Relationship between insulin-mediated glucose disposal and lipid metabolism in man.

To assess the possible effects of lipid metabolism on insulin-mediated glucose disposal, 18 nondiabetic Pima Indian women (age 18-35 yr) were studied using 1-14C-palmitate infusion to measure free fatty acid turnover rate followed by a euglycemic clamp (clamp) to measure in vivo insulin-mediated glucose disposal (M). Indirect calorimetry was performed in the basal state and during the clamp. This was used to assess glucose oxidation rate, lipid oxidation rate, and to calculate nonoxidative glucose disposal (storage). Basal and clamp lipid oxidation rate correlated with basal plasma free fatty acid concentration (r = 0.81, P less than or equal to 0.0001, r = 0.67, P less than 0.003, respectively). The fall in lipid oxidation was highly correlated with the increase in glucose oxidation during the insulin infusion (r = 0.96, P less than or equal to 0.0001). The clamp lipid oxidation rate negatively correlated with the glucose oxidation rate (r = -0.85, P less than 0.0001) and with the M value (r = -0.60, P less than 0.01) but was not correlated with the clamp glucose storage (r = -0.2, P = 0.4). On the other hand, glucose storage appeared to make a greater contribution to the difference in M value between the upper and lower extremes of M than did glucose oxidation, as evidenced by an increase in glucose storage of 0.59 mg/kg fat-free mass times minute per 1 mg/kg fat-free mass times minute increase in glucose disposal. The M value was negatively correlated with obesity as measured by percent body fat (r = -0.64, P less than 0.004), but neither basal free fatty acid concentration, basal free fatty acid turnover, basal lipid oxidation, nor clamp lipid oxidation correlated with percent body fat. We conclude that an interaction of lipid and glucose metabolism in a glucose fatty acid cycle, as proposed by Randle et al. (1), may be operative in the regulation of glucose oxidation in man. The disposal of glucose however has two components. The storage component does not appear to be associated with lipid oxidation in the way that the oxidative component is and may be regulated by a different mechanism. Since the results show that the glucose storage component plays a significant role in distinguishing between those with low and high M values, we suggest that the glucose fatty acid cycle can, at best, only partially explain impaired in vivo insulin-mediated glucose disposal. Furthermore, the data suggest that the impact of obesity on in vivo insulin resistance appears to be mediated by factors other than changes in lipid availability or metabolism.     

Expression of the N-myc oncogene in Wilms' tumour and related tissues

Tissue samples and cell cultures from Wilms' tumour matched histologically normal kidney samples and EBV transformed B cells from the same patients, were analysed to detect changes in the structure and expression of the N-myc oncogene. The levels of expression of HLA class I and hypoxanthine guanine phosphoribosyl transferase were also measured in the various RNA preparations. Related tissue samples, from sources including congenital mesoblastic nephroma, paediatric neuroblastoma and a number of foetal tissues were also tested. Northern blot analysis indicated that the levels of N-myc were higher in Wilms' tumour tissues (with no parallel increase in gene copy number) compared to all other sources of material including foetal kidney. Particularly high levels of expression were observed in a number of the Wilms' tumours, several of which produced metastases. In situ hybridization, using [35S]-labelled RNA probes, confirmed that the high levels of N-myc RNA were present in the blastemal elements in the Wilms' tumour. All the tissue cultures, and tissue samples from other sources, except foetal brain and neuroblastoma, contained uniformly low levels of N-myc RNA.     

Baclofen induces spontaneous, rhythmic sharp waves in the rat hippocampal slice

In rat hippocampal slices, low concentrations of (+/-) baclofen (0.1 to 1.5 microM) elicited spontaneous, rhythmic sharp waves (SRSWs). These low amplitude (0.1 to 0.3 mV) SRSWs were visible with high amplification in the extracellular recordings from the CA1, CA2, and CA3 regions and were roughly synchronous in all areas. SRSW amplitude increased and frequency decreased as baclofen concentration increased up to 1.5 microM, but SRSWs were suppressed at concentrations of 5 microM and higher. The amplitude of the SRSWs was greater in the strata radiatum and the lacunosum moleculare than in the stratum pyramidale. (-)-Baclofen was much more potent in eliciting SRSWs than (+)-baclofen. Low concentrations of baclofen also caused the extracellular excitatory postsynaptic potential in the stratum radiatum of CA3b evoked by stimulation of the Schaffer collaterals to broaden and develop a secondary peak. Slices pretreated with pertussis toxin required much higher concentrations of baclofen to elicit the SRSWs, indicating that the baclofen may be eliciting the SRSWs through a G protein-sensitive mechanism. Baclofen has both inhibitory and disinhibitory effects on neurons. The appearance of these spontaneous population events suggests that, at low concentrations, the disinhibitory effects may be more powerful than the inhibitory effects.     

