Intensity-modulated radiotherapy (55 Gy in 20 fractions) for high-grade laryngeal dysplasia: report of acute toxicity and functional outcome.

OBJECTIVE: Radiotherapy is an option to treat high-grade laryngeal dysplasia. This study aimed to evaluate the use of intensity-modulated radiotherapy, 55 Gy in 20 daily fractions, in treating this disease. METHODS: Acute toxicity was evaluated in all 14 patients treated. In 10 patients, functional voice outcome was measured using the Voice Handicap Index, and the Grade, Roughness, Breath, Asthenia, Strain ('GRBAS') scale. These measurements were performed pre-treatment and three months after intensity-modulated radiotherapy. RESULTS: All but one patient managed to complete radiotherapy. Acute toxicity was significant (one patient developed grade 4 and three patients developed grade 3 dysphagia). Four patients required hospital admission. In 9 out of 10 patients, radiotherapy improved voice quality. CONCLUSION: This radiotherapy regimen using intensity-modulated radiotherapy for laryngeal dysplasia is feasible and provided excellent functional outcome, but acute toxicity was significant. Dose de-escalation can be considered in the framework of clinical trials.

Insights into the pathophysiology of catch-up compared with non-catch-up growth in children born small for gestational age: an integrated analysis of metabolic and transcriptomic data.

Small for gestational age (SGA) children exhibiting catch-up (CU) growth have a greater risk of cardiometabolic diseases in later life compared with non-catch-up (NCU) SGA children. The aim of this study was to establish differences in metabolism and gene expression profiles between CU and NCU at age 4-9 years. CU children (n=22) had greater height, weight and body mass index standard deviation scores along with insulin-like growth factor-I (IGF-I) and fasting glucose levels but lower adiponectin values than NCU children (n=11; all P<0.05). Metabolic profiling demonstrated a fourfold decrease of urine myo-inositol in CU compared with NCU (P<0.05). There were 1558 genes differentially expressed in peripheral blood mononuclear cells between the groups (P<0.05). Integrated analysis of data identified myo-inositol related to gene clusters associated with an increase in insulin, growth factor and IGF-I signalling in CU children (P<0.05). Metabolic and transcriptomic profiles in CU SGA children showed changes that may relate to cardiometabolic risk.

A novel deletion partly removing the AVP gene causes autosomal recessive inheritance of early-onset neurohypophyseal diabetes insipidus.

Familial neurohypophyseal diabetes insipidus (FNDI) typically presents with age-dependent penetrance and autosomal dominant inheritance caused by missense variations in one allele of the AVP gene encoding the arginine vasopressin (AVP) prohormone. We present the molecular genetic characteristics underlying an unusual form of FNDI occurring with very early onset and seemingly autosomal recessive inheritance. By DNA amplification and sequencing, we identified a novel variant allele of the AVP gene carrying a 10,396 base pair deletion involving the majority of the AVP gene as well as its regulatory sequences in the intergenic region between the AVP and the OXT gene, encoding the oxytocin prohormone. We found two chromosomes carrying the deletion in affected family members and one in unaffected family members suspected to transmit the deleted allele. Whole-genome array analysis confirmed the results and excluded the presence of any additional major pathogenic abnormalities. The deletion is predicted to abolish the transcription of the AVP gene, thus the fact that family members heterozygous for the deletion remain healthy argues, in general, against haploinsufficiency as the pathogenic mechanism FNDI. Accordingly, our data is strong support to the prevailing idea that dominant inheritance of FNDI is due to a dominant-negative effect exerted by variant AVP prohormone.

Syndromic obesity and diabetes: changes in body composition with age and mutation analysis of ALMS1 in 12 United Kingdom kindreds with Alstrom syndrome.

CONTEXT: Alström syndrome (AS) is a monogenic form of infancy-onset obesity and insulin resistance, caused by ALMS1 mutations. The natural history of the insulin resistance is unknown, in particular how this relates to changes in body composition. It is also unclear how ALMS1 mutations relate to the characteristic phenotype. OBJECTIVES: Our objectives were to characterize body composition and metabolic parameters, to establish ALMS1 mutation spectrum of United Kingdom AS patients, and to determine whether a genotype-phenotype correlation exists. DESIGN AND PATIENTS: We conducted a cross-sectional cohort study of 12 unrelated subjects with AS. Age-standardized body composition was assessed by anthropometry and dual-energy x-ray absorptiometry and insulin sensitivity by homeostasis model assessment. The exons and intron-exon boundaries of ALMS1 were directly sequenced. SETTING: The study was performed during the annual Alström Syndrome UK multidisciplinary screening clinic. RESULTS: AS patients have early-onset obesity, but body mass index, waist circumference, and body fat from dual-energy x-ray absorptiometry were negatively correlated with age (r = -0.37, P = 0.2; r = -0.84, P = 0.002; and r = -0.6, P = 0.05). Despite this, insulin resistance increased, demonstrated by raised fasting insulin and fall in homeostasis model assessment insulin sensitivity with age (r = -0.64, P = 0.02). ALMS1 mutations were identified in 10 of 12 patients, with a potential founder mutation in exon 16 present in five [np 10775del (C); Del3592fs/ter3597]. No genotype-phenotype correlation was observed. CONCLUSIONS: We identified mutations in ALMS1 in more than 80% of patients with no genotype-phenotype correlation. In AS, severe childhood obesity, waist circumference, and body fat decrease with age, whereas insulin resistance increases. The abdominal obesity, insulin resistance, diabetes, hypertriglyceridemia, and hypertension suggest that AS could represent a monogenic model for the metabolic syndrome.

Noise problem in a polyester fiber plant in Pakistan.

Noise study has been undertaken in the three units of a polyester fiber plant. The level and frequency characteristics of the prevailing noise have been studied and speech interference levels evaluated. The results are discussed with reference to the maximum permissible occupational noise exposure limits as allowed by the ISO and other national standards. Some recommendations have also been made to provide safety measures to the workers against high level noise in these units.

Determination of ethylene and other reactive hydrocarbons in tobacco smoke and evaluation of risk from their inhalation.

The levels of the reactive hydrocarbons ethylene, propene and 1-butene were determined in cigarette and bidi (Indian cigar) smoke. Cigarette and bidi smoke was collected under standard smoking conditions, using an automatic smoking machine. A gas chromatograph equipped with a selective chemiluminescent detector was used for measurements. The range of concentrations of ethylene, propene and 1-butene obtained for cigarette and bidi smoke are compared with values from the literature. An evaluation of the risk due to inhalation of the reactive hydrocarbons in cigarette smoke was made and compared with the risk of inhalation of these present as urban air pollutants.

Total particulate matter in cigarette and bidi smoke.

It has been well established that smoking causes lung cancer and many other chest diseases. To study the harmful effects of smoking, an automatic smoking machine was developed in this laboratory. Cigarette smoke contains many known carcinogens. The amounts of various carcinogens are proportional to the total particulate matter. Hence variation in total particulate matter (TPM) of different brands of cigarettes, bidis and cheruts (Indian cigars) was studied for various smoking parameters. An attempt has been made to arrive at some intake values of TPM from cigarettes and bidis smoked by the automatic smoking machine under different simulated smoking conditions.