Branchial Cyst with Branchial Fistula: A Rare Association.

Branchial arch anomalies are the most common congenital neck masses. The second branchial arch anomalies followed by first arch anomalies are seen commonly in the descending order. They originate from remnants of branchial arches and clefts. They may present as cysts, sinus tracts, fistulae or cartilaginous remnants. They are mostly located in the lateral aspect of the neck anterior to the sternocleidomastoid, anterior to the hyoid bone, preauricular region or at the angle of the mandible. A complete fistula communicating with a branchial arch cyst is a very rare congenital anomaly of the branchial apparatus. These patients are generally asymptomatic but may present with mucoid discharge from the tract. Here we present a case of branchial fistula associated with a branchial cyst in a 11 year old child.

NRAS mutations in de novo acute leukemia: prevalence and clinical significance.

The activating mutations of the Ras gene or other abnormalities in Ras signaling pathway lead to uncontrolled growth factor-independent proliferation of hematopoietic progenitors. Oncogenic mutations in NRAS gene have been observed with variable prevalence in hematopoietic malignancies. In the present study, NRAS mutations were detected using bidirectional sequencing in 264 acute leukemia cases--129 acute lymphocytic leukemia (ALL) and 135 acute myeloid leukemia (AML) and 245 age- and gender-matched controls. Missense mutation was observed only in the 12th codon of NRAS gene in 4.7% of AML and 3.16% of ALL cases. The presence of NRAS mutation did not significantly influence blast % and lactate dehydrogenase (LDH) levels in AML patients. When the data were analyzed with respect to clinical variables, the total leukocyte count was elevated for mutation positive group, compared to negative group. In AML patients with NRAS mutations, 60% failed to achieve complete remission (CR), as compared to 34.8% in mutation negative group. These results indicated that NRAS mutations might confer poor drug response. In AML, disease free survival (DFS) in NRAS mutation positive group was lesser, compared to mutation negative group (9.5 months vs. 11.68 months). In ALL patients, DFS of NRAS mutation positive group was lesser than mutation negative group (9.2 months vs. 27.5 months). The CR rate was also lower for mutation-positive patients group, compared to mutation-negative group. In conclusion, these results suggested that presence of NRAS mutation at 12th codon was associated with poor response and poorer DFS in both ALL and AML.

Intronic SNPs of TP53 gene in chronic myeloid leukemia: Impact on drug response.

BACKGROUND: TP53, located on chromosome 17p13, is one of the most mutated genes affecting many types of human cancers. Thus, we aimed at investigating the association of SNPs in TP53 gene with chronic myeloid leukemia (CML). MATERIALS AND METHODS: A total of 236 CML and 157 control samples were analysed for mutations in TP53 gene using polymerase chain reaction followed by direct sequencing. RESULTS: Sequencing analysis for mutations in exons 7-9 of the TP53 gene revealed four SNPs, three in intron 7 (C14181T, T14201G, and C14310T) and one SNP in intron 6 (A13463G) of TP53 gene. The mutation C14181T is located at position 72 base pairs downstream of the 3'-end of exon 7 of the P53 gene. This mutation is in complete linkage disequilibrium with a T14201G mutation, 20 base pairs further downstream occurring at position 14201. This mutation occurred only in the presence of C14181T mutation and these mutations showed association with advanced phase and cytogenetic poor response. Another two novel mutations, C14310T in intron 7 and A13463G in intron 6 were also found to be associated with cytogenetic poor response. CONCLUSION: Our study suggests that TP53 intronic SNPs might have a strong influence on disease progression and poor response in CML patients.

Environmental and familial risk factors of Parkinsons disease: case-control study.

