Phenylketonuria and its variants: observations on intellectual functioning.

The age at diagnosis, dietary treatment and intelligence quotient (IQ) of 119 patients with phenylketonuria (PKU) and its variants who were under long-term observation were studied. In 27 of the 79 patients with classic PKU the diagnosis had been made and treatment begun late (after 2 months of age). The mean IQ of these 27 patients was 57.6 when they were in their early 20s (although 2 had normal IQs). In contrast, among the 52 patients with classic PKU who were not treated late the mean IQ was 93.6 for the 27 who were still receiving dietary therapy. The mean IQs were 99.3 and 92.7 at ages 5 (when the diet was discontinued) and 15 years respectively for the 12 who had been treated "adequately". It was 76.0 for the 13 who were "over-treated" (malnourished) in the first 6 months of life. Among the patients with atypical PKU, who were treated early, the mean IQs were 110.0 for the 7 who were still receiving dietary therapy and 102.7 for the 12 who were not. The 21 patients with persistent benign hyperphenylalaninemia, who were not treated, had a mean IQ of 104.2. The most important factor in the ultimate IQ of patients with classic PKU is very early diagnosis (by 2 weeks of age) along with immediate initiation of dietary therapy.     

Prognosis in Early Adult Life of Coeliac Children Treated with a Gluten-free Diet

Long-term follow up of 57 young adults with coeliac disease diagnosed in childhood showed that 13 had relapsed clinically and had resumed a gluten-free diet Of the remainder, who were taking a normal diet and were apparently normal, 19 had low serum folate levels and 11 low serum iron levels. Pregnancy was found particularly likely to provoke an overt relapse.Only six patients were found to be stunted in height, while the menarche had occurred within the average range. The study also confirmed the very low present-daymortality rate of coeliac disease in childhood, which at the Hospital for Sick Children in London has been 0·4% between 1951 and 1968. In view of the finding that childhood coeliac disease usually persists, even though not causing symptoms, it is suggested that the use of a gluten-free diet should be lifelong.     

Impairment of hepatic pyruvate metabolism in phenylketonuria

In patients with untreated classical phenylketonuria, elevated plasma levels of pyruvate, lactate, phenylalanine and phenylpyruvate were observed. After about 10 days on a low-phenylalanine diet, the levels of pyruvate, lactate and phenylpyruvate in plasma of treated patients returned to normal; the concentrations of phenylalanine in plasma were markedly lowered. In plasma from hyperphenylalaninemic subjects, phenylpyruvate was not detectable; pyruvate and lactate were within normal limits. Phenylpyruvate at a concentration of about 1 mM inhibited pyruvate carboxylation by human and rat liver homogenates by about 50%; phenylalanine had no effect on this process. The values of apparent Km for pyruvate and Ki for phenylpyruvate of human liver pyruvate carboxylase were approximately 0.27 mM and 1.4 mM, respectively. These studies suggest an impairment in hepatic pyruvate metabolism in untreated phenylketonuric patients.     

Reduced intrafollicular androstenedione and estradiol levels in early-treated prenatally androgenized female rhesus monkeys receiving follicle-stimulating hormone therapy for in vitro fertilization

Five early-treated and four late-treated prenatally androgenized and five normal female rhesus monkeys were studied to determine whether prenatal testosterone propionate exposure beginning Gestational Days 40-44 (early-treated) or 100-115 (late-treated) affects follicular steroidogenesis during recombinant human FSH (rhFSH) treatment. All monkeys underwent rhFSH injections, without human chorionic gonadotropin administration, followed by oocyte retrieval. Serum FSH, LH, estradiol (E2), progesterone (P), 17alpha-hydroxyprogesterone (17 OHP), androstenedione (A4), testosterone, and dihydrotestosterone were measured basally during rhFSH therapy and at oocyte retrieval. Follicle fluid (FF) sex steroids, oocyte fertilization, and embryo development were analyzed. Circulating FSH, E2, 17 OHP, A4, and dihydrotestosterone levels increased similarly in all females. Serum LH levels decreased from basal levels in normal and late-treated prenatally androgenized females but were unchanged in early-treated prenatally androgenized females. Serum P levels at oocyte retrieval were comparable with those before FSH treatment in all females. All prenatally androgenized females showed reduced FF levels of A4 and E2 but not P or dihydrotestosterone. Intrafollicular T concentrations also were significantly lower in late-treated compared with early-treated prenatally androgenized females or normal females. In early-treated prenatally androgenized females, but not the other female groups, intrafollicular A4 and E2 levels were reduced in follicles containing oocytes that failed fertilization or produced zygotes with cleavage arrest before or at the five- to eight-cell embryo stage. Therefore, in monkeys receiving rhFSH therapy alone without human chorionic gonadotropin administration, early prenatal androgenization reduced FF concentrations of E2 and A4 in association with abnormal oocyte development, without having an effect on P, testosterone, or dihydrotestosterone concentrations.     

