Prognosticators of survival in differentiated thyroid carcinoma

Differentiated carcinoma of the thyroid has good prognosis, even in patients presenting in the late stage and with distant metastasis. In India, the incidence of papillary carcinoma and follicular carcinoma are in the ratio of 60∶40. A retrospective study was carried out to determine the impact of patient and tumor factors on survival, and to develop a simple rish group staging system to predict survival in patients with differentiated thyroid carcinomas. Four hundred and seventeen (417) patients undergoing primary treatment at our hospital between 197–1985, were entered to the study. There were 198 follicular carcinomas and 219 papillary carcinomas. Impact of patient and tumor variables were studied by drawing Kaplan Meier curves and comparing them by the Chi Sq Test. Age<=40 years (p=0.00001), tumor size <5cms (p=0.01), extrrathyroidal spread (p=0.001) and distant metastasis (p=0.00001) had significant impact on survival. These finding were true for a subset analysis follicular and papillary carcinomas separately. A Cox Regression Analysis was also performed and this showed the above factors to impact significantly on survival. Basing on the regression analysis we devised a simple risk group system and classified the patients as high and low risk. Low risk group patients had a significant survival advantage. Our findings show that the incidence of follicular carcinoma is significantly high in india (48%) and that 65% of our patients are in the high risk group. Incidence of contralateral lobe disease on completion thyroidectomy is as high as 53%. Hence, a more aggressive treatment policy is warranted and total thyroidectomy is the appropriate treatment of choice in our patients.     

Immunohistochemical assessment of Survivin and Bcl3 expression as potential biomarkers for NF‐κB activation in the Barrett metaplasia–dysplasia–adenocarcinoma sequence

Non‐dysplastic Barrett's oesophagus (NDBE) occurs as a consequence of an inflammatory response triggered through prolonged gastro‐oesophageal reflux and it may precede the development of oesophageal adenocarcinoma. NF‐κB activation as a result of the inflammatory response has been shown in NDBE, but the possible mechanism involved in the process is unknown. The aim of this study was to assess, using immunohistochemistry, Survivin and Bcl3 expression as potential biomarkers for NF‐κB activation along the oesophageal metaplasia–dysplasia–adenocarcinoma sequence. Survivin is an NF‐κB‐inducible anti‐apoptotic protein, and Bcl3 is a negative regulator of NF‐κB. There was progressive upregulation of Survivin expression along the oesophageal metaplasia–dysplasia–adenocarcinoma sequence. Bcl3 expression was upregulated in non‐dysplastic Barrett's oesophagus, low‐grade, high‐grade dysplasia and oesophageal adenocarcinoma when compared to squamous group. The study shows the differential expression of Bcl3 between the squamous and Barrett's stage, suggesting that Bcl3 could be a surrogate marker for early event involving constitutive NF‐κB activation. In addition, the study suggests that NF‐κB activation may infer resistance to apoptosis through the expression of anti‐apoptotic genes such as Survivin, which showed progressive increase in expression throughout the oesophageal metaplasia–dysplasia–adenocarcinoma sequence. This ability to avoid apoptosis may underlie the persistence and malignant predisposition of Barrett's metaplasia.     

