Biomedical subjects
K Hendricks
Publications and source records attributed to K Hendricks.
BRG1, a component of the SWI-SNF complex, is mutated in multiple human tumor cell lines.
Human BRG1 is a component of the evolutionarily conserved SWI-SNF chromatin remodeling complex. BRG1 has been implicated in growth control through its interaction with the tumor suppressor pRb and may consequently serve as a negative regulator of proliferation. Postulating that BRG1 may itself be a tumor suppressor gene, we screened a panel of tumor cell lines to determine whether the gene is targeted for mutation. We report that the COOH-terminal region of BRG1 is homozygously deleted in two carcinoma cell lines, prostate TSU-Pr1 and lung A-427. In addition, biallelic inactivations of BRG1 were observed in four other cell lines derived from carcinomas of the breast, lung, pancreas, and prostate; their mutations in BRG1 included three frameshift lesions and one nonsense lesion. Point mutations were also discovered in a number of other cell lines, however in most cases any effect of these mutations on BRG1 function remains to be established. A variety of different mutations within BRG1, in several cell lines, suggest that BRG1 may be targeted for disruption in human tumors. Significantly, reintroduction of BRG1 into cells lacking BRG1 expression was sufficient to reverse their transformed phenotype inducing growth arrest and a flattened morphology. These data strongly support the model that BRG1 may function as a tumor suppressor and strengthen the hypothesis that the regulation of gene expression through chromatin remodeling is critical for cancer progression. It will be important to confirm these observations in primary tumors.
Investigation of folate pathway gene polymorphisms and the incidence of neural tube defects in a Texas hispanic population.
Neural tube defects (NTDs) are multifactorial in their etiology, having both genetic and environmental factors contributing to their development. Recent evidence demonstrates that periconceptional supplementation of the maternal diet with a multivitamin containing folic acid significantly reduces the occurrence and recurrence risk for having a pregnancy complicated by NTDs. Unfortunately, the mechanism underlying the beneficial effects of folic acid remains unknown. NTD surveillance data from the Texas-Mexico border show that the high NTD rate (28/10,000 live births) noted during the 1990-1991 Cameron county NTD cluster was superimposed on a background Cameron county NTD rate (16/10,000 live births) which is considerably higher than that generally noted in the United States (8-10/10,000 live births). These data suggest that genetic factors as well as transient environmental factors may contribute to the etiology of the NTDs. Furthermore, clinical and experimental evidence imply that allelic forms of genes involved with folate metabolism and/or transport may explain some of the observed variation in the NTD rates found across different populations. Two folate pathway genes were selected for evaluation in this study. The loci investigated included two known alleles of the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene, as well as the promoter region of the folate receptor-alpha (FR-alpha) gene. Odds ratios (ORs) for the C677T polymorphism in the MTHFR gene were 1.8 (CI 0.47-6.8) for heterozygosity and 1.8 (CI 0.35-9.4) for homozygosity for the mutant 677T allele, relative to wildtype homozygotes. The odds ratio for the heterozygosity for the A1298C polymorphism in the same gene was 1.1 (CI 0.09-14). No individuals homozygous for the 1298C allele were observed. The OR for heterozygosity of FR-alpha gene polymorphisms detected at nucleotide 762 and at nucleotides 610/631 was 1.4 and 0.7, respectively. Neither of the FR-alpha polymorphisms was observed in the homozygous condition. No statistically significant associations were observed for any of the polymorphisms examined, as the 95% confidence intervals for all of the ORs included one. However, the frequency of the MTHFR 677T allele in the largely Hispanic control group from Texas was significantly different from other populations (P < 0.005), and among the highest reported for any control populations examined.
Ebola (subtype Reston) virus among quarantined nonhuman primates recently imported from the Philippines to the United States.
