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Lung squamous cell carcinoma producing both parathyroid hormone-related peptide and granulocyte colony stimulating factor.

An autopsy case of a 61 year old male with primary squamous cell carcinoma of the lung with associated marked leukocytosis and hypercalcemia is reported. High levels of serum parathyroid hormone-related peptide (PTHrP) and granulocyte colony stimulating factor (GCSF) were detected. The tumor cells distinctly showed positive cytoplasmic immunoreactions with anti-PTHrP and anti-GCSF antibodies. Marked granulocytosis and thin bony trabeculae lacking osteoblasts were observed in the vertebral bone. Calcium deposits were found in the proximal tubules of the kidneys. Infarcts were seen as a result of fibrin thrombosis of the splenic artery. The tumor was successfully transplanted into nude mice in which the high levels of serum PTHrP and GCSF were reproduced. These results indicate that the tumor simultaneously produced both PTHrP and GCSF causing the paraneoplastic syndromes of hypercalcemia and leukocytosis.

Animals↗

Clostridium difficile lacks detectable superantigen activity.

Clostridium difficile colitis causes striking leukocytosis. We examined the possibility that toxins A or B, or other nontoxin products of C. difficile, act as superantigens, thereby stimulating leukocytosis. Our results failed to show major histocompatibility complex class II-dependent T lymphocyte proliferation, the hallmark of superantigen activity. Elevated white blood cell counts in C. difficile colitis are probably due to increased generation of cytokines such as interleukin-6 (IL-6) or IL-8.

Animals↗

Efficacy of recombinant human granulocyte-macrophage colony-stimulating factor in rhesus monkeys.

The glycosylated and the non-glycosylated recombinant human granulocyte-macrophage colony-stimulating factor (rh GM-CSF) expressed in Chinese hamster ovary cells and E. coli, respectively, were administered in rhesus monkeys either by the subcutaneous (three times daily) or intravenous route (6-hr infusions) for seven consecutive days. Within 24 hr peripheral white blood cells (WBC) increased 2-3 fold over normal values. Thereafter, the WBC increased steadily in a dose-dependent manner to reach maximum levels on the last day of or one day after the treatment period. The differential counts showed that neutrophils contributed to 50-80%, eosinophils to 10-20%, monocytes to 2-7%, and lymphocytes to 15-30% of the WBC rise. No effect was found on platelets and erythrocytes. After termination of treatment, WBC counts returned to normal levels within one week. Subcutaneously administered CSF was more effective in inducing leukocytosis than that injected intravenously In addition to the rise in WBC, the administered rh GM-CSF also enhanced the oxidative metabolism and bactericidal activity of the circulating mature granulocytes isolated from the blood of monkeys treated with rh GM-CSF. These results show that glycosylated or non-glycosylated rh GM-CSF is both an effective stimulator of leukocytosis and a potent activator of the functional activity of mature granulocytes in vivo.

Animals↗

Thrombocytosis in 24 horses (1989-1994).

The records of horses presented to the Veterinary Teaching Hospital of North Carolina State University College of Veterinary Medicine between January 1, 1989 and April 30, 1994 were evaluated to determine risk factors associated with thrombocytosis. Of the 2,346 horses for which a CBC was performed, 24 (1.0%) had a platelet count > 400,000/microL. Demographic, diagnostic, physical examination, and clinicopathologic variables from these cases were compared with a reference population consisting of 189 horses with a normal platelet count presenting during the same period. Infectious/ inflammatory disorders were observed more commonly in horses with high platelet counts than in horses with normal platelet counts. Initial independent evaluation of demographic variables revealed that horses more than 3 years of age, females, and geldings were less likely to have thrombocytosis than were younger horses or stallions. Independent analysis of clinicopathologic variables revealed that horses with thrombocytosis were more likely to have hyperfibrinogenemia, leukocytosis, hypoproteinemia, and anemia than were horses with normal platelet counts. Physical examination parameters associated with thrombocytosis included tachycardia and pyrexia. In the final multivariable model, the variables with the strongest association with thrombocytosis included leukocytosis, anemia, and hyperfibrinogenemia. Thrombocytosis rarely causes clinical problems in horses and is not likely to require specific antiplatelet therapy. The strong association of thrombocytosis with infectious/inflammatory disorders, however, should lead clinicians to suspect these types of conditions in horses with high platelet counts.

