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Impaired DNA crosslink repair leads to Fanconi anemia (FA), characterized by a unique manifestation of bone marrow failure and pancytopenia among diseases caused by DNA damage response defects. As a germline disorder, why the hematopoietic hierarchy is specifically affected is not fully understood. We find that reprogramming transcription during hematopoietic differentiation results in an overload of genotoxic stress, which causes aborted differentiation and depletion of FA mutant progenitor cells. DNA damage onset most likely arises from formaldehyde, an obligate by-product of oxidative protein demethylation during transcription regulation. Our results demonstrate that rapid and extensive transcription reprogramming associated with hematopoietic differentiation poses a major threat to genome stability and cell viability in the absence of the FA pathway. The connection between differentiation and DNA damage accumulation reveals a novel mechanism of genome scarring and is critical to exploring therapies to counteract the aplastic anemia for the treatment of FA patients.

Antioxidants are molecules that restrain the process of oxidation. Anti-mutagens are the medium to prevent any DNA transformation. Irreversible DNA damage is caused by mutagens and carcinogens. Defective metabolism occurs due to oxidative stress which can be avoided by antioxidants. The tumour causing ability of nitrosamines, which is commonly referred as chemical carcinogenesis, is been associated with oxidative stress. Several herbals, which play a significant role as anti-oxidants and as medium to inhibit oxidative stress are summarised in this article. The defective metabolism of Reactive Oxygen Species (ROS) which is the scenario linked with cellular disorder due to oxygenate function is prevented by the active participation of antioxidants. The article provides a better platform to review the importance of antioxidants, anti-mutagens and anti-carcinogens. As DNA is the main part of a living being, any damage to its structure and cleavage results in serious disorder and hence focussing on DNA protection, their role is primarily highlighted.

The year 2015 has seen great progress in the renal fibrosis field, as key studies began to build a consensus on the importance of epithelial-to-mesenchymal transition, cell cycle arrest, and defective metabolism in the pathogenesis of kidney fibrosis. New findings also point to a role of developmental signalling in renal fibrogenesis.

Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder characterized by bilateral renal cyst formation. The disease is caused by mutations in either the PKD1 or the PKD2 gene. Progress has been made in understanding the molecular basis of the disease leading to the general agreement on ADPKD being a loss-of-function disease. Identification of signalling cascades dysfunctional in the cystic epithelia has led to several pre-clinical studies of animal models using a variety of inhibitors to slow disease progression. These were followed by clinical trials, some of which generated promising results, although an approved therapy is still lacking. Here, we summarize and discuss recent work providing evidence that metabolic alterations can be observed in ADPKD. In particular, we will focus our discussion on the potential role of glucose metabolism in the pathogenesis of ADPKD. These recent findings provide a new perspective for the understanding of the pathobiology of ADPKD and open potential new avenues for therapeutical approaches. At the same time, these studies also raise important and intriguing biological and medical questions that will need to be addressed experimentally prior to embracing a more enthusiastic view of the applicability of the results.

The principal health outcome of exposure to toluene is dysfunction of the central nervous system. Effects range from fatalities and severe neurological disorders in toluene abuse situations to deficits in neurobehavioral function in occupational populations. An Inhalation Reference Concentration (RfC) of 0.4 mg toluene/m3 or 0.1 ppm was developed by the U.S. EPA to protect general populations chronically exposed to toluene. The RfC was derived from results of an occupational study involving Asian workers who developed neurobehavioral deficits at a mean toluene exposure level at the time of the study of 88 ppm. The derivation incorporated several uncertainty factors, one of which was a factor of 10 to account for sensitive subpopulations. Recent evidence indicates that some Japanese and possibly other Asian populations harbor a defective gene for aldehyde dehydrogenase, and thus exhibit a decreased rate of toluene metabolism. Although it is not known if reduced metabolism by aldehyde dehydrogenase also was a factor in the occupational study, preshift blood levels of toluene were considerably higher than preshift levels from non-Asian workers exposed to similar air levels of toluene. The elevated blood levels are consistent with defective metabolism but remain to be confirmed. Inasmuch as air levels of toluene in urban environments are about 10-fold lower than the RfC, an adequate measure of protection is afforded by the RfC with or without an uncertainty factor for sensitive subgroups. However, the uncertainty factor for sensitive subgroups should be retained because there is no information regarding toluene metabolism in children.