In April 1996, laboratory testing of imported nonhuman primates (as mandated by quarantine regulations) identified 2 cynomolgus macaques (Macaca fascicularis) infected with Ebola (subtype Reston) virus in a US-registered quarantine facility. The animals were part of a shipment of 100 nonhuman primates recently imported from the Philippines. Two additional infected animals, who were thought to be in the incubation phase, were identified among the remaining 48 animals in the affected quarantine room. The other 50 macaques, who had been held in a separate isolation room, remained asymptomatic, and none of these animals seroconverted during an extended quarantine period. Due to the rigorous routine safety precautions, the facility personnel had no unprotected exposures and remained asymptomatic, and no one seroconverted. The mandatory quarantine and laboratory testing requirements, put in place after the original Reston outbreak in 1989-1990, were effective for detecting and containing Ebola virus infection in newly imported nonhuman primates and minimizing potential human transmission.
Fumonisins and neural tube defects in South Texas.
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Constraints to adoption of appropriate breast feeding practices in a squatter settlement in Karachi, Pakistan.
Appropriate breast feeding practices (ABFP) are important for successful lactation. Constraints to adoption of ABFP by mothers in a squatter settlement in Karachi, Pakistan are reported. One hundred and two mother-infant pairs were followed from birth to 16 weeks of age. Eighty-seven infants received prelacteal feeds of honey as a quasi-religious ritual, 16 received ghutti for "cleansing of stomach", other prelacteal feeds were given as substitutes for breast feeding. Twenty nine mothers initiated breast feeding within 4 hours of birth. Supplemental water was given to 53 infants; major reasons being mothers' perception of thirst and diarrhoea in the infant. Supplemental milk was given to 24 infants. Insufficient milk and work load of mothers were main reasons for supplementation. Home remedies were given in 36 instances for prevention/treatment of indigestion or colds. Quasi-religious ritual of giving honey, perception that child birth was a major stress and early initiation of breast feeding adds to that stress, fear of dehydration and perception of insufficient breast milk were the major constraints to adoption of appropriate breast feeding practices.
Influence of chronic angiotensin-converting enzyme inhibition on anesthetic induction.
BACKGROUND: Several cases of hypotension have been reported in patients who received angiotensin-converting enzyme inhibitors (ACEIs) before a surgical procedure, suggesting that interactions between ACEIs and anesthesia may be neither beneficial nor predictable. To determine if continuation of ACEI therapy until the morning of surgery leads to an unacceptable decrease in blood pressure on induction, we investigated 51 vascular surgical patients that were chronically treated for hypertension with either captopril or enalapril. METHODS: After randomization, ACEI therapy was either continued until the morning of surgery or stopped at the time of the preanesthetic visit, at least 12 h (captopril) or 24 h (enalapril) before surgery. Each patient received a standardized anesthetic induction. If systolic blood pressure (monitored using a radial artery cannula) decreased to less than 90 mmHg in response to induction, ephedrine was administered. RESULTS: A marked decrease in plasma converting-enzyme activity was found in patients who received enalapril until the morning of the surgical procedure, and 100% of them required ephedrine after induction. In patients who received their usual dose of captopril on the morning of surgery, plasma converting-enzyme activity was reduced to a lesser extent (when compared with patients who received enalapril). Finally, in the patients in whom ACEI therapy, either enalapril or captopril, was stopped of the evening before surgery, the incidence of induction-induced hypotension was significantly less when enalapril or captopril therapy has been discontinued. CONCLUSIONS: These data indicate that in hypertensive patients chronically treated with ACEIs, maintenance of therapy until the day of surgery may increase the probability of hypotension at induction.
Nutrient absorption and weight gain in persistent diarrhea: comparison of a traditional rice-lentil/yogurt/milk diet with soy formula.
We prospectively studied clinical outcome and nutrition absorption in male children (6-36 months of age) with persistent diarrhea (PD) and severe protein-energy malnutrition (mean z score for age, -4.2 +/- 0.8). Fifty-one children were randomly allocated to receive a combination of khitchri, a rice-lentil mixture, yogurt, and half-strength buffalo milk (group A; n = 26) or full-strength soy formula (group B; n = 25) for 14 days. The initial caloric intake (p < 0.02) and mean weight gain (p < 0.02) were greater in the group B patients. The mean stool volume and frequency were comparable between the two groups. Seven children in group A were considered clinical failures by criteria of weight loss and PD, compared to three in group B. The coefficients of absorption (COA) for protein were similar between the two groups, but group B patients had higher values of COA for energy and fat (p < 0.05) in the second week of nutritional rehabilitation. The majority (63%) of the children improved on the khichri-yogurt-milk diet but the nutritional outcome was not as good as with the soy formula. These data indicate that a traditional diet can be successfully used in the dietary management of PD and severe malnutrition but that a more optimal composition, yielding a higher success rate, should be sought.
