Structure-Guided Approach to Relieving Transcriptional Repression in Resistance to Thyroid Hormone α.

Mutations in thyroid hormone receptor α (TRα), a ligand-inducible transcription factor, cause resistance to thyroid hormone α (RTHα). This disorder is characterized by tissue-specific hormone refractoriness and hypothyroidism due to the inhibition of target gene expression by mutant TRα-corepressor complexes. Using biophysical approaches, we show that RTHα-associated TRα mutants devoid of ligand-dependent transcription activation function unexpectedly retain the ability to bind thyroid hormone. Visualization of the ligand T3 within the crystal structure of a prototypic TRα mutant validates this notion. This finding prompted the synthesis of different thyroid hormone analogues, identifying a lead compound, ES08, which dissociates corepressor from mutant human TRα more efficaciously than T3. ES08 rescues developmental anomalies in a zebrafish model of RTHα and induces target gene expression in TRα mutation-containing cells from an RTHα patient more effectively than T3. Our observations provide proof of principle for developing synthetic ligands that can relieve transcriptional repression by the mutant TRα-corepressor complex for treatment of RTHα.

Deoxyfluorination with CuF2 : Enabled by Using a Lewis Base Activating Group.

Deoxyfluorination is a primary method for the formation of C-F bonds. Bespoke reagents are commonly used because of issues associated with the low reactivity of metal fluorides. Reported here is the development of a simple strategy for deoxyfluorination, using first-row transition-metal fluorides, and it overcomes these limitations. Using CuF2 as an exemplar, activation of an O-alkylisourea adduct, formed in situ, allows effective nucleophilic fluoride transfer to a range of primary and secondary alcohols. Spectroscopic investigations have been used to probe the origin of the enhanced reactivity of CuF2 . The utility of the process in enabling 18 F-radiolabeling is also presented.

Inferior right hepatic vein on routine contrast-enhanced CT of the abdomen: prevalence and correlation with right hepatic vein size.

AIM: To determine the prevalence of the inferior right hepatic vein (IRHV) in patients undergoing routine contrast-enhanced computed tomography (CECT) of the abdomen and to compare it with the size of the right hepatic vein (RHV). MATERIALS AND METHODS: Two hundred and twenty-four consecutive patients who underwent routine CECT abdomen, with adequate venous opacification, were included in the study. The number and diameter of IRHVs and the diameter of the RHV was noted in each case. RESULTS: A total of 214 IRHVs were detected in 126 cases (56.2%) with a mean diameter of 4.15±1.44 mm. The number of IRHVs ranged from one to four (more than one IRHV was present in 39.7% [50/126] of cases). In approximately one-third of cases (46/126), an IRHV ≥5 mm was found. A weak negative correlation was found between size of the RHV and IRHV (Pearson's correlation coefficient -0.222; p=0.01). The RHV was smaller in size in patients with an IRHV (7.34±1.88 mm) than in patients without an IRHV (8.47±1.99 mm) on CECT abdomen. A larger IRHV was associated with a smaller RHV (6.91±2.05 mm). CONCLUSION: The presence of IRHV on routine CECT abdomen is frequent, and it is not uncommon to encounter more than one IRHV. The diameter of the IRHV has a weak negative correlation with the diameter of the RHV, and a smaller RHV is found in patients with an IRHV.

Long-term outcome of combined trabeculotomy-trabeculectomy by a single surgeon in patients with primary congenital glaucoma.

PurposeAssess long-term outcome of combined trabeculotomy-trabeculectomy (CTT) in primary congenital glaucoma (PCG).MethodsData of PCG patients treated with CTT by a single surgeon between 1976 and 1993 were reviewed for reduction in intraocular pressure (IOP), visual acuities, surgical success rates, and need for repeat surgeries at last follow-up (FU). At the last FU, IOP<21 mm Hg without any topical antiglaucoma medication (TAM) was complete success and with 1-2 TAMs was qualified success. IOP reduction ≥30% without any TAM was modified complete success and with 1-2 TAMs was modified qualified success. IOP>21 mm Hg, IOP reduction <30%, or use of >2 TAM at last FU, or need for additional surgery was considered as failure.ResultsTwo hundred thirty eyes of 121 patients had been followed up for 21.5-38 years (mean 28.87±2.77 years). Eyes that were pthisical (3), had immeasurable IOP (2), or IOP<6 mm Hg (3) were excluded from the success analysis. At last FU, mean IOP reduction was 22.71±11.28 mm Hg and TAM score was 1.71 (0-4). Complete success was achieved in 14 (6.3%), modified complete success in 14 (6.3%), qualified success in 148 (66.7%), and modified qualified success in 140 (63.1%). Success probability was 95% till 25 years and 92, 90, 85, 79 and 68% at 26, 27, 28, 29, and 30 years, respectively. Severe visual impairment or functional blindness was found in only 13 (10.7%) patients.ConclusionCTT shows long-term success in PCG patients. All patients must be monitored for IOP control to avoid need for repeat surgeries.

