of diabetes.     

A Critical Point of Male Gonad Development: Neuroendocrine Correlates of Accelerated Testicular Growth in Rats during Early Life

Testis growth during early life is important for future male fertility and shows acceleration during the first months of life in humans. This acceleration coincides with the peak in gonadotropic hormones in the blood, while the role of hypothalamic factors remains vague. Using neonatal rats to assess this issue, we found that day 9 of life is likely critical for testis development in rats. Before this day, testicular growth was proportional to body weight gain, but after that the testes showed accelerated growth. Hypothalamic kisspeptin and its receptor mRNA levels begin to elevate 2 days later, at day 11. A significant increase in the mRNA levels for gonadotropin-releasing hormone (GnRH) receptors in the hypothalamus between days 5 and 7 was followed by a 3-fold decrease in GnRH mRNA levels in this brain region during the next 2 days. Starting from day 9, hypothalamic GnRH mRNA levels increased significantly and positively correlated with accelerated testicular growth. Triptorelin, an agonist of GnRH, at a dose that had no effect on testicular growth during “proportional” period, increased testis weights during the period of accelerated growth. The insensitivity of testicular growth to GnRH during “proportional” period was supported by inability of a 2.5-fold siRNA knockdown of GnRH expression in the hypothalamus of the 7-day-old animals to produce any effect on their testis weights. GnRH receptor blockade with cetrorelix was also without effect on testis weights during “proportional” period but the same doses of this GnRH antagonist significantly inhibited “accelerated” testicular growth. GnRH receptor mRNA levels in the pituitary as well as plasma LH concentrations were higher during “accelerated” period of testicular growth than during “proportional” period. In general, our data defined two distinct periods in rat testicular development that are primarily characterized by different responses to GnRH signaling.     

Untangling the Influences of Voluntary Running,Environmental Complexity,Social Housing and Stress on Adult Hippocampal Neurogenesis

Environmental enrichment (EE) exerts powerful effects on brain physiology, and is widely used as an experimental and therapeutic tool. Typical EE paradigms are multifactorial, incorporating elements of physical exercise, environmental complexity, social interactions and stress, however the specific contributions of these variables have not been separable using conventional housing paradigms. Here, we evaluated the impacts of these individual variables on adult hippocampal neurogenesis by using a novel “Alternating EE” paradigm. For 4 weeks, adult male CD1 mice were alternated daily between two enriched environments; by comparing groups that differed in one of their two environments, the individual and combinatorial effects of EE variables could be resolved. The Alternating EE paradigm revealed that (1) voluntary running for 3 days/week was sufficient to increase both mitotic and post-mitotic stages of hippocampal neurogenesis, confirming the central importance of exercise; (2) a complex environment (comprised of both social interactions and rotated inanimate objects) had no effect on neurogenesis itself, but enhanced depolarization-induced c-Fos expression (attributable to social interactions) and buffered stress-induced plasma corticosterone levels (attributable to inanimate objects); and (3) neither social isolation, group housing, nor chronically increased levels of plasma corticosterone had a prolonged impact on neurogenesis. Mouse strain, handling and type of running apparatus were tested and excluded as potential confounding factors. These findings provide valuable insights into the relative effects of key EE variables on adult neurogenesis, and this “Alternating EE” paradigm represents a useful tool for exploring the contributions of individual EE variables to mechanisms of neural plasticity.     

The effect of hemolysis on plasma oxidation and nitration in patients with sickle cell disease

Abstract

This study aimed to determine the effect of haemolysis on plasma oxidation and nitration in sickle cell disease (SCD) patients. Blood was collected from haemoglobin (Hb)A volunteers and homozygous HbSS patients who had not received blood transfusions in the last 3 months. Haemolysis was characterised by low levels of haemoglobin and haptoglobin and high levels of reticulocyte, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), plasma cell-free haemoglobin, bilirubin, total lactate dehydrogenase (LDH) and dominance of LDH-1 isoenzyme. Plasma 8-isoprostane, protein carbonyl and nitrotyrosine levels were measured to evaluate oxidised lipids, oxidised and nitrated proteins, respectively. Plasma nitrite–nitrate levels were also determined to assess nitric oxide (NO) production in both SCD patients and controls. Markers of haemolysis were significantly evident in SCD patients compared to controls. Plasma 8-isoprostane, protein carbonyl and nitrotyrosine levels were markedly elevated in SCD patients compared to controls. Linear regression analysis revealed a significant inverse correlation between haemoglobin and reticulocyte counts and a significant positive correlation of plasma cell-free haemoglobin with protein carbonyl and nitrotyrosine levels. The obtained data shows that increased haemolysis in SCD increases plasma protein oxidation and nitration.     

