Growth in patients with mucopolysaccharidosis type III (Sanfilippo disease)

Background

Mucopolysaccharidosis III (MPS III), known as Sanfilippo disease, is a lysosomal storage disorder mainly characterized by progressive neurodegeneration with cognitive decline and relatively attenuated somatic signs and symptoms. Although short stature is invariably present in patients with the other mucopolysaccharidoses, it has not been sufficiently addressed in MPS III. The aim of this study was to investigate growth data of a large Dutch MPS III cohort in order to construct growth charts for MPS III patients.

Methods

Height, weight, head circumference (HC), and body mass index (BMI) data from 118 MPS III patients were used to construct reference curves, using the lambda, mu, sigma (LMS) method. Genotype-group comparisons for height standard deviation scores (SDS) were performed by Kruskal–Wallis analysis for different age groups.

Results

Birth weight and length were within normal ranges for gestational age and showed a significantly stunted growth from age 6 years onward. Mean final heights were 169.7 cm (?2.0 SDS) and 165.4 cm (?0.84 SDS) for adult male and female, patients, respectively. Phenotypic severity, as assessed by genotyping, correlated with growth pattern and final height. In addition, mean BMI and HC SDS were significantly higher when compared with Dutch standards for both boys and girls.

Conclusions

Growth in MPS III is stunted mainly in patients with the severe phenotype. We provide disease-specific growth references that can be used for clinical management of MPS III patients and may be of value for future treatment studies.     

A physiological threshold for protection against menadione toxicity by human NAD(P)H:quinone oxidoreductase (NQO1) in Chinese hamster ovary (CHO) cells

NAD(P)H:quinone oxidoreductase 1 (NQO1) has often been suggested to be involved in cancer prevention by means of detoxification of electrophilic quinones. In the present study, a series of Chinese hamster ovary (CHO) cell lines expressing various elevated levels of human NQO1 were generated by stable transfection. The level of NQO1 over-expression ranged from 14 to 29 times the NQO1 activity in the wild-type CHO cells. This panel of cell lines, allowed investigation of the protective role of NQO1 in quinone cytotoxicity. It could be demonstrated that menadione toxicity was significantly reduced in all NQO1-transfected CHO clones compared to the wild-type cells, but the clones did not show differences in their level of protection against menadione. This observation pointed at a critical threshold concentration of NQO1 above which a further increase does not provide further protection against quinone cytotoxicity. Additional studies in which the NQO1 activity was inhibited by dicoumarol showed that only dicoumarol concentrations of about five times the EC(50) for NQO1 inhibition were able to reduce NQO1 levels below the apparent threshold, making the cells more sensitive. The level of this threshold was estimated to be in the range of base line NQO1 activities observed in several tissues and species. Thus, the results of the present study indicate that beneficial effects of NQO1 induction by, for example, cruciferous vegetables might be absent or present depending on the NQO1 activity threshold for optimal protection and the basal level of NQO1 expression in the tissue and species of interest.     

Overexpression of arginase I in enterocytes of transgenic mice elicits a selective arginine deficiency and affects skin,muscle, and lymphoid development

BACKGROUND: Arginine is required for the detoxification of ammonia and the synthesis of proteins, nitric oxide, agmatine, creatine, and polyamines, and it may promote lymphocyte function. In suckling mammals, arginine is synthesized in the enterocytes of the small intestine, but this capacity is lost after weaning. OBJECTIVE: We investigated the significance of intestinal arginine production for neonatal development in a murine model of chronic arginine deficiency. DESIGN: Two lines of transgenic mice that express different levels of arginase I in their enterocytes were analyzed. RESULTS: Both lines suffer from a selective but quantitatively different reduction in circulating arginine concentration. The degree of arginine deficiency correlated with the degree of retardation of hair and muscle growth and with the development of the lymphoid tissue, in particular Peyer's patches. Expression of arginase in all enterocytes was necessary to elicit this phenotype. Phenotypic abnormalities were reversed by daily injections of arginine but not of creatine. The expression level of the very arginine-rich skin protein trichohyalin was not affected in transgenic mice. Finally, nitric oxide synthase-deficient mice did not show any of the features of arginine deficiency. CONCLUSIONS: Enterocytes are important for maintaining arginine homeostasis in neonatal mice. Graded arginine deficiency causes graded impairment of skin, muscle, and lymphoid development. The effects of arginine deficiency are not mediated by impaired synthesis of creatine or by incomplete charging of arginyl-transfer RNA.     

Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors.

PURPOSE: To investigate the feasibility and pharmacokinetics of the combination cisplatin, gemcitabine, and SU5416. PATIENTS AND METHODS: Patients received cisplatin 80 mg/m(2) on day 1, gemcitabine 1,250 mg/m(2) on days 1 and 8, repeated every 3 weeks, and SU5416 (85 and 145 mg/m(2)) intravenously twice weekly. Pharmacokinetics of all three agents, side effects, and antitumor response were investigated in patients with solid tumors amenable to therapy with cisplatin/gemcitabine. RESULTS: In the first cohort of three patients entered at the 85 mg/m(2) dose, no dose-limiting toxicities were observed. In the next cohort (145 mg/m(2)), three patients developed a thromboembolic event. After entry was restricted to patients with low thromboembolic risk, three additional patients enrolled at 145 mg/m(2) developed a thromboembolic event. The dose was then reduced to 85 mg/m(2) in all patients still on the study, and three additional patients were entered on this dose level. In 19 treated patients, eight patients developed nine thromboembolic events (three transient ischemic attacks, two cerebrovascular accidents, and four deep venous thromboses). The most common toxicities observed were those previously reported for SU5416 alone (headache and phlebitis) and for this chemotherapy regimen (nausea, thrombocytopenia, and leucopenia). No significant pharmacologic interaction among the three drugs was observed. Response rates were similar to those expected in the patient population selected for this study. Analysis of variables of the coagulation cascade and of vessel wall activation was performed in three patients and showed significant increases in thrombin generation and endothelial cell perturbation in a treatment cycle-dependent manner. CONCLUSION: The incidence of thromboembolic events, possibly related to the particular regimen tested in this study, discourages further investigation of this regimen.     

Onlay grafts in combination with endosseous implants in severe mandibular atrophy: one year results of a prospective, quantitative radiological study

In taking an overall view of the radiographs made of patients that underwent simultaneous onlay-grafting and implant placement in the anterior mandible, changes are seen in the grafts. The impression arose that a number of stages could be distinguished in this process of remodelling of the graft. The purpose of the present study was to objectivate the existence of those stages in the first year after bone-grafting by densitometric and height measurements of the onlay grafts using standardized extraoral radiographs (OLCR) and densitometric analysis in a group of 8 patients. OLCRs were taken at regular intervals in the first year after surgery. The measurements were performed in three fixed fields, both ventrally and dorsally of each implant. Generally the densitometric measurement fields were located at the (upper) cortex, the upper spongiosa and the lower spongiosa of the onlay graft. The OLCRs were also used for measurements of the height of the complete graft and of the thickness of the cortex of the graft, using a gauged caliper. The results indicate the following remodelling of the structure of the onlay grafts: 1) decrease in the thickness and the radiographic density of the (upper) cortex of the onlay graft predominantly in the first 6-month period; 2) no significant changes in the radiographic density of the upper spongeous part of the graft; 3) a decrease of approximately 25% in the overall height of the graft, particularly during the first 6-month period; 4) an increase in the radiographic density of the lower part of the spongeous bone in the second 6-month period. It is concluded that the remodelling of the graft has a predictable pattern in time: the first half year being dominated by bone resorption, mainly confined to the cortex of the graft, whereas the second half year is characterized by an increase in bone density in the (remaining) cortex as well as the lower spongeous parts of the graft.     