Distribution of in vivo insulin action in Pima Indians as mixture of three normal distributions

If a single gene produced insulin resistance, with environmental effects creating some additional variance, insulin action might be distributed as a mixture of two normal distributions if the gene is dominant or recessive or as a mixture of three normal distributions if the gene is codominant. To estimate maximal insulin-stimulated glucose uptake rates (MaxMs), hyperinsulinemic-euglycemic clamps were performed on 245 nondiabetic Pima Indians (126 men, 119 women). Five models (for 1, 2, 3, 4, or 5 components each, normally distributed with a common variance) were fitted to the frequency distribution of MaxM by iterative maximum-likelihood estimation. The three-component model fit the data significantly better than a single normal distribution (chi 2 = 14.3 with 4 df P less than .01) or a mixture of two normal distributions (chi 2 = 9.9 with 2 df, P less than .01). Mixtures of four or five normal distributions did not fit the data significantly better than a mixture of three normal distributions. The first component of the distribution comprised 23%, the second 48%, and the third 29% of the total distribution. Similarly, the frequency distributions of fasting plasma insulin concentrations and a principal component score derived from MaxM and fasting insulin were best fitted by a mixture of three normal distributions. These results are consistent with the hypothesis that among Pimas, insulin resistance is determined by a single gene with a codominant mode of inheritance. Segregation analyses of studies performed in pedigrees are indicated to prove or disprove this genetic hypothesis.     

Paroxysmal block in phase 4 of the bundle of His]

Five cases of chronic paroxysmal atrio-ventricular block are reported, being unusual in the siting of the conduction defect within the trunk of the bundle of His, and in the "paradoxical" mode of onset of the block. The ventriculograms which were carried out, and the escapes, were of normal duration in four cases and the intracavitary recordings showed a double His potential in all patients. In one case, the block during phase 4 seemed to occur at the height of the trunkal Wenkebach periods, and in another it could be brought on by manipulation of the vagus. In all five cases, a favorable conduction zone could be calculated, the block to the P waves in phase 4 occuring in an arithmetical fashion after a critical lengthening of the PR interval. The return to sinus rhythm was always related to an escape (or to an electrically induced ventricular complex), but the explanation of the initial capture on electrophysiological grounds is obscure.     

Intranodal reciprocal dual rhythm]

In a patient with spells of paroxysmal supraventricular tachycardia of two types, the stimulation tests demonstrated a dual intranodal conduction responsible sometimes for "usual" reciprocal rhythms (slow anterograde pathway and rapid retrograde pathway), sometimes for "reversed" reciprocal rhythms (rapid anterograde pathway and slow retrograde pathway). The latter contrasted with the lack of discontinuity of the retrograde nodal function curve (V1-V2 versus A1-A2).     

Multidisciplinary assessment at a child development centre: do we conform to recommended standards?

BACKGROUND: A proposed standard for the multidisciplinary assessment (MDA) of children with autism has been recently published by the National Autistic Society. This prompted a review of current practice at the child development centre in our local centre, to judge whether we were able to conform to the proposed national standard. The recommendation is that a child should complete a three-stage assessment process from referral to completion of assessment within 30 weeks, with set times for completion of each stage (6, 7 and 17 weeks respectively). We applied this assessment model to children with a range of neurodevelopment problems, as the process of MDA is the same, irrespective of diagnosis. METHODS: A retrospective analysis of medical and therapy records of all MDAs was carried out between April 2001 and March 2002. RESULTS: In the 12-month period studied, 52 MDAs were performed. Delays occurred, as judged by the standard, at all three stages of the assessment process. A total of 42% of children were seen within 6 weeks of initial referral, 37% within a further 7 weeks for specialist assessment, and 37% within a further 17 weeks for completion of MDA. As delays occurred at all stages, the cumulative total showed that only 19% of children completed all three stages within the recommended 30-week standard. Barriers encountered included waiting times to see professionals, parental non-attendance and prolonged assessment of complex problems. Some of these factors are outside our control, and on removing these factors the data were re-analysed. This resulted in a slight improvement to 45%, 48% and 49% for completion of stages 1, 2 and 3 respectively. The major reason for delay remained the service capacity. CONCLUSION: In our experience the standards proposed by the National Autistic Society are not practical within present resources. We suggest that a reasonable expectation is to complete all assessments, from first concern to completed MDA, should be carried out within 52 weeks with present levels of resources. Any further improvement will require additional resources to reduce waiting times and increase the capacity.     

Benign mesenchymoma of the chest wall in infancy

Chest wall mesenchymoma is a rare tumour in childhood and often presents in the neonatal period. In the past all patients have received surgical treatment with quite a high morbidity. We present here three further cases that presented in infancy, two of which received minimal therapy with good results in each case. We would propose from these cases that once the diagnosis has been established by biopsy that total surgical resection not be carried out unless cardiac or respiratory embarrassment is present.