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We have investigated the association between APOE genotypes and C-reactive protein (CRP) levels in a cohort of approximately 600 individuals who were candidates for statin therapy. An association had been previously reported between the APOE3 allele and elevated CRP levels. That study only examined men. We have reproduced that association in men and have extended the finding to women. We also investigated the effect of the interaction between APOE genotype and hormone replacement therapy (HRT) status on CRP levels, adjusting for body mass index (BMI) and other covariates. BMI and HRT are also significant predictors of CRP, as previously reported. The effect of HRT is strong enough that the contribution of APOE genotype is no longer statistically significant among women on HRT. We also demonstrate that the presence or absence of the single SNP Cysl30Arg (which distinguishes APOE4 from APOE2 and APOE3) is sufficient to determine whether an individual is predisposed to higher or lower CRP levels. Essentially, the presence of one or two copies of APOE4 is associated with a reduction of CRP levels by approximately 34% relative to individuals with zero copies (1.73 mg/L for subjects with one or two copies versus 2.63 mg/L for subjects with zero copies of APOE4). We also tested previously reported associations between CRP levels and polymorphisms in the CRP and IL6 genes. These associations were not reproduced in our cohort.

Determining the extent to which hominid- and carnivore-derived components of fossil bone palimpsests formed independently of each other can provide valuable information to paleoanthropologists interested in reconstructing the foraging adaptations of hominids. Because stone tool cutmarks, hammerstone percussion marks, and carnivore tooth marks are usually only imparted on bone during nutrient extraction from a carcass, these bone surface modifications are particularly amenable to the types of analyses that might meet this goal. This study compares the percentage of limb bone specimens that preserve evidence of both hominid- and carnivore-imparted bone damage from actualistic control samples and several Plio-Pleistocene archaeofaunas, including new data from Swartkrans Member 3 (South Africa). We argue that this procedure, which elucidates the degree of hominid-carnivore independence in assemblage formation, will allow researchers to extract for focused analyses high integrity components (hominid and carnivore) from presumably low integrity sites. Comparisons suggest that the hominid- and carnivore-derived components from sites in Olduvai Gorge Bed II (Tanzania), the ST Site Complex at Peninj (Tanzania), and Swartkrans Member 3 formed largely independent of each other, while data from the FLK 22 Zinjanthropus (FLK Zinj) site (Olduvai Gorge Bed I) indicate significant interdependence in assemblage formation. This contrast suggests that some Early Stone Age assemblages (e.g., the Olduvai Gorge Bed II sites, the Peninj ST Site Complex, and Swartkrans Member 3) are probably more useful than others (e.g., FLK Zinj) for assessing the maximal carcass-acquiring abilities of early hominids; in such assemblages as those in the former set, sole hominid-contribution is more confidently discerned and isolated for analysis than in assemblages such as FLK Zinj.

The ca. 1.0 myr old fauna from Swartkrans Member 3 (South Africa) preserves abundant indication of carnivore activity in the form of tooth marks (including pits) on many bone surfaces. This direct paleontological evidence is used to test a recent suggestion that leopards, regardless of prey body size, may have been almost solely responsible for the accumulation of the majority of bones in multiple deposits (including Swartkrans Member 3) from various Sterkfontein Valley cave sites. Our results falsify that hypothesis and corroborate an earlier hypothesis that, while the carcasses of smaller animals may have been deposited in Swartkrans by leopards, other kinds of carnivores (and hominids) were mostly responsible for the deposition of large animal remains. These results demonstrate the importance of choosing appropriate classes of actualistic data for constructing taphonomic inferences of assemblage formation. In addition, they stress that an all-encompassing model of assemblage formation for the hominid-bearing deposits of the Sterkfontein Valley is inadequate and that each must be evaluated individually using not just analogical reasoning but also incorporating empirical data generated in the preserved fossil samples.