To assess the usefulness of newborn mass screening by ESI-MS/MS in Japan, an acylcarnitine analysis of blood spots on filter paper from collected from newborn infants at the age of 5 days was retrospectively conducted on 18 cases of inherited metabolic diseases that had already been diagnosed. The patients had organic acid disorders in 8 cases, fatty acid oxidation disorders in 7 cases, and amino acid disorders in 3 cases. The time of onset was from 0 days to 1 year 8 months of age. In 16 out of the 18 cases studied, it was confirmed that the analysis of the blood spots on filter paper collected during the newborn period could detect disorders. One case each of CPT-2 deficiency and citrin deficiency could not be detected in the newborn period. Regarding CPT-2 deficiency, the establishment of sufficient nutrition might have interfered with the detection of the disorder because the blood was collected at 5 days of age. The disorders occurred within 1 week after birth in 4 out of 18 cases, 2 of which died at an early stage. Among 13 cases in which the disorders occurred after 1 month, 10 cases were caused by defective metabolism due to infections. The prognoses of inherited metabolic diseases that occur in the early newborn period are limited. However, this study suggests that prognoses of metabolic disorders that occur after the newborn period can expect to be improved by early detection.

HDL protects against atherosclerosis development. Defective functioning of HDL in type 2 diabetes may be one cause of increased cardiovascular disease associated with type 2 diabetes. HDL modulates LDL oxidation through the action of paraoxonase-1 (PON1), which is one of the major mechanisms by which HDL is antiatherogenic. We have compared the ability of HDL from people with type 2 diabetes (n = 36) with no coronary heart disease (CHD) to metabolize oxidized palmitoyl arachidonyl phosphatidylcholine (ox-PAPC), a major product of LDL oxidation and a PON1 substrate, with that of HDL isolated from healthy control subjects (n = 19) and people with CHD but no diabetes (n = 37). HDL from people with type 2 diabetes metabolized 11% less ox-PAPC, and HDL from people with CHD metabolized 6% less, compared with HDL from control subjects (both P < 0.01). The ability of HDL from control and type 2 diabetic subjects containing the PON1-192RR alloform to metabolize ox-PAPC was significantly reduced compared with PON1-192QQ or QR genotypes (P < 0.05). The defective ability of HDL to metabolize ox-PAPC was reflected in a significant increase in circulating plasma oxidized LDL concentration in the two patient groups (37 ± 5, 53 ± 7, and 65 ± 7 mmol/l for control, CHD, and type 2 diabetic subjects, respectively; P < 0.001), with PON1-192RR genotype carriers having the highest concentrations. In the control group, there was a significant negative correlation between serum PON1 activity and oxidized LDL concentration (r = 0.856, P < 0.001); however, this correlation was not evident in the patient groups. HDL from type 2 diabetic subjects without CHD had a decreased ability to metabolize oxidized phospholipids, which could lead to increased susceptibility to develop cardiovascular disease.

Several studies have implicated altered poly(ADP-ribose) metabolism in the disease systemic lupus erythematosus (SLE). For example, circulating antibodies to poly(ADP-ribose) (1, 2) and poly(ADP-ribose) polymerase (3) have been reported in patients with SLE. In addition, Sibley et al. (4) have reported a 70 percent decrease in the accumulation of ADP-ribose polymers of peripheral blood lymphocytes of patients with SLE. We have confirmed this finding and report here studies on the mechanism of this defective metabolism.