BACKGROUND: While the cause of Parkinson's disease (PD) remains unknown, evidence suggests certain environmental factors, such as well water drinking, herbicides, pesticides exposure and neurotoxins, may trigger the chain of oxidative reactions culminating in the death of dopaminergic neurons in substantia nigra to cause Parkinsonism. To investigate the possible impact of environmental risk factors for idiopathic PD, a case-control study was performed in the Eastern India. METHODS: During the period from January 1st, 2006 and December 10th, 2009, 175 PD patients (140 men, 35 women) and 350 non-Parkinson age-sex matched controls were included in the study. Subjects were given a structured neurological examination and completed an administered questionnaire which elicited detailed information on demographic data, pesticides, herbicides family history, occupation, dietary and smoking habits. RESULTS: The multivariate analysis revealed that family history of PD, pesticide exposure, exposure to toxins other than pesticides and herbicides, rural living and previous history of depression were associated with increased risk of PD, whereas, smoking appeared to be a protective factor. Well water drinking for at least five years, though a significant risk factor on univariate analysis (OR = 4.5, 95% CI = 2.1-9.9), could not be proved significant in multivariate analysis. Head trauma, vegetarian dietary habit, occupation involving physical exertion and exposure to domestic pets were not as significant risk factors. CONCLUSION: Results of our study support the hypothesis of multifactorial etiology of PD with environmental factors acting on a genetically susceptible host.

Fms like tyrosine kinase (FLT3) and nucleophosmin 1 (NPM1) mutations in de novo normal karyotype acute myeloid leukemia (AML).

Mutations in FLT3 and NPM1 are important prognostic factors in AML, influencing outcome in normal karyotype cases. We here analysed incidences of FLT3/ITD, D 835 and NPM1 mutations in patients with de novo normal karyotype AML using PCR and gene sequencing, along with laboratory parameters and treatment outcomes. There were 128 patients with a median age of 45 years (range, 19-65). FLT3/ITD mutations were detected in 26 (20.3%), FLT3/D835 in 8 (6.2%) and NPM1 in 22 (17.1%). The incidence of FLT3/ITD was higher in those with elevated lactate dehydrogenase (LDH) and peripheral blasts (p=< 0.002, < 0.001) while NPM1 mutations or both NPM1 and FLT3/ITD was more common in elevated total leukocyte counts (TLC), LDH and peripheral blasts (p=<0.0001). Complete response and disease free survival were lower in those with FLT3/ITD mutations (p=0.04, 0.03). The incidence of FLT3 and NPM1 mutations was found to be low in Indian patients with normal karyotype AML.

Serum levels of bone alkaline phosphatase in breast and prostate cancers with bone metastasis.

BALP activity in the sera of metastatic patients of breast and prostate malignancy has increased significantly. Our studies with patients in India conform the earlier reports that BALP may have a useful complementary role in the early diagnosis of bone metastases.

Expression cloning of protein targets for 3-phosphorylated phosphoinositides.

The phosphatidylinositol 3-kinase (PI 3'-K) family of lipid kinases play a critical role in cell proliferation, survival, vesicle trafficking, motility, cytoskeletal rearrangements, and oncogenesis. To identify downstream effectors of PI 3'-K, we developed a novel screen to isolate proteins that bind to the major products of PI 3'-K: phosphatidylinositol-3,4-bisphosphate (PtdIns-3,4-P(2)) and PtdIns-3,4,5-trisphosphate (PtdIns-3,4,5-P(3)). This screen uses synthetic biotinylated analogs of these lipids in conjunction with libraries of radiolabeled proteins that are produced by coupled in vitro transcription/translation reactions. The feasibility of the screen was initially demonstrated using avidin-coated beads prebound to biotinylated PtdIns-3,4-P(2) and PtdIns-3,4,5-P(3) to specifically isolate the pleckstrin homology domain of the serine/threonine kinase Akt. We then demonstrated the utility of this technique in isolating novel 3'-phosphorylated phosphatidylinositol (3'-PPI)-binding proteins through the preliminary screening of in vitro transcribed/translated cDNAs from a small pool expression library derived from mouse spleen. Three proteins were isolated that bound specifically to 3'PPIs. Two of these proteins have been previously characterized as PIP3BP/p42(IP4) and the PtdIns-3,4,5-P(3)-dependent serine/threonine kinase phosphoinositide-dependent kinase 1. The third protein is a novel protein that contains only a Src homology 2 domain and a pleckstrin homology domain; this protein has a higher specificity for both PtdIns-3,4,5-P(3) and PtdIns-3,4-P(2) than for PtdIns-4, 5-bisphosphate. Transcripts of this novel gene are present in every tissue analyzed but are most prominently expressed in spleen. We have renamed this new protein PHISH for 3'-phosphoinositide-interacting Src homology-containing protein. This report demonstrates the utility of this technique for isolating and characterizing 3'-PPI-binding proteins and has broad applicability for the isolation of binding domains for other lipid products.

