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The current study parsed out the distinct components of attention-deficit/hyperactivity disorder (ADHD) symptomatology to examine differential relations with language and social ability. Using a research domain criteria (RDoC) framework, we administered standardized tests and previously developed and validated questionnaires to assess levels of inattention and/or hyperactivity/impulsivity symptomatology, language, social responsivity and social competency in 98 young adults. Those with higher inattention and/or hyperactivity/impulsivity symptomatology had reduced language comprehension, social responsivity, and social competency. Inattention and hyperactivity/impulsivity both predicted language comprehension, but not language production. Interestingly, inattention uniquely contributed to social responsiveness and social competency, but hyperactivity/impulsivity did not. Findings suggest that inattention and/or hyperactivity/impulsivity symptoms, inattention in particular, may be especially important for social skills programs geared towards individuals with attention limitations.

Background: Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) show high rates of comorbidity. Restricted interests and repetitive behaviors (RRBs) are a core symptom of ASD and commonly occur in ADHD. However, little is known about how RRBs manifest in ADHD, nor how they relate to cognitive abilities and sex across these disorders. Methods: This study investigated the joint factor structure of RRBs in a large sample of children with ASD and ADHD using (1) exploratory factor analysis, and (2) analysis of factorial invariance across diagnostic status (ASD versus ADHD). Subsequently, relations for these factors with sex and IQ were evaluated. Children (N=1,082; 78% male) were identified with primary diagnoses of ASD (n=634) or ADHD (n=448). RRBs were measured using the Repetitive Behavior Scale-Revised (RBS-R). Results: A 4-factor solution provided the best fit to the data and yielded four psychologically meaningful factors, including (1) Stereotypy, (2) Self-Injury, (3) Compulsions, and (4) Ritualistic/Sameness. The four-factor solution was equivalent across diagnostic status, as imposition of weak (△RMSEA=.001) and strong (△RMSEA=.003) invariance did not significantly diminish model fit. IQ was negatively associated with Stereotypy, Self-Injury and Compulsions in ASD, and negatively associated with Compulsions and Ritualistic/Sameness behaviors in ADHD. A main effect of sex on Self-Injury was observed, whereby females displayed higher levels of Self-Injury in ASD but not ADHD. Conclusions: Our results underscore a common 4-factor structure across ASD and ADHD, which simplifies prior models of the RBS-R and indicates a similar pattern of occurrence of RRBs across these disorders.

Scientists often turn to farmers to understand soil management. This process reveals differences and overlaps between local and scientific soil knowledge but rarely considers women and gender issues. This paper examines men's and women's local knowledge of soils in upland, smallholder farms in two villages in Mindanao, the Philippines, using focus group discussions, semi-structured household interviews, field visits, GIS and soil testing. Farmers' field areas were calculated and delineated based on their perceptions of the different types of soils on their land. Men and women chose the same plots for what they considered their best soil but differed on what they felt were their worst. The fertility of the soils that women considered to be the best and worst was not significantly different from that of the men's respective choices. There was a difference in fertility, however, between the best and worst soils regardless of gender. Although soil fertility analyses showed that the women's chosen soils were similar to men's, analyses of qualitative data showed that their knowledge of soils was different and was based in part on a gendered division of labour. A multidisciplinary approach helped bridge the gap between sociocultural and physical research.

This research identifies gender-based constraints and opportunities for the adoption of conservation agriculture production systems based on a case-study with smallholder farmers in two villages in Misamis Oriental, Northern Mindanao, Philippines. Using a livelihoods framework, we explore gendered dimensions of access to assets or resources, agricultural practices, and knowledge and perceptions in the context of food security and soil conservation. Our mixed methods approach includes focus group discussions, household interviews, participatory mapping, and GPS mapping. We found that men and women have different access to assets, gender roles, and soil perceptions that could have implications for whether farmers adopt conservation agriculture (CA) in the Philippines. This paper also discusses how development activities like CA could affect gender relations in a site-specific context and provides recommendations for increasing gender equity and the likelihood of adoption.