Isolation and some effects of functional, low-phenylalanine kappa-casein expressed in the milk of transgenic rabbits

Patients suffering certain metabolic diseases (e.g. phenylketonuria) need a low-phenylalanine diet throughout their lives. Transgenic rabbits were created to express low-phenylalanine kappa-casein in their milk. The aim was to demonstrate for the first time the feasibility of producing a modified milk protein in addition to normal milk proteins. A gene construct containing the coding region of the rabbit kappa-casein gene was modified by site-specific oligonucleotide directed mutagenesis. Four of the five phenylalanine amino acids present in the mature protein were mutated and the gene construct was used to create two transgenic rabbit lines. The transgenic rabbits produced the recombinant kappa-casein at a high level in their milk causing a reduction in the average size of the casein micelles. The low-phenylalanine kappa-casein was digestible with chymosin and it was separated from its native counterpart and from the other milk proteins by a one-step HPLC method on a reversed-phase column. In the future, low-phenylalanine casein produced in transgenic animals could be used as dietary replacements to meet the special requirements of certain consumer groups.     

City of purposes: free life and libertarian activism in London

This essay looks at the ideas and practice of libertarian activists in London. It focuses on the value placed on purposefulness, and on the city as the terrain for a free life. These libertarians' activism is explored through an engagement with the centrality of ‘freedom’ in the emergent anthropology of ethics, and by reference to alternative theories of power or action. In particular, attention falls on the challenge of representing subjects who seem to embody and profess overly familiar theories of individual freedom and responsibility. The essay is meant as a contribution to political and urban anthropology, and the ethnography of Britain.     

Treatment of phenylketonuria with a formula consisting of low-phenylalanine peptide. A collaborative study

A method of preparation of a more palatable therapeutic formula for phenylketonuria (PKU), consisting of low-phenylalanine peptide (LPP), was reported. There were no adverse effects and, in fact, there was a reduced frequency of diarrhea in patients who received LPP formula for more than 6 months. The LPP formula can be used not only as a more palatable therapeutic milk for PKU, but also as an ingredient to make more palatable foods of low-phenylalanine content.     

The Relationship of Genotype to Phenotype in Phenylalanine Hydroxylase Deficiency1

Seventy-two adults with phenylketonuria were evaluated to investigate the genotypic relationship to phenotype. Patient data were collected by chart review and medical follow-up as well as current psychological evaluation. Nineteen diagnosed neonatally had remained on a phenylalanine-restricted diet all their lives, whereas 34 who were also diagnosed on newborn screening had discontinued dietary restriction during childhood. Nineteen others who were born prior to newborn screening were diagnosed later than the newborn period on clinical grounds but have remained on dietary restriction. Comparison between intellectual ability, academic achievement, and mental illness was made with degree of diet control as defined by range of blood phenylalanine levels over time. Diet discontinuation in childhood did not significantly lower IQ per se but appeared to diminish academic achievement. The lowest IQ scores were associated with poor dietary restriction of phenylalanine in the diet during childhood. While there appears to be a strong genotypic relationship to phenotypic metabolic parameters in phenylketonuria, there does not seem to be a similar relationship to intellectual ability in adults. Mutation R408W was not strongly related to the occurrence of mental illness in this sample. We conclude that dietary restriction of phenylalanine neonatally and good control contributed to normal intellectual development. Continuation of dietary treatment into adulthood appeared to improve academic achievement in patients with severe phenylalanine hydroxylase mutations.     

