Gene expression profile in obesity and type 2 diabetes mellitus

Obesity is an important component of metabolic syndrome X and predisposes to the development of type 2 diabetes mellitus. The incidence of obesity, type 2 diabetes mellitus and metabolic syndrome X is increasing, and the cause(s) for this increasing incidence is not clear. Although genetics could play an important role in the higher prevalence of these diseases, it is not clear how genetic factors interact with environmental and dietary factors to increase their incidence. We performed gene expression profile in subjects with obesity and type 2 diabetes mellitus with and without family history of these diseases. It was noted that genes involved in carbohydrate, lipid and amino acid metabolism pathways, glycan of biosynthesis, metabolism of cofactors and vitamin pathways, ubiquitin mediated proteolysis, signal transduction pathways, neuroactive ligand-receptor interaction, nervous system pathways, neurodegenerative disorders pathways are upregulated in obesity compared to healthy subjects. In contrast genes involved in cell adhesion molecules, cytokine-cytokine receptor interaction, insulin signaling and immune system pathways are downregulated in obese. Genes involved in signal transduction, regulation of actin cytoskeleton, antigen processing and presentation, complement and coagulation cascades, axon guidance and neurodegenerative disorders pathways are upregulated in subjects with type 2 diabetes with family history of diabetes compared to those who are diabetic but with no family history. Genes involved in oxidative phosphorylation, immune, nervous system, and metabolic disorders pathways are upregulated in those with diabetes with family history of diabetes compared to those with diabetes but with no family history. In contrast, genes involved in lipid and amino acid pathways, ubiquitin mediated proteolysis, signal transduction, insulin signaling and PPAR signaling pathways are downregulated in subjects with diabetes with family history of diabetes. It was noted that genes involved in inflammatory pathway are differentially expressed both in obesity and type 2 diabetes. These results suggest that genes concerned with carbohydrate, lipid and amino acid metabolic pathways, neuronal function and inflammation play a significant role in the pathobiology of obesity and type 2 diabetes.     

Is phenytoin contraindicated in patients receiving cranial irradiation ?

Three recent publications have reported the development of erythema multiforme and Stevens-Johnson syndrome in patients receiving cranial irradiation and sodium phenytoin. Some authors have recommended that patients receiving whole brain radiation therapy and who have had seizures should not be prescribed phenytoin but an alternative anticonvulsant. This article reviews the current literature pertaining to the development of this potentially lethal complication in patients receiving whole brain radiation and phenytoin, with reference to the single recorded case of Stevens-Johnson syndrome in a patient receiving cranial irradiation and phenytoin in Auckland, New Zealand. While the clinical picture in the 16 patients reported in the literature and the current case report differed from the classical form of erythema multiforme, a similar pattern of presentation and outcome appeared in all patients reviewed, suggesting that the combination of phenytoin, cranial irradiation and the gradual reduction of concomitant steroids seem to lead to the development of erythema multiforme and/or Stevens-Johnson syndrome. The data presented, although sparse, suggest that phenytoin should not be prescribed in patients receiving cranial irradiation.     

Intestinal permeability in the newborn

Passive intestinal permeability in 33 newborn babies was studied using feeds containing lactulose and mannitol. Each marker is thought to pass across the gut wall by a different route; lactulose by a paracellular and mannitol by a transcellular pathway. Neither is metabolised and both are wholly and solely excreted by the kidney; urinary recovery is a measure of the intestinal uptake. Babies born before 34 weeks' gestation exhibited a higher intestinal permeability to lactulose than more mature babies, and all preterm babies showed an appreciable decline in lactulose absorption during the first week of oral feeds. Babies of 34 to 37 weeks' gestation achieved a 'mature' intestinal permeability to lactulose within four days of starting oral feeds. These findings may reflect the immaturity of the gut of the preterm baby rather than a process essential to adaptation to enteral nutrition.     

Ki-ras mutations are an early event and correlate with tumor stage in transplacentally-induced murine lung tumors

A previous study from this laboratory demonstrated that treatment of pregnant mice with 3-methylcholanthrene (MC) caused lung tumors in the offspring at 1 year after birth, the incidence of which correlated with fetal inducibility of Cyp1a1. Analysis by PCR amplification and allele- specific hybridization (ASO) of paraffin-embedded tumors generated from that study revealed the presence of point mutations in exon 1 of the Ki- ras gene. This work has now been expanded by PCR amplification and ASO analysis of 31 additional lesions. Point mutations were found in 37 of the 47 (79%) lesions analyzed in this and the previous study, the majority of which were G-->T transversions in the first or second base of codon 12. The mutational spectrum appeared to be dependent on the relative stage of differentiation of the lesion, as both the incidence of mutation and type of mutation produced correlated with malignant progression. Mutations occurred in 60% of the hyperplasias, 80% of the adenomas and 100% of the adenocarcinomas. In the lesions with mutations, GLY12-->CYS12 transversions occurred in 100% of the hyperplasias, 42% of the adenomas and 14% of the adenocarcinomas. The GLY12-->VAL12 transversions occurred in none of the hyperplasias, 42% of the adenomas and 57% of the adenocarcinomas. The remaining mutations, which consisted of ASP12 transitions and ARG13 transversions, occurred only in adenomas (17%) and adenocarcinomas (29%). Between this study and our previous analyses, the identity of the mutations obtained by ASO were confirmed by sequence analysis of eight of the 37 lesions that harbored mutations at the Ki-ras gene locus. There were no differences in the type or incidence of mutations relative to the metabolic phenotype or sex of the mice. These data suggest that mutational activation of the Ki-ras gene locus is an early event in transplacental lung tumorigenesis, and that the type of mutations produced by exposure to chemical carcinogens can influence the carcinogenic potential of the tumor. This may have prognostic significance in determining the malignant progression of the neoplasm.      

