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G Rothstein

Publications and source records attributed to G Rothstein.

At least 37 records · Page 2Linked to original sources
PubMed1984

Pre- and postnatal development of granulocytic stem cells in the rat.

Bacterial sepsis is a relatively common problem in the neonatal period, particularly among prematurely delivered infants. The newborn rat has been widely used as a model for sepsis neonatorum, and in that model incomplete development of the neutrophil system has been postulated to be an important factor predisposing neonates to death from bacterial infection. In this study, that hypothesis was further tested by assessing neutrophil development in rats of various pre- and postnatal ages. Using standard soft agar colony techniques for detecting granulocyte-macrophage progenitor cells [CFU(c)], the number of CFU(c)/g of body weight was seen to increase from 0.5 + 0.1 X 10(3) at 19-20 days gestation to 10.5 +/- 0.2 X 10(3) at 4 weeks. The anatomic location of CFU(c) changed from totally hepatic at 16 days gestation to almost totally myeloid at 4 weeks. Lastly, the proportion of mature, stored neutrophils/CFU(c) decreased from 2440 +/- 40 at 19-20 days gestation to 430 +/- 75 at 4 weeks.

Animals↗
PubMed1984

Treatment of experimental group B streptococcal infection with hybridoma antibody.

Previous studies have shown a reduction in mortality rate from 90% to zero when neonatal rats, inoculated with group B streptococci (GBS) were injected with type-specific IgM antibody. However, in those studies, the antibody was administered simultaneously with the bacteria and at the same site, unlike the situation which would exist if antibody was used clinically to treat established infection. In the present experiments, we administered antibody intraperitoneally at various intervals following intrathoracic inoculation of GBS. When antibody was administered immediately after, or up to 2 h following bacterial inoculation, all animals survived. When antibody administration was delayed for 4, 5, or 6 h, survival rates of 92, 60, and 29% were observed. When antibody administration was delayed for more than 6 h, no survival occurred. Failure of antibody to protect animals from death coincided temporally with profound depletion of the neutrophil storage pool. In other experiments, depletion of the neutrophil storage pool was produced by a separate, noninfectious mechanism (subcutaneous implantation of sterile polyvinyl sponge discs) after which animals were inoculated with GBS. Antibody did not provide protection from death in animals with neutrophil storage pool depletion.

Animals↗
PubMed1983

Nafcillin-induced platelet dysfunction and bleeding.

This paper describes two cases of nafcillin-induced platelet dysfunction, with positive rechallenge data for one patient. Nafcillin resulted in abnormal bleeding times in both patients and a clinically apparent bleeding episode in one of the cases. Platelet function tests were performed on one patient during the initial therapy and after rechallenge with nafcillin. Platelet aggregation showed abnormal responses to ADP, collagen, and epinephrine. Platelet count and morphology were normal. Nafcillin should be recognized as another antibiotic which causes platelet function abnormalities and clinical bleeding episodes.

Adolescent↗
PubMed1983

Granulocytic stem cell (CFUc) proliferation in experimental group B streptococcal sepsis.

Adult rats infected with group B streptococci (GBS) develop neutrophilia and display a marked increase in granulocytic stem cells (CFUc). In contrast, infected neonatal rats develop a profound neutropenia and their CFUc do not increase. In order to better understand this phenomenon, we assessed the CFUc proliferative rate in control and infected adult and neonatal rats using the technique of [3H]-thymidine suicide. Beginning only 3 h after GBS inoculation, adult rats increased CFUc proliferative activity, as illustrated by an increase in thymidine suicide, from 38 +/- 2% cell kill in control animals to 70 +/- 2% when infected (mean + S.E., P less than 0.001). In contrast, the CFUc thymidine suicide rate did not increase in infected neonates. It was noted, however, that the baseline CFUc thymidine suicide rate in uninfected neonatal rats exceeded the rate in uninfected adult rats by 2-3-fold. The CFUc thymidine suicide rate was therefore determined in uninfected premature (74 +/- 1%), newborn (70 +/- 2%), 1-wk-old (70 +/- 1%), 6-wk-old (32 +/- 1%) and 6-month-old (37 +/- 3%) rats. These findings suggest that the proliferative rate of granulocytic stem cells is already maximal or near maximal in noninfected neonatal animals. In contrast to adults, the neonates' granulocyte production from stem cells can not significantly increase, even if bacterial infection is present.