A chemically synthesized version of the insect antibacterial glycopeptide, diptericin, disrupts bacterial membrane integrity.

Insects protect themselves against bacterial infection by secreting a battery of antimicrobial peptides into the hemolymph. Despite recent progress, important mechanistic questions, such as the precise bacterial targets, the nature of any cooperation that occurs between peptides, and the purpose of multiple peptide isoforms, remain largely unanswered. We report herein the chemical synthesis and preliminary mechanistic investigation of diptericin, an 82 residue glycopeptide that contains regions similar to two different types of antibacterial peptides. A revised, highly practical synthesis of the precursor N(alpha)-Fmoc-Thr(Ac(3)-alpha-D-GalNAc) allowed us to produce sufficient quantities of the glycopeptide for mechanistic assays. The synthetic, full-length polypeptide proved to be active in growth inhibition assays with an IC(50) of approximately 250 nM, a concentration similar to that found in the insect hemolymph. Biological analysis of diptericin fragments indicated that the main determinant of antibacterial activity lay in the C-terminal region that is similar to the attacin peptides, although the N-terminal segment, related to the proline-rich family of antibacterial peptides, augmented that activity by 100-fold. In all assays, activity appeared glycosylation independent. Circular dichroism of unglycosylated diptericin indicated that the peptide lacked structure both in plain buffer and in the presence of liposomes. Diptericin increased the permeability of the outer and inner membranes of Escherichia coli D22 cells, suggesting possible mechanisms of action. The ability to access glycopeptides of this type through chemical synthesis will facilitate further mechanistic studies.

Circulating levels in serum of total sialic acid, lipid-associated sialic acid, and fucose in precancerous lesion and cancer of the oral cavity.

Total sialic acid (TSA), lipid-associated sialic acid (LASA), and fucose were estimated in sera of 35 patients with precancerous lesion of the oral cavity, 68 patients with cancer of the oral cavity, and 25 age- and sex-matched non-chewers of both tobacco and betal nut and nonsmokers as controls. Significant elevation in the serum levels of TSA and LASA were observed in patients with the precancerous and cancer lesions when compared with the controls. Serum TSA levels were elevated significantly in patients with cancer when compared with those with precancerous lesions. Circulating TSA and LASA levels were found to reflect tumor burden and correlated well with stage of the disease. However, serum fucose levels did not show an increase corresponding to stage of the disease. The results suggests that combined evaluation of these markers may be useful in predicting early malignant change and also in assessing the spread and invasiveness of the disease in cancer of the oral cavity.

Serum vitamins' status in oral leucoplakias--a preliminary study.

Vitamins, such as A, beta carotene, C, E, B12 and folate, are the micronutrients with the strongest evidence of having a link to cancer prevention and control. Deficiency of these vitamins at the dietary, systemic or mucosal level will interact with tobacco use and increase the risk of oral precancerous lesions. The objective of this study was to (1) establish the baseline circulating levels of these vitamins in our normal population with and without tobacco use and (2) compare these levels with the values obtained in cases of oral leucoplakias. 50 normal controls with 25 each in chewers and non-chewers, matched for age and sex, were selected. 50 cases of oral leucoplakias (clinically detectable white patches) from the field constituted the study group. Simultaneous measurement of serum vitamin B12 and folate were carried out by radioassay. The other serum vitamins were estimated spectrophotometrically. Except for serum vitamin E, all the other serum vitamin levels were significantly decreased in oral leucoplakias compared to the controls. Cancer chemopreventive agents acting as inhibitors of both initiation and promotion, as analysed in our population, is promising for further intervention trials.