Is rice based oral rehydration therapy effective in young infants?
Rice based oral rehydration therapy (ORT) solutions have been shown to be superior to glucose oral rehydration salts (World Health Organisation (WHO) ORS) in reducing stool volume and duration of diarrhoea in children and adults. Rice based ORT has been used only sparingly in young infants, however, because of theoretical concerns about digestibility. A randomised controlled trial of rice based ORT (50 g rice and electrolytes identical to WHO ORS) and WHO ORS was carried out in 52 male infants less than 6 months old with moderately severe acute diarrhoea to evaluate efficacy and digestibility. Nineteen (70%) of 27 children who received rice based ORT and 18 (72%) of 25 children who received WHO ORS were treated successfully. The mean (SD) diarrhoeal stool output for the first 24 hours of treatment was significantly lower in the infants receiving the rice based ORT than in those receiving WHO ORS (101.0 (60.5) v 137.1 (74.6) g/kg). The stool output was also significantly less in the rice based ORT group in the second 24 hours. Infants in the rice based ORT group drank significantly less rehydration solution than infants in the WHO ORS group (mean (SD) 165.4 (77.4) v 217.9 (86.1) during the first 24 hours of treatment. There was no difference in the duration of diarrhoea between the groups. The volume of breast and formula feeding was similar in the two groups. No difference was seen in the frequency of finding reducing substances or acid pH in the stools of either group of children. The results suggest that rice based ORT is as effective as WHO ORS in infants with moderately severe diarrhoea and that rice based ORT is as well tolerated as WHO ORS in infants.
Use of cyclic parenteral nutrition in infants less than 6 months of age.
Cyclic parenteral nutrition is the technique of infusing the intravenous solution in less than 24 hours, during a portion of the day or night, allowing the patient freedom from the intravenous tubing and pump apparatus. In addition, adverse effects of long-term parenteral therapy, such as liver complications, were reported to be decreased with the use of cyclic parenteral nutrition in adult patients. Literature on the method and effects of cycling in young infants is minimal. This report describes cyclic parenteral nutrition use with guidelines for cycling and the potential beneficial metabolic effects in 10 infants less than 6 months of age who required long-term parenteral nutrition support. Diagnosis, gestational age, length of time on parenteral nutrition, macronutrient intake, growth, and biochemical parameters for the patients are presented. Overall, cyclic parenteral nutrition was well tolerated without clinical symptoms of hypoglycemia, elevated capillary blood glucose concentrations, or abnormal urine glucose levels. The direct bilirubin concentrations showed a decrease or stabilization after cycling was initiated in eight of 10 patients.
Antisense DNA delivery in vivo: liver targeting by receptor-mediated uptake.
UNLABELLED: Antisense oligodeoxynucleotides coupled to asialoglycoprotein carrier molecules were evaluated in terms of their ability to accumulate preferentially in the liver and thus potentially serve as an important method to regulate liver gene expression. METHODS: Native and asialo-human alpha-1 acid glycoproteins were derivatized with low molecular weight poly(L)lysine and complexed with an antisense DNA (67 mer) complementary to the 5' end of rat serum albumin mRNA. The asialoglycoprotein antisense complex (conjugate) was characterized with respect to size, stability, and anti-sense loading, and the biodistribution of the conjugate was determined for normal rats at 5 min and 1, 6, and 24 hr after intravenous injection. In vivo stability of the anti-sense asialoglycoprotein complex was also evaluated using double-labeled (32P-antisense and 3H-glycoprotein) preparations. RESULTS: The results of the conjugate characterization studies demonstrated that at least 30% of the anti-sense DNA dissociated from the carrier after 7 min under chromatographic conditions. When the conjugate was incubated with PBS, MEM or MEM plus 10% FBS for 1 hr at 37 degrees C, about 85% of the antisense DNA was dissociated from the carrier. The results of the biodistribution studies showed that the accumulation of the asialo-glycoprotein anti-sense complex in the liver was rapid and greatly exceeded the accumulation of the sialo-glycoprotein antisense analog or antisense alone. CONCLUSION: These findings have significant implications for the targeted delivery of therapeutic antisense molecules to the liver.
