Biomedical subjects

M M Ziegler

Publications and source records attributed to M M Ziegler.

At least 19 recordsLinked to original sources

PubMed1992

Impairment of macrophage activation and granuloma formation by protein deprivation in mice.

Protein-calorie malnutrition predisposes to infection by intracellular pathogens, but the basis for this predisposition is unclear. We studied the effect of protein deprivation on mouse peritoneal macrophage function and on granuloma formation during infection by bacille Calmette-Gueŕin (BCG). Injection of lipopolysaccharide (LPS) to induce inflammation elicited fewer peritoneal cells from mice fed a 2.5% protein diet than from mice fed an isocaloric chow in which protein calories constituted 24% of the total. LPS-elicited macrophages from protein-deprived mice demonstrated a reduction in spreading, total cell protein, cell lactate dehydrogenase, and release of superoxide anion (O2-) in response to stimulation. Priming in vitro by interferon (IFN)-gamma for enhanced release of O2- was also significantly impaired in protein-deprived mice. This defect was reversible by repletion with 24% protein diet for 10 days. Impairment of macrophage function in protein-deprived mice was further evidenced by an impaired capacity to express Ia antigen in response to IFN-gamma and by reduced production of IL-1 activity in response to LPS. Infection by BCG in protein-deprived mice was characterized by impaired granuloma development in liver, lungs, and spleen. Thus, in this model, protein deprivation significantly impaired macrophage activation, as assessed by morphologic, metabolic, and functional criteria. This impairment might compromise immune effector mechanisms dependent on macrophage activation, including rejection of intracellular pathogens.

Animals↗

PubMed1992

Establishment of animal liver metastatic model for C-1300 murine neuroblastoma and immunotherapy for it using OK-432, streptococcus preparation.

Intrasplenic administration of 1 x 10(6) C-1300 murine neuroblastoma cells induced spleen tumor in 78.6% of mice and liver metastasis in 64.3%. When mice were pretreated with carrageenan, an antimacrophage agent, the incidence of spleen and liver tumors in this system was lower, possibly due to the rebound increase in macrophage activity following the disappearance of the carrageenan effect. Continuous daily intraabdominal injection of 1 KE of OK-432 streptococcus preparation markedly reduced the appearance of liver metastasis (P less than 0.01), whereas the spleen mass was not reduced to such an extent. However, the survival rate of the OK-432-treated group did not differ greatly from that of the nontreated group. These results demonstrate the usefulness of the model of liver metastasis induced by intrasplenic administration of tumor cells and the effectiveness of OK-432 against liver metastasis formation.

Animals↗

PubMed1992

Management and survival of meconium ileus. A 30-year review.

Cystic fibrosis patients born with meconium ileus (MI) have had an improved outcome over the last three decades. The authors reviewed the impact of surgical management and long-term nutritional care on the survival of patients with MI. Of the 59 cases of MI seen from 1959 to 1989, 48 cases were managed operatively using either the Bishop-Koop ileostomy (BK), the Mikulicz ileostomy, primary resection and anastomosis (RA), or ileostomy. Six-month survival of MI has improved from 37% to 100%. Nonoperative cases (n = 11) had 100% long-term survival. The RA survivors required less late operative intervention (20%) as compared with other surgical patients (81%). A comparison of serial growth percentiles of CF patients with MI with those of their non-MI CF peers showed similar long-term decreases. These data confirm: (1) There is an improved survival for MI independent of the surgical procedure; (2) The BK ileostomy is an effective and time-tested MI treatment; (3) Primary resection and anastomosis in selected cases may have a lower surgical morbidity rate; and (4) Meconium ileus does not adversely affect the long-term nutritional outcome of CF patients.

Chi-Square Distribution↗

PubMed1991

Low-dose interferon gamma renders neuroblastoma more susceptible to interleukin-2 immunotherapy.

