MnTMPyP, a superoxide dismutase/catalase mimetic, decreases inflammatory indices in ischemic acute kidney injury

Objective  

This study investigates the effect of a superoxide dismutase mimetic, MnTMPyP, on pro- and anti-inflammatory cytokines in acute renal ischemia–reperfusion (IR).     

Synthesis and structure-activity relationships of 6,7-disubstituted 4-anilinoquinoline-3-carbonitriles. The design of an orally active,irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor-2 (HER-2)

A series of of 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile derivatives that function as irreversible inhibitors of EGFR and HER-2 kinases have been prepared. These inhibitors have, at the 6-position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or mixed anhydrides. We performed competitive reactivity studies showing that attaching a dialkylamino group onto the end of the Michael acceptor results in compounds with greater reactivity due to intramolecular catalysis of the Michael addition. This, along with improved water-solubility results in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. One compound, 5 (EKB-569), which shows excellent oral in vivo activity, was selected for further studies and is currently in phase I clinical trials for the treatment of cancer.     

Ultrasonography: Its role in nodular thyroid disease

Objective The objective was to correlate the number, size and extent of the nodules as determined during the preoperative clinical examination of the thyroid gland, USG, intra-operative examination and histopathology. Also, FNAC (with or without USG guidance) and USG findings suggestive of malignancy were correlated with the final histopathology. Setting Tertiary referral centre Patients A retrospective chart review was done for 106 patients who underwent surgery for benign or malignant nodular thyroid disease in our center, between Jan 2004–Dec 2006. Results USG has 7 times higher predictive value than clinical examination in detecting number of nodules and determining size of nodules. USG guided FNAC has a sensitivity of 85.71% and specificity of 90.0% in detecting malignancy in nodular thyroid disease. However for predicting malignancy in thryoid nodules, this study shows that USG has a sensitivity of 20.0% and specificity of 97.67%. Conclusion In patients with nodular thyroid disease, USG can accurately determine the number and the size of the nodules. It is extremely useful in guiding FNAC; However its role in predicting malignancy is doubtful. We therefore recommend that USG guided FNAC be carried out as a routine in the evaluation of thyroid nodules.     

Molecular modeling of the aldose reductase-inhibitor complex based on the X-ray crystal structure and studies with single-site-directed mutants

Aldose reductase (AR) has been implicated in the etiology of the secondary complications of diabetes. This enzyme catalyzes the reduction of glucose to sorbitol using nicotinamide adenine dinucleotide phosphate as an essential cofactor. AR has been localized at the sites of tissue damage, and inhibitors of this enzyme prevent the development of neuropathy, nephropathy, retinopathy, and cataract formation in animal models of diabetes. The crystal structure of AR complexed with zopolrestat, a potent inhibitor of AR, has been described.(1) We have generated a model of the AR-inhibitor complex based on the reported Calpha coordinates of the protein and results of a structure-activity relationship study using four structurally distinct classes of inhibitors, recombinant human AR, and four single-site-directed mutants of this enzyme. The effects of the site-directed mutations on residues within the active site of the enzyme were evaluated by average interaction energy calculations and by calculations of carbon atom surface area changes. These values correlated well with the IC(50) values for zopolrestat with the wild-type and mutant enzymes, validating the model. On the basis of the zopolrestat-binding model, we have proposed binding models for 10 other AR inhibitors. Our models have enabled us to gain a qualitative understanding of the binding domains of the enzyme and how different inhibitors impact the size and shape of the binding site.     

Chronic treatment with lisinopril decreases proliferative and apoptotic pathways in autosomal recessive polycystic kidney disease

Angiotensin converting enzyme (ACE) inhibition is a common therapeutic modality in the treatment of autosomal recessive polycystic kidney disease (ARPKD). This study was designed to investigate whether chronic inhibition of ACE would have a therapeutic effect in attenuating the progression of renal cystogenesis in an orthologous rat model of ARPKD, the polycystic kidney (PCK) rat. Lisinopril (3 mg/kg per day) was administered orally for a period of 12 weeks, beginning at post-natal week 4. Lisinopril treatment resulted in an ∼30% improvement in the collecting duct cystic indices (CT CI) of PCK animals. Activation of extracellular signal-regulated kinase 1 (ERK1) and 2 (ERK2), proliferative signaling markers, and proliferating cell nuclear antigen (PCNA), an end-point marker for proliferation, was reduced following chronic treatment with lisinopril compared to that in vehicle-treated PCK rats. To assess whether apoptotic pathways were altered due to chronic ACE inhibition, we examined p38 mitogen activated protein kinase (MAPK) and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), which are markers of apoptotic signaling cascades. p38 MAPK was significantly reduced (P < 0.0001) following chronic treatment with lisinopril, but no change in the activation of SAPK/JNK could be detected by immunoblot analysis. Lisinopril treatment resulted in a significant reduction (P < 0.01) in cleaved caspase-7 levels, but not caspase-3 activity, in PCK rat kidneys compared to the vehicle-treated PCK rat kidneys. Proteinuria was completely ameliorated in the presence of chronic ACE inhibition in the lisinopril-treated rats compared with the vehicle-treated PCK rats. In all, these findings demonstrated that chronic ACE inhibition can beneficially alter proliferative and apoptotic pathways to promote therapeutic reductions in renal cyst development in ARPKD.     