Fifteen newly recognized hominid postcranials from Swartkrans are described here and compared with a sample of previously described early hominids, African apes and modern humans. Ten of the new specimens are from Member 1. Two are from Member 2 and three are from Member 3. Nine of the fossils are referred to Paranthropus, three to Homo, and three specimens cannot be assigned at present. The collection of hominid postcranials from Members 1-3 at Swartkrans now numbers more than 70 specimens. With the description of two new, small femoral heads, SKW 19 and SK 3121, there are now four proximal femora from Swartkrans. When SK 82 and SK 97 are compared with SKW 19 and SK 3121, the two sets offer important insights into body size and sexual dimorphism in Paranthropus robustus.A new distal femur, SK 1896 and other bones attributed to Homo cf. erectus, indicate that male Homo were larger than Paranthropus at Swartkrans., (Copyright 2001 Academic Press.)

As I am not a neuroscientist, it is an unexpected pleasure for me to contribute a lecture to the James Arthur series on the Evolution of the Human Brain. By contrast, I am an African naturalist, and what I have to say will be very much from the perspective of African cave taphonomy, a recent and rather macabre discipline that uses fossils in an attempt to reconstruct the circumstances of death of the animals involved, as well as to gain insights into their behavior and the paleoecology of the time. The lecture's focus will be on predation, to which I am largely indebted to Professor Raymond Dart, who provoked me into devoting many years of my life developing the principles of cave taphonomy and interpreting the bone accumulations in southern African caves where hominid fossils have been found.

Objectives: To investigate the relation between cranial irradiation received during treatment for childhood leukaemia and obesity at final height., Design: Retrospective cross sectional study., Setting: Paediatric oncology centres at Great Ormond Street Hospital for Children and the Royal Marsden Hospital., Subjects: Survivors of childhood leukaemia who received cranial irradiation, were in continuous first remission, and had reached final height. An unirradiated group of patients from the United Kingdom acute lymphoblastic leukaemia XI trial was also included; these patients were in continuous first remission and had been followed for at least four years from diagnosis., Main Outcome Measures: Body mass index standard deviation score (BMI z score) at final height for irradiated patients and at most recent follow up for unirradiated patients. Regression analysis was used to examine the effect on BMI z score of sex, age at diagnosis, and the dose of radiation received., Results: For cranially irradiated patients, an increase in the BMI z score at final height was associated with female sex and lower radiation dose, but not with age at diagnosis. Severe obesity, defined as a BMI z score of > 3 at final height, was only present in girls who received 18-20 Gy irradiation and had a prevalence of 8%. Both male and female unirradiated patients had raised BMI z scores at latest follow up and there was no association with age at diagnosis., Conclusions: These data are further evidence for a sexually dimorphic and dose dependent effect of radiation on the human brain.

McCune-Albright syndrome consists of fibrous dysplasia of bone, café-au-lait skin pigmentation, and endocrine dysfunction (usually precocious puberty). Other endocrine abnormalities occur in a minority of patients, and of these, Cushing's syndrome is the least often recognized. We present 5 children (4 girls) with features of McCune-Albright syndrome who had Cushing's syndrome in the infantile period (<6 months). In 2 children spontaneous resolution occurred, but the remaining 3 required bilateral adrenalectomy. In addition, all 4 girls have experienced precocious puberty, and 3 children demonstrated radiologic evidence of nephrocalcinosis. Understanding of the underlying defect causing McCune-Albright syndrome emphasizes the importance of searching for other endocrine dysfunction in these children.

Familial male-limited precocious puberty (FMPP) is a form of luteinizing hormone-releasing hormone (LHRH)-independent isosexual precocious puberty caused by gain-of-function mutations of the luteinizing hormone/chorionic gonadotropin receptor (hLHR). The most common mutation is 1733 A>G, which causes substitution of Asp-578 by Gly. In this study, a male infant presented at the age of 20 months with accelerated sexual development was analyzed for the presence of activating mutations of the hLHR. Analysis of exon 11 of the hLHR gene by genomic polymerase chain reaction (PCR), asymmetric PCR, and dideoxy sequencing identified a single base substitution, 1734 T>A, which led to the replacement of Asp-578 by Glu. The same mutation was found in the mother. Expression of the mutated hLHR in HEK 293 cells demonstrated elevated basal levels of intracellular cAMP in the transfected cells confirming the constitutive activating nature of the mutated hLHR. A possible genotype-phenotype relationship of the hLHR mutations was examined by a comparison of the in vitro activities of the hLHRs carrying the Asp578Gly, Asp578Tyr, Asp578Trp, and Asp578Glu mutations in HEK 293 cells. A positive correlation between the size of the substituting amino acid and the basal level of intracellular cAMP of cells expressing the mutated receptor was demonstrated., (Copyright 1999 Academic Press.)