Neuroblastoma remains a common and deadly childhood tumor, resistant to both surgical and chemo/radiotherapeutic intervention in its advanced stages. The role of immunotherapy in such cancers has yet to be defined. In previous work, we found that the addition of interferon gamma (IFN-gamma) to 3-day in vitro tissue cultures of the murine neuroblastoma C1300, led not only to the tumor's increased cell surface expression of the immunologically important major histocompatibility complex (MHC) class I antigen, but also to an increased susceptibility of such modified tumor to subsequent lymphokine activated killer (LAK) cell lysis. In this study, we sought to determine the in vivo applicability of these findings. Initial dose-response studies helped define a regimen of rIFN-gamma's administration that upregulated MHC class I without activating host natural killer (NK) activity. A/J mice bearing 7-day-old subcutaneous C1300 were randomized to receive daily morning injections of either 0, 25,000, 50,000, or 100,000 U of rIFN-gamma intraperitoneally for 6 days. Animals were killed at days 3, 6, and 9 after initiation of rIFN-gamma therapy, and tumors were excised, digested, and stained for both MHC class I and II expression. At the time of sacrifice, splenocytes from each animal were tested for NK cytotoxicity toward YAC (an NK-sensitive lymphoma) and C1300. These studies defined 3 days of therapy with 25,000 U as a "priming" dose that increased expression of class I with minimal impact on NK activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

PubMed1991

The role of reperfusion injury in occlusive intestinal ischemia of the neonate: malonaldehyde-derived fluorescent products and correlation of histology.

Oxygen free radical reperfusion products may play a critical role in neonatal occlusive intestinal ischemia. We report a comparative analysis of light microscopy- and malonaldehyde (MDA)-derived fluorescent products as a measure of lipid peroxidation in occlusive intestinal ischemia in the rat. Weanling rats (n = 25) underwent cross clamping of the common mesenteric artery followed by various intervals of reperfusion; blood was sampled from the common mesenteric vein and the ileum was simultaneously biopsied. Blind-light microscopic scoring of the ischemic intestine was used. Fluorescent products were extracted using a chloroform/methanol/acidic water solvent extraction and measured with a spectrophotofluorometer using excitation/emission wavelengths of 360 and 430 nm, respectively. A trend was observed with prolonged reperfusion. Accumulation of fluorescent products correlated directly with the interval of reperfusion. Graded intervals of vascular occlusion produced progressive intestinal injury, but light microscopic analysis was not a sensitive index to distinguish the influence of graded reperfusion intervals. These data confirm a role for both ischemia and reperfusion in occlusive intestinal injury in the neonate and suggest that MDA accumulation may be a sensitive index of the reperfusion component of such injury.

Animals↗

PubMed1991

Influence of nutrition on anti-tumor activity.

Nutritionally supporting the malnourished tumor bearing host may not benefit the disease outcome, but, rather, may preferentially "feed the cancer". We hypothesized that repletion is beneficial only when it augments an anti-tumor immune response. To support this hypothesis, 240 A/J mice were assigned to isocaloric dietary groups (24%, 5%, or 2.5% protein). On day 14 the mice received either immunogenic C1300- neuroblastoma (NB) or non-immunizing TBJ-NB. On day 21 half of the restricted animals were repleted with 24% protein chow. At day 35, chromium-release cell-mediated cytotoxicity was measured. In the group of mice that received 2.5% protein chow, nutritional repletion specifically augmented anti-tumor activity for C1300-NB which elicits a host immune response (33.78 L.U. (repleted) vs 3.47 L.U. (depleted) p less than 0.01), in contrast, nutritional repletion was detrimental for non-immunizing TBJ-NB, where further depression of cytotoxicity was seen (1.37 L.U. (repleted) vs 2.06 L.U. (depleted) 0 less than 0.01). This suggests that the influence of nutritional repletion in tumor nearing animals is dependent on the integrity of host's anti-tumor immunity.

Animals↗

PubMed1990

Tumor immunization. Improved results after vaccine modified with recombinant interferon gamma.

The purpose of this study was to determine if a 3-day in vitro culture of the murine neuroblastoma C1300 with 500 U/mL of recombinant interferon gamma resulted in a protective crossreactivity to parent C1300. Twenty A/J mice received either a vaccine of 1 x 10(6) irradiated C1300 tumor cells intradermally or an equivalent inoculum of C1300 that had been incubated in recombinant interferon gamma (C1300*). One week later, all animals were rechallenged with 1 x 10(6) viable C1300. Animals immunized with C1300* had a significantly delayed early tumor incidence that translated into a survival advantage for the group. At the time of tumor rechallenge, a significantly increased level of nonspecific systemic immunity was conferred by the C1300* immunization. Thus, modification of tumor with recombinant interferon gamma before introduction as a vaccine may improve that vaccine's protective capability.

Animals↗

PubMed1990

The newborn piglet: a model of neonatal gastrointestinal motility.