Ultrasonography: Its role in nodular thyroid disease

Objective

The objective was to correlate the number, size and extent of the nodules as determined during the preoperative clinical examination of the thyroid gland, USG, intra-operative examination and histopathology. Also, FNAC (with or without USG guidance) and USG findings suggestive of malignancy were correlated with the final histopathology.

Setting

Tertiary referral centre

Patients

A retrospective chart review was done for 106 patients who underwent surgery for benign or malignant nodular thyroid disease in our center, between Jan 2004–Dec 2006.

Results

USG has 7 times higher predictive value than clinical examination in detecting number of nodules and determining size of nodules. USG guided FNAC has a sensitivity of 85.71% and specificity of 90.0% in detecting malignancy in nodular thyroid disease. However for predicting malignancy in thryoid nodules, this study shows that USG has a sensitivity of 20.0% and specificity of 97.67%.

Conclusion

In patients with nodular thyroid disease, USG can accurately determine the number and the size of the nodules. It is extremely useful in guiding FNAC; However its role in predicting malignancy is doubtful. We therefore recommend that USG guided FNAC be carried out as a routine in the evaluation of thyroid nodules.     

Cloning and characterization of a sixth adenylyl cyclase isoform: types V and VI constitute a subgroup within the mammalian adenylyl cyclase family.

A sixth member of the mammalian adenylyl cyclase family has been isolated from a canine cardiac cDNA library. This isoform is more highly homologous to type V than to the other adenylyl cyclase types; sequence similarity is apparent even in the transmembrane regions where the greatest divergence among the types exists. Type VI mRNA expression is most abundant in heart and brain; however, unlike type V, a low level of expression is also observed in a variety of other tissues examined. Type VI adenylyl cyclase can be stimulated by NaF, guanosine 5'-[gamma-thio]triphosphate, and forskolin but not by Ca2+/calmodulin, whereas it is inhibited by adenosine and its analogues. Comparison of both their structural and biochemical properties suggests that types V and VI constitute a distinct subgroup of the mammalian adenylyl cyclase family.     

Sentinel Lymph Node Localization Using 1 % Isosulfan Blue Dye in Cases of Early Oral Cavity and Oropharyngeal Squamous Cell Carcinoma

To study the use of 1 % isosulfan blue dye in identifying sentinel node, sensitivity and specificity of frozen section and predictive value of sentinel node in predicting other nodal status in the cases of oral cavity and oropharyngeal squamous cell carcinoma. 15 patients of oral cavity and oropharyngeal SCC with clinically N0 neck, who required WLE of the primary lesion as well as neck dissection as per recommended treatment protocol, were selected from OPD. 1 % Isosulfan dye was injected peritumorally intraoperatively after the induction of general anaesthesia. Neck dissection was performed and first node taking up the blue dye was identified, dissected, removed and was sent for frozen section. In two of the 15 cases a sentinel node was identified (sensitivity of the technique—13 %). Both the sentinel nodes were positive for presence of metastasis on final histopathology (specificity—100 %). However, five cases had nodal metastasis on final histopathological examination of the neck dissection specimen (sensitivity of sentinel lymph node biopsy—40 %). Frozen section examination had a sensitivity and specificity of 100 %. All data was analyzed using SPSS 16 software. Use of 1 % Isosulfan Dye for identification of sentinel node is a simple and cheap technique, however, it has low sensitivity as compared to the use of triple diagnostic procedure consisting of lymphoscintigraphy, per op gamma probe localization and using isosulfan dye for sentinel node identification. Sentinel lymph node is representative of nodal status and correlates well with the final histopathological examination of the dissected neck nodes.