Bipedal distribution of human vestibular-evoked postural responses during asymmetrical standing

Galvanic vestibular stimulation (GVS) evokes responses in muscles of both legs when bilateral stimuli are applied during normal stance. We have used this technique to assess whether asymmetrical standing alters the distribution of responses in the two legs. Subjects stood either asymmetrically with 75 % of their body weight on one leg or symmetrically with each leg taking 50 % of their body weight. The net response in each leg was taken from changes in ground reaction force measured from separate force plates under each foot. The net force profile consisted of a small initial force change that peaked at ∼200 ms followed by an oppositely directed larger component that peaked at ∼450 ms. We analysed the second force component since it was responsible for the kinematic response of lateral body sway and tilt towards the anode. In the horizontal plane, both legs produced lateral force responses that were in the same direction but larger in the leg ipsilateral to the cathodal ear. There were also vertical force responses that were of equal size in both legs but acted in opposite directions. When subjects stood asymmetrically the directions of the force responses remained the same but their magnitudes changed. The lateral force response became 2-3 times larger for the more loaded leg and the vertical forces increased 1.5 times on average for both legs. Control experiments showed that these changes could not be explained by either the consistent (< 5 deg) head tilt towards the side of the loaded leg or the changes in background muscle activity associated with the asymmetrical posture. We conclude that the redistribution of force responses in the two legs arises from a load-sensing mechanism. We suggest there is a central interaction between load-related afferent input from the periphery and descending motor signals from balance centres.     

Malaria transmission and naturally acquired immunity to PfEMP-1

Why there are so few gametocytes (the transmission stage of malaria) in the blood of humans infected with Plasmodium spp. is intriguing. This may be due either to reproductive restraint by the parasite or to unidentified gametocyte-specific immune-mediated clearance mechanisms. We propose another mechanism, a cross-stage immunity to Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP-1). This molecule is expressed on the surface of the erythrocyte infected with either trophozoite or early gametocyte parasites. Immunoglobulin G antibodies to PfEMP-1, expressed on both life cycle stages, were measured in residents from an area where malaria is endemic, Papua New Guinea. Anti-PfEMP-1 prevalence increased with age, mirroring the decline in both the prevalence and the density of asexual and transmission stages in erythrocytes. These data led us to propose that immunity to PfEMP-1 may influence malaria transmission by regulation of the production of gametocytes. This regulation may be achieved in two ways: (i) by controlling asexual proliferation and density and (ii) by affecting gametocyte maturation.     

Intestinal metaplasia in endoscopic biopsy specimens of gastric mucosa

A total of 1412 consecutive cases of endoscopic gastric biopsy, carried out over a four year period, were reviewed and specimens were examined histochemically to determine the prevalence of intestinal metaplasia and its variants. Three types were characterised: complete intestinal metaplasia and two classes of incomplete intestinal metaplasia (type IIa and type IIb) depending on the absence or presence, respectively, of sulphomucins within mucin secreting columnar cells. Type IIb intestinal metaplasia was significantly more common in patients with gastric carcinoma (p less than 0.001) and in those with dysplasia (p less than 0.001) than in patients with benign gastric pathology. No such association was found with either type I or type IIa intestinal metaplasia. In addition to those present in the columnar cells of type IIb intestinal metaplasia, sulphomucins were also commonly found in goblet cells of all three types of metaplasia. The presence of sulphomucins in goblet cells, however, was not significantly associated with gastric carcinoma or dysplasia. The significance of the different types of intestinal metaplasia in relation to the pathological findings is discussed.     

The potentiating effect of rheumatoid arthritis serum in the immediate phase of nephrotoxic nephritis

Nephrotoxic nephritis induced in rats was employed as an experimental model to investigate the possible effects of rheumatoid factor on in vivo antigen–antibody reactions. Rats injected simultaneously with rheumatoid arthritis serum and rabbit nephrotoxic globulin showed a three-fold increase in immediate proteinuria compared with rats injected with nephrotoxic globulin alone. This potentiating effect of rheumatoid arthritis serum was evident even when the serum was injected 48 hr after the nephrotoxic globulin and was also apparent to a lesser extent in rats decomplemented by a prior injection of aggregated human IgG. Normal human serum had no effect on the proteinuria produced by a standard dose of nephrotoxic globulin while rheumatoid arthritis serum injected with normal rabbit globulin did not increase urinary protein excretion above baseline levels. In rats injected with rheumatoid arthritis serum and nephrotoxic globulin, human IgM (presumably rheumatoid factor) was detected by immunofluorescence on the glomerular basement membrane along with the nephrotoxic globulin and rat complement and persisted at this site for as long as 42 days after the initial injections. Rheumatoid factor activity was also recovered by elution from glomeruli isolated from rat kidneys 24 hr after the injection of rheumatoid arthritis serum and nephrotoxic globulin.     