Small intestinal myoelectric activity has been studied extensively in adult humans and in many animal models. However, little is known about gut myoelectrical activity in newborns, a population susceptible to primary and secondary motility disorders. We report the development of a chronic neonatal piglet model for assessment of gastric and small intestinal myoelectric activity. Six piglets aged 12 to 27 days and weighing 2.3 to 4 kg underwent laparotomy and implantation of four to six bipolar serosal electrodes along the small intestine; and selectively on the gastric antrum. Myoelectric records were obtained daily after operation in awake animals using low (0.16 Hz) and high (30 Hz) frequency filters. Electrical control activity (ECA) was observed in the stomach (4 to 5 cycles per minute) and in the duodenum (14 to 15 cycles per minute) on postoperative day 1; along with random bursts of spiking activity. The migrating myoelectric complex (MMC) appeared on postoperative day 2 or 3. In piglets followed for a week or more, the MMC cycle duration and phase III duration (period of maximal spiking activity) were longer in the proximal small intestine than at the terminal ileum (80 +/- 5 versus 47 +/- 3 minutes and 5.1 +/- 0.3 versus 3.7 +/- 0.1 minutes, respectively; mean +/- SEM, P less than .005), suggesting that some MMCs arise spontaneously in the distal small bowel without traversing the upper intestine. The antral and duodenal ECA frequencies are similar to values reported in human adults; the MMC cycle duration is slightly shorter.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Management of congenital microgastria.

Congenital microgastria is a rare anomaly. Only 22 cases have been reported in the literature. Its clinical manifestations depend on the stage at which the embryologic development of the stomach is arrested. The outcome of most patients with severe microgastria previously reported has either been death or extreme malnutrition. Since 1978, four patients with congenital microgastria have been managed at The Children's Hospital of Philadelphia. All patients had severe feeding intolerance and associated congenital malformations. Three patients were treated with a double lumen Roux-en-Y jejunal reservoir (Hunt-Lawrence pouch). This treatment improved the nutritional management of these patients. On follow-up two patients are at the 50th percentile for height and weight, and one is at the 25th percentile. One patient with associated severe congenital heart disease was treated nonoperatively. Her nutritional management was difficult, and she ultimately died of congestive heart failure at 3 years of age. In patients with the most severe forms of microgastria, early operative treatment improves nutritional management and facilitates the achievement of normal growth and development.

Anastomosis, Roux-en-Y↗

PubMed1990

The role of leukocytes in mediating mucosal injury of intestinal ischemia/reperfusion.

The source of oxygen-free radicals in putative intestinal reperfusion injury is unknown. To define the role of the circulating leukocyte in this pathophysiology, we report a rat model of ex vivo intestinal perfusion that permits alteration of the intravascular perfusate. The validity of the model is proven by the degree of intestinal injury produced by reperfusion following occlusive ischemia. Severe damage was noted in the animals reperfused with normal blood; however, reperfusion with a white blood cell-free perfluorochemical significantly ameliorated this damage. The addition of leukocytes to the perfluorochemical negated the previously seen protection of the leukocyte-free perfusate. This study strongly suggests that the intravascular leukocyte is an important mediator of intestinal ischemia/reperfusion injury.

Animals↗

PubMed1990

Immunologic effects of arginine supplementation in tumor-bearing and non-tumor-bearing hosts.

Supplemental dietary arginine has anti-tumor properties but the degree and mechanisms are unclear. In non-tumor-bearing CBA/J mice (n = 60), 1% arginine supplementation significantly enhanced thymic weight, spleen cell mitogenesis, and interferon-activated natural killer cell activity; no further enhancement was observed with 2% or 4% supplementation. Supplemental 1% arginine, when compared with 1.7% glycine, enhanced interferon-induced natural killer cell activity, lymphokine-activated killer cell generation, and macrophage cytotoxicity. In A/J mice (n = 420), bearing either a moderately immunogenic (C1300) or weakly immunogenic (TBJ) murine neuroblastoma, 1% arginine significantly (p less than 0.05) retarded tumor growth and prolonged median survival time compared with glycine or no supplementation. Dietary arginine enhanced T-cell function and significantly increased responsiveness to autologous C1300 tumor in a mixed lymphocyte tumor cell culture (MLTC). The immunomodulatory effects of arginine provide nutritional and immunologic support of the tumor-bearing host and may be helpful when given concommitant with immunotherapy.