Simultaneous covalent conjugation and cleavage of aspartyl peptides observed in model experiments may give an explanation of some aggregative phenomena in defective metabolism as well as of decomposition during processing and storage of peptides and proteins.

A defective metabolism of collagen fibrils is the suspected cause of juvenile hyaline fibromatosis (JHF), a rare autosomal recessive disorder characterized by multiple skin tumors, hypertrophic gingivae, flexion contractures and osteolytic bone lesions. All these sites predominantly harbor type-I (TIC) and type-III (TIIIC) collagens. Therefore we analyzed fibroblasts from macroscopically normal, biopsied skin of a JHF patient and a normal individual for markers of TIC and TIIIC metabolism, i.e. propeptides PICP (TIC synthesis), ICTP (TIC degradation) and PIIINP (TIIIC metabolism). All experiments were done in triplicates using cell number-matched supernatants. Data are given as mean μg/flask. Both PICP and ICTP were significantly higher in JHF (24,I and 0,516) than in the controls (12,6 and 0,324), but their ratio remained unchanged, indicating an accelerated yet balanced TIC metabolism. PIIINP was markedly decreased in JHF (1,05 vs. 1,65), being reduced by 50% relative to TIC. The diminished stability of collagen molecules in JHF might be explained by reduced enzymatic removal of these TIIIC-terminal propeptides, which is necessary for regular crosslinking of collagen fibrils. We suggest that the increased TIC turnover, as well as the exessive production of extracellular matrix as observed previously in histological investigations of JHF tissues, are secondary effects of an upset TIIIC metabolism instrumentally involved in the pathogenesis of this disease.

Methylmalonate metabolism was investigated in fibroblasts and leukocytes of two unrelated patient with a B12-nonresponsive type of congenital methylmalonic acidemia. Intact fibroblasts from both patients showed a defective metabolism of methyl-14 c-malonate to 14CO2, whereas no such defect was found in their intact peripheral leukocytes. In disrupted fibroblasts, the conversion of methylmalonyl coenzyme A to succinyl coenzyme A was markedly reduced but was completely normalized by the addition of 5'-deoxyadenosylcobalamin (AdoCb1; 10(-5) mol/l), the specific coenzyme of methylmalonyl coenzyme A mutase. Assays with decreasing concentrations of AdoCbl (10(-5)-10(-11) mol/l) suggested a reduced affinity of the mutase apoenzyme for its coenzyme, implicating yet another variant of this heterogeneous disease.

A disorder of platelet function was found in 7 members belonging to 3 generations of a family with a mild bleeding tendency. Only the platelet aggregation with arachidonate was deficient. Other inducers gave normal platelet responses. The metabolism of arachidonic acid by the platelets could be investigated in one proband. A defect suggesting a cyclo-oxygenase deficiency was found. The results indicate that the metabolites of arachidonate cannot be directly involved in the transmission of stimuli causing platelet aggregation, at least not under all conditions.

Fibroblasts from a patient with B 12 responsive methylmalonicaciduria and from a second patient with methylmalonicaciduria plus abnormal sulfur amino acid metabolism were examined for their ability to accumulate the two B 12 coenzymes, deoxyadenosyl-B 12 ∗ and methyl-B 12 , and for N 5 -methyltetrahydrofolate homocysteine methyltransferase activity. Cells from the first patient accumulated very little deoxyadenosyl-B 12 but accumulated methyl-B 12 normally. His cells had normal methyltransferase activity when assayed with and without added methyl-B 12 coenzyme. In contrast, cells from the second patient accumulated neither coenzyme. Methyltransferase activity was very low when assayed without added methyl-B 12 but increased markedly when coenzyme was added. We conclude that both patients have primary defects in vitamin B 12 metabolism and that these defects are biochemically distinct.

