Slowly progressive d-bifunctional protein deficiency with survival to adulthood diagnosed by whole-exome sequencing.

d-Bifunctional protein (DBP) deficiency is an autosomal recessive disorder of peroxisomal fatty acid oxidation caused by mutations in HSD17B4. It is typically fatal by the age of two years with symptom onset during the neonatal period, and survival until late childhood is rare. We herein report the case of a patient with DBP deficiency surviving until adulthood, who showed severe sensorineural deafness, disturbances in language acquisition, slowly progressive cerebellar ataxia, and peripheral neuropathy. This patient, in whom findings of prior investigations were nondiagnostic, had been followed up as having an early-onset spinocerebellar degeneration of unknown etiology. Whole-exome sequencing analysis at the age of 36 showed two heterozygous variants in the gene HSD17B4, which encodes DBP in this patient. A panel of peroxisomal investigations showed normal levels of very long chain fatty acids (VLCFAs) in plasma and elevated serum phytanic acid levels. Recently, an increasing number of patients with DBP deficiency surviving until adolescence/adulthood have been reported, in whom abnormalities in the levels of VLCFAs and other peroxisomal metabolites are marginal or nonexistent. Genetic analysis of HSD17B4 should be considered in adult patients with cerebellar ataxia, peripheral neuropathy, and pyramidal signs in addition to sensorineural auditory disturbance since childhood.

Taurine supplementation preserves hypothalamic leptin action in normal and protein-restricted mice fed on a high-fat diet.

Malnutrition programs the neuroendocrine axis by disruption of food-intake control, leading to obesity. Taurine (Tau) is neuroprotective and improves anorexigenic actions in the hypothalamus. We evaluated the hypothalamic gene-expression profile and food-intake control in protein-restricted mice submitted to a high-fat diet (HFD) and Tau supplementation. Mice were fed on a control (14 % protein-C) or a protein-restricted diet (6 % protein-R) for 6 weeks. Thereafter, mice received, or not, HFD for 8 weeks (CH and RH) with or without 5 % Tau supplementation (CHT and RHT). Protein restriction led to higher food intake, but calories were matched to controls. Excessive calorie intake occurred in HFD mice and this was prevented by Tau supplementation only in the CH group. Additionally, RH and CH mice developed hypothalamic leptin resistance, which was prevented by Tau. Global alterations in the expressions of genes involved in hypothalamic metabolism, cellular defense, apoptosis and endoplasmic reticulum stress pathways were induced by dietary manipulations and Tau treatment. The orexigenic peptides NPY and AgRP were increased by protein restriction and lowered by the HFD. The anorexigenic peptide Pomc was increased by HFD, and this was prevented by Tau only in CH mice. Thus, food intake was disrupted by dietary protein restriction and obesity. HFD-induced alterations were not enhanced by previous protein deficiency, but the some beneficial effects of Tau supplementation upon food intake were blunted by protein restriction. Tau effects upon feeding behavior control are complex and involve interactions with a vast gene network, preventing hypothalamic leptin resistance.

Insufficient Protein Intake Is Associated With Increased Mortality in 630 Patients With Cirrhosis Awaiting Liver Transplantation.

BACKGROUND: For patients awaiting liver transplantation, we aimed to determine the prevalence and predictors of insufficient protein intake as well as to determine whether very low protein intake was an independent predictor of malnutrition and mortality. MATERIALS AND METHODS: Adults with cirrhosis who were activated on our local liver transplant waiting list between January 2000 and October 2009 were included. Estimated protein intake was derived from dietary records. Patients with incomplete dietary records were excluded. Multivariable logistic regression and competing risk analysis were used. RESULTS: Of 742 potential patients, 112 were excluded due to insufficient data, leaving 630 patients for evaluation. Mean protein intake was 1.0 ± 0.36 g/kg/d and only 24% of patients met the expert consensus recommended threshold of > 1.2 g/kg of protein per day. Very low protein intake (< 0.8 g/kg/d) was associated with worse liver disease severity (as measured by Child-Pugh or MELD). Protein intake below 0.8 g/kg/d was an independent predictor both of malnutrition as measured by the subjective global assessment (adjusted odds ratio [95% confidence interval (CI)]: 2.0 [1.3-3.0]) and of transplant waiting list mortality (adjusted hazard ratio [95% CI]: 1.8 [1.2-2.7]). CONCLUSION: In this large cohort of liver transplant waitlisted patients, very low protein intake was prevalent and independently associated with malnutrition and mortality. Unlike many other prognostic factors, protein intake is potentially modifiable. Prospective studies are warranted to evaluate the effect of targeted protein repletion on clinically relevant outcomes such as muscle mass, muscle function, immune function, and mortality.