Experiencia con el uso del registrador implantable de eventos en una serie de personas mayores con caídas y sospecha de síncopes de origen arrítmico

Objective

To review our experience on using an implantable loop recorder (ILR) in patients with recurrent falls, when an arrhythmogenic cause is suspected.

Material and methods

This is a retrospective, observational study of patients with repetitive unexplained falls, suspected syncope, or electrocardiographic abnormalities. All of them had been evaluated by a cardiologist, who decided to implant a loop recorder (ILR) for an accurate diagnosis.

Results

A total of 13 patients received an ILR. The average falls rate for the sample was 3.3. The mean age was 78 years, and 46% were female, with a mean follow-up period of 24 months. During this time, three patients did not suffer from a new fall. An arrhythmogenic diagnosis was obtained in 5 patients: bradycardia was identified in 4 cases, and tachycardia in one of them. The symptoms did not coincide with a documented arrhythmia in the rest of the patients.

Conclusion

ILR is a helpful tool to establish an arrhythmogenic cause of unexplained and recurrent falls, in this selected sample of older adults.     

Relevance of increased serum thyroxine concentrations associated with normal serum triiodothyronine values in hypothyroid patients receiving thyroxine: a case for "tissue thyrotoxicosis".

Fifteen patients receiving standard thyroxine replacement therapy (100-200 micrograms daily) for primary hypothyroidism and who had persistently raised free thyroxine concentrations in their serum were investigated to see whether the dose being given was too high. In addition to the usual thyroid hormone assays systolic time intervals (which indicate left ventricular contractility) were calculated as accurate reflectors of tissue thyroid activity. All patients showed the expected increased free and total thyroxine concentrations; but mean total and free concentrations of triiodothyronine were normal, while reverse triiodothyronine values were raised. Mean systolic time intervals were significantly reduced as compared with normal and fell within the thyrotoxic range. Seven patients subsequently had their doses of thyroxine reduced by 50 micrograms daily and were reinvestigated one month later. All showed significant falls in circulating thyroxine and triiodothyronine concentrations and an increase in mean systolic time intervals to the normal range. In patients receiving thyroxine replacement therapy for primary hypothyroidism a raised serum thyroxine concentration may indicate tissue thyrotoxicosis and should prompt a reduction of the thyroxine dose.     

Modification of brain deoxyribonucleic acid base content with maturation in normal and malnourished rats.

The mol percentage of 5-hydroxymethylcytosine is 2.2 times greater in the adult than in 2-day-old rat brain DNA. The concentration of 5-hydroxymethylcytosine falls in corresponding liver DNA preparations. This normal increase in brain 5-hydroxymethylcytosine is abolished in rats placed on an 8%-protein diet 5 days after birth.     

Randomised trial of safety and efficacy of immediate postoperative enteral feeding in patients undergoing gastrointestinal resection.

OBJECTIVES: To assess whether immediate post-operative enteral feeding in patients who have undergone gastrointestinal resection is safe and effective. DESIGN: Randomised trial of immediate post-operative enteral feeding through a nasojejunal tube v conventional postoperative intravenous fluids until the reintroduction of normal diet. SETTING: Teaching hospitals in London. SUBJECTS: 30 patients under the care of the participating consultant surgeon who were undergoing elective laparotomies with a view to gastrointestinal resection for quiescent, chronic gastrointestinal disease. Two patients did not proceed to resection. MAIN OUTCOME MEASURES: Nutritional state, nutritional intake and nitrogen balance, gut mucosal permeability measured by lactulose-mannitol differential sugar absorption test, complications, and outcome. RESULTS: Successful immediate enteral feeding was established in all 14 patients with a mean (SD) daily intake of 6.78 (1.57)MJ (1622 (375) kcal before reintroduction of oral diet compared with 1.58 (0.14) MJ (377 (34) kcal) for those on intravenous fluids (P < 0.0001). Urinary nitrogen balance on the first postoperative day was negative in those on intravenous fluids but positive in all 14 enterally fed patients (mean (SD) - 13.2 (11.6) g v 5.3 (2.7) g; P < 0.005). There was no difference by day 5. There was no change in gut mucosal permeability in the enterally fed group but a significant increase from the test ratios seen before the operation in those on intravenous fluids (0.11(0.06) v 0.15 (0.12); P < 0.005). There were also fewer postoperative complications in the enterally fed group (P < 0.005). CONCLUSIONS: Immediate postoperative enteral feeding in patients undergoing intestinal resection seems to be safe, prevents an increase in gut mucosal permeability, and produces a positive nitrogen balance.     

