An oro-facial disease 'noma (cancrum oris)' in a Japanese monkey (Macaca fuscata): clinical signs, clinicopathological features, and response to treatment

BACKGROUND: A Japanese monkey developed severe oro-facial lesions that were called noma in humans. Although extensive destruction of both the buccal regions occurred with rapid progress, author successfully treated the lesions with povidone-iodine, enrofloxacin, chymotrypsin, a glycyrrhizin preparation, and a basic fibroblast growth factor. METHODS: Author clinicopathologically investigated this disease during the treatment. RESULTS: In the subcutaneous and muscular tissues, the lesions developed characteristic changes such as dissolving collagen fibers and muscular tissues phagocytosed by giant and epitheloid cells. The monkey showed a notable increase in creatine kinase activities. The present examinations revealed severe invasive findings in muscular tissues, which were accompanied by infections of beta-hemolytic streptococcus Group C. This monkey was negative for simian immunodeficiency virus antibody; however, infection with simian D retrovirus was not ruled out. CONCLUSIONS: Simian noma was a rapidly devastating disease, which destroyed the muscle tissues of oro-facial structure. Nonhuman primates are the only species that develop oro-facial lesions, corresponding to noma in humans.     

Intracellular cytokine profile of T cells from children with acute lymphoblastic leukemia

Purpose: During an ongoing immune response, cytokines produced by T helper types 1 (Th1) and 2 (Th2) together with T cytotoxic types 1 (Tc1) and 2 (Tc2) are critical to the effectiveness of that response. Dysregulated expansion of one or the other subset may contribute to the impaired function of the T-cell-mediated immune system in cancer patients. In the present study we have investigated whether such dysregulation might exist in children with acute lymphoblastic leukemia (ALL). Methods: We analyzed 61 blood samples from 45 children with B cell precursor ALL and 16 healthy children. Interleukin(IL)-2, IL-4, and interferon γ (IFNγ) production of their respective purified CD4⁺ and CD8⁺ T cells were assessed at the single-cell level by intracellular-cytokine-staining flow cytometry. Results: At the time of diagnosis, IL-2-producing cell populations in CD4⁺ and CD8⁺ T cells were reduced below the normal range in 31 of 44 (70.5%) and 23 of 38 (60.5%) cases respectively. Similarly, IFNγ-producing cell populations in CD4⁺ and CD8⁺ T cells decreased in 17 of 44 (38.6%) and 18 of 38 (47.4%) cases respectively. Conversely cell populations capable of IL-4 production in CD4⁺ and CD8⁺ T cell subsets were increased in 13 of 30 (43.3%) and 15 of 30 (50.0%) cases respectively. Therefore, the Th1-to-Th2 and Tc1-to-Tc2 ratios (1.6 ± 2.2 and 7.7 ± 6.7 respectively) were significantly lower in peripheral blood T cells of ALL patients (n = 30) than those (6.0 ± 2.9 and 20.1 ± 10.3 respectively) in 15 healthy controls (P < 0.0001). Although both CD45RA⁺/CD4⁺ and CD45RA⁺/CD8⁺ cells significantly increased in 43 ALL patients (P < 0.05), there existed no apparent correlation between CD45 isoform expression and cytokine (IL-2 and IFNγ) production. Interestingly, the ability to produce both IL-2 and IFNγ was recovered in 8 cases examined, after complete remission had been achieved. Conclusion: These observations suggest that, in both CD4⁺ and CD8⁺ T cells of ALL patients, there is a dysregulation in the functionality of Th1 (Tc1) and Th2 (Tc2) cells with a gross reduction of Th1 (Tc1) cell populations and an expansion in Th2 (Tc2). Received: 12 November 1999 / Accepted: 2 January 2000     

Bacterial diversity in oral samples of children in niger with acute noma, acute necrotizing gingivitis, and healthy controls

Background

Noma is a gangrenous disease that leads to severe disfigurement of the face with high morbidity and mortality, but its etiology remains unknown. Young children in developing countries are almost exclusively affected. The purpose of the study was to record and compare bacterial diversity in oral samples from children with or without acute noma or acute necrotizing gingivitis from a defined geographical region in Niger by culture-independent molecular methods.