One important aspect of insulin drug development is to ascertain that short-acting insulins mimic the normal mealtime insulin release in healthy subjects. Therefore, it is important to identify metrics that allow identification of unique characteristics of insulin products based on pharmacokinetic (PK) (time-concentration) or glucodynamic (time course of action) profiles. Current development programs use metrics such as "onset of action" to characterize insulin products, in addition to peak and area under the curve parameters for PK and glucodynamic profiles. However, in current practice, onset of action parameter is often interchangeably used with rate of action for insulin products, which points to existence of confusion about their definitions and methods of determination. In this paper, we discuss these two parameters with an underlying objective to prompt discussion on development of a quantitative standard for insulin products based on the onset and/or rate of action. This paper presents euglycemic clamp and meal challenge study data using a hypothetical insulin product and attempts to clear confusion by emphasizing on the distinct properties of these parameters.

All medications currently approved by the Food and Drug Administration (FDA) for the treatment of type 2 diabetes mellitus are indicated to improve glycemic control. Since 1995, FDA has used HbA1c as the primary basis for approval of these therapies because a reduction in blood glucose lessens the symptoms of hyperglycemia and lowering of HbA1c has been shown to reduce the risk for some of the chronic complications of diabetes. Despite evidence of clinical benefit with therapies that reduce HbA1c, concerns have been raised that some diabetes medications may increase cardiovascular risk in a patient population that is already vulnerable to cardiovascular disease. Therefore, FDA convened a public advisory committee meeting to discuss the role of cardiovascular assessment in the pre-approval and post-approval settings for medications developed for the treatment of type 2 diabetes. After considering the advisory panel’s recommendations and other data, FDA published a guidance document requesting evidence showing that new treatments for type 2 diabetes do not result in an unacceptable increase in cardiovascular risk. This review article begins by summarizing the events leading up to publication of this guidance. Subsequent sections discuss the guidance itself as well as general considerations for implementing the new cardiovascular recommendations. The new approach to developing medications for the treatment of type 2 diabetes will lead to evaluation in patients more representative of those who will use these therapies, if approved, and will help healthcare providers make informed decisions when choosing a medication within the growing treatment armamentarium for type 2 diabetes.

On January 25, the FDA approved liraglutide, a glucagon-like-peptide-1 receptor agonist that can improve glycemic control in adults with type 2 diabetes. Drs. Mary Parks and Curtis Rosebraugh discuss the benefits and potentially serious safety concerns associated with this new therapy.

Publisher Summary This chapter deals primarily with drug development in the United States. Biologics and medical devices are regulated somewhat differently, but most rules, practices, and principles are similar. It focuses on the Center for Drug Evaluation and Research (CDER) and the drug regulatory environment. The Office of New Drugs (OND) within CDER has primary regulatory responsibility for review and approval of all drugs and therapeutic biologics in the United States. This includes not only approval of new products, but also applications for expanded indications and new formulations of existing products. The Food and Drug Administration (FDA) plays a key role in determining whether a medical product is safe for testing in humans and whether the product is safe and effective for initial and continued use as a marketed therapy for patients in the United States. In addition, the FDA provides critical input and actively guides development of medical products throughout their life cycle. The FDA publishes general and drug-class specific guidance documents, has meetings with manufacturers at key time points during product development, and provides feedback on the appropriateness of study protocols and other scientific and regulatory aspects related to investigational products under development.

Maintenance of blood volume and pressure that is adequate for perfusion of vital body tissues and organs is crucial for the survival of organisms during periods of acute stress, such as critical illnesses. As might be expected of such important functions, many complex and overlapping physiological defense mechanisms have evolved to defend body fluid homeostasis during such periods. The efficacy of these mechanisms is attested to by the fact that derangements of body water and electrolytes do not occur even more frequently during disease states. Nonetheless, hypo- and hypernatremia represent the most common electrolyte disorders encountered in clinical practice today, and in order to understand both the pathogenesis and the appropriate therapy of these disorders in critically ill patients, it is crucial to understand body water metabolism and its disorders, since this accounts for the major part of regulation of the concentration in the extracellular fluid and blood. This chapter briefly summarizes the normal regulation of body water and then reviews in greater detail specific disorders associated with disruption of this normally finely tuned system for maintaining body fluids at physiologically appropriate volumes and solute concentrations.