Fanconi anaemia complementation groups in Germany and The Netherlands

Fanconi anaemia (FA) is an autosomal recessive chromosomal instability disorder with extensive genetic heterogeneity. We determined the genetic subtypes in 28 ethnically and clinically unselected FA patients from Germany and The Netherlands, by complementation analysis. All five currently known complementation groups (FA-A to FA-E) appeared to be represented in the sample studied. The distribution of subtypes differed markedly in the two countries: FA-A patients were most prevalent in Germany (13/22, 59%), whereas in The Netherlands, the majority of patients were FA-C (4/6, 67%). This geographical inhomogeneity has implications for mutation-screening strategies in European FA patients.Dedicated to Professor Traute Schroeder-Kurth on the occasion of her retirement from the chair of Cytogenetics, University of HeidelbergEuropean Fanconi Anaemia Research (EUFAR) is a concerted action of nine research institutions in five European Union countries, supported by the Commission of the European Union, contract no PL931562. Principal investigators: E. Gluckman (project-leader), E. Moustacchi (Paris); T. Schroeder-Kurth (Heidelberg); H. Hoehn (Würzburg); M. Digweed (Berlin); C. Mathew (London); A. Savoia (S. Giovanni-Rotondo); F. Arwert, H. Joenje, A. Westerveld (Amsterdam); M.Z. Zdzienicka (Leiden). EUFAR relies on collaboration with many clinicians from Europe and elsewhere who supply samples from FA families for EUFAR's research programme. Clinical coordinators are for Germany: T. Schroeder-Kurth, Heidelberg; W. Ebell, Hannover; W. Friedrich, Ulm; for The Netherlands: M.L. Kwee, L.P. ten Kate, Amsterdam     

Cognitive function and behavioural status in paediatric heart and heart-lung transplant recipients: the Harefield experience.

OBJECTIVE--To assess the psychological impact of cardiac and cardiopulmonary transplantation on children. DESIGN--Retrospective cross sectional study. SETTING--One British centre performing paediatric heart and heart-lung transplant operations, four cardiac units in London, three London schools, two London health centres, and the dental department of a London children''s hospital. SUBJECTS--65 children who had been given heart or heart-lung transplants and two reference groups of 52 children who had had other types of cardiac surgery and 45 healthy children. MAIN OUTCOME MEASURES--Development, cognition, and behaviour at home and at school as assessed by measures with proved validity and reliability. RESULTS--Developmental and cognitive measures indicated that children given transplants had significantly lower scores on several parameters, particularly in terms of development in children under 4 1/2 years of age. Performance on all tests, however, was within the normal range. There were no significant differences in behavioural ratings between the transplant and reference groups, though problem behaviour at home was more prevalent in the transplant group. CONCLUSIONS--Though cognitive development may be within the normal range, there are adverse psychological effects associated with cardiac and cardiopulmonary transplantation. These data indicate the need for a controlled prospective study in which children and their families are seen before and at regular intervals after transplantation. Interventions should be developed that are tailored to the particular needs of this very specialised group of paediatric patients and their families.     

Alpha gliadin antibody levels: a serological test for coeliac disease.