Age Factors↗
PubMed1983

The effect of hybridoma antibody administration upon neutrophil kinetics during experimental type III group B streptococcal sepsis.

Groups of newborn rats were transthoracically inoculated with 1 X 10(6) type III group B streptococci/g body wt, either alone or in combination with 1.5 microgram/g body wt of type-specific antibody derived from hybridoma cell lines. Ninety-four percent of the animals who received bacteria alone died. In contrast, none of those treated with antibody died (P less than 0.005). Kinetic studies suggested that antibody may have offered protection, In part, by facilitating the neutrophil response. Animals who received only bacteria exhibited a marked neutropenia (20 +/- 18/mm3, mean +/- S.E.M.) whereas infected animals treated with antibody did not (3800 +/- 30/mm3, P less than 0.001). Furthermore, within 2 h of inoculation, antibody-treated animals mobilized and stored neutrophils, whereas significant neutrophil mobilization did not occur in the animals which received bacteria alone until 6 h. In the animals receiving bacteria alone, exhaustion of the neutrophil supply quickly occurred (remaining storage neutrophils at 6 h, 0.2 +/- 0.1 X 10(6) cells). In contrast, animals, which received antibody, maintained an adequate supply of stored neutrophils (7.0 +/- 0.4 X 10(6) P less than 0.001). The migration of neutrophils to the site of inoculation was measured by assaying the lungs' content of myeloperoxidase, a marker enzyme for granulocytes. The right and left lungs of animals not receiving antibody accumulated the same quantity of neutrophils, with peak pulmonary neutrophil accumulation occurring 6 h after the infection. In antibody recipients, however, the inoculated lung accumulated significantly more neutrophils than the opposite lung and peak pulmonary neutrophil accumulation occurred at 2 rather than 6 h.

Animals↗
PubMed1983

The neutrophil response to polyvinyl sponge implantation.

Neutrophil release and migration in mice were studied over a 24-hr period after the sc implantation of a single polyvinyl sponge. The release of neutrophils from the marrow was evaluated by directly counting the residual neutrophils in the femoral marrow of animals with sponges. Sponge and tissue neutrophil content was determined by extraction and assay of myeloperoxidase (MPO), a marker enzyme for neutrophils. A maximum depletion of 48% of the mature neutrophils in the marrow was observed 5 hr after sponge implantation, in keeping with significant release of neutrophils for migration to the sponge. The released cells were not found in the circulating granulocyte pool, since neutropenia was noted. The accumulation of neutrophils in the sponge increased throughout the 24-hr period, whereas in the tissue adjacent to the sponge maximum accumulation of neutrophils occurred within 7 hr. In fact, neutrophils migrated to at least three sites--the sponge, the skin overlying the sponge, and the skin in which an incision had been made to insert the sponge. The sponge content of neutrophils represented 0.3-33% of the neutrophils migrating to the combined lesion (sponge and skin sites). Therefore, if the neutrophil response to foreign body implantation is to be measured in its entirety, it is necessary to quantify not only the neutrophils within the foreign body but also those in the tissues surrounding it. These studies describe an animal model for neutrophil release and migration to tissues following a standard stimulus. It is proposed that this model may be useful in exploring the factors which influence the release and migration of neutrophils in vivo.

Animals↗
PubMed1982

Review: deficiencies in the neutrophil system of newborn infants, and the use of leukocyte transfusions in the treatment of neonatal sepsis.

Bacterial sepsis is a major cause of morbidity and mortality in the neonatal period. Deficiencies in neutrophil chemotaxis, phagocytosis, and bacterial killing have all been proposed as factors possibly responsible for this problem. In addition, the neutrophil storage pool, or all segmented neutrophils, band neutrophils, and metamyelocytes/kg body weight stored within the marrow, appears to be very small in neonates compared to that in adults, and when an infection develops in a neonate, neutrophil production from stem cells may be limited. In this paper we review the evidence for these neonatal neutrophil deficiencies and examine the animal and clinical studies which have tested leukocyte transfusion as a possible adjunctive therapeutic modality for sepsis neonatorum.

Adult↗
PubMed1982

Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker.

