Childhood craniopharyngioma: greater hypothalamic involvement before surgery is associated with higher homeostasis model insulin resistance index

<p>Abstract</p> <p>Background</p> <p>Obesity seems to be linked to the hypothalamic involvement in craniopharyngioma. We evaluated the pre-surgery relationship between the degree of this involvement on magnetic resonance imaging and insulin resistance, as evaluated by the homeostasis model insulin resistance index (HOMA). As insulin-like growth factor 1, leptin, soluble leptin receptor (sOB-R) and ghrelin may also be involved, we compared their plasma concentrations and their link to weight change.</p> <p>Methods</p> <p>27 children with craniopharyngioma were classified as either grade 0 (n = 7, no hypothalamic involvement), grade 1 (n = 8, compression without involvement), or grade 2 (n = 12, severe involvement).</p> <p>Results</p> <p>Despite having similar body mass indexes (BMI), the grade 2 patients had higher glucose, insulin and HOMA before surgery than the grade 0 (P = 0.02, <0.05 and 0.02 respectively) and 1 patients (P < 0.02 and <0.03 for both insulin and HOMA). The grade 0 (5.8 ± 4.9) and 1 (7.2 ± 5.3) patients gained significantly less weight (kg) during the year after surgery than did the grade 2 (16.3 ± 7.4) patients. The pre-surgery HOMA was positively correlated with these weight changes (P < 0.03).</p> <p>The data for the whole population before and 6–18 months after surgery showed increases in BMI (P < 0.0001), insulin (P < 0.005), and leptin (P = 0.0005), and decreases in sOB-R (P < 0.04) and ghrelin (P < 0.03).</p> <p>Conclusion</p> <p>The hypothalamic involvement by the craniopharyngioma before surgery seems to determine the degree of insulin resistance, regardless of the BMI. The pre-surgery HOMA values were correlated with the post-surgery weight gain. This suggests that obesity should be prevented by reducing inn secretion in those cases with hypothalamic involvement.</p

Deleterious GRM1 Mutations in Schizophrenia

We analysed a phenotypically well-characterised sample of 450 schziophrenia patients and 605 controls for rare non-synonymous single nucleotide polymorphisms (nsSNPs) in the GRM1 gene, their functional effects and family segregation. GRM1 encodes the metabotropic glutamate receptor 1 (mGluR1), whose documented role as a modulator of neuronal signalling and synaptic plasticity makes it a plausible schizophrenia candidate. In a recent study, this gene was shown to harbour a cluster of deleterious nsSNPs within a functionally important domain of the receptor, in patients with schizophrenia and bipolar disorder. Our Sanger sequencing of the GRM1 coding regions detected equal numbers of nsSNPs in cases and controls, however the two groups differed in terms of the potential effects of the variants on receptor function: 6/6 case-specific and only 1/6 control-specific nsSNPs were predicted to be deleterious. Our in-vitro experimental follow-up of the case-specific mutants showed that 4/6 led to significantly reduced inositol phosphate production, indicating impaired function of the major mGluR1signalling pathway; 1/6 had reduced cell membrane expression; inconclusive results were obtained in 1/6. Family segregation analysis indicated that these deleterious nsSNPs were inherited. Interestingly, four of the families were affected by multiple neuropsychiatric conditions, not limited to schizophrenia, and the mutations were detected in relatives with schizophrenia, depression and anxiety, drug and alcohol dependence, and epilepsy. Our findings suggest a possible mGluR1 contribution to diverse psychiatric conditions, supporting the modulatory role of the receptor in such conditions as proposed previously on the basis of in vitro experiments and animal studies

Management of childhood craniopharyngioma: can the morbidity of radical surgery be predicted?

Seventy-five children treated for craniopharyngioma between 1973 and 1994 were studied to demonstrate which pre- and intraoperative factors were indicative of a poor outcome as defined by a quantitative assessment of morbidity. This involved a retrospective review of 65 patients and a prospective study of 10 patients focused on clinical details and cranial imaging and a follow-up "study assessment" of 66 survivors performed over the last 2 years. As part of the assessment, 63 patients underwent magnetic resonance imaging with a three-dimensional volume acquisition sequence 1.5 to 19.2 years after initial surgery. Predictors of high morbidity included severe hydrocephalus, intraoperative adverse events, and young age ( &lt; or = 5 years) at presentation. Predictors of increased hypothalamic morbidity included symptoms of hypothalamic disturbance already established at diagnosis, greater height ( &gt; or = 3.5 cm) of the tumor in the midline, and attempts to remove adherent tumor from the region of the hypothalamus at operation. Large tumor size, young age, and severe hydrocephalus were predictors of tumor recurrence, whereas complete tumor resection (as determined by postoperative neuroimaging) and radiotherapy given electively after subtotal excision were less likely to be associated with recurrent disease. Based on these findings, the authors propose an individualized, more flexible treatment approach whereby surgical strategies may be modified to provide long-term tumor control with the lowest morbidity