Attenuation of arsenic neurotoxicity by curcumin in rats

In view of continued exposure to arsenic and associated human health risk including neurotoxicity, neuroprotective efficacy of curcumin, a polyphenolic antioxidant, has been investigated in rats. A significant decrease in locomotor activity, grip strength (26%) and rota-rod performance (82%) was observed in rats treated with arsenic (sodium arsenite, 20 mg/kg body weight, p.o., 28 days) as compared to controls. The arsenic treated rats also exhibited a decrease in the binding of striatal dopamine receptors (32%) and tyrosine hydroxylase (TH) immunoreactivity (19%) in striatum. Increased arsenic levels in corpus striatum (6.5 fold), frontal cortex (6.3 fold) and hippocampus (7.0 fold) associated with enhanced oxidative stress in these brain regions, as evident by an increase in lipid perioxidation, protein carbonyl and a decrease in the levels of glutathione and activity of superoxide dismutase, catalase and glutathione peroxidase with differential effects were observed in arsenic treated rats compared to controls. Simultaneous treatment with arsenic (sodium arsenite, 20 mg/kg body weight, p.o., 28 days) and curcumin (100 mg/kg body weight, p.o., 28 days) caused an increase in locomotor activity and grip strength and improved the rota-rod performance in comparison to arsenic treated rats. Binding of striatal dopamine receptors and TH expression increased while arsenic levels and oxidative stress decreased in these brain regions in co-treated rats as compared to those treated with arsenic alone. No significant effect on any of these parameters was observed in rats treated with curcumin (100 mg/kg body weight, p.o., 28 days) alone compared to controls. A significant protection in behavioral, neurochemical and immunohistochemical parameters in rats simultaneously treated with arsenic and curcumin suggest the neuroprotective efficacy of curcumin.     

The “Rubber Band” and “Slingshot” Effects of the Posterior Airway Space in Mandibular Orthognathic Surgeries

Introduction

Mandibular surgeries are the most common orthognathic procedures that are undertaken. The pharyngeal airway space (PAS) is influenced by the changes in the sagittal changes of the mandible. Mandibular advancement surgeries are used to an advantage in obstructive sleep apnea cases to improve the airway space. On the contrary, there can be a considerable decrease in the airway space during mandibular setback procedures. Numerous studies have been conducted to study the effect of changes in the PAS during mandibular procedures. However, a combined radiographic and endoscopic analysis of the airway space has been sparsely done in recent literature

Materials and methods

Thirty-one patients with mandibular discrepancies who needed mandibular surgeries were chosen. The assessment of PAS was done using both lateral cephalograms and endoscopic examination.

Results

As lateral cephalograms can study only the two-dimensional changes in the PAS, endoscopic examination both pre operatively and post operatively enabled the exact assessment of mandibular surgeries on the PAS. The PAS responds to setback mandibular surgery by modifying itself- called the “Rubber band” effect and in advancement surgeries as “Slingshot effect”.     

Developmental up-regulation of the potassium–chloride cotransporter type 2 in the rat lumbar spinal cord

The classical GABA/glycine hyperpolarizing inhibition is not observed in the immature spinal cord. GABA_A and glycine receptors are anions channels and the efficacy of inhibitory transmission in the spinal cord is largely determined by the gradient between intracellular and extracellular chloride concentrations. The concentration of intracellular chloride in neurons is mainly regulated by two cation–chloride cotransporters, the potassium–chloride cotransporter 2 (KCC2) and the sodium–potassium–chloride co-transporter 1 (NKCC1). In this study, we measured the reversal potential of IPSPs (E_IPSP) of lumbar motoneurons during the first postnatal week and we investigated the expression of KCC2 and NKCC1 in the ventral horn of the spinal cord from the embryonic day 17 to the postnatal day 20 in the rat. Our results suggest that the negative shift of E_IPSP from above to below the resting membrane potential occurs during the first postnatal week when the expression of KCC2 increases significantly and the expression of NKCC1 decreases. KCC2 immunolabeling surrounded motoneurons, presumably in the plasma membrane and NKCC1 immunolabeling appeared outside this KCC2-labeled fine strip. Taken together, the present results indicate that maturation of chloride homeostasis is not completed at birth in the rat and that the upregulation of KCC2 plays a key role in the shift from depolarizing to hyperpolarizing IPSPs.     