Parkinson's disease (PD) has been proposed to result from the interaction of aging and environment in susceptible individuals. Defective metabolism of debrisoquine, inherited as an autosomal recessive, has been associated with this susceptibility. In 35 PD patients and 19 age-matched controls, no significant differences in debrisoquine metabolism were found, although a trend to impaired metabolism was noted in patients with disease onset less than or equal to 40. Foci of PD patients were associated with rural living and well water drinking, or rural living coupled with market gardening or wood pulp mills. In a questionnaire survey, patients with PD onset less than or equal to age 47 were significantly more likely to have lived in rural areas and to have drunk well water than those with onset greater than or equal to age 54 (p less than or equal to 0.01). Because of population mobility in North America, a case-control study designed to test environmental, occupational, dietary and other proposed risk factors for PD was conducted in China, where the population is more stationary and the environment more stable. No significant differences in incidences of head trauma, smoking or childhood measles were found between patients and controls.

Eight healthy volunteers received oral metoprolol 200 mg once daily for a week. The AUC, half-life and duration of beta-adrenoceptor blockade on day 7 was much greater in two subjects than in the remaining six. This suggested that the metabolism of metoprolol was impaired in two and the effect was therefore prolonged. Subsequent testing of oxidation phenotype with oral debrisoquine showed that the subjects with high metoprolol availability were also poor hydroxylators of debrisoquine. The urinary debrisoquine/4-hydroxydebrisoquine ratio was highly correlated with metoprolol AUC, half-life and beta-adrenoceptor blockade at 24 h. Thus patients with a genetic defect in drug oxidation, when treated with metoprolol, are likely to have high plasma concentrations and a prolonged effect.

Since several metabolites and analogues of vitamin D have become available, their physiological and therapeutic potential have been studied in various disorders of mineral metabolism, particularly those classically termed vitamin D-resistant. In some instances this resistance appears to be due to defective metabolism of vitamin D or to defective target organ responses, but in others it is not. Although the precise effect of vitamin D or its metabolites on mineralization of bone is still unknown there is some evidence that the metabolites differ in their relative effects on intestine, bone, muscle and parathyroid glands. These differences may eventually have therapeutic value. At present the major advantage of 1alpha-hydroxylated derivatives of vitamin D over other compounds resides in their more rapid onset and reversal of action which makes them much easier and safer to use.

Acrodermatitis enteropathica is a rare disease of infancy characterized by distinctive epidermal lesions, diarrhea, and growth failure. A patient is described in whom study of the serum fatty acids in response to various treatments revealed defective interconversion of the unsaturated fatty acids, in particular, in the synthesis of the essential fatty acids.

So many factors have been adduced in the etiology of kidney-stones, and so many differences of opinion on these various factors have been current among men of high authority, that this condition seems somewhat analogous to the diseased conditions which have so many remedies offered for them that none of them is likely to be of value. Thus, the theory held by many that disturbances in the digestive processes and in the general metabolism of the body are etiologic factors seems to have been fairly well supported, but Watson and Cunningham state that the correctness of this view is now doubted. Dr. A. B. Johnson puts it lightly by saying that "in general, defective metabolism from any cause seems strongly to predispose to renal calculus." He further says that mode of life, apparently, has some influence; a sedentary life, a nitrogenous diet and the use of alcohol seem, in some

Evidence that genetic factors contribute to the development of atherosclerosis is not new (Adlersberg et al., 1949; Gertler and White, 1954; Thomas and Cohen, 1955; Russek and Zohman, 1958; Adlersberg and Schaefer, 1959; Shanoff et al., 1961; Rose, 1964; Walker, 1964; Slack and Evans, 1966; Suri et al., 1966). All writers on atherosclerosis and coronary heart disease usually refer to the role of heredity as an important etiologic factor, but hard data on the nature of the heredity unfortunately are lacking. Medical geneticists and public health specialists are attracted to genetic studies of atherosclerosis since genetically defined subpopulations at significantly higher risk might exist and elucidation of the pathophysiology of the defective metabolism could lead to possible prevention of premature coronary heart disease. The potential pay-off of genetic strategies in atherosclerosis research, therefore, is high.