Anemia↗

Biological activities of crystalline pertussigen from Bordetella pertussis.

We studied various biological activities of crystalline pertussigen and found that in mice as little as 0.5 ng of pertussigen induced hypersensitivity to histamine, 8 to 40 ng induced leukocytosis, 2 ng increased production of insulin, 0.1 ng increased production of immunoglobulin E and immunoglobulin G1 antibodies to hen egg albumin, 9.5 ng increased susceptibility to anaphylactic shock, and 0.5 ng increased the vascular permeability of striated muscle. We also found that in Lewis rats 20 ng of pertussigen promoted the induction of hyperacute experimental allergic encephalomyelitis. Pertussigen given intraperitoneally was toxic to mice at a dose of 546 ng. Treatment of pertussigen with glutaraldehyde eliminated this toxicity. Mice immunized with 1,700 ng of detoxified pertussigen were protected against intracerebral challenge with 3 x 10(4) viable Bordetella pertussis cells. When as little as 0.5 ng of pertussigen was given intravenously to mice, the increased susceptibility of the animals to histamine could still be detected 84 days later. The biological properties of crystalline pertussigen indicate its similarity to leukocytosis-promoting factor, Islet-activating protein, late-appearing toxic factor, and mouse-protective antigen of B. pertussis.

Anaphylaxis↗

Systemic injection of group A streptococcal peptidoglycan-polysaccharide complexes elicits persistent neutrophilia and monocytosis associated with polyarthritis in rats.

The perpetuation of inflammatory changes within joints elicited by persisting, poorly biodegradable group A streptococcal cell walls (peptidoglycan-polysaccharide complexes [PG-PS]) is well documented. Chronic changes in the bloodstream induced by PG-PS have not been described previously. We demonstrated that leukocytosis occurs within 3 days after intraperitoneal injection of PG-PS and remains elevated 20 weeks later. Chronic neutrophilia, monocytosis, and lymphocytosis were observed in all experiments. Chronic changes in platelet, erythrocyte, and reticulocyte counts were not seen. The newly documented leukocytosis, lasting for months after PG-PS administration, provided a circulating pool of leukocytes that may participate in chronic inflammatory events in the joint. Although the central role of the macrophage in PG-PS-mediated inflammation has been emphasized (F. G. Dalldorf, W. J. Cromartie, S. K. Anderle, R. L. Clark, and J. H. Schwab, Am. J. Pathol. 100:383-402, 1980), the polymorphonuclear cell may be involved in periods of exacerbation of streptococcal cell wall-mediated polyarthritis. This was supported by our observations that neutrophilia and monocytosis correlate well with the degree of chronic joint inflammation.

Animals↗

Differences in coughing and other responses to intrabronchial infection with Bordetella pertussis among strains of rats.

Four strains of rats were each infected intrabronchially with approximately 10(8) CFU of Bordetella pertussis 18-323 encased in fine agarose beads. After 8 days, Sprague-Dawley rats developed the highest incidence of coughing paroxysms, as monitored with voice-activated tape recorders; Brown Norway, Lewis, and Hooded Lister rats coughed significantly less frequently. Marked leukocytosis, with counts up to four times the normal levels, and retardation of normal weight gain occurred in all four rat strains. Both coughing and leukocytosis were greater in animals that were infected at 4 weeks of age than in those infected at 6 weeks of age. Total serum immunoglobulin E (IgE) rose in all four rat strains 9- to 244-fold by day 8 after infection and returned to near preinfection levels at 6 weeks. Sprague-Dawley and Lewis rats, which had the lowest basal levels of total IgE in serum, showed the greatest degrees of elevation. All four rat strains had IgG to B. pertussis whole-cell sonicate and to filamentous hemagglutinin in 6-week-postinfection sera. However, the strains differed in production of IgG to pertussis toxin, with Sprague-Dawley rats having the highest titers and Hooded Lister and Lewis rats being nonresponders. These studies highlight the importance of rat strain as a variable in the coughing-rat model of pertussis and validate the choice of the Sprague-Dawley rats in previous studies.