Suboptimal inhibition of protease activity in human immunodeficiency virus type 1: effects on virion morphogenesis and RNA maturation

Protease activity within nascently released human immunodeficiency virus type 1 (HIV-1) particles is responsible for the cleavage of the viral polyproteins Gag and Gag–Pol into their constituent parts, which results in the subsequent condensation of the mature conical core surrounding the viral genomic RNA. Concomitant with viral maturation is a conformational change in the packaged viral RNA from a loosely associated dimer into a more thermodynamically stable form. In this study we used suboptimal concentrations of two protease inhibitors, lopinavir and atazanavir, to study their effects on Gag polyprotein processing and on the properties of the RNA in treated virions. Analysis of the treated virions demonstrated that even with high levels of inhibition of viral infectivity (IC₉₀), most of the Gag and Gag–Pol polyproteins were processed, although slight but significant increases in processing intermediates of Gag were detected. Drug treatments also caused a significant increase in the proportion of viruses displaying either immature or aberrant mature morphologies. The aberrant mature particles were characterized by an electron-dense region at the viral periphery and an electron-lucent core structure in the viral center, possibly indicating exclusion of the genomic RNA from these viral cores. Intriguingly, drug treatments caused only a slight decrease in overall thermodynamic stability of the viral RNA dimer, suggesting that the dimeric viral RNA was able to mature in the absence of correct core condensation.     

Stoichiometry of the antiviral protein APOBEC3G in HIV-1 virions

A host cytidine deaminase, APOBEC3G (A3G), inhibits replication of human immunodeficiency virus type 1 (HIV-1) by incorporating into virions in the absence of the virally encoded Vif protein (Deltavif virions), at least in part by causing G-to-A hypermutation. To gain insight into the antiretroviral function of A3G, we determined the quantities of A3G molecules that are incorporated in Deltavif virions. We combined three experimental approaches-reversed-phase high-pressure liquid chromatography (HPLC), scintillation proximity assay (SPA), and quantitative immunoblotting-to determine the molar ratio of A3G to HIV-1 capsid protein in Deltavif virions. Our studies revealed that the amount of the A3G incorporated into Deltavif virions was proportional to the level of its expression in the viral producing cells, and the ratio of the A3G to Gag in the Deltavif virions produced from activated human peripheral blood mononuclear cells (PBMC) was approximately 1:439. Based on previous estimates of the stoichiometry of HIV-1 Gag in virions (1400-5000), we conclude that approximately 7 (+/-4) molecules of A3G are incorporated into Deltavif virions produced from human PBMCs. These results indicate that virion incorporation of only a few molecules of A3G is sufficient to inhibit HIV-1 replication.     

Loss of the PTCH1 gene locus in cardiac fibroma.

BACKGROUND: Cardiac fibroma (CF) is a rare benign tumor that is poorly characterized genetically. CF is more commonly encountered in patients with Gorlin syndrome (3%) than the general population. Mutations of the tumor suppressor gene PTCH1 are the underlying cause of Gorlin syndrome. METHODS: Conventional cytogenetic analysis was performed on a peripheral blood and a CF sample from a 2-week-old male. In addition, fluorescence in situ hybridization (FISH) studies were performed to assess the copy number of the PTCH1 gene locus (9q22.3) on metaphase and interphase cells from these same specimens using yeast artificial protein (YAC) probe 891G1 and on representative paraffin-embedded tissue sections of two additional CFs (one arising in a 2-month-old female and the other in a 13-week-old male). None of the patients had Gorlin syndrome. RESULTS: Karyotypically, the following abnormal chromosomal complement was detected in the 2-week-old male's CF: 46,XY,del(9)(q22q34)[15]. FISH studies revealed homozygous loss of the PTCH1 locus in the cytogenetically analyzed CF and in the CF arising in the 13-week-old male. Heterozygous loss of this locus was identified in the remaining CF from the 2-month-old female. A mutational mechanism other than deletion may be responsible for PTCH1 inactivation on the other locus in this latter patient. Conventional cytogenetic and FISH studies of the peripheral blood sample from the 2-week-old male were normal. CONCLUSION: These data support a tumor suppressor gene role for PTCH1 in nonsyndromic or sporadic CFs.