Differential effects of unusual climatic stress on capuchin (Cebus capucinus) and howler monkey (Alouatta palliata) populations on Barro Colorado Island, Panama.

Though the harmful effects anthropogenic disturbances pose to wild primates are well appreciated, comparatively little is known about the effects of natural disturbances. From December 2010 to January 2011, different mortality patterns were observed for two primate species, capuchins and howler monkeys, on Barro Colorado Island (BCI), Panama. Unusually high rainfall in 2010 was associated with census and cadaver data indicating the rapid loss of >70% of the capuchin population in late 2010 to early 2011. In contrast, over this same period, no decline was documented for howler monkeys and cadaver data for howlers was unexceptional. The high mortality experienced by the capuchin population was unexpected and its extent was not fully appreciated until the event was largely over. Explanations proposed for it included effects of hypothermia, disease or a shortage of some essential nutrient(s). Of these, the dietary explanation seems most probable. BCI capuchins depend most heavily on arthropod foods in December, when few higher quality ripe fruits are available. The unprecedented high rainfall in December 2010 is hypothesized to have largely eliminated the arthropod peak expected on BCI each December. A lack of protein-rich arthropods, when coupled with the climatic and nutritional stress capuchins generally experience at this time of year, appears to have precipitated the rapid die-off of most of the island's capuchin population. As howler monkeys obtain dietary protein primarily from leaves, a shortage of edible arthropods would not affect howler numbers. Comparison of our 2010 data with similar data on earlier primate/mammalian mortality events reported for BCI and for Corcovado, Costa Rica indicates that our understanding of the effects of natural disturbances on wild primate populations is not profound. We suggest that more research be devoted to this increasingly timely topic, so important to conservation policy.

Hematologic and bone marrow changes in children with protein-energy malnutrition.

BACKGROUND: All systems in an organism are affected by protein-energy malnutrition (PEM), but one of the worst affected is the hematopoietic system. Today PEM remains a very serious problem in developing countries. We examined the relationships between clinical features, hematological, and bone marrow changes with severe PEM from Turkey. METHOD: We evaluated 34 (11 females and 23 males) consecutive cases of severe PEM, with no underlying diseases aged 3-20 months. The clinical nutritional conditions of the patients were determined using the Wellcome-Trust PEM classification. Ten of the patients were in the Marasmic-Kwashiorkor (M-K) group, 10 were in the Kwashiorkor (KW) group, and 14 were in the Marasmic (M) group. Full blood count, protein, albumin, serum iron (SI), iron-binding capacity (TIBC), ferritin, vitamin B12, folic acid, complement-3 (C3), complement-4 (C4), and bone marrow were investigated in all groups. RESULTS: Anemia was detected in 97% of patients. We determined serum iron levels were low in 67.6% of the patients, TS levels were low in 76.4% of the patients and ferritin levels were low in 20.5%. The level of vitamin B12 was normal in all patients. Bone marrow analysis showed erythroid series hypoplasia in 28.5% of patients in the M group, 50% in the KW group, and 30% in the M-K group. Marrow iron was absent in 58.8% of patients. CONCLUSION: The most common hematologic change in the children with PEM was anemia and major cause of anemia was iron deficiency in this study. Patients with severe PEM have normal Vit B12 and serum folate levels. Most of the patients with severe PEM had normal cellularity with megaloblastic and dysplastic changes in bone marrow due to the inadequate and imbalanced intake of protein and energy.