Age Factors↗

Granulocyte-macrophage colony-stimulating factor-deficient mice have impaired resistance to blood-stage malaria.

The contribution of granulocyte-macrophage colony-stimulating factor (GM-CSF), a hematopoietic and immunoregulatory cytokine, to resistance to blood-stage malaria was investigated by infecting GM-CSF-deficient (knockout [KO]) mice with Plasmodium chabaudi AS. KO mice were more susceptible to infection than wild-type (WT) mice, as evidenced by higher peak parasitemia, recurrent recrudescent parasitemia, and high mortality. P. chabaudi AS-infected KO mice had impaired splenomegaly and lower leukocytosis but equivalent levels of anemia compared to infected WT mice. Both bone marrow and splenic erythropoiesis were normal in infected KO mice. However, granulocyte-macrophage colony formation was significantly decreased in these tissues of uninfected and infected KO mice, and the numbers of macrophages in the spleen and peritoneal cavity were significantly lower than in infected WT mice. Serum levels of gamma interferon (IFN-gamma) were found to be significantly higher in uninfected KO mice, and the level of this cytokine was not increased during infection. In contrast, IFN-gamma levels were significantly above normal levels in infected WT mice. During infection, tumor necrosis factor alpha (TNF-alpha) levels were significantly increased in KO mice and were significantly higher than TNF-alpha levels in infected WT mice. Our results indicate that GM-CSF contributes to resistance to P. chabaudi AS infection and that it is involved in the development of splenomegaly, leukocytosis, and granulocyte-macrophage hematopoiesis. GM-CSF may also regulate IFN-gamma and TNF-alpha production and activity in response to infection. The abnormal responses seen in infected KO mice may be due to the lack of GM-CSF during development, to the lack of GM-CSF in the infected mature mice, or to both.

Anemia↗

7-Nitroindazole, but not aminoguanidine, attenuates the acute inflammatory responses and brain injury during the early phase of Escherichia coli meningitis in the newborn piglet.

We evaluated the anti-inflammatory and neuroprotective effects of the selective neuronal nitric oxide synthase inhibitor 7-nitroindazole and aminoguanidine, which predominantly inhibits inducible nitric oxide synthase, during the early phase of experimental bacterial meningitis in the newborn piglet. Meningitis was induced by intracisternal injection of 10(8) colony-forming units of Escherichia coli in 100 microl of saline. 7-Nitroindazole significantly attenuated the meningitis-induced acute inflammatory responses such as increased intracranial pressure, decreased cerebrospinal fluid (CSF) glucose concentration, and CSF leukocytosis at 2 h. However, meningitis-induced CSF leukocytosis at 4 h and increased CSF lactate and tumor necrosis factor alpha levels were not significantly attenuated. Reduced cerebral cortical cell membrane Na(+),K(+)-ATPase activity and increased lipid peroxidation products, indicative of meningitis-induced brain cell membrane dysfunction, were also significantly improved with 7-nitroindazole treatment. In contrast, although aminoguanidine significantly attenuated the increase in the CSF tumor necrosis factor alpha level, it failed to attenuate the acute inflammation and the ensuing brain injury in bacterial meningitis. In summary, 7-nitroindazole, but not aminoguanidine, significantly attenuated the acute inflammatory responses and brain injury during the early phase of neonatal bacterial meningitis.

Animals↗

Overexpression of CXC chemokines by an adrenocortical carcinoma: a novel clinical syndrome.