We examined the hypothesis that myeloperoxidase (MPO), a plentiful constituent of neutrophils, might serve as a marker for tissue neutrophil content. To completely extract MPO from either neutrophils or skin, hexadecyltrimethylammonium bromide (HTAB) was used to solubilize the enzyme. With this detergent treatment, 97.8 +/- 0.2% of total recoverable MPO was extracted from neutrophils with a single HTAB treatment; 93.1 +/- 1.0% was solubilized with a single treatment of skin. Neutrophil MPO was directly related to neutrophil number; with the dianisidine-H2O2 assay as few as 10(4) neutrophils could be detected. The background level of MPO within uninflamed tissue was 0.385 +/- 0.018 units per gram of tissue, equivalent to only 7.64 +/- 0.36 X 10(5) neutrophils. In experimental staphylococcal infection, skin specimens contained 34.8 +/- 3.8 units MPO per gram, equivalent to 8.55 +/- 0.93 X 10(7) neutrophils. These studies demonstrate that MPO can be used as a marker for skin neutrophil content: it is recoverable from skin in soluble form, and is directly related to neutrophil number. Further, normal skin possesses a low background of MPO compared to that of inflamed skin.

Animals↗
PubMed1982

Supply and release of storage neutrophils. A developmental study.

Depletion of the mature neutrophil reserve during bacterial sepsis is rare in adults but common in neonates; when it occurs, a fatal outcome is likely. Neutrophil reserve depletion was investigated in groups of premature, 1-day-old and 1-, 2-, and 4-week-old rats by measuring: (1) the size of the neutrophil storage pool, and (2) the proportion of this pool which was released from the storage compartment when a weight-standardized release stimulus was applied. It was found that the premature rat has a small neutrophil storage pool containing 1.29 +/- 0.07 X 10(6) cells/g body weight (mean +/- SE). This pool size increases to contain 4.35 +/- 0.23 X 10(6) cells/g in the 4-week-olds (p less than 0.001). With a standard neutrophil storage pool release stimulus, the premature rats depleted 68 +/- 4% of their neutrophil stores, vs. a depletion o only 13 +/- 6% of the stores in the 4-week-olds (p less than 0.001). The small neutrophil reserve and the exaggerated release of stored neutrophils in neonatal animals are factors which predispose neonates to neutrophil reserve exhaustion during bacterial sepsis.

Aging↗
PubMed1982

Granulocyte transfusion in septic canine neonates.

Newborn dogs were inoculated intratracheally with 0.5-1.0 X 10(8) Staphylococcus aureus/g body weight. Neutropenia (490 +/- 280 neutrophils/mm 3 versus 8,390 +/- 490 control, mean +/- S.E., P less than 0.001), and depletion of the marrow neutrophil storage pool (3 +/- 1% versus 27 +/- 2% storage neutrophils, P less than 0.001) occurred 5-6 h following the inoculation. All animals died at 6-10 h. Additional inoculated pups were selected at random to receive transfusions of either granulocytes, plasma or red blood cells. Granulocyte transfusions (3 X 10(9) neutrophils/kg) improved survival (P less than 0.005), but plasma and red blood cells did not.

Animals↗
PubMed1982

Cellular and extracellular myeloperoxidase in pyogenic inflammation.

We explored the effect of in vitro phagocytosis and in vivo inflammation on the MPO content of functioning neutrophils and on the ability of these cells to export active MPO into the extracellular environment. After ingestion of staphylococci, neutrophils retained 52% of their MPO and released 8% into the medium in active form; the remaining 40% of their MPO could no longer be detected. During bacterial infection induced by intradermally injecting staphylococci, neutrophils harvested from minced infected lesions contained 52% of the MPO of circulating neutrophils that had not reached the lesions. Extracellular fluid from the lesions contained active MPO secreted by the neutrophils, and concentrations of 10-45 U/ml were detected. These data demonstrate that functioning neutrophils can lose approximately half of their MPO. In vitro, 4%-8% of neutrophilic MPO appears in the extracellular space and 40% is inactivated. In vivo, the MPO content of inflammatory neutrophils also decreases, and MPO appears in the extracellular fluid in active form where it is available to participate in a variety of physiologic processes.

Animals↗
PubMed1982

Granulocyte transfusions in neonates with bacterial infection, neutropenia, and depletion of mature marrow neutrophils.