The diagnostic value in coeliac disease of circulating antibodies to casein, crude gliadin, and alpha gliadin was assessed using an adaption of the enzyme linked immunosorbent assay system. alpha Gliadin was the only antigen which consistently separated 26 patients with untreated coeliac disease from 26 normal controls and 13 patients with chronic inflammatory bowel disease. The mean assay index for the 26 patients was 3.1 (SD 1.2) compared with 1.05 (0.5) for the normal controls and 1.1 (0.6) for patients with chronic inflammatory bowel disease. The alpha gliadin antibody levels of six patients with coeliac disease who had maintained a gluten free diet for at least two years were not significantly higher than normal (1.0 (0.4)). The validity of the test was determined in 90 consecutive patients who were being investigated for the presence of coeliac disease. Levels of alpha gliadin antibody were raised in 36 out of 44 patients found to have histologically proved coeliac disease and in six out of 46 subjects whose jejunal mucosa was normal. Serial alpha gliadin concentrations were measured in 12 patients with coeliac disease who had repeat jejunal biopsies performed six months after starting a gluten free diet. The levels of antibody fell in seven of the eight patients whose jejunal mucosa improved on maintaining the diet. They remained raised in four patients who did not adhere to the diet and whose mucosa did not improve. Although a test measuring alpha gliadin antibodies is unlikely to replace jejunal biopsy in the diagnosis of coeliac disease it may be useful in screening for the disease among outpatients.     

Results of treatment of dermatitis herpetiformis with a gluten-free diet after one year

Twenty-one patients with dermatitis herpetiformis initially controlled by dapsone or sulphonamides have been treated with a gluten-free diet and reassessed at intervals for up to 15 months (mean 11·9 months). According to routine histological and dissecting microscope criteria the small-bowel lesion improved in 10, but when mean epithelial cell height was used as a measure 15 patients improved. Five of the patients with diarrhoea improved after withdrawing gluten from the diet but none reverted to completely normal bowel habit. The tests for malabsorption showed little improvement in the treatment period. Twelve patients needed less dapsone to control their skin complaint, the mean dose falling from 144 mg. to a mean of 70 mg. per day; of these three stopped using this drug altogether.     

Effects of growth hormone treatment on cognitive function and head circumference in children born small for gestational age

Short stature is not the only problem faced by children born small for gestational age (SGA). Being born SGA has also been associated with lowered intelligence, poor academic performance, low social competence and behavioural problems. This paper summarizes the results of a randomized, double-blind, growth hormone (GH) dose-response study (1 or 2 mg/m2/day [ approximately 0.035 or 0.07 mg/kg/day]) on growth, intelligence quotient (IQ) and psychosocial functioning in 79 children born SGA at the start, and after 2 and 8 years of GH therapy, and addresses the associations with head circumference. Mean age at start of therapy was 7.4 years; mean duration of GH treatment was 8.0 years. In 2001, 91% of children born SGA had reached a normal height (> -2.0 standard deviation score [SDS]). Block-design s-score (Performal IQ) and Total IQ score increased (p < 0.001 for both indices) from scores significantly lower than those of Dutch peers at the start of therapy (p < 0.001) to scores that were comparable to those of Dutch peers in 2001. Vocabulary s-score (Verbal IQ) was normal at the start of therapy and remained so over time. Externalizing Problem Behaviour SDS and Total Problem Behaviour SDS improved during GH therapy (p < 0.01-0.05) to scores comparable to those of Dutch peers. Internalizing Problem Behaviour SDS was comparable to that of Dutch peers at the start of therapy and remained so, whereas Self-Perception improved from the start of GH therapy until 2001 (p < 0.001), when it reached normal scores. Head circumference SDS at the start of GH therapy and head growth during GH therapy were positively related to all IQ scores (p < 0.01), whereas neither were related to height SDS at the start of, or to its improvement during, GH therapy. A significant improvement in height and head circumference in children born SGA was seen after only 3 years of GH therapy, in contrast to randomized SGA controls. In conclusion, most children born SGA showed a normalization of height during GH therapy and, in parallel to this, a significant improvement in Performal IQ and Total IQ. In addition, problem behaviour and self-perception improved significantly. Interestingly, Performal, Verbal and Total IQ scores were positively related to head circumference, both at the start of, and during, GH therapy; head circumference increased in GH-treated children born SGA, but not in untreated SGA controls. These results are encouraging but also warrant confirmational studies and further investigations into the effects of GH on the central nervous system.     