A patient with adrenocortical carcinoma presented with fever, leukocytosis, and increased acute phase reactants. The tumor was infiltrated with neutrophils. Immunohistochemical staining of the tumor showed positive signal for epithelial neutrophil-activating protein-78, an angiogenic and chemotactic CXC chemokine. Conditioned medium from tumor-derived cells (RL-251) showed high concentration of IL-8, epithelial neutrophil-activating protein-78, Gro alpha, and Gro gamma, angiogenic CXC chemokines with a potential role in tumorigenesis. An adrenal cancer/severe combined immunodeficiency mouse chimera was developed. Mice grew tumors rapidly, and circulating levels of IL-8 and epithelial neutrophil-activating protein-78 were detected. In contrast, animals transplanted with NCI-H295 cells, a nonchemokine-secreting cell line, grew tumors more slowly and did not have detectable chemokine levels. Similar to the patient, mice with RL-251 tumors developed marked leukocytosis and neutrophilia, and their tumors were infiltrated with neutrophils. Mice were passively immunized with epithelial neutrophil-activating protein-78 antisera. A marked decrease in tumor growth was observed. Potential for chemokine production by other adrenocortical tumors was investigated by RT-PCR in archival material. Six of seven adrenal carcinomas and one of three adenomas had cDNA for IL-8; six of seven carcinomas and the three adenomas had cDNA for epithelial neutrophil-activating protein-78. We concluded that the clinical presentation of this case resulted from increased tumor production of chemotactic chemokines. Through their angiogenic and chemotactic properties these chemokines may play an important role in adrenal tumorigenesis.

17-Hydroxycorticosteroids↗

Species differences in actions of islet-activating protein, pertussis toxin.

Islet-activating protein (IAP) is one of the pertussis toxins. The ability of IAP to cause potentiation of insulin secretory responses and promotion of leukocytosis was studied in six animal species (hamsters, rats, guinea pigs, rabbits, dogs and monkeys). The action of IAP on insulin secretion in the animals was estimated by three kinds of tests: effects on epinephrine hyperglycemia, plasma insulin and blood glucose concentrations following the injection of stimuli, and glucose tolerance. Of all animals tested, IAP was most effective in hamsters. Marked hyperinsulinemia was also shown in IAP-treated dogs, rats and monkeys in response to insulin secretagogues, but their sensitivity to IAP was inferior to that of hamsters. In rabbits, IAP was markedly toxic, and the effect on insulin secretion was observed only slightly at a dose close to its minimal lethal dose. In addition, no significant effects of IAP were shown in guinea pigs in the present experiment. On the other hand, leukocytosis promoting activity of IAP appeared in a dose-dependent manner in all animal species; rabbits were the most sensitive to IAP in this regard. It is concluded that both actions of IAP appear differently in different animal species, and the species difference of the effect on insulin secretory responses is in agreement with that on histamine sensitizing activity.

Animals↗

Pneumococcal facial cellulitis in children.

OBJECTIVE: To review the epidemiology and clinical course of facial cellulitis attributable to Streptococcus pneumoniae in children. DESIGN: Cases were reviewed retrospectively at 8 children's hospitals in the United States for the period of September 1993 through December 1998. RESULTS: We identified 52 cases of pneumococcal facial cellulitis (45 periorbital and 7 buccal). Ninety-two percent of patients were <36 months old. Most were previously healthy; among the 6 with underlying disease were the only 2 patients with bilateral facial cellulitis. Fever (temperature: >/=100.5 degrees F) and leukocytosis (white blood cell count: >15 000/mm(3)) were noted at presentation in 78% and 82%, respectively. Two of 15 patients who underwent lumbar puncture had cerebrospinal fluid with mild pleocytosis, which was culture-negative. All patients had blood cultures positive for S pneumoniae. Serotypes 14 and 6B accounted for 53% and 27% of isolates, respectively. Overall, 16% and 4% were nonsusceptible to penicillin and ceftriaxone, respectively. Such isolates did not seem to cause disease that was either more severe or more refractory to therapy than that attributable to penicillin-susceptible isolates. Overall, the patients did well; one third were treated as outpatients. CONCLUSIONS: Pneumococcal facial cellulitis occurs primarily in young children (<36 months of age) who are at risk for pneumococcal bacteremia. They present with fever and leukocytosis. Response to therapy is generally good in those with disease attributable to penicillin-susceptible or -nonsusceptible S pneumoniae. Ninety-six percent of the serotypes causing facial cellulitis in this series are included in the heptavalent-conjugated pneumococcal vaccine recently licensed in the United States.