DNA Barcoding and Species Boundary Delimitation of Selected Species of Chinese Acridoidea (Orthoptera: Caelifera)

We tested the performance of DNA barcoding in Acridoidea and attempted to solve species boundary delimitation problems in selected groups using COI barcodes. Three analysis methods were applied to reconstruct the phylogeny. K2P distances were used to assess the overlap range between intraspecific variation and interspecific divergence. “Best match (BM)”, “best close match (BCM)”, “all species barcodes (ASB)” and “back-propagation neural networks (BP-based method)” were utilized to test the success rate of species identification. Phylogenetic species concept and network analysis were employed to delimitate the species boundary in eight selected species groups. The results demonstrated that the COI barcode region performed better in phylogenetic reconstruction at genus and species levels than at higher-levels, but showed a little improvement in resolving the higher-level relationships when the third base data or both first and third base data were excluded. Most overlaps and incorrect identifications may be due to imperfect taxonomy, indicating the critical role of taxonomic revision in DNA barcoding study. Species boundary delimitation confirmed the presence of oversplitting in six species groups and suggested that each group should be treated as a single species.     

Androgen Function in “Psychogenic” and “Constitutional” Types of Impotence

Androgen function was studied in twenty-five physically healthy “primarily” impotent males classified on clinical criteria into “psychogenic” or “constitutional” groups. The mean urinary testosterone level in the former was significantly higher than in the latter group (P<0·005). Important variables associated significantly with higher urinary testosterone levels (P<0·05) were (a) “late onset” impotence, (b) shorter duration than two years, (c) stronger “sex drive,” and (d) an alternative sexual outlet to orgasm and ejaculation in the three months preceding referral; the last-mentioned appeared to be the single most important discriminatory feature.It is suggested that testosterone excretion patterns—namely, high, average, and low—may be one method of classifying impotence.     

Comparative Study of the Absorption,Plasma Levels,and Urinary Excretion of the “New” and the “Old” Lanoxin

A comparative study was performed of the absorption, the plasma level at equilibrium, and the urinary excretion of digoxin using two types of Lanoxin tablets, those produced before and after the 1972 alteration of the tablet manufacture.After a single dose the absorption rate of the new tablets was about twice as great as the old, both in young subjects and in the elderly patients. There were no significant differences in the plasma levels of digoxin for the two tablets 15 hours after the last administration in patients on an equal maintenance dose. The urinary excretion of digoxin increased about 40% when the “old” Lanoxin was replaced by the “new.” In elderly patients a daily dose of 0·125 mg twice daily of the new tablets should be sufficient to reach the therapeutic range. Young people need a higher dosage. If the kidney function is reduced by as much as 50% the dose should be reduced.     

On the persistence of memory: Soft clocks and terrestrial biosphere-atmosphere interactions

The circadian clock is considered a central “orchestrator” of gene expression and metabolism. Concomitantly, the circadian clock is considered of negligible influence in the field and beyond leaf levels, where direct physiological responses to environmental cues are considered the main drivers of diel fluctuations. I propose to bridge the gap across scales by examining current evidence on whether circadian rhythmicity in gas exchange is relevant for field settings and at the ecosystem scale. Nocturnal stomatal conductance and water fluxes appear to be influenced by a “hard” clock that may override the direct physiological responses to the environment. Tests on potential clock controls over photosynthetic carbon assimilation and daytime transpiration are scant yet, if present, could have a large impact on our current understanding and modeling of the exchanges of carbon dioxide and water between terrestrial ecosystems and the atmosphere.