We previously identified a nonsense mutation (Cys545Stop) in the paternal human LH/CG receptor (hLHR) allele in a family with two 46,XY children afflicted with Leydig cell hypoplasia. This mutation abolished the signal transduction capability of the affected hLHR. We have now examined all coding exons and the transcript of both alleles of the hLHR gene of the affected children. A 33-bp in-frame insertion was found in the maternal hLHR allele. This insertion occurred between nucleotide 54 and 55 and might be the result of a partial gene duplication. Genomic DNA-PCR showed that this defective maternal hLHR allele was inherited by the two affected children. However, examination of the inheritance of the 935-A/G polymorphism of the hLHR by genomic- and RT-PCR indicated that the maternal hLHR allele was not expressed in cultured fibroblasts of the patients. The effect of the in-frame insertion on the biological activity of the hLHR was examined by expressing the mutated hLHR construct, generated by site-directed mutagenesis, in HEK 293 cells. The expression of the mRNA for the mutant hLHR in HEK 293 cells was not affected. Response of cells expressing the mutated hLHR to hCG stimulation was impaired as demonstrated by reduced intracellular cAMP biosynthesis. This change in signal transduction was the result of a profound reduction in hormone binding at the cell surface due to altered expression and processing of the mutated receptor. We conclude that Leydig cell hypoplasia in this family is the result of compound heterozygous loss-of-function mutations of the hLHR gene.

Studies to date on the treatment with insulin-like growth factor I (IGF-I) of children with growth hormone (GH) insensitivity syndrome (GHIS) have concentrated principally on the effects of IGF-I therapy on the GH-IGF-I axis and on growth velocity. Little is known, however, about the metabolic status of children with GHIS and the consequences of IGF-I treatment on circulating intermediary metabolites involved in glucose homeostasis. We have studied 5 children with GHIS, aged 4.5-9 years, 3 male and 2 female, before and after 3 months of treatment with recombinant IGF-I, 80 microg/kg s.c. twice a day. The children were short (height SDS -3.8 to -7.3) and growing slowly (height velocity 1.8-3.4 cm/year). All were neurodevelopmentally normal at the time of the study with no history of severe symptomatic hypoglycaemia, in particular during the neonatal period. Before treatment, 4 of the 5 children demonstrated spontaneous hypoglycaemia (blood glucose <2.6 mmol/l), particularly at night, accompanied by substantial hyperketonaemia (range 1.43-4. 63 mmol/l) and hyperfattyacidaemia (range 1.11-3.08 mmol/l). After 3 months of IGF-I treatment, the blood glucose concentrations in the diurnal profile were increased, with improvement in spontaneous hypoglycaemia and with increased fasting tolerance. The postprandial insulin-to-glucose ratio was reduced. GHIS is thus associated with asymptomatic nocturnal hypoglycaemia without apparent neurological deficit. Despite functional GH deficiency, brisk counter-regulation to hypoglycaemia occurred as evidenced by hyperfattyacidaemia and hyperketonaemia. Treatment with IGF-I twice a day improved fasting glucose tolerance, diurnal blood glucose concentrations, and postprandial insulin-to-glucose ratios. There was no exacerbation of hypoglycaemia on treatment. We suggest that in severe GH resistance, a protective mechanism exists for the brain from the effects of hypoglycaemia, at least partially mediated by excessive production of counter-regulatory metabolic fuels.