Cellulitis↗

Clinical, biochemical, and hematological characteristics, disease prevalence, and prognosis of dogs presenting with neutrophil cytoplasmic toxicity.

Neutrophil cytoplasmic toxicity is manifested as an abnormality in cell size or the cytoplasmic content upon examination of Romanowsky-stained blood smears, and is traditionally associated with infection and inflammation. The purpose of this retrospective study was to investigate the association of such changes with clinical and clinicopathologic characteristics, diseases, and prognoses in dogs. Dogs with neutrophil toxicity (n = 248) were compared with negative controls (n = 248). Statistical analyses included chi-square tests, independent t-tests, nonparametric Mann-Whitney tests, the chi-square trend test, and survival analysis. Dogs with neutrophil toxicity had a significantly higher prevalence of pale mucous membranes, tachycardia, fever, abdominal organomegaly, icterus, melena, and hematuria. Most mean hematologic variables were significantly different between groups. Dogs with neutrophil toxicity had a significantly (P < .05) higher prevalence of leukocytosis, leukopenia, neutrophilia, neutropenia, anemia, hyponatremia, hypokalemia, hypoproteinemia, hypoalbuminemia, and hypocalcemia. The prevalence of pyometra, parvovirus infection, acute renal failure, peritonitis, immune-mediated hemolytic anemia, disseminated intravascular coagulation, pancreatitis, septicemia, and neoplastic disorders was significantly higher among these dogs. Case fatality, hospitalization length, and treatment cost were significantly (P < .001) higher in dogs with neutrophil toxicity. Neutrophil toxicity severity was significantly (P < .0035) and positively associated with neutropenia, and negatively associated with leukocytosis and neutrophilia. A significant trend (P = .05) toward increasing case fatality with an increase of neutrophil toxicity was observed. In the neutrophil toxicity group, dogs with leukopenia (<5.0 X 10(3)/mm3) had a significantly (P < .0001) higher case fatality compared to dogs with normal or high leukocyte counts. We conclude that evaluation of blood smears for neutrophil cytoplasmic toxicity provides useful clinical information and can serve as a good prognostic predictor.

Age Factors↗

The production of colony-stimulating factors by thyroid carcinoma is associated with marked neutrophilia and eosinophilia.

Cancers producing colony-stimulating factors and associated with marked leukocytosis are relatively rare. We report here a case of a thyroid cancer producing both granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). A 72-year-old woman had a thyroid carcinoma with significant neutrophilia and eosinophilia without any evidence of infection. The serum concentrations of both G-CSF and GM-CSF were elevated significantly in this patient, which might have induced the leukocytosis. Furthermore, the G-CSF concentrations in thyroid tumor tissue and metastatic lesions in the lung and skin examined at autopsy also were extremely high.

Aged↗

Squamous cell carcinoma of the lung producing granulocyte colony-stimulating factor and resembling a malignant pleural mesothelioma.

A 65-year-old was admitted to our hospital and was diagnosed as having squamous cell carcinoma originating in the right upper bronchus. He underwent both chemotherapy and radiation therapy, but these therapies were ineffective and thereafter the developed radiation pneumonitis and carcinomatous pleuritis. Finally, he died of bacterial pneumonia in the opposite normal lung of four months duration. From one month before his death, laboratory data indicated marked leukocytosis, and his granulocyte colony-stimulating factor (G-CSF) serum level was high. At autopsy, squamous cell carcinoma was found in the right hilus region of the lung, with a spreading form resembling a malignant pleural mesothelioma mainly occupying the pleural cavity. Based on positive staining method with specific monoclonal antibodies against G-CSF, it was considered that the leukocytosis was caused by G-CSF producing tumor.