Activating mutations of rhodopsin and other G protein-coupled receptors.

Rhodopsin, the visual pigment of rod photoreceptors cells, is a member of the large family of G protein-coupled receptors. Rhodopsin is composed of two parts: a polypeptide chain called opsin and an 11-cis-retinal chromophore covalently bound to the protein by means of a protonated Schiff base linkage to Lys296 located in the seventh transmembrane segment of the protein. Several mutations have been described that constitutively activate the apoprotein opsin. These mutations appear to activate the protein by a common mechanism of action. They disrupt a salt-bridge between Lys296 and the couterion Glu113 that helps constrain the protein to an inactive conformation. Four of the mutations have been shown to cause two different diseases of the retina, retinitis pigmentosa and congenital night blindness. Recently, several other human diseases have been shown to be caused by constitutively activating mutations of G protein-coupled receptors.

Balloon angioplasty of the femoro-popliteal segment: follow up results from southern India.

BACKGROUND: Disease of the femoral and popliteal arteries, though one of the commonest manifestations of atherosclerosis, is under-recognized because the morbidity it produces is less catastrophic than coronary or cerebrovascular arterial involvement. Percutaneous transluminal angioplasty is performed for femoro-popliteal lesions at different centres in India, but post-angioplasty follow up data are scarce. We present our results after femoro-popliteal balloon angioplasty in 140 lesions. METHODS: Between 1986 and 1993, 140 femoro-popliteal angioplasties were performed in 119 patients with symptomatic limb ischaemia. Seventy-one per cent of patients had claudication and the others also had tissue loss. Eighty-two per cent of the lesions were occlusions. The average length of the lesions was 10.7 cm. Conventional wire-balloon angioplasty was performed in 128 lesions; in 12 others, laser-assisted balloon angioplasty was performed using an Nd-YAG laser thermal probe. Patients were followed up at regular intervals for any recurrence of symptoms and for objective evidence of restenosis or re-occlusion. RESULTS: Despite a technical success in 83% of the lesions, cumulative primary patency calculated by the life-table method showed a slow decline which plateaued at 40% after 36 months. Long occlusions and multifocal stenoses showed shorter cumulative patency following angioplasty (27 months and 5.8 months respectively). Extensive luminal irregularity due to post-angioplasty intimal flaps was reduced by using warm contrast for balloon dilatation in 16 patients. In 14 patients who had repeat angioplasty for restenosis, the secondary patency showed a satisfactory figure of 84% at 60 months. CONCLUSION: Percutaneous transluminal angioplasty is a satisfactory alternative to surgery in femoro-popliteal stenotic or occlusive disease. Regular follow up of such patients is essential in the first three years because re-occlusion can occur. We found that patency remained fairly constant after 36 months. Repeated angioplasty can maintain patency in patients with restenosis.

A novel application of a competitive binding model in dioxin risk assessment.

The EPA-recommended toxicity equivalence factor (TEF) approach to estimating the lifetime incremental cancer risks for dioxins does not address (a) differences in the severity of toxicity according to the composition of chemical mixture and (b) potentials for modification of tissue-level doses of congeners in mixtures and consequently the cancer risk estimates. Our earlier efforts to model the binding of congeners to the Ah receptor in the low-dose range and to develop quantitative estimates for the formation of fractions of Ah receptor-congener complexes resulted in the definition of a unique parameter, defined as competitive binding ratio (CBR), to adjust tissue-level doses for mixture exposure. We made an effort to incorporate CBR values in the dose-response analysis and risk characterization of congeners in two distinct exposure scenarios. The modified approach to estimating tissue-level doses of congeners in mixtures by the use of a competitive binding model indicated that (a) the Ah receptor affinity is an important criterion in the determination of tissue-level dose of congeners, (b) the TEF doses calculated by using the model algorithms modified the tissue-level doses for congeners in mixture exposures, and (c) the combined lifetime incremental cancer risks for all congeners were generally lower when model algorithms were used in the dose-response analysis. However, the percentage contribution of toxic congeners was significantly higher when model algorithms were used. The percentage contribution of higher congeners with low toxicity was considerably reduced when model algorithms were used.(ABSTRACT TRUNCATED AT 250 WORDS)

Focal occlusive disease of the common femoral artery: a report of 20 cases.

