Encephalopathy associated with acute measles

Thirty children presenting with acute encephalopathic illness within a month of measles were studied. A male preponderance was found and 83.3% of cases were below 5 years of age. The interval between onset of measles rash and that of encephalopathy ranged from 0 to 20 days. Fever (96.6%), convulsions (70%), and coma (90%) were found in a high percentage of cases, while focal neurological deficits and abnormal movements were found in a small number of patients (3.3% and 16.6% respectively). Signs of cerebellar or medullar involvement were not seen. Only 1 (3.3%) case had pleocytosis in the cerebrospinal fluid. Eleven (36.6%) patients died in hospital. The pathogenesis of acute encephalopathy following measles is discussed. An erratum to this article is available at .     

G6PD deficiency in newborn infants

Five hundred consecutive newborns were screened for erythrocytic G6PD deficiency in cord blood. The overall incidence of G6PD deficiency was found to be 2.80 percent. The incidence of G6PD deficiency was higher among males (3.77%) compared to females (1.44%). The incidence of erythrocytic G6PD deficiency was higher in Muslims (16.67%) compared to Hindus (2.63%). No definite relationship of erythrocytic G6PD deficiency was observed with consanguinity. Fifty per cent mothers of G6PD deficient newborns were also found to be G6PD deficient. Among brothers and sisters of G6PD deficient children the incidence of G6PD deficiency was 50.00 and 9.10 per cent respectively. There was no significant difference in the incidence of hyperbilirubinemia between erythrocytic G6PD deficient and non deficient newborns.     

Endoscopic versus open saphenous vein harvest: a comparison of postoperative wound complications

BACKGROUND: Wound complications associated with long incisions used to harvest the greater saphenous vein are well documented. Recent reports suggest that techniques of endoscopic vein harvest may result in decreased wound complications. A prospective, nonrandomized study was developed to compare outcomes of open versus endoscopic vein harvest procedures. METHODS: There were 106 patients in the open vein harvest group, and 154 patients in the endoscopic vein harvest group. Patient characteristics and demographics were similar in both groups. Wound complications identified were dehiscence, drainage for greater than 2 weeks postoperatively, cellulitis, hematoma, and seroma/lymphocele. RESULTS: Wound complications were significantly less in the endoscopic vein harvest group (9 of 133, 6.8%) versus the open vein harvest group (26 of 92, 28.3%), p less than 0.001. By multivariable analysis with logistic regression, the open vein harvest technique was the only risk factor for postoperative leg wound complication (relative risk 4.0). CONCLUSIONS: Endoscopic vein harvest offered improved patient outcomes in terms of wound healing compared with the open vein harvest technique.     

Distribution of furamidine analogues in tumor cells: targeting of the nucleus or mitochondria depending on the amidine substitution

Diphenylfuran diamidines represent an important class of DNA minor groove binders of high therapeutic interest as antiparasitic or antitumor agents depending on the compounds structures. To exert their cytotoxic action, the compounds must first get into the cell and reach the nuclear compartment where the main target, DNA, is located. The forces that drive the drugs into cell nuclei, as well as the influence of the molecular structures on the cell distribution, are not known. To address these issues, we took advantage of the fluorescence of the molecules to analyze their intracellular distribution profiles in tumor cells of different origins (B16 melanoma, MCF7 mammary adenocarcinoma, A549 lung carcinoma, HT29 colon carcinoma, LNCaP, and PC3 prostatic carcinoma) by epifluorescence and confocal microscopy. A homogeneous series of synthetic bis-substituted alkyl or phenyl amidine and reverse amidine derivatives of furamidine was used to dissect the molecular mechanisms that control the distribution of the drugs into the cytoplasm or the nucleus of the cells. The amidine (DB75) and the various N-alkyl derivatives were found to accumulate selectively in the cell nuclei. This is also the case for a guanidine derivative but not for the phenyl-substituted compound DB569, which essentially localizes in cytoplasmic granules. Similar cytoplasmic patterns were observed with a reverse amidine analogue and a pyridine-substituted compound indicating that the presence of aromatic rings on the terminal side chain is the limiting factor that restricts the uptake of the compounds in the nuclear compartment. The use of different organelle-selective fluorescent probes, such as JC-1 and chloromethyl-X-rosamine, both specific to mitochondria and neutral red considered as a lysosome-selective probe, suggests that DB569 preferentially accumulates in mitochondria. Competition experiments with the antitumor drug daunomycin reveal that the diphenylfurans are attracted into the nuclei by the DNA. The DNA minor groove-drug interactions provide the driving force that permits massive accumulation of the fluorescent molecules in the nuclei. The DNA binding properties of the diphenylfuran derivatives were investigated by DNase I footprinting and surface plasmon resonance biosensor experiments to measure sequence selectivity and binding affinities, respectively. Furamidine and its phenyl-substituted analogue that accumulate in the cell nuclei and mitochondria, respectively, share a common selectivity for AT sites and bind equally tightly to these sites. Therefore, it is possible to modulate the intracellular distribution of the furamidine derivatives without affecting their DNA binding and sequence recognition properties. The introduction of aromatic substituents on diphenylfuran diamidines represents a novel strategy to control the intracellular compartmentalization of these DNA binding agents and directs them to mitochondria. This drug design strategy may prove useful to trigger drug-induced apoptosis.     

Aberrant promoter methylation profile of prostate cancers and its relationship to clinicopathological features.