Circulating immune complexes, complement and complement component levels in childhood Hodgkin's disease.

Serum levels of circulating immune complexes (CIC) assayed by the Raji cell radioimmunoassay, total haemolytic complement (TCH50), Clq and C3 were correlated with clinical stage, histological type, age, sex and treatment of eighty-six children with Hodgkin's disease over a period of 4 years. Most significant findings were the changes of levels of CIC, TCH50, Clq and C3 during disease activity and following treatment. Significant perturbations were also seen in association with relapse. Levels of C and CIC were significantly elevated (P less than 0.001) at the time of diagnosis prior to splenectomy and/or any treatment. In the group before treatment, 81 percent of CIC levels were above 16 micrograms/ml with a maximum value of 1120 micrograms/ml. During treatment 33 percent were still above normal with a maximum of 320 micrograms/ml. Within 1 year after cessation of treatment, 37 percent also remained above normal levels with a maximum of 240 micrograms/ml. At relapse prior to treatment, 63 percent were again elevated with a maximum of 1280 micrograms/ml. The most significant difference on TCH50 levels relates to treatment periods. Sera of patients with active disease who are previously untreated show elevation of TCH50 levels (P less than 0.001) (average 127 CH50 mu/ml. During and after treatment eht TCH50 levels drop to 96 and 102 CH50 mu/ml, as compared to normal control of 100 CH50 mu/ml. In sera of patients at the first, second or third relapse, the combined TCH50 levels are significantly different from controls and across treatment periods (P less than 0.005).     

SCA8 CTG repeat: en masse contractions in sperm and intergenerational sequence changes may play a role in reduced penetrance

We recently described an untranslated CTG expansion that causes a previously undescribed form of spinocerebellar ataxia (SCA8). The SCA8 CTG repeat is preceded by a polymorphic but stable CTA tract, with the configuration (CTA)(1-21)(CTG)(n). The CTG portion of the repeat is elongated on pathogenic alleles, which nearly always change in size when transmitted from generation to generation. To better understand the reduced penetrance and maternal penetrance bias associated with SCA8 we analyzed the sequence configurations and instability patterns of the CTG repeat in affected and unaffected family members. In contrast to other triplet repeat diseases, expanded alleles found in affected SCA8 individuals can have either a pure uninterrupted CTG repeat tract or an allele with one or more CCG, CTA, CTC, CCA or CTT interruptions. Surprisingly, we found six different sequence configurations of the CTG repeat on expanded alleles in a seven generation family. In two instances duplication of CCG interruptions occurred over a single generation and in other instances duplications that had occurred in different branches of the family could be inferred. We also evaluated SCA8 instability in sperm samples from individuals with expansions ranging in size from 80 to 800 repeats in blood. Surprisingly the SCA8 repeat tract in sperm underwent contractions, with nearly all of the resulting expanded alleles having repeat lengths of <100 CTGs, a size that is not often associated with disease. These en masse repeat contractions in sperm likely underlie the reduced penetrance associated with paternal transmission.     

Null mutation in human ciliary neurotrophic factor gene confers higher body mass index in males

Ciliary neurotrophic factor (CNTF) administration reduces weight in leptin-resistant mice via the signalling pathway normally activated by leptin. A G>A null mutation in the CNTF gene results in complete absence of protein. We hypothesised that absence of CNTF could lead to diminished initiation of anorectic pathways, with consequent increase in body mass. In 575 Caucasian men aged 59-73 years, the A/A genotype (frequency 1.9%) was associated with a 10 kg increase in weight (P=0.03, 2 df) and 3 kg/m(2) greater BMI (P=0.02, 2 df). There was no effect in women. The CNTF G>A null mutation therefore confers a moderate effect on obesity in males of A/A genotype, who represent 1% of the general population.