Aged↗

Clinical signs and clinicopathologic abnormalities in dogs with clinical spirocercosis: 39 cases (1996-2004).

OBJECTIVE: To determine clinical signs and clinicopathologic abnormalities in dogs with naturally occurring clinical spirocercosis. DESIGN: Retrospective case series. ANIMALS: 39 dogs with spirocercosis. PROCEDURES: Medical records were reviewed, and information on signalment, residence (rural vs urban), owner complaints, physical examination findings, clinicopathologic abnormalities, radiographic and endoscopic findings, and concurrent systemic diseases was recorded. RESULTS: Hellenic hounds and mixed-breed dogs were overrepresented, compared with a group of 117 control dogs without spirocercosis that were examined because of gastrointestinal tract disease, and mean body weight of dogs with spirocercosis was significantly higher than mean body weight of control dogs. Odynophagia (34 [87%]), regurgitation (24 [62%]), and excessive salivation (14 [36%]) were the most common clinical findings. The most common radiographic abnormalities were a mass in the caudodorsal aspect of the mediastinum (15/35 [43%]) and spondylitis of the caudal thoracic vertebrae (10 [29%]). Parasitic nodules were seen during esophagoscopy in all 39 dogs. Normocytic, normochromic, nonregenerative anemia; neutrophilic leukocytosis; hyperproteinemia; and high alkaline phosphatase activity were significantly more common in dogs with spirocercosis than in a control group of 56 healthy dogs. Concurrent systemic diseases, mainly leishmaniosis, dirofilariosis, and monocytic ehrlichiosis, were documented in 14 (36%) dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that clinical spirocercosis occurs more often in young-adult, large-breed dogs. Nonregenerative anemia, neutrophilic leukocytosis, hyperproteinemia, and high alkaline phosphatase activity may be useful clinicopathologic indicators of this disease.

Age Factors↗

Histological response of bovine mammary tissue to an intracisternal bead device.

Placement of an intracisternal bead device into teat cisterns of dairy cows at drying off was studied. Histological analysis of teat cisternal tissues from quarters fitted with devices demonstrated significant elevation in leukocyte infiltration and hypertrophy of the epithelial lining. Tissue changes ranged from degeneration and sloughing of surface cells of double-layered epithelia to marked thickening and lysis of cisternal epithelium, leaving only the basement membrane intact. Quantification of mammary parenchymal components from quarters fitted with devices demonstrated no differences in percentage area occupied by alveolar epithelium, lumen, and intraalveolar stroma from unfitted control quarters. However, quantification of leukocyte numbers demonstrated slightly greater leukocytosis into tissues of quarters fitted with devices in comparison with controls. Devices were successful in stimulating a localized leukocytosis into teat cisternal tissues, which may serve to amplify the leukocyte response to mastitis-causing organisms once they penetrate the teat duct.

Animals↗

[Association of chronic myelosis and cancer].

During the period between 1948-1963 a total of 3,200 tumor patients were treated in the First and Second Medical Clinics of Tg.-Mures. In these tumor patients as well as the skin cancer patients who were treated with radiotherapy the authors found in 1.5% of the patients a leukocytosis of more than 20,000. In the last ten years (1964-1974), however, in the Second Medical Clinic only, 5% of 516 tumor patients showed a leukocytosis exceeding 20,000. In the first group of patients (3,200 cases) 0.03% showed more than 50,000 leukocytes, in the other group of 516 patients 0.2% showed more than 50,000 leukocytes. These values point towards a leukemoid reaction. A shift to the left to the myelocytes or beyond in the blood picture was found in the Second Medical Clinic in 10% of patients with carcinoma during the year of 1974. In 6% of the cases erythroblasts in the peripheral blood were seen, too. This deviation occurred often independent of the total number of leukocytes and was of a temporary nature. During the same time (1949-1974) 128 patients with chronic myeloid leukemia were treated in both departments as in-patients. 6 cases (i.e., 4.6%) had a chronic myelosis simultaneous with carcinoma, in one case together with an osteosarcoma. The diagnosis was confirmed in all cases by autopsy.

Autopsy↗