The management of acute abdominal pain in children

Objective : Acute abdominal pain is a common problem in childhood, and appendicitis is frequently diagnosed by general practitioners and doctors working in emergency departments. The objective of the present report was to determine the frequency of appendicitis in a group of children with acute abdominal pain presenting to the emergency department of a general hospital, as well as attempting to analyse the manner in which these patients were managed.
Methodology : The initial assessment in hospital (by resident hospital staff) of the study group of patients was analysed and their subsequent clinical progress documented.
Results : The present report shows that the vast majority of children with acute abdominal pain do not have appendicitis and that appendicitis is significantly over-diagnosed by junior hospital doctors.
Conclusions : Appendicitis is a clinical diagnosis, best made by an experienced member of the paediatric surgical team. Frequent review, with a minimum of investigations, provides the best means of making a rational decision regarding surgery.     

Evaluation of low birthweight in African Americans

This study evaluates risk factors associated with low birthweight in an African-American population. Records of 225 women delivering liveborn, nonanomalous singletons weighing < 2500 g were reviewed. The next parturient, matched for race only, of a similar infant weighing > or = 2500 g constituted the control. This case-control study was conducted among women delivering at University Hospital in New Orleans during 1996-1997. Mothers of infants weighing < 2500 g were more likely to not have finished high school (49% versus 38%), to have received no prenatal care (26% versus 7%), or to have five or fewer visits if care was obtained (52% versus 33%). The mother was more likely to weigh < 60 kg (49% versus 32%), to smoke (24% versus 11%), or to have used cocaine (18% versus 5%) or alcohol (11% versus 5%). Parturients of low birthweight newborns were more likely to have had a prior low birthweight infant (44% versus 19%) and themselves to have had a birthweight < 2500 g (30% versus 13%). Regression analysis confirmed the importance of three parameters as associated with low birthweight: no prenatal care (odds ratio [OR] = 6.0 [1.1-31.4]), alcohol use (OR = 5.2 [1.1-24.8], and low maternal birthweight (OR = 3.9 [1.9-7.9]. These results indicate that evaluations of low birthweight in African Americans should consider maternal birthweight and that efforts to improve pregnancy outcome should be structured in terms of generations.     

Quality control of the private veterinary profession in The Netherlands

It was as early as the 19th Century when attempts were first made to organise the veterinary profession in The Netherlands into a professional association. Since then, the Royal Veterinary Association of The Netherlands has developed into an organisation which fully promotes the interests of the profession. From the beginning, the issues of professional standards and veterinary legislation were given high priority, and codes of conduct were established with the aim of improving the quality of professional veterinary practice. Having some form of independent regulatory body has always been important for maintaining these professional standards, even if history has taught us that establishing such independent testing and sanctioning facilities is a laborious process that requires perseverance and patience. By organising the control of animal diseases and promoting public health (e.g. meat inspection), the veterinary profession has always had a key role to play in the food production industry, and quality control programmes that monitor the food production chain now make use of veterinary surgeons tested by external organisations. To avoid any semblance of a conflict of interest, a new organisational structure has been developed recently: the Veterinary Quality Organisation (VKO: Veterinair Kwaliteits Orgaan). The VKO maintains the register of qualified veterinarians, upholds standards and organises the independent quality control of the profession.     

Arginine deficiency affects early B cell maturation and lymphoid organ development in transgenic mice

Apart from its role in the synthesis of protein and nitric oxide (NO), and in ammonia detoxification, the amino acid arginine exerts an immunosupportive function. We have studied the role of arginine in immune defense mechanisms in the developing postnatal immune system. In suckling mice, arginine is produced in the small intestine. In F/A-2(+/+) transgenic mice, which overexpress arginase in their enterocytes, circulating and tissue arginine concentrations are reduced to 30-35% of controls. In these mice, the development and composition of the T cell compartment did not reveal abnormalities. However, in peripheral lymphoid organs and the small intestine, B cell cellularity and the number and size of Peyer's patches were drastically reduced, and serum IgM levels were significantly decreased. These phenotypes could be traced to an impaired transition from the pro- to pre-B cell stage in the bone marrow. Cytokine receptor levels in the bone marrow were normal. The development of the few peripheral B cells and their proliferative response after in vitro stimulation was normal. The disturbance in B cell maturation was dependent on decreased arginine levels, as this phenotype disappeared upon arginine supplementation and was not seen in NO synthase- or ornithine transcarbamoylase-deficient mice. We conclude that arginine deficiency impairs early B cell maturation.