Na+- and K+-dependent adenosine triphosphatase [(Na+ + K+)-ATPase] was studied in microdissected samples from sections of histologically active and inactive plaques of multiple sclerosis. In active plaques the enzyme was found to be markedly reduced in activity, whereas in old, chronic plaques ATPase activities were higher than those of unaffected white matter. White matter from control patients and normal-appearing white matter from MS patients did not differ with regard to ATPase activities. The results suggest that reversible changes in the sodium pump mechanism may be involved in the pathophysiology of multiple sclerosis.

— Sensitive micromethods were used to study the plaques, adjacent white matter and remote, grossly normal white matter from two cases of multiple sclerosis and to compare them with white matter from normal controls. Lipid-free dry wt/unit of volume was found to be similar for plaques and for normal white matter, reflecting a high water content of plaque tissue and establishing a base for comparison of enzyme activities. Elevations of acid proteinase in and around plaques were confirmed, but they were far exceeded by the increases in acid phosphatase; other acid hydrolases (β-galactosidase, β-glucuronidase and dipeptidyl arylamidase II) showed no significant or consistent changes. However, an acid lipase-esterase hydrolysing 4-methylumbelliferyl oleate was about 30% as active in plaques as in normal-appearing white matter. Glucose-6-phosphate dehydrogenase was unchanged except in one plaque, but lactic dehydrogenase was markedly elevated both in plaques and adjacent white matter. The grossly normal white matter of MS patients, although histologically far from normal (showing gliosis, perivascular infiltrations and small plaques), did not differ significantly from controls with regard to the activity of any of the enzymes studied. DNA levels were much reduced in plaques, but comparisons were difficult because of the apparent gliosis in normal white matter. Decreases in dry wt/unit vol, reflecting partial demyelination, could be shown to extend in a gradient to a distance of about 2 mm. from the edge of certain plaques.

— A thiol dependent proteolytic enzyme (tentatively identified as carboxypeptidase B) which liberates phenylalanine from CBZ-glutamyl-phenylalanine at pH 5.3 was shown, by a sensitive micromethod, to be greatly increased in activity in and around MS plaques. These increases exceeded those of other hydrolases previously measured. Plaque tissue, on the basis of lipid-free dry weight, is up to 3-fold richer in this enzyme than control white matter, and most samples of apparently uninvolved MS white matter already show elevated activities. The enzyme is highly dependent on the presence of dithiothreitol. It is unaffected by diisopropyl fluorophosphate and pepstatin, but inhibited by iodoacetate and leupeptin. Macrophages or lymphocytic infiltrations in the tissue do not appear to be the main source of the enzyme. In conjunction with measurements of DNA, reflecting gliosis, invasion by hematogenom cells and proliferation of phagocytes as well as oligodendrocyte loss, and acid lipase-esterase, indicative of the survival or degeneration of oligodendrocytes, these results are interpreted as probably reflecting predominantly the activity of astrocytes. The incidental finding that most samples of unaffected white matter from MS patients contain more DNA per unit lipid free dry weight than average control white matter is considered significant in pointing to more widespread tissue changes independent of or preceding plaque formation.

A new, fluorometric method was used to assay acid proteinase in tissue samples at great sensitivity. Digestion of hemoglobin at pH 3.8 (in brain mostly due to cathepsin D) was measured in individual nerve cell bodies and neuropil from the anterior horn of the spinal cord, and in the molecular and granular layers and while matter of cerebellum, in man and in monkey. Anterior horn cell perikarya were about 25 times more active than neuropil, and the granular layer of cerebellum had about three times the activity of the molecular layer. This predominantly neuronal localization resembles the distribution of other lysosomal hydrolases. The high capacity for protein breakdown found in neurons is in accord with their known high rates of protein synthesis and turnover.

Determinations of NAD-ase activities by the alcohol dehydrogenase method show that the enzyme activity in rat liver cell mitochondria is approximately 30 times greater than in Ehrlich-Lettre carcinoma cell mitochondria; and the NAD-ase activity of liver cell sap is 8–10 times greater than in the carcinoma cell sap. The addition of liver cell mitochondria to tumor cell sap greatly reduces the glycolysis of the cell sap. Furthermore, nicotinamide when added to the liver mitochondria-cell sap system causes a threefold increase in glycolysis. The data suggests that NAD-ase has a controlling action on glycolysis of liver and Ehrlich carcinoma cell particulates.