Diagnóstico social, nutricional y clínico del anciano hospitalizado / Hospitalized elderly patients: clinical, nutricional and social aspects

Con la finalidad de determinar algunas características sociales, nutricionales y clínicas del anciano hospitalizado, se estudio a 73 pacientes mayores de 65 años de las salas de medicina-varones del Hospital Dos de Mayo de Lima, entre febrero y abril de 1989. Se realizó un trabajo prospectivo y transversal que incluyó: Historia social; medidas antropométricas: peso(P), talla (T), indice P/T2, circunferencia del brazo, espesor del pliegue tricipital, cálculo de la circunferencia muscular del brazo; dosaje de albúmina plasmática y determinación del hematocrito, número de dientes, estadía hospitalaria, diagnósticos y causas de muerte. Las medidas antropométricas y el Hematocrito fueron comparados con los de una población de ancianos de un albergue local. Encontramos: provincianos 72.6 por ciento, residentes en Lima 86.3 por ciento, analfabetos 11.0 por ciento, trabajan 32.9 por ciento, dependientes económicamente 74.0 por ciento. Valores antropométricosy hematocrito menores que el grupo de control (p<0.001); hipoalbuminemia 48.4 por ciento, anemia 45.4 por ciento; edéntulos 21.9 por ciento, ausencia de correlación entre número de dientes y parámetros nutricionales; no caminaban 35.6 por ciento. Promedio de estadía hospitalaria de 33.8 días; 18.5 por ciento de enfermedades infecciosas, 44.4 por ciento de mortalidad por shock séptico. Se enfatiza que: El paciente no cuenta con la protección de una adecuada previsión social. Existe desnutrición calórico proteica que no se puede cuantificar por ausencia de tablas antropométricas propias. Se requiere especial atención para este grupo etario debido a factores que limitan su supervivencia

Early maternal behaviors predictive of the survival of suckling rats with intergenerational malnutrition.

Mother-pup interactions during the first 12 hours post partum were studied in intergenerationally malnourished and control rats. Pup mortality during the suckling period was found to be associated with nutritional status with only 50% survival in the malnourished series, as compared to 100% survival in the control series. Litters with subsequent high pup mortality were distinguished by abnormal mothering patterns during the first 12 hours of life and reduced pup weight at the end of this period. High pup mortality was associated with increased active nursing, and reductions in passive nursing, pup licking, amount of contact with the pups and time spent in the nest by the lactating female. Thus, the stimulus to active nursing is most intense under conditions where the pups are least likely to survive, whereas the amount of stimulation provided to such pups is reduced. Maximal associations between early mother-pup interactions and subsequent pup weight and survival were present 7-9 hours after birth.

Influence of level and type of dietary protein, and of level of feeding on feed utilization by rainbow trout.

In the first experiment, diets with 40%, 50% and 60% protein containing herring and soybean meals, and diets with 50% and 60% protein containing herring and soybean protein concentrates were fed at 100%, 85% and 70% of the ad libitum intake. Both increasing the protein level and using the concentrated protein sources resulted in lower gains, and in increases in the amounts of digestible protein and energy consumed for the deposition of protein and energy in the fish carcasses. This difference between the herring and soybean meals, and protein concentrates was not due to differences between their digestibilities. Restriction of feed intake reduced gain, but within these lower levels of gain, the 50% and 60% protein diets have higher final body weights than the 40% protein diet. Restriction of feed intake resulted in carcasses with higher protein and lower fat contents. In the second experiment, two series of diets containing either 40%, 35%, 30% or 25% protein from both herring and soybean meals, or 35%, 30% and 25% protein from herring meal were fed. Reducing the protein level below 40% resulted in lower final body weights, higher feed: gain ratios and carcasses with more protein and less fat. Comparisons of the isonitrogenous pairs of diets showed no differences in final body weights, feed: gain ratios and carcass composition. Reducing the protein level in the diet reduced the amount of protein consumed per unit protein level in the diet reduced the amount of protein consumed per unit protein deposition, but increased the amount of gross energy per unit energy deposited in the carcass.

Influence of protein restriction on immune functions in NZB mice.

The influence of a low protein (6%) diet on the immunologic function of NZB mice was investigated. The low protein intake was associated with decreased weight gain in both male and female NZB mice. The mice fed the low protein diet did not develop splenomegaly, which generally occurs by 7 to 10 months of age in NZB mice fed a normal amount of protein. Further, 7- to 10-month-old NZB mice fed the low protein(6%) diet, maintained: 1) more vigorous antibody production to sheep red blood cells; 2) greater capacity to produce graft-vs-host reactions, and 3) more vigorous cell-mediated "killer" cell immunity after immunization against DBA/2 mastocytoma cells than did NZB mice on a normal (22%) protein diet. The decrease of PHA and Con A response which normally occurs with aging in NZB mice was abrogated to some degree by protein restriction. However, response to LPS, which also declines with age in NZB mice, did not appear to be influenced by diet.