Leptin, acylcarnitine metabolites and development of adiposity in the Rhea mother-child cohort in Crete, Greece.

OBJECTIVE: This study aims to investigate relations of serum leptin at age 4 with development of adiposity and linear growth during 3 years of follow-up among 75 Greek children and to identify serum metabolites associated with leptin at age 4 and to characterize their associations with adiposity gain and linear growth. METHODS: Linear regression models that accounted for maternal age, education and gestational weight gain and child's age and sex were used to examine associations of leptin and leptin-associated metabolites measured at age 4 with indicators of adiposity and linear growth at age 7. RESULTS: Each 1-unit increment in natural log-(ln)-transformed leptin corresponded with 0.33 (95% CI: 0.10, 0.55) units greater body mass index-for-age z-score gain during follow-up. Likewise, higher levels of the leptin-associated metabolites methylmalonyl-carnitine and glutaconyl-carnitine corresponded with 0.14 (95% CI: 0.01, 0.27) and 0.07 (95% CI: -0.01, 0.16) units higher body mass index-for-age z-score gain, respectively. These relationships did not differ by sex or baseline weight status and were independent of linear growth. CONCLUSIONS: These findings suggest that leptin, methylmalonyl-carnitine and possibly glutaconyl-carnitine are associated with weight gain during early childhood. Future studies are warranted to confirm these findings in other populations.

Standardization of serum free media for cryopreservation of RK13 cells.

Foetal calf serum present in the media used for cryopreservation was replaced by various synthetic polymer such as gelatin, glycerol, carboxymethyl cellulose and dimethyl sulphoxide at various concentration. Growth pattern of cells, % survival and karyological studies have been done in the present study. It was found that optimum concentration of carboxymethyl cellulose was 0.1% in combination with 10% glycerol and 10% DMSO. At this concentration percentage survival of cells was found maximum and karyotype was found normal without any abnormality in the chromosomes. It was concluded from the study that serum free media can be employed for the cryopreservation of these cells which are further used for production of tissue culture vaccines without causing any adverse affects.

Effect of garlic (Allium sativum L.) extract on degree of hydration, fructose, sulphur and phosphorus contents of rat eyelens and intestinal absorption of nutrients.

Influence of aqueous garlic extract on degree of hydration, fructose, sulphur and phosphorus contents of rat eyelens and intestinal absorption of nutrients were assessed. Inclusion of garlic extract in culture medium containing glucose and xylose inhibited the hydration of rat eyelens, whereas galactose evinced the reverse trend. Aqueous garlic extract in general decreased the concentration of fructose and phosphorus, whereassulphur concentration increased when rat eyelenses, were incubated with galactose and xylose. Garlic extract inhibited intestinal absorption of glutamic acid, sucrose and glucose to different extents. The rate of absorption of glutamic acid was found to be considerably higher than that of glucose and sucrose.

Gibberellic acid (GA3) induced changes in proanthocyanidins and malt quality of two- and six-row husked barleys.

Analysis of husked barleys for proanthocyanidins and malt quality attributes has shown that not a single variety is free of proanthocyanidins. The proanthocyanidins in barley grains varied from 3.85 to 4.94 mg/g as catechin equivalent. The concentration of proanthocyanidins decreased, while total soluble sugars, reducing sugars, diastatic power and beta-amylase activity increased during maltings as well as with exogenous gibberellic acid (GA3) application. Alfa 93 (two-row) and RD2560 (six-row) varieties appeared to be superior for malting and brewing purposes on the basis of proanthocyanidins, total phenols, diastatic power and beta-amylase activity. It is suggested that exogenous application of GA3 at 15 ppm may be useful for producing good quality malt from barley grains.

Primary glaucomas: current concepts and management.