Update on the research agenda and care for the poor child. Steps forward, steps backward.
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Effect of collagen gel configuration on the cytoskeleton in cultured rat hepatocytes.
The cytoskeleton is important in the maintenance of cellular morphology and differentiated function in a number of cell types, including hepatocytes. In this study, adult rat hepatocytes sandwiched between two layers of collagen gel were compared to cells cultured on a single collagen gel for differences in the organization and expression of the cytoskeletal proteins actin and tubulin. Hepatocytes cultured between two layers of hydrated rat tail tendon collagen (sandwich gel) morphologically resembled cells in intact liver for several weeks. Actin filaments (F-actin) in these hepatocytes were concentrated under the plasma membrane in regions of cell-cell contact. In contrast, hepatocytes cultured on a single collagen gel were flattened and motile and had F-actin containing stress fibers. This was accompanied by a severalfold increase in actin mRNA. Microtubules formed an interwoven network in hepatocytes cultured in a sandwich gel, but in single gel cultures they formed long parallel arrays extending out to the cell periphery. Tubulin mRNA was severalfold greater in hepatocytes cultured on a single gel. Fibronectin and laminin staining were greater in single gel cultures, and these proteins were concentrated in fibrils radiating from the cell periphery. Overlaying a second collagen gel onto hepatocytes that had been cultured on a single gel (double gel rescue) reversed cell spreading and reduced stress fibers. Double gel rescue also resulted in a decrease in actin and tubulin mRNA to levels present in sandwich gel cultures and freshly isolated hepatocytes. These results show that the configuration of the external matrix has a dynamic effect on cytoskeletal proteins in cultured rat hepatocytes.
Vitamin A status of children in the urban slums of Karachi, Pakistan, assessed by clinical, dietary, and biochemical methods.
We assessed the vitamin A status of 532 children with an age range of 6-60 months who were living in slum areas of Karachi, Pakistan, using three methodologies: clinical eye examination, dietary vitamin A intake, and serum retinol level. No definite clinical signs of xerophthalmia were observed in any of these children. The mean +/- SD vitamin A intake estimated from a food frequency questionnaire for the group with inadequate (low and deficient) serum retinol levels (< 20 micrograms/dl) was 362 +/- 332 retinol equivalents (RE) compared with 431 +/- 332) RE in the group with adequate serum levels (P < 0.005). Deficient serum retinol levels (< 10 micrograms/dl) were present in 12 children (2%); two of these had a healed corneal scar. Low serum retinol levels (10-19 micrograms/dl) were present in 46%, while 51% children had adequate levels (> or = 20 micrograms/dl). The mean +/- SD serum retinol level for the inadequate (< 20 micrograms/dl) and adequate groups were 15.3 +/- 2.8 and 26.6 +/- 6.7 micrograms/dl, respectively. These results suggest that a significant number of children in these communities have low vitamin A levels and thus may constitute an at risk group. These results also suggest that the dietary intake method may be a simple and inexpensive screening tool for assessment of vitamin A status in communities.
Is anemia an accurate predictor of vitamin A status in Pakistani children?
Serum retinol and hemoglobin levels were determined in 532 children aged 6-60 months living in urban slums of Karachi, Pakistan. Overall 67% (358 of 532) of children had hemoglobin levels of less than 11 g/dl, the World Health Organization definition of anemia for this age group. Estimations for red blood cell indices (hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and red blood cell count) were done on a sample of 391 children to classify anemia morphologically. A similar percentage (69.8% [273 of 391 children]) of anemia was found in this group. The anemia was predominantly microcytic and hypochromic. Normocytic normochromic anemia was present in only 16.5%. Serum retinol levels were significantly correlated with hemoglobin (P < 0.002), hematocrit (P < 0.01), and red blood cell (P < 0.001) levels. However, anemia was found to be a poor predictor (positive predictive value [PPV] = 2.5%) for the presence of vitamin A deficiency (retinol < 10 micrograms/dl). The PPV increased to 54% if 20 micrograms/dl, which is an indicator of marginal vitamin A status, was used as the cutoff point. The sensitivity of the hemoglobin test was found to be 75% in correctly identifying vitamin A deficiency when retinol levels of 10 micrograms/dl and 20 micrograms/dl were both used as the cutoff points for deficiency. The specificity for the hemoglobin test varied from 33% to 40% when levels of 10 micrograms/dl and 20 micrograms/dl were used as the cutoff points for vitamin A deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)
Nutritional management of persistent diarrhea: factors predicting clinical outcome.