Effects of a low-protein diet during pregnancy of the rhesus monkey I. Reproductive efficiency.

Pregnant rhesus monkeys were fed a control diet of modified cow's milk or an experimental diet containing only 25% as much as protein but made isocaloric with supplemental lactose. The ad libitum consumption of the control and experimental diets provided about 2 and 0.5 g of protein/kg of body weight per day, respectively. Total volume and energy consumption of control and experimental animals were generally comparable per kilogram of body weight, with groups showing a reduction in intake of about 20% during the latter part of pregnancy. Control females gained an average of 1.3 kg during pregnancy compared to 0.02 kg by the monkeys fed the low-protein diet. One of 15 infants born to control animals died shortly after birth; eight of 16 pregnancies in animals on the low-protein diet resulted in maternal and fetal death, stillbirth, or death in the newborn period. The birth weight of full term infants from mothers fed the low-protein diet was depressed by about 15%, and fetal linear growth was affected very little, but fetal and perinatal survival were low. We conclude that growth measurements of the newborn infants were relatively insensitive indices of the severity of the maternal nutritional deficiency and of the prognosis for the infant.

Twelve generations of marginal protein deficiency.

1. Colonies of rats have been maintained for twleve generations on diets adequate (dietary protein energy: total metabolizable energy (NDp: E) 0-1) or marginally deficient in protein (NDp: E 0-068). 2. In the malnourished colony, the proportion of "small-for-gestational-age" offspring was ten times as high as amongst the well-nourished colony, growth was slow, sexual maturation delayed, especially in the females, and, when adult, both sexes were significantly lighter and shorter than adults of the well-nourished colony. Organs, other than the eye, weighed less than those of well-nourished "age" controls, but when expressed relative to body-weight, the brain, pituitary, thyroid, adrenals, testes, thymus and eyes were larger, the pancreas unchanged and the kidneys smaller than those of the well-nourished "age" controls. The relative weight of the liver showed little change, being slightly increased in the males and, like the ovaries, slightly reduced in the females. On a body-weight basis, the brains were about 50 percent heavier than normal, but in absolute terms were 5-5-5 percent lighter than those of the well-nourished animals, the cerebellum (10-5 percent lighter in males and 12-9 percent lighter in females) being more severely affected than the cerebrum (4 percent lighter). 3. The young malnourished rats showed increased exploratory activity, transient head tremors and an increased sensitivity to noises, the latter being long-lasting if not permanent. When adult, they showed marked differences in behaviour and learning patterns and it was difficult to attract and hold their attention. In situations demanding a choice the animals were very excited, emitted loud squeals and tried to escape from what was clearly a stressful situation. However, a casual examination of the malnourished adults revealed a rather small, badly groomed, excitable rat without gross abnormalities. 4. The findings are discussed in relation to changes found in malnourished human communities.

Studies of the energy and protein requirements of the growing guinea-fowl.

1. Guinea-fowl of both sexes and female chickens were fed from 1 to 12 weeks on diets the energy concentration of which was constant at either 2-6, 2-9 or 3-2 Mcal/kg (10-8, 12-1 or 13-4 MJ/kg) while the calorie to protein ratios were changed, for some groups, from 124 to 157 or 200 at 4 and 8 weeks. 2. Guinea-fowl, but not chickens, were unable to overconsume when the protein concentration was low with the result that the body fat content was not reduced when the protein concentration was increased. 3. In the second trial the ME level of the diets was fixed at 12-6 MJ/kg while the protein content was varied, from 21 to 28% in the diets fed to 6 weeks of age and from 15 to 24% in those fed from 6 to 12 weeks. 4. It is concluded that for the growing guinea-fowl the diet should contain 12-6 MJ ME/kg, the protein concentration reducing from 24 to 26% in the period 0 to 4 weeks to 19 to 20% in the period 4 to 8 weeks and to 16% or less in the period 8 to 12 weeks.