PURPOSE: We investigated the aberrant methylation profile of prostate cancers and correlated the data with clinical findings. EXPERIMENTAL DESIGN: Gene promoter methylation was analyzed in 101 prostate cancer samples. In addition, we analyzed 32 nonmalignant prostate tissue samples, which included 25 with benign disease, benign prostatic hypertrophy, or prostatitis, and 7 normal tissues adjacent to cancer. The methylation status of 10 genes was determined. The methylation index (MI) was calculated as a reflection of the methylated fraction of the genes examined. RESULTS: Methylation percentages of the genes tested in prostate cancers were: RARbeta, 53%; RASSF1A, 53%; GSTP1, 36%; CDH13, 31%; APC, 27%; CDH1, 27%; FHIT, 15%; p16(INK4A), 3%; DAPK, 1%; and MGMT, 0%. Methylation percentages in nonmalignant tissues were much lower. For clinicopathological correlations, we divided the cancer cases into low (6 or less) or high (7 or more) Gleason score (GS) groups, and into low (8 ng/ml or less) or high (greater than 8 ng/ml) preoperative serum prostate-specific antigen (PSA) groups. Methylation of RASSF1A, GSTP1, RARbeta, and CDH13 genes was significantly more frequent in the high GS group than in the low GS group. Methylation of RASSF1A, CDH1, and GSTP1 genes was significantly more frequent in the high PSA group than in the low PSA group. The median MIs were significantly higher in the high GS and the high PSA groups. According to the Spearman rank-correlation test, there was significant correlation between MI and GS (coefficient = 0.43, P < 0.0001) and the preoperative serum PSA (coefficient = 0.37, P = 0.0003). CONCLUSIONS: Our results indicate that the methylation profile of prostate cancers correlates with clinicopathological features of poor prognosis.     

Adenosine 5'-triphosphate-citrate lyase activity in mammalian spermatozoa: A new radiometric method and characterization of the enzyme in spermatozoa

A simple radiochemical method was developed for determining the ATP-citrate lyase activity in mammalian spermatozoa. The determination of enzyme activity was followed by the measurement of the incorporation of the [1-¹⁴C]acetyl group from [1,5-¹⁴C]citrate into [1-¹⁴C]acetylcoenzyme A (ACoA). Separation of ¹⁴C-labeled ACoA from the reactants and their products was achieved by rapid anion exchange chromatography. The optimum pH was 6.4 for rat spermatozoal ATP-citrate lyase. The activity was not altered by dithiothreitol. MgCl₂ (l0mM) caused a 50 per cent inhibition in the enzyme activity. ATP-citrate lyase activities in rat and human spermatozoa were 154 ± 14 and 90 ± 12 nmoles of ACoA formed/mg of protein/5 min. Citrate may serve as an acetyl source for acetylcholine formation by spermatozoa.     

Differential molecular interactions between the crystalline and the amorphous phases of celecoxib

We have investigated the differences in molecular interactions between the crystalline (ordered) and amorphous (disordered) phase of a poorly soluble drug, celecoxib. Molecular interactions in the crystalline phase were investigated with the help of Mercury software, using single crystal X-ray diffractometric data for celecoxib. A simulated annealing molecular dynamics approach was used for the assessment of altered molecular interactions in the amorphous phase. Crystalline celecoxib was found to contain an ordered network of H-bonding between all its electron donors (-S=O group, 2-N of pyrazole ring and -C-F) and the acceptor (-N-H). Amorphous celecoxib retained all these interactions in its disordered molecular arrangement, with a relatively stronger H-bonding between the interacting groups, as compared with crystalline celecoxib. However, these inter-molecular interactions differed in strength in the two solid-state forms. The altered configurations of the molecular arrangement in the two phases were supported by the shifts observed in the Fourier-transform infra-red vibrational spectra of respective states. These interactions could have strong implications on devitrification kinetics of amorphous celecoxib, and could further guide the choice of stabilizers for the amorphous form.     

Gas chromatographic-mass spectrometric differentiation of atenolol, metoprolol, propranolol, and an interfering metabolite product of metoprolol

Over a 10-year period, 1993-2002, Federal Aviation Administration identified 50 pilot fatalities involving atenolol, metoprolol, and propranolol, which is consistent with the fact that these drugs have been in the lists of the top 200 drugs prescribed in the U.S. In a few of the 50 pilot fatality cases, initial analysis suggested the presence of atenolol and metoprolol. However, there was no medical history with these cases supporting the use of both drugs. Therefore, atenolol, metoprolol, and/or propranolol, with their possible metabolite(s), were re-extracted from the selected case specimens, derivatized with pentafluoropropionic anhydride (PFPA), and analyzed by gas chromatography-mass spectrometry (GC-MS). The MS spectra of these three antihypertensives and a metoprolol metabolite are nearly identical. All of the PFPA derivatives had baseline GC separation, with the exception of a metoprolol metabolite product, which co-eluted with atenolol. There were four primary mass fragments (m/z 408, 366, 202, and 176) found with all of the PFPA-beta-blockers and with the interfering metabolite product. However, atenolol has three unique fragments (m/z 244, 172, and 132), metoprolol has two unique fragments (m/z 559 and 107), propranolol has four unique fragments (m/z 551, 183, 144, and 127), and the metoprolol metabolite product has two unique fragments (m/z 557 and 149). These distinctive fragments were further validated by using a computer program that predicts logical mass fragments and performing GC-MS of deuterated PFPA-atenolol and PFPA-propranolol and of the PFPA-alpha-hydroxy metabolite of metoprolol. By using the unique mass fragments, none of the pilot fatality cases were found to contain more than one beta-blocker. Therefore, these mass ions can be used for differentiating and simultaneously analyzing these structurally similar beta-blockers in biological samples.     

Acute renal failure following multiple wasp stings

We report the cases of two patients who developed acute renal failure following multiple wasp stings. Both patients required dialysis and recovered within 4 weeks. The kidney biopsy from one patient showed acute tubular necrosis with interstitial nephritis. One patient had complete recovery of renal function on follow-up, while the other was lost to follow-up.