Animals↗

PubMed1990

Nutrition and cancer in children.

The information generated to date regarding the nutritional status of children with cancer indicates that malnutrition is seen in patients in the later stages of their malignant disease or is iatrogenic because of their intensive therapy. Malnourished children suffer from inadequate growth, including the potential of delayed cerebral development, and they are more susceptible to infection. Nutritional therapy has been shown to reverse the malnutrition independent of the cancer treatment. In doing so, the nutritional support aids in the delivery of and tolerance to the antitumor therapy. What is not possible, however, is making ineffective or marginally effective anticancer therapies effective by nutritional support. Therapy that is ineffective, such as chemotherapy for Stage III or IV neuroblastoma in children, cannot be altered by nutritional support. However, a patient's nutritional state may affect the disease outcome in that complication rates are much higher in malnourished patients. In such children with PCM, nutritional support may make delivery of therapy possible, but it will not affect the ultimate disease outcome unless the anticancer therapy is inherently successful. A well-nourished child is easier to treat and is physiologically more stable. Such children, therefore, have an improved prognosis and lower morbidity and mortality, provided effective therapy is available for the cancer.

Cachexia↗

PubMed1989

The influence of natural killer cells in neuroblastoma.

Human neuroblastoma (NRB) cell lines are markedly sensitive to natural killer (NK) cell lysis in vitro, but patients with NRBs have low or absent NK activity. This study evaluated the NK sensitivity of murine NRBs (C1300 and TBJ) in the regulation of NRB growth and determined the effects of recombinant (r) interferon gamma and recombinant interleukin 2 (rIL-2). Both basal (8% +/- 3% specific cytotoxicity) and induced (20% +/- 3%) NK lyses of C1300-NRB were observed. In vivo depletion of NK cells with anti-asialo GM-1 significantly enhanced growth of C1300-NRB and decreased survival. Treatment with r-interferon gamma or rIL-2 on days 1 through 3 after C1300-NRB inoculation significantly prolonged the mean tumor latency period, decreased the tumor growth rate, and enhanced in vitro NK killing of C1300-NRB and YAC-1. The effects of r-interferon gamma and IL-2 were abrogated by pretreatment with anti-asialo GM-1. These results demonstrated that NK cells form one important component of regulation of a murine NRB, but immunomodulation with potent lymphokines requires cooperation of more than one cell type.

Animals↗

PubMed1989

Site-directed mutagenesis of bacterial luciferase: analysis of the 'essential' thiol.

It has been appreciated for many years that the luciferase from the luminous marine bacterium Vibrio harveyi has a highly reactive cysteinyl residue which is protected from alkylation by binding of flavin. Alkylation of the reactive thiol, which resides in a hydrophobic pocket, leads to inactivation of the enzyme. To determine conclusively whether the reactive thiol is required for the catalytic mechanism, we have constructed a mutant by oligonucleotide directed site-specific mutagenesis in which the reactive cysteinyl residue, which resides at position 106 of the alpha subunit, has been replaced with a seryl residue. The resulting alpha 106Ser luciferase retains full activity in the bioluminescence reaction, although the mutant enzyme has a ca 100-fold increase in the FMNH2 dissociation constant. The alpha 106Ser luciferase is still inactivated by N-ethylmaleimide, albeit at about 1/10 the rate of the wild-type (alpha 106Cys) enzyme, demonstrating the existence of a second, less reactive, cysteinyl residue that was obscured in the wild-type enzyme by the highly reactive cysteinyl residue at position alpha 106. An alpha 106Ala variant luciferase was also active, but the alpha 106Val mutant enzyme was about 50-fold less active than the wild type. All three variants (Ser, Ala and Val) appeared to have somewhat reduced affinities for the aldehyde substrate, the valine mutant being the most affected. It is interesting to note that the alpha 106 mutant luciferases are much less subject to aldehyde substrate inhibition than is the wild-type V. harveyi luciferase, suggesting that the molecular mechanism of aldehyde substrate inhibition involves the Cys at alpha 106.

Aldehydes↗

PubMed1989

Beneficial effects following carbon dioxide laser excision on experimental neuroblastoma.