Between 8% and 16% (2.5 to 4.9 million) of the elder population have experienced food insecurity within a 6-month period. Federal programs to combat food insecurity reach only one-third of needy elders. While hunger and poverty are linked directly to malnutrition, the multifaceted nature of elderly malnutrition cuts across all economic, racial, and ethnic groups. Malnourished patients experience 2 to 20 times more complications, have up to 100% longer hospital stays, and compile hospital costs $2,000 to $10,000 higher per stay. Dietitians can advocate routine nutrition screening to target elders at highest risk and lobby for expansion of appropriate nutrition services in home, community, and institutional settings.

Aim: To analyse critically a protocol for the investigation of girls presenting with virilisation in childhood., Methods: Twenty five girls aged 1.6-8.7 years with features of virilisation were evaluated. Twenty four had presented with pubic hair, eight with auxilliary hair, seven with facial acne, four with clitoromegaly, and 10 with tall stature. They underwent clinical assessment (height, weight, height velocity, staging of puberty, physical examination for acne, body odour, and clitoromegaly) and laboratory assessment comprising basal concentrations of cortisol, 17 OH-progesterone (17 OHP), androstenedione, dehydroepiandrosteronesulphate (DHEAS), testosterone, and oestradiol. The above steroids were also measured during the short synacthen test (0.25 mg intramuscularly) in 16 subjects and low dose dexamethasone suppression tests (0.5 mg at six hourly intervals over 48 hours). Pelvic ultrasound, computed tomography and magnetic resonance imaging of adrenals were carried out when the biochemical findings suggested that there might be an autonomous source of androgen secretion., Results: Clinical and laboratory assessments differentiated the patients into three diagnostic categories: adrenarche (18 cases), congenital adrenal hyperplasia (five cases), and adrenocortical tumour (two cases). The last had elevated concentrations of DHEAS, 1.5 and 19.1 mumol/l (normal value < 0.5 mumol/l), androstenedione, 24.6 and 21.8 nmol/l (normal < 1 nmol/l), and testosterone, 4.5 and 2.4 nmol/l (normal < 0.8 nmol/l), with none suppressing on dexamethasone suppression. Congenital adrenal hyperplasia subjects had elevated basal serum concentrations of 17 OHP (n = 4): 250, 140, 14, and 14.1 nmol/l (normal < 10 nmol/l) and elevated peak values of 17 OHP after synacthen (n = 3): 76, 179.5, and 175 nmol/l. Adrenarche patients had elevated basal concentrations of DHEAS (median: 2.3 mumol/l; n = 17) and androstenedione (median 2.6 nmol/l; n = 17). Nine patients also had elevated basal serum testosterone concentrations (median 0.9 nmol/l). Peak values of 17 OHP after synacthen were significantly different from baseline (n = 12) and were < 50% of the lowest value in congenital adrenal hyperplasia. Serum DHEAS, androstenedione, and testosterone suppressed following dexamethasone suppression (n = 16), thereby distinguishing adrenarche patients from adrenal tumour patients. Clinical details did not distinguish patients, except for clitoromegaly which was present only in the tumour and congenital adrenal hyperplasia patients., Conclusions: This protocol proved useful and practical in cases of virilisation presenting particular diagnostic difficulty.