Introduction The investigations of Ballantyne, 1 Friedenwald, 2 and Ashton 3 have shown that the earliest recognizable (ie, recognizable by ophthalmoscopy or by various histological methods) lesions of diabetic retinopathy are the microaneurysms. While these microaneurysms are universally accepted as the characteristic feature of diabetic retinopathy, no one has been able to explain satisfactorily how and why these microaneurysms develop with such regularity in this disease. Since the pioneering work of Ballantyne, there have been many attempts, in both the clinical and the experimental field, to find the cause for the development of these microaneurysms or at least offer reasonable postulates. More recently Ashton 4 and Bloodworth 5 have offered interesting theories along these lines; they believe that there is an accumulation of metabolic waste products in the diabetic retina; ie, there is an incomplete or defective metabolism in the diabetic retina. Postulating that the basic lesion before the development

RECENTLY McKusick et al 1 have drawn attention to the broad spectrum of clinical disorders which may be associated with defective metabolism of mucopolysaccharides and suggested that there exist at least five different but related clinical entities. The criteria which were used for this classification were based upon clinical and genetic data as well as the urinary excretion of abnormal amounts and types of mucopolysaccharide. Several cases were described which could not be classified but which showed features suggestive of one or more of the proposed categories. In the present report two siblings are presented and discussed who have manifested a condition characterized by progressive dementia associated with diffuse involvement of the reticuloendothelial system. This condition has been difficult to diagnose but has many features of the disorders attributed to deranged mucopolysaccharide metabolism. The delayed development of direct evidence of abnormal storage and excretion of mucopolysaccharides in these cases

MMA may be caused by at least three different enzyme defects: l)Defect of methylmalonyl-CoA(MMCoA)mutase-apoenzyme; 2)Defective metabolism or transport of the coenzyme of MMCoA mutase, 5'-deoxyadenosylcobalamin(dA-Bl2), or of its precursor, vitamin B12; 3) Deficiency of MMCoA racemase. -We have studied methylmalonate metabolism in leucocytes and cultured skin fibroblasts of 5 p. with MMA (1 p.B12-responsive, 4 p. clinically non-responsive). Intact fibroblasts of all 5 p. failed to metabolize 2-methyl-14C-malonate (MM-14C)to 14CO2, whether or not vitamin B12 or dA-B12 (10−5M) were added; whereas in intact leucocytes of the 3 p. so far investigated, 14CO2 formation from MM-14C was always present and similar to controls. Disrupted fibroblasts were studied using a specific enzyme assay with propionyl-CoA and NaH14CO3 as substrates. Methylmalonate metabolism was absent or severely impaired in all p. as revealed by methylmalonate accumulation and succinate formation. While addition of vitamin B12 (10−11 to 10−5M) had no effect in any of the p., addition of dA-B12 (10−7 to 10−5M) did not enhance succinate formation in 2 p., but fully restored enzyme activity in 2 other p. These data suggest a defective metabolism rather than a defective transport mechanism of the B12-coenzyme in the latter 2 p.

The enumeration of the more important points in treating pathologic conditions of the eye by means of sweat baths and the most successful means for their application are here attempted. As in other organs of the body, the complete performance of absorption and elimination are constantly going on in the eye without any disturbance of its other functions. When this fails to take place deleterious products accumulate in the vascular and lymphatic systems from the non-elimination of poisons or toxins and pathologic changes manifest themselves. On what disturbing influences these ocular diseases depend we are still in a large percentage of cases somewhat in the dark. Although syphilis and rheumatism frequently act as predisposing causes they can not be held accountable for all; many of them are probably the result of defective metabolism obscure in origin. The inflammatory affections, in which we may expect to derive the most satisfactory