During a three-year period, 26 neonates with bacterial infection and neutropenia were studied. In order to assess the marrow neutrophil reserves, bone marrow aspirates were obtained from each of these patients. The neutrophil storage pool (percent polymorphonuclear + band neutrophils + metamyelocytes in 1,000 nucleated marrow cells) was significantly greater in those who survived their infection (mean = 20.1%, range 3.2% to 60.8%) than in those who died (mean = 1.9%, range 0.4% to 5.2%, P less than .002). In an attempt to improve survival in this group, seven neutrophil-depleted patients with sepsis were given granulocyte transfusions and all survived. In contrast only one of nine nontransfused and all survived. In contrast only one of nine nontransfused, neutrophil-depleted infants with sepsis survived (P less than .01). The seven granulocyte recipients were examined for possible adverse effects of the transfusions and none were detected. It is suggested that infected, neutropenic neonates with depletion of mature marrow neutrophils are at high risk for death from sepsis, and that these infants may benefit from granulocyte transfusion therapy.

Agranulocytosis↗
PubMed1981

The leukocyte left shift in clinical and experimental neonatal sepsis.

The leukocyte left shift is commonly used as an adjunct to the early diagnosis of bacterial infection. Many different methods have been employed for its quantification, such as the absolute band count, band/seg ratio, band/total neutrophil ratio, and immature/total neutrophil ratio. We examined blood and bone marrow samples in groups of noninfected and infected neonatal dogs and human beings in order to determine which method most clearly reflects an increased call upon marrow neutrophil reserves and which correlates best with the presence and severity of infection. We found that the neutrophil ratios were more frequently abnormal during neonatal sepsis than was the the absolute band count. All subjects, canine and human, in whom the immature/total neutrophil ratio exceeded 0.800 were found to have depletion of the marrow neutrophil reserves, and those with the most profound depletion died. This study supports the concept that an elevated immature/total neutrophil ratio can aid in the diagnosis of bacterial infection in the newborn infant and suggests that the degree of elevation may serve as a method for detecting subjects at high risk for depletion of the marrow neutrophil reserves and death from sepsis.

Animals↗
PubMed1980

Circulating and storage neutrophil changes in experimental type II group B streptococcal sepsis.

The availibility of neutrophils is an important factor in host resistance to bacterial infection. Therefore, circulating and storage neutrophil quantification was carried out on groups of neonatal rats intranasally inoculated with type II group B streptococci. The dose of type II group B streptococci used produced 56% mortality in 48 neonatal rats with death being due to pneumonia and sepsis. Neutropenia (1300 +/- 150/mm3 versus 2300 +/- 170/mm3; mean +/- S.D.; P < 0.01) and an elevation in band/polymorphonuclear ratio (0.98 +/- 0.04 versus 0.30 +/- 0.04; P < 0.01) were observed in infected neonatal rats 24 hr following inoculation. Femoral marrow as well as splenic and hepatic neutrophil storage compartment quantification revealed dimunition of postmitotic (polymorphonuclear, band, and metamyelocyte) neutrophils in the infected group (P < 0.01) with sparing of the proliferative neutrophils (myeloblasts, promyelocytes, and myelocytes). Repletion of the myeloid but not the splenic or hepatic neutrophil storage compartments with normalization of the neutrophil count and band/polymorphonuclear ratio occurred in animals surviving 72 hr. These studies establish that neutropenia and neutrophil storage pool depletion are prominent features of experimental type II group B streptococci infection in neonates.

Animals↗
PubMed1980

Neutropenia and thrombocytopenia in renal allograft recipients treated with trimethoprim-sulfamethoxazole.

Hematologic toxicity occurred when trimethoprim-sulfamethoxazole was given for prolonged periods to renal allograft subjects also treated with azathioprine. In six such patients, the incidences and duration of neutropenia and thrombocytopenia were greater than in 25 similar allograft recipients treated with azathioprine alone. In bone marrow culture, the antifolate action of trimethoprim-sulfamethoxazole enhanced the marrow-suppressive effect of 6-mercaptopurine, the active moiety cleaved from azathioprine. These studies show that in renal allograft recipients treated with azathioprine, the prolonged use of trimethoprim-sulfamethoxazole may result in life-threatening hematotoxicity.

Adult↗