A number of fluorometric assays of hydrogen peroxide-producing oxidases are based on the formation of highly fluorescent products from homovanillic acid or related compounds by horseradish peroxidase. We report the observation that under continuous uv illumination at the wavelengths used for excitation in these methods, brain or muscle homogenates produce fluorescence increases in the absence of any exogenous enzyme substrate; when uv light is excluded, such increases are negligible. Arachidonic and linolenic acids also produce this effect. For this reason, measurements of H2O2 based on this principle are valid only if this nonspecific effect has been excluded, and should preferably be carried out as end-point rather than continuous assays. It is believed that the effect of uv light on the reaction is due to formation of H2O2 and/or oxygen free radicals, and polyunsaturated lipids appear to be involved as intermediates. Thus, the homovanillic acid-horseradish peroxidase system may prove useful in investigations of the effect of uv on the production of oxygen free radicals and lipid peroxidation.

Protein profiles of sarcolemma from primary cultures of normal adult rat skeletal muscle are presented. Sarcolemma was obtained by high-velocity gas dissection which yields small amounts of membranes of great purity. A micromethod for SDS—polyacrylamide gel electrophoresis combined with the use of a silver stain permits analysis of samples containing as little as 2 μg protein. The approach should prove useful for the study of possible membrane protein abnormalities in the muscular dystrophies.

3-Hydroxyacyl-CoA dehydrogenase (HAD) has been widely used to assess the capacity for fatty acid oxidation by different muscle fiber types, with various Krebs cycle enzymes as a base for comparison. We have measured this enzyme in individual lyophilized fibers of the guinea pig soleus and the white and red portions of the vastus lateralis, and compared its activity in each fiber with that of lipoamide dehydrogenase (LAD), which as a part of the pyruvate dehydrogenase complex fulfills a function similar to HAD in forming acetyl-CoA, but from pyruvate and, thus, mainly from a carbohydrate source. The mean HAD/LAD ratio was 17.2 +/- 3 in the red vastus, 24.9 +/- 3 in the white vastus, and 43.7 +/- 10 in the soleus, all differences being highly significant. The two types of fast fibers were not distinguished from one another by the enzyme ratio within either the white or the red portion of the vastus lateralis. Data from all of the fast fibers taken together indicate a close correlation (0.93) between the two enzymes, whereas values from the soleus indicate a specialization of the mitochondria of the slow muscle fibers for the oxidation of fatty acids.

—In Lewis rats with experimental allergic encephalomyelitis (EAE), quantitative histochemical techniques were used to measure the activities of several hydrolytic enzymes, especially acid proteinases, and their levels were correlated with the concentrations of DNA and total lipids. Only those samples which contained lesions (visualized directly or in stained nearby sections) had elevated acid hydrolase activities. A lipase-esterase hydrolysing a fluorogenic substrate at pH 5.0 was more active in lesions; activity on the same substrate at pH 7.2 was not elevated. β-Glucuronidase rather than acid proteinase or cathepsin D was the enzyme showing the greatest differences. In a monkey with EAE, studied for comparison, a massive inflammatory lesion appeared to leak β-glucuronidase to a distance of about 2.5 mm beyond its margin.

Recent work has implicated plasminogen activator released from macrophages as a possible mediator of the demyelinating process in experimental allergic encephalomyelitis and multiple sclerosis (MS). We have studied the capacity of white matter and plaques from MS patients to break down fibrin clots, using a histochemical technique. Fibrinolytic activity was localized exclusively to areas around blood vessels and capillaries in both patients and controls. While there was marked variation between individuals, the unaffected white matter from MS patients was, on the average, not more active than that of controls, but plaques tended to show more numerous foci of lysis, often also more intense, than adjacent white matter; there was no correlation with disease activity or age of the plaques as determined by histological criteria. The localization and degree of fibrinolysis observed were not related to the presence of lymphocytic infiltrates, gliosis, or macrophages. However, the findings do not exclude an involvement of fibrinolytic enzymes (although originating from vascular endothelium rather than macrophages) in the genesis of the MS plaque, which commonly starts around a small vein.