Objective: Conventional treatment of familial hypophosphaiaemic rickets with oral phosphate and 1 alpha-hydroxycholecalciferol (1 alpha HCC) does not satisfactorily correct the metabolic or physical defects of the disease and can have adverse effects, such as nephrocalcinosis. Hyperoxaluria from increased oral phosphate intake may contribute to nephrocalcinosis. Growth hormone enhances renal tubular phosphate reabsorption and 1,25-dihydroxy-cholecalciferol production in normal and in GH deficient individuals, and may thus be of benefit to patients with familial hypophosphataemic rickets., Patients: We have assessed the acute effects of GH on phosphate and calcium metabolism in 6 children (age 4-14 years) with familial hypophosphataemic rickets., Design: Each patient served as his/her own control and received the following in a sequential non-randomized design: conventional treatment with oral phosphate 1.0-3.4 mmol/kg/day in 3-6 divided doses and 1 alpha HCC 18-31 ng/kg/day-no treatment-GH 0.05 mg/kg daily-GH and 1 alpha HCC-and GH with phosphate and 1 alpha HCC. Each treatment was given for 7 days with 7 day periods of no treatment in between., Measurements and Results: Glomerular filtration rate, tubular maximum rate of phosphate reabsorption per litre of glomerular filtrate (TmP/GFR) and serum 1,25-dihydroxycholecalciferol increased with GH. Mean 24-hour plasma phosphate concentrations did not increase with GH but were higher in the treatment phases which included phosphate and 1 alpha HCC (P = 0.002). Serum PTH was higher when GH was given in combination with phosphate and 1 alpha HCC compared to other phases. Urine oxalate excretion did not differ between the treatment phases., Conclusions: GH seemed to partially correct the defects in renal tubular phosphate transport and 1 alpha-hydroxylation of 25-hydroxycholecalciferol. We speculate that the net effect of GH treatment was an increase in body phosphate, although this was not reflected in a change in plasma phosphate. Therefore, GH in combination with 1 alpha HCC may act as a phosphate sparing agent, permitting treatment with lower and less frequent doses of oral phosphate and reducing adverse effects such as nephrocalcinosis.

Craniometaphyseal and craniodiaphyseal dysplasia are rare genetic disorders of bone due to modelling errors of long bones and skull bones. These syndromes present with multiple ENT symptomatology from an early age. The diagnostic distinction can now be made radiologically by serial skeletal survey which is important for prognosis. We review the clinical, radiological, computed tomography (CT) scan, otological, audiological and histopathological findings in two cases with craniodiaphyseal, and two cases with craniometaphyseal dysplasia, and report our experiences of medical and surgical treatment to date. In the craniodiaphyseal dysplasia, the hearing abnormality progressed from an initial conductive to a mixed loss on serial audiometric follow up. Temporal bone CT scans showed narrowing of the middle ear cavity, internal auditory meatus, and facial nerve canal at the geniculate ganglion. Benefits from choanal stenosis surgery, craniofacial remodelling and dacrocystorhinostomy were shortlived. Calcitriol therapy with a low calcium diet did not alter the clinical course of progression in our cases. The underlying defect, causing net bone formation in these phenotypically similar syndromes, appears to be different when based on the differing biochemical responses to calcitriol and bone biopsy findings. Increased numbers of osteoblasts were found in bone biopsies from both cases with craniodiaphyseal dysplasia. Early recognition is crucial in these conditions as therapy directed at the underlying bony defect has the best chance of success if initiated in infancy.

Leydig cell hypoplasia (LCH) is a form of male pseudohermaphroditism in which Leydig cell differentiation and testosterone production are impaired. This report describes the first case of a nonsense mutation (A1635C) in exon 11 of the human luteinizing hormone receptor (hLHR) gene in two sisters with LCH. This mutation causes loss of function of the receptor by introducing a stop codon at residue 545 in transmembrane helix 5 of the hLHR. Surface expression of the truncated hLHR (hLHR-t545) in human embryonic kidney cells stably transfected with cDNA encoding hLHR-t545 was diminished compared to the wild-type hLHR and hCG-induced cAMP accumulation was impaired. These results establish that single base mutations in exon 11 of the hLHR gene can produce inactivation as well as activation of the hLHR. Furthermore, they demonstrate that functional domains between transmembrane helix 5 and the C-terminal cytoplasmic tail of the hLHR are required for normal cell surface expression of the receptor and signal transduction.

Two young (< 2 years old) elephants (Loxodonta africana) died suddenly and simultaneously at Ongava Game Reserve bordering on the Etosha National Park, Namibia. Both elephants showed lung congestion, epi- and endocardial haemorrhages and hyperaemic areas in the mucosa of the stomach and small intestine. Histopathology of the myocardium showed multifocal degeneration and necrosis of muscle fibres accompanied by haemorrhages. Parts of the leaves of the alien plant Cryptostegia grandiflora (Asclepiadaceae) were found in the intestinal tracts of the elephants. These findings suggested that the elephants died from heart failure after ingesting this plant which contains cardiac glycosides.