Circulating lipids and glycaemic control in insulin dependent diabetic children

The prevalence of dyslipidaemia in children with insulin dependent diabetes mellitus (IDDM) and its relation to glycaemic control was studied in a group of 51 diabetic children and a control population of 132 schoolchildren. The prevalence of dyslipidaemia in the fasting state was increased in the diabetic group (39%) compared with control subjects (17%). Serum cholesterol concentration alone was raised in 25% of diabetic subjects while serum cholesterol and triglycerides were raised in 14%, compared with 16% and 0.7% respectively in control subjects. Serum total cholesterol (5.1 v 4.5 mmol/l), low density lipoprotein cholesterol (3.2 v 2.6 mmol/l), non-esterified fatty acids (0.91 v 0.50 mmol/l), and triglycerides (0.94 v 0.76 mmol/l) were higher in diabetic children. Serum total cholesterol, triglycerides, and apolipoprotein (apo)B concentrations increased with worsening control, while serum high density lipoprotein cholesterol and apoA-I concentrations were unaltered. There were also positive correlations between glycated haemoglobin and total cholesterol, triglycerides, and apoB in diabetic children. Thus, abnormalities in circulating lipids are common in young subjects with IDDM but largely disappear if blood glucose concentrations are reasonably controlled.     

Oligodendroglioma: an analysis of prognostic factors and treatment results

This study, an analysis of variable prognostic factors affecting the treatment outcome for patients with oligodendroglioma, included a retrospective analysis of the medical charts of patients diagnosed with oligodendroglioma treated at our institution between 1975 and 1997. The endpoints analyzed were the progression-free survival (PFS), as well as the overall survival. The factors analyzed included extent of surgery, postoperative radiotherapy, pathologic grade, performance status, age, and sex. Of a total of 37 cases, 19 were male and 18 were female. The median age at diagnosis was 30 years. The most common presenting symptoms were headache (78%), seizures (43%), motor symptoms (38%), and to a lesser extent behavioral changes (16%). The median duration of symptoms was 9 months. The most common location on computed tomography or magnetic resonance imaging scans was the frontal region (43%). Low grade tumors (grades I and II) were found in 60% of patients, and the remaining 40% had high grade tumors (grades III and IV). Eight patients had complete surgical excision, whereas 27 patients had partial excision, and two patients had biopsy only. The operative mortality rate was 14%. There were 24 patients who received postoperative radiotherapy, and only 3 patients received adjuvant chemotherapy. The median postoperative radiation dose was 5,580 cGy. With a median follow-up of 7 years, the 5-year PFS and overall survival for the whole group were 58% and 67%, respectively. The pathologic grade of the tumor was the only prognostic factor significantly affecting both PFS and overall survival. The 5-year PFS for patients with low grade tumors was 79% in comparison to 32% for patients with high grade tumors (p < 0.01). Patients with good performance status at initial presentation (performance status of 1 and 2) had a higher 5-year PFS in comparison to those with poor performance status (62% vs. 38%, respectively); however, this difference did not reach statistical significance. Similarly, patients who were subjected to complete surgical excision had a marginally higher PFS in comparison to those who had biopsy or partial excision (75% vs. 53%). There was no difference in the 5-year PFS between patients who received postoperative irradiation versus those who did not (51% vs. 47%, respectively). Patients with high grade oligodendrogliomas have a relatively poor prognosis. The pathologic grade of the tumor was the single most important prognostic factor significantly affecting both the PFS and overall survival. A prospective randomized clinical trial is needed to address the impact of postoperative irradiation on PFS of those tumors. In view of the poor outcome for patients with high grade oligodendroglioma, the use of adjuvant systemic chemotherapy should be studied in future multicenter randomized trials.     

Vaginal misoprostol before copper IUD insertion after previous insertion failure: a double-blind,placebo-controlled,parallel-group,randomised clinical trial

Objective: The aim of the study was to assess whether vaginal administration of misoprostol before copper intrauterine device (IUD) insertion increased the success of the procedure among parous women with previous insertion failure.

Methods: A single-centre, parallel-group, double-blind, placebo-controlled, randomised clinical trial was conducted at Ain Shams University Maternity Hospital, Cairo, Egypt, between October 2015 and August 2016. The study comprised 90 parous women undergoing TCu380A IUD insertion after a failed attempt. A computer-generated list of random numbers was used to assign participants to receive either misoprostol 200?μg or a placebo tablet, applied vaginally 10?h and 4?h prior to the second attempted IUD insertion, without ultrasound guidance. The primary outcome was the success of IUD insertion. Secondary outcomes were to establish the effect on insertion success of cervical dilation, cervical softening and previous mode of delivery.

Results: Forty-two women (93.3%) in the misoprostol group and 24 women (53.3%) in the placebo group had a successful IUD insertion (p?<?.001). Cervical dilation was required in 24 women in the misoprostol group and 44 women in the placebo group. Misoprostol application significantly increased insertion success in women with previous caesarean delivery (p?<?.001) but did not affect insertion success in women with previous vaginal delivery (p?=?.481).

Conclusion: Vaginal misoprostol before IUD insertion in parous women with previous insertion failure increased the rate of successful insertion, particularly in women with previous caesarean delivery.