Effect of topical application of a juvenile hormone mimic on the duration of the moulting cycle in fifth instar Rhodnius

Fifth instar Rhodnius prolixus given a single topical application of synthetic juvenile hormone (JH) on one of the first 12 days after feeding showed a sigmoid relationship between day of treatment and duration of the moulting cycle. A similar relationship was observed between day of treatment and mean ‘juvenile score’ in subsequently emerging insects. The linear relationship between mean ‘juvenile score’ and duration of the moulting cycle suggests that the increased time from feeding to ecdysis for late-treated insects is a result of the morphogenetic effects of the JH treatment. Some of the partially juvenilized insects obtained by treatment after day 5 produced an odour characteristically detected only from adult insects. The possible significance of this observation is discussed.     

Nocturnal blood pressure in normotensive subjects and those with white coat,primary, and secondary hypertension.

OBJECTIVE--To compare the mean nocturnal blood pressure of patients with various forms of renal and endocrine hypertension with that in patients with primary and white coat hypertension, and normal blood pressure. DESIGN--Ambulatory monitoring of blood pressure over 24 hours in a prospective study. SETTING--Two German centres for outpatients with hypertension and kidney diseases. SUBJECTS--176 normotensive subjects, 490 patients with primary hypertension including mild and severe forms, 42 with white coat hypertension, 208 patients with renal and renovascular hypertension, 43 with hypertension and endocrine disorders, and three with coarctation of the aorta. MAIN OUTCOME MEASURES--Fall in nocturnal blood pressure. RESULTS--Blood pressure in normotensive subjects fell by a mean of 14 mm Hg (11%) systolic and 13 mm Hg (17%) diastolic overnight (2200 to 0600). The falls in patients with primary and white coat hypertension were not significantly different. In all patients with renal and renovascular hypertension, however, the fall was significantly reduced (range of fall from 3/3 mm Hg to 7/9 mm Hg). In patients with hypertension and endocrine disorders the pattern of night time blood pressure was not uniform: patients with hyperthyroidism, primary hyperaldosteronism, and Cushing''s syndrome had significantly smaller reductions in blood pressure (6/8, 4/7, 3/6 mm Hg, respectively). In patients with phaeochromocytoma the mean night time blood pressure increased by 4/2 mm Hg. In patients with hypertension, primary hyperparathyroidism, and unoperated coarctation of the aorta the falls in blood pressure were normal. CONCLUSIONS--In normotensive subjects and those with primary hypertension there is usually a reduction in blood pressure at night. In all renal forms of secondary hypertension and in most endocrine forms the reduction in blood pressure is only a third to a half of normal. Patients with primary hyperparathyroidism and unoperated coarctation of the aorta show a normal reduction.     

Effect of intestinal microfloras from vegetarians and meat eaters on the genotoxicity of 2-amino-3-methylimidazo[4,5-f]quinoline, a carcinogenic heterocyclic amine

Aim of this study was to investigate the impact of intestinal microfloras from vegetarians and non-vegetarians on the DNA-damaging activity of 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline (IQ), a carcinogenic heterocyclic amine that is found in fried meats. Floras from four vegetarians (Seventh Day Adventists) and from four individuals who consumed high amounts of meats were collected and inoculated into germfree F344 rats. The rats were kept on isocaloric diets that either contained animal derived protein and fat (meat consumers group) or proteins and fat of plant origin (vegetarian groups). IQ (90 mg/kg bw) was administered orally, after 4 h the extent of DNA-damage in colon and liver cells was determined in single cell gel electrophoresis assays. In all groups, the IQ induced DNA-migration was in the liver substantially higher than in the colon. In animals harbouring floras of vegetarians, the extent of damage was in both organs significantly (69.2% in the liver, P<0.016 and 64.7%, P<0.042 in the colon, respectively) lower than in the meat consumer groups. Our findings show that diet related differences in the microfloras have a strong impact on the genotoxic effects of IQ and suggest that heterocyclic amines are less genotoxic and carcinogenic in individuals that consume mainly plant derived foods.