Glaucoma is a leading cause of blindness. Delay in diagnosis of open angle glaucoma (OAG) results from lack of symptoms. In angle closure glaucoma (ACG) there is often neglect of symptoms. Creating awareness about the disease and screening the high risk groups would reduce the burden of irreversible blindness due to glaucoma. Adequate therapy in the form of drops, lasers and surgery is available. Close interaction with the physician is important as many topical antiglaucoma medications have adverse systemic side-effects and many drugs used for systemic diseases raise the intra-ocular pressure (IOP). All drugs currently available for glaucoma lower IOP but new drugs for neuroprotection may change the future management strategies. While drugs and surgery are the mainstay for OAG, laser iridotomy is the definitive treatment for ACG.

Variability in physicochemical and nutritional quality traits of parents, F2 and F3 generations of lentil crosses.

Ten physicochemical and nutritional quality traits (100-seed weight, seed volume, seed density, bulk density, hydration capacity, hydration index, swelling capacity, protein, tryptophan and energy value) were examined in the seed samples of parents, F2 and F3 generations of three microsperma x microsperma and two microsperma x macrosperma crosses of lentils. Significant variation for different traits was observed among the genotypes in both the groups and also among both types of crosses in F2 and F3 generations. Ranges, means and coefficients of variation (CV %) for various traits among parents, F2 and F3 generations of different crosses, along with the deviations between F2 and F3 generation means for various traits in different crosses are discussed. Also suggested is a breeding strategy for evolving lentil varieties with improved seed yield and nutritional quality parameters.

Whistle (EB.) in tracheobronchial tree (in paediatric age group) - 4 years study.

Segmented whistles found in compressible toys often get lodged in the tracheobronchial tree of infants and children and may remain asymptomatic as patients keep on breathing normally through the lumen of the whistle without much difficulty. Here 10 such cases are reported. The problems encountered in their management are also discussed.

Sterilisation of tonometers and gonioscopes.

Precautions to prevent spread of infection through tonometers and gonioscopes are described in this article. Tonometers and gonioscopes should not be used in the presence of clinically manifest conjunctivitis and keratitis. The Schiotz tonometer should be dipped in a 1:1000 merthiolate solution, and rinsed in saline/distilled water prior to use. The Goldmann applanation prism tip can be wiped with gauze soaked in 70% isopropyl alcohol and then dried before use. Gonioscopes should be cleaned in running water, wiped with gauze soaked in 70% isopropyl alcohol, and then dried before use. Koeppes and goniotomy lenses can be sterilized with ethylene oxide, prior to use in surgery.

Isolation of poliovirus from cases of acute flaccid paralysis.

OBJECTIVE: To evaluate the frequency of isolation of polio and other viruses from fecal samples in subjects with acute flaccid paralysis in northern parts of India. SETTING: Rural and Urban Immunization Centers used for Expanded Programme on Immunization. METHODS: 219 fecal samples were collected by anal tube in 1992 from Punjab, Haryana, Himachal Pradesh and Chandigarh and processed for virus isolation. RESULTS: Of 219 fecal samples, 103 (47%) were positive for viruses in the age group of 3 mo to 5 yr. Amongst the positive samples, the predominant isolated was poliovirus type 1 (70.9%) from all the States. Non polio enteroviruses were isolated from 20.4% of fecal samples. CONCLUSION: Even though poliovirus is still the most common etiologic agent for acute flaccid paralysis in northern India, non polio enteroviruses are also emerging as important causal pathogens in this condition.

Comparison of two methods for determining in vitro intestinal absorption of nutrients using rats fed different diets.

Absorption of sucrose, glucose, leucine and aspartate was studied using intestinal everted sac of rats fed on french bean diets namely PDR-14, HUR-137 and HUR-15 using casein as a control. Absorption of nutrients was monitored spectrophotometrically and by 14C radio assay of metabolites using scientillation counting. The absorption pattern of amino acids was found to be similar but of glucose and sucrose differed. Glucose was found to be more absorbed than sucrose in spectrophotometer assay and the pattern reversed in radio assay. Absorption of sucrose and leucine were higher by rats fed on HUR-137 diet and similarly, more aspartate was absorbed when fed on HUR-15 diet as demonstrated by both the methods. Rats fed on HUR-137 diet exhibited higher glucose absorption as shown by spectrophotometric assay, but rats on HUR-15 diet by radio assay. Absorption of nutrients differed significantly between casein and french beans.