The consequences of IBD during childhood and adolescence may be devastating in terms of loss of growth potential, particularly if there has been a clinical course of frequent relapses resulting in inadequate nutrition and associated with repeated courses of steroid treatment. There is to date, however, a paucity of data recording final adult heights in such patients. The anticipation of relapse should become easier with increasing awareness of the importance of parameters of growth and pubertal development. Early and intensive nutritional support, and the use of steroid-sparing agents should help reduce the frequency and severity of any height deficit. The performance and timing of surgery must take into account the child's status in terms of height velocity and pubertal development. The importance of inducing the remission before the onset of puberty is stressed and this remission should be sustained at all costs during the pubertal years so that valuable height is not lost as a consequence of a missed pubertal growth spurt. Thus, increasing awareness of the issues of growth and development in these patients should improve the accuracy of initial diagnosis and early recognition of relapse, such that these children are ensured the best possible provision for achieving their full height potential.

We studied 11 normal adult males. Six subjects (Study A) received a bolus of saline or of 50 mU biosynthetic human growth hormone (r-hGH) or a one hour iv infusion of r-hGH (80 mU/h) in random order. On each occasion this was followed by an iv bolus of GHRH (1-29) NH2 (100 micrograms) 90 minutes after the first event. Five subjects (Study B) received a bolus iv injection of saline or of 500 mU r-hGH followed by iv GHRH (1-29) NH2 (100 micrograms) 90 minutes later. There was no significant difference in the serum GH concentrations achieved following the 50 mU bolus or iv infusion of r-hGH (range 5.6-67.0 mU/l). Higher concentrations of GH (mean +/- SE, 238.4 +/- 21.3 mU/l) were achieved with the 500 mU bolus of r-hGH. The peak GH responses to iv GH-RH (1-29) NH2 were similar in all instances. The most important factor determining the response to exogenous GHRH (1-29) NH2 was the serum GH concentration at the time that the GHRH (1-29) NH2 was administered and the mode of r-hGH administration (iv bolus or iv infusion). These data demonstrate that within the range of physiological serum GH concentrations the mode of presentation of GH (bolus or infusion) and GH secretory status are the most important factors in determining GH responsivity to GHRH. Under these circumstances GH would appear not to participate in a rapid-acting short-loop negative feedback mechanism in man as the response to exogenous GHRH was not attenuated.

Ninety-three healthy children attending routine school and community medical examinations were questioned about tinnitus, 27 of them (29%) described tinnitus. Nine children (9.6%) were bothered by their symptom, the others were not. The incidence of tinnitus in this group was compared with that in a group of 109 children with ear disease. Forty-two children (38.5%) in this group reported tinnitus. This difference is not statistically significant. Details of children attending paediatric ENT clinics were recorded by two ENT surgeons. Four hundred and three children were seen during the study period and of these 13 (3%) reported tinnitus spontaneously. All these children had evidence of ear disease at the time of the consultation. The incidence of tinnitus in those members of this group with abnormal ears was significantly higher than in those children with no evidence of ear disease (P = less than 0.02). Tinnitus may be a manifestation of ear disease in children, but may also be described by children with normal ears.

The parents of children with secretory otitis media and the parents of healthy children attending for routine school or community medical examinations have been questioned about previous acute otitis media, aural discharge, chronic nasal symptoms and allergic disorders. Eighty-nine pairs of children, matched for age and sex, were available for analysis. There was a significantly higher incidence of acute otitis media, aural discharge and chronic nasal symptoms in the secretory otitis group (P = less than 0.001). Amongst the allergic symptoms and disorders, the only significant differences demonstrated were for drug allergy, eye itching and eye running (P = less than 0.05). The results confirm that a relationship exists between acute otitis media and secretory otitis media and also support the conventional image of the child with secretory otitis as a mouth breather with nasal symptoms. They do not lend support to the view that allergy is an important factor in the pathogenesis of secretory otitis.