Occlusive disease localized to the common femoral artery without contiguous involvement of the external iliac and superficial femoral arteries is distinctly uncommon in vascular surgical practice. Twenty patients with focal occlusive disease in 21 common femoral arteries are featured in this report. All except one had severe disabling symptoms: Fontaine classification was stage I in one patient, stage IIb in 13, and stage III in six patients. The probable aetiology, based on clinical features and angiographic observations, was identified as atherosclerosis (nine cases), thromboangiitis obliterans (three) and Takayasu's arteritis (two). Histological features of mucoid vasculopathy, a novel disorder, was seen in one patient while no specific aetiology was evident in five patients. Associated lesions were seen in fourteen patients: aortoiliac in one, femoropopliteal in seven (without any continuity to the common femoral lesion), internal iliac in three and tibial in three. Balloon angioplasty of the common femoral artery lesions was attempted in 14 patients with successful outcome in nine. Three patients (including two with failed balloon angioplasty), underwent thromboendarterectomy and two bypass procedures (iliofemoral, one; femoropopliteal, one). Late reocclusion occurred in one patient each in the angioplasty and surgical groups. There were no procedure-related complications in either group.

Angiographic analysis and results of endovascular therapy of aneurysm of vein of Galen.

Angioarchitecture of the aneurysmal malformation of the vein of Galen in 9 patients is analysed. An arterial maze arborised directly into the vein of Galen in 6 patients. Direct fistulous communication from one or two pedicles was noted in three children. Unilateral choroidal arterial contribution via an eccentric cul-de-sac in two infants suggested embryonic involvement of the ipsilateral internal cerebral vein along with the median prosencephalic vein of Markowski. Unusually, a sylvian branch of the middle cerebral artery drained directly into the basal vein of Rosenthal which in turn communicated to the aneurysm of vein of Galen in another patient. Two adult patients had curvilinear rim calcification of the venous sac with rapid circulation. All but two showed venous sinus anomalies. Two children had prior shunt surgery at the referring hospitals. The pathophysiology of hydrocephalus and the possible consequences of shunt, question the need for CSF diversion as a routine in these patients. Percutaneous trans-arterial embolotherapy, in five patients achieved complete obliteration of the malformation in four patients and partial reduction of flow in another. While transvenous/trans-torcular approach is reserved for selected patients and direct surgery carries high morbidity, this report emphasises the efficacy of trans-arterial embolotherapy.

Self-expandable stents for tracheal stenosis: experience in two patients.

Two patients with cervical tracheal stenosis, following prolonged ventilatory support, underwent balloon dilatation and expandable stainless steel stent placement across the stenoses. Following the successful release of the stent, there was gradual widening of the stenosed trachea in one patient, while in the other re-stenosis occurred due to columns of tracheal tissue projecting between the limbs of the stent. In the chronically ill and debilitated, use of expandable stents provides a good alternative to complex reconstructive surgery.

Logistic regression of inhalation toxicities of perchloroethylene--application in noncancer risk assessment.