In a prospective study we randomized 102 male children (age 6-36 months) with persistent diarrhea to receive a traditional rice-lentil (Khitchri) diet and yogurt (K-Y) or a soy formula (alone for seven days and then in combination with K-Y for seven days). Of 73 children satisfying the study criteria, 66 were successfully treated and there were 7 treatment failures. There was poor concordance between parental accounts of severity of diarrhea or vomiting and that observed after admission. Significant risk factors associated with treatment failure included younger age (p < 0.005) and vomiting at presentation (p < 0.02). The greatest number of risk factors associated with delayed recovery (> 10 days) were identified during an initial evaluation period (the first 8 h after admission). These included greater severity of watery diarrhoea (p < 0.01) and increased ORS intake (p < 0.02). Our data suggest that an initial evaluation period, including objective observations, may identify children with persistent diarrhea who are at greatest need of hospitalization.
A traditional diet as part of oral rehydration therapy in severe acute diarrhoea in young children.
Recently, the role of feeding as treatment of acute diarrhoea has received increasing attention. To assess the efficacy of early feeding in acute diarrhoea, we conducted a randomised, clinical trial of a traditional legume-based weaning diet khitchri in boys 9 to 48 months old with moderate to severe dehydration. Khitchri is composed of rice and lentils cooked with cottonseed oil. Children were randomly allocated to 2 groups: group A received only WHO ORS but no food for the first 24 hours and then khitchri and half-strength cow's milk formula freely; group B received khitchri and the half-strength formula in addition to ORS after the initial rehydration period of 4 to 6 hours. The mean period of evaluation was 3 days. 69 patients were admitted into the study, 33 in group A and 36 in group B. The initial mean purging rate for the children was greater than 200 g/kg/day. Six children did not complete the study because they developed intercurrent infections or were removed by their parents for non-medical reasons. Of the 63 patients who were evaluated, 44 (70%) were successfully treated, 21 in group A and 23 in group B. There were no significant differences in the 2 groups in mean stool output, number of stools, or weight gain, although a trend toward earlier improvement was seen in group B. These data indicate that early feeding of khitchri and WHO/ORS may be as well tolerated as WHO/ORS alone in the first 24 hours treatment of severe acute diarrhoea in young children.
Dietary management of persistent diarrhea: comparison of a traditional rice-lentil based diet with soy formula.
Recent studies have indicated that enteral diets can play an important role in the treatment of persistent diarrhea. Khitchri, a local weaning food in Pakistan, is composed of rice and lentils, which have previously been shown to be well tolerated in many children with acute diarrhea. The effectiveness of a khitchri and yogurt (KY) diet, which is inexpensive and widely available in Pakistan, was studied. One hundred two weaned boys (6 to 36 months old) with persistent diarrhea were randomly assigned to receive either soy formula (group A) or the KY diet (group B) for 14 days. Group A also received the KY diet in addition to formula for days 8 through 14. Twenty-nine children did not complete the study because of severe infection (13) or their family's decision to leave the study early (9 in group A and 7 in group B). Sixty-six children successfully completed the study protocol; there were five clinical failures in group A and two in group B. On a comparable caloric intake, there was a significantly lower stool volume (group B: 38 +/- 16 [mean +/- SD] vs group A: 64 +/- 75 g/kg per day, P less than .05) and frequency (B: 4.4 +/- 2.0 vs. A: 6.6 +/- 4.2 stools per day, P less than .005) in children fed KY during the first week of therapy. Group B children also had a significantly greater weight gain than children in group A during the first week (B: 468 +/- 373 g/wk vs A: 68 +/- 286 g/wk, P less than .005).(ABSTRACT TRUNCATED AT 250 WORDS)