— The localization of an acid lipase-esterase which cleaves the fluorogenic substrate 4-methyl-umbelliferyl oleate at pH 5 was studied, because previous experiments has shown this activity to be reduced in the plaques of multiple sclerosis. In the human cerebellum, quantitative histochemical methods showed the activity to be relatively low in the molecular layer, compared to the granule cell layer; but the underlying white matter was the most active. In the human spinal cord, anterior horn cell bodies were richest in acid lipase, but white matter was, on a dry weight basis, as active as neuropil. Oligodendrocytes obtained in bulk from bovine white matter according to Poduslo & Norton (1972) had a specific activity up to 20 times greater than the crude myelin fraction. While it remains possible that in myelin the enzyme is in an inactive or inhibited state, the results indicate that the enzyme is localized in oligodendroglial cell bodies and suggest its use as a marker.

MULTIPLE SCLEROSIS (MS) is a neurological disease of unknown aetiology which involves the destruction of central nervous system myelin1. Although recent results have implicated a possible viral agent2,3, the search continues to identify an antigen which might provoke a postulated autoimmune reaction4. Such a role has been suggested not only for proteins, but recently also for myelin glycolipids, particularly galactocerebroside5,6. However, to demonstrate immunological reactions against lipid antigens presents special problems: solubility, accessibility of reactive groups, the anticomplementarity of many lipids and the requirement for auxiliary lipids, lecithin and cholesterol7. We have used a model membrane system which obviates these difficulties to survey sera from MS patients for reactivity against crude extracts of white matter lipids as well as various glycolipids. This test demonstrated antibodies reacting against cerebrosides, gangliosides and white matter lipids in some of the MS sera tested, but reactions against digalactosyl diglyceride (an α-galactoside) were more frequent, and were found more often in MS patients than in normal controls, or those with other neurological diseases.

An increase in the carbon dioxide tension of the body fluids is accompanied by an increase in the concentration of bicarbonate bound base, a fact which minimizes the change in pH that would otherwise ensue (1, 2). A priori, it is evident that an elevated plasma bicarbonate concentration can be maintained only by enhancement of the rate of renal tubular reabsorption of bicarbonate. That such enhancement occurs in response to acute respiratory acidosis has been established by experiments performed in our laboratory as well as in other laboratories (3-5). It has also been shown that the elevated pCO2, and not the change in pH, is the stimulus responsible for enhancing this tubular activity.

Lactate dehydrogenase X, a sixth LDH isozyme in testes and mature sperm, has been purified to homogeneity from adult mouse testes. The isozyme has a molecular weight of 139,000 ± 6000. Dissociation of the molecule with 6 m guanidine produced a homogeneous material with mol wt 37,700 ± 800. Pyruvate at 37 ° was reduced optimally at about pH 7.25 and a concentration of 0.25 m m . Alpha-ketobutyrate has an optimum pH of 7.75 and concentration of 0.5 m m for reduction with a rate about 50% greater than that of pyruvate. Alpha-ketoglutarate has an optimum pH of about 5.5 and is reduced at only about one-fourth the rate of pyruvate. Pyruvate reduction is considerably inhibited by 2.5 m m lactate. Alpha-hydroxybutyrate and α-hydroxyvalerate are oxidized at about the same rate and under similar optimum conditions as lactate. Alpha-hydroxyglutarate is oxidized at only about one-twentieth the rate of lactate.

Glycolytic intermediates have been determined in whole tumor and tumor cells, before and after washing, at intervals of time after glucose and glucose plus iodoacetate (IAA) addition to washed tumor cells. The influences of IAA on glycolysis and respiration have been determined on washed mitochondria plus cell sap. The effects of added α-glycerophosphate (α-GP), pyruvate, and both on glycolytic intermediates and respiration of washed whole cells and of mitochondria plus cell sap also have been determined, and the oxidation of α-GP and appearance of dihydroxyacetone phosphate (DHAP) were measured in five-times washed mitochondria. The findings definitely show that the addition of an optimum amount of iodoacetate to either whole cells or mitochondria plus cell sap causes an increased accumulation of DHAP and α-GP, as well as pyruvate, which in turn is responsible for a stimulation of respiration.