Treatment of neuroblastoma in children consists of primary excision with adjuvant radiation and chemotherapy. When the tumor invades surrounding structures that cannot be safely excised or when distant metastasis is present, the patient has a poor prognosis. Because the CO2 laser can be used to excise malignant tumors without seeding the surrounding tissue and because the defocused beam can vaporize malignant cells, we compared partial scalpel excision and partial laser excision of C1300 murine neuroblastoma to the growth rate of residual tumor. In 25 mice, 75% of the tumor was excised with a scalpel, and in another 25, the same percentage was excised with the CO2 laser (10 W). CO2 laser excision significantly decreases the growth of residual neuroblastoma (P less than .01). However, the effect appears to be a function of increased tumor immunogenicity after laser excision rather than the increased tumor kill. We conclude that CO2 laser excision of neuroblastoma may prove to be superior to scalpel excision for primary surgical treatment of neuroblastoma.

Animals↗

PubMed1989

Systematic analysis of the immunoregulation of murine neuroblastoma.

If immunoregulation of cancer is to be effective, the tumor must express immunogenicity and the host immune mechanism must be capable of responding to that stimulus. Though neuroblastoma (NB) might be such a tumor, a systematic assessment of this complex host-tumor interaction is lacking. We report such an analysis using the murine NB system. C1300-NB is highly antigenic, locally growing, and nonmetastasizing, while its clonal counterpart, TBJ-NB, is minimally antigenic and demonstrates not only aggressive local growth but systemic metastases as well. We analyzed A/J mouse antitumor naturally occurring killer lymphocyte (NK cells), cytotoxic lymphocyte (CTL cells), and suppressor lymphocyte (SC cells) function in response to these tumor lines. NK and CTL activity was measured in 40 mice after 3 weeks of growth of either C1300-NB or TBJ-NB using a cold target inhibition test to either the YAC-1 or P815 mastocytoma cell line, respectively. SC activity was analyzed in an additional 24 mice treated with an SC destroying 15 mg/kg of cyclophosphamide (CYA) three days after tumor inoculation. After 4 weeks of tumor growth spleens were harvested, cell-mediated cytotoxicity was measured by chromium 51 release assay and tumor cell lysis was expressed as lytic unit 30 (LU-30), an arbitrary definition of the number of lymphocytes needed to lyse 30% of target cells. By increasing the concentration of the NK-sensitive YAC-1 cold target, there was a 56.8% inhibition of lymphocytotoxicity to C1300-NB, contrasting with this was the lack of inhibition (17.8%) by the non-NK sensitive P815 cell line.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Resting energy expenditure in children following major operative procedures.

Resting energy expenditure (REE) is reported to increase by 24% in adults following elective operations; however, similar data are not available for children. We studied REE in 12 children (14 operative procedures) to test the hypothesis that children experience a similar rise in REE as adults following operation. The operations included endorectal pull-through, gastric resection, ileostomy closure, and other major abdominal procedures. REE was measured daily by indirect calorimetry using a computerized bedside metabolic cart. All subjects (7 males, 5 females; age range, 8 to 19 years; mean age, 14.7 years) were measured supine, in bed, and after an overnight fast. REE was expressed as kilocalories per unit body surface area (BSA) per day. In addition, respiratory quotient (RQ) was calculated for each patient. Contrary to adults, these children did not demonstrate a significant increase in REE following major operative procedures. Furthermore, there was no change in RQ postoperatively. These data demonstrate that children might have a different response to surgical stress than adults. We theorize that children are able to convert energy expended on growth to energy spent on wound repair and healing, thus avoiding the overall increase in energy expenditure seen in the adult population.

Adolescent↗

PubMed1989

Partial splenectomy: the preferred alternative for the treatment of splenic cysts.

We report six pediatric patients who had a partial splenectomy for splenic cysts and a seventh patient who had a total splenectomy. There were six epidermoid cysts and one traumatic cyst. All patients had benign postoperative courses. All patients who underwent partial splenectomy had a significant postoperative rise in platelet count that subsequently returned toward baseline. This rise implies a loss of splenic function, although the exact meaning of this is unclear. All patients had late postoperative liver-spleen scans that showed mean spleen size and function to be normal. We have described several methods of partial splenectomy used at Children's Hospital of Philadelphia. Recommendations for patients undergoing partial splenectomy include preoperative pneumococcus and Hemophilus influenzae vaccinations and prophylactic antibiotics postoperatively. The antibiotics are terminated if a liver-spleen scan and platelet count at the end of 3 months' time are normal.

Adolescent↗