Unlike the impressive advancement of cancer risk assessment, the "cutoff approach" based on hazard quotient in noncancer risk assessments recommended by the EPA has crucial deficiencies. Several alternative approaches have been suggested in the literature to modify the noncancer risk characterization based on reference doses. Recent studies have indicated that the effects of perchloroethylene (PERC) on the central nervous system (CNS) is a much more sensitive noncancer endpoint than cancer which is currently the basis for deriving its public health criteria and standards. Studies indicate that 20 ppm of inhaled PERC concentration elicited adverse effects on the CNS in experimental animals and humans. However, the existing EPA oral reference dose (RfD), a noncancer toxicity parameter for PERC (0.01 mg/kg/day), is based on the induction of hepatotoxicity and increased body weight gain induced by PERC in rats. An attempt was made in this paper to examine whether logistic regression of dose-response data could be applied to assess the noncancer risks. In order to perform logistic regression the inhalation toxicity data of PERC were classified according to the severity of toxicity paradigm used in toxicity analysis. Based on the sensitive noncancer endpoints identified from severity classification, a logistic regression analysis of the data was performed and its potential applicability in noncancer risk characterization was described for workers exposure to PERC in dry-cleaning operations.

Total occlusion of iliac arteries: results of balloon angioplasty.

Fifty-six occluded iliac arteries (mean length 6.1 cm; range 1-17 cm) in 50 patients were treated by percutaneous transluminal angioplasty (PTA) or laser-assisted PTA (bilateral lesions in 6 patients). Twenty-seven patients (54%) were at high risk for surgery. Patients were followed for a maximum period of 72 months (mean 23.12 months; median 20 months). The initial success rate was 78.57% for arteries and 82% for patients. Laser-assisted PTA was attempted in 11 occluded arteries (19.64%) and was successful in 4 arteries (7.14%). Conventional PTA was successful in 71.4% of arteries including all 7 arteries for which laser-assisted PTA failed (76% of patients). PTA was unsuccessful in 12 arteries (21.43%). Urokinase was used before PTA in 1 artery. The effect of PTA was evident clinically by relief of rest pain (66.66%), healing of ulcer (57%), increased claudication distance or no claudication (79%) in limbs, and objectively, by improvement in ankle/arm index (AAI) (an increase of 0.16 to 0.91) and increased exercise tolerance. Continuous improvement in AAI was observed after PTA on follow-up in 9 limbs. One patient died during follow-up. On follow-up, 3 arteries were occluded, 6 showed evidence of stenosis, and 1 showed fusiform dilatation at the PTA site. The long-term results using the life-table method determined a 76% primary patency rate and 81% secondary patency rate for 72 months. The overall patency including failures was 63%. Age of the patients (p = 0.0169) and hypertension (p = 0.0015) significantly affected the long-term patency of the artery but not the initial success. The major complications were arterial rupture in a repeat procedure in 1 artery, axillary artery thrombosis in 1, and distal thromboembolic occlusion during PTA in 4. The long-term patency rates suggest that PTA of totally occluded iliac arteries is a safe and effective procedure and provides a long-term benefit.

Binary combination effects of some pharmacologically active chemicals as promoters of tumorigenesis.

Identification of potential interactions in exposures either to simultaneous or sequential combinations of carcinogenic chemicals and chemicals that modify carcinogenesis poses considerable difficulties in human health risk assessments. Studies of experimental carcinogenesis over the past four decades have revealed that many pharmacologically active agents possess tumorigenesis-promoting properties. The effort to identify the possible chemical structural basis of interactions of binary combinations of carcinogenic chemicals and chemical agents that modify carcinogenesis led to the identification of a class of structurally diverse and pharmacologically active tumorigenesis promoters that are known as pharmaceuticals. The chemical class-class interactions of carcinogens and pharmaceutical agents with reported tumorigenesis-promoting properties and the possible biochemical mechanism(s) that underlie such interactions are discussed.

Hyperperfusion syndrome following balloon angioplasty and bypass surgery of aortic arch vessels: a report of 3 cases.

Hyperperfusion syndrome is a rare complication following revascularization for severe cerebrovascular occlusive disease. We report 2 cases with milder manifestations of this syndrome in the form of unilateral headache following balloon angioplasty of brachiocephalic arteries, and 1 case with massive cerebral hemorrhage after aorto-carotid bypass surgery. The mechanism of autoregulation of cerebral blood flow and the pathophysiology of cerebral hyperperfusion are discussed. The importance of recognizing this phenomenon and possible means of preventing its occurrence are emphasized.