Methods and Principal Findings

Gingival samples from 23 healthy children, nine children with acute necrotizing gingivitis, and 23 children with acute noma (both healthy and diseased oral sites) were amplified using “universal” PCR primers for the 16 S rRNA gene and pooled according to category (noma, healthy, or acute necrotizing gingivitis), gender, and site status (diseased or control site). Seven libraries were generated. A total of 1237 partial 16 S rRNA sequences representing 339 bacterial species or phylotypes at a 98–99% identity level were obtained. Analysis of bacterial composition and frequency showed that diseased (noma or acute necrotizing gingivitis) and healthy site bacterial communities are composed of similar bacteria, but differ in the prevalence of a limited group of phylotypes. Large increases in counts of Prevotella intermedia and members of the Peptostreptococcus genus are associated with disease. In contrast, no clear-cut differences were found between noma and non-noma libraries.

Conclusions

Similarities between acute necrotizing gingivitis and noma samples support the hypothesis that the disease could evolve from acute necrotizing gingivitis in certain children for reasons still to be elucidated. This study revealed oral microbiological patterns associated with noma and acute necrotizing gingivitis, but no evidence was found for a specific infection-triggering agent.     

Inflammatory cytokine profile and circulating cortisol levels in malnourished children with necrotizing ulcerative gingivitis

Necrotizing ulcerative gingivitis (NUG), a periodontal disease traditionally associated with stressful lifestyles in young adults in developed countries, is very prevalent in socioeconomically deprived Nigerian children. Random incident cases (153) of NUG, along with their neighborhood village counterparts of comparable age and without NUG, as control, were recruited for this study. Anthropometric evaluation revealed widespread malnutrition and poor health in both groups of children, with more severe stunting in NUG cases. The poor nutritional status of the village children, with and without NUG, was also confirmed by markedly reduced levels of circulating micronutrients. Compared with the neighborhood children, NUG victims showed significant (p < 0.05 or < 0.001) increases in serum levels of interleukin (IL)-8 (+ 233%), IL-18 (+ 30%), IL-6 (+ 190%), IL-1beta (+ 341%), IL-10 (+ 186%), with a small decrease in interferon (IFN)-gamma (-19%) and nonsignificant increases in soluble tumor necrosis factor (TNF) receptors (sTNFR-p55, p75). Associated with NUG was a significant, 38% (p < 0.05) increase in plasma cortisol above the already high levels observed in the neighborhood village children, as well as some micronutrient deficiencies. The findings suggest that NUG is associated with dysregulated cytokine production, with a complex interplay of elevated levels of pro- and anti-inflammatory mediators. Such changes may serve as the common link between the seemingly unrelated risk conditions (e.g. stressful life styles, smoking, microbial infections, diabetes, malnutrition, alcoholism) traditionally implicated in the genesis of NUG, and all known to promote an increase in the blood level of cortisol, as well as a Th(1) to Th(2) cytokine shift.     

Influence of an immunopotentiator Polyoxidonium on cytokine profile and antibody production in children vaccinated with Priorix

60 children aged 1-2 years old (32 boys and 28 girls) were vaccinated with Priorix. Vaccinated children included healthy control (19 children, group 1), and children with immunological disturbances such as episodes of respiratory infection. From the latter group, 20 children did not receive (group 2), and 21 children received 0.15 mg/kg of Polyoxidonium simultaneously with the vaccine (group 3).On days 7 and 30 after vaccination, CD-markers on lymphocytes and concentration of specific antibodies, as well as levels of 11 cytokines in serum were evaluated by flow cytometry, ELISA, and multiplex techniques respectively. It was found that injection of Polyoxidonium skewed T helper differentiation to Th2 type. Antibody responses were significantly higher in children with preferable Th2 responses. Children from group 3 possessed higher titers of specific IgG-antibodies. Our study shows that Polyoxidonium could smooth out the immune reaction on vaccination. It is important for children with some immunological disturbances.     

Unique cytokine secretion profile in children with both type I diabetes and asthma distinct from that of solely diabetic or asthmatic children

Asthma and type I diabetes are major causes of chronic illness in childhood which, according to the current paradigm, have mutually antagonistic immunopathologies. Nonetheless, the disorders appear to preferably coexist both on population and individual levels. To assess whether children with asthma and type I diabetes might have a common immunoregulatory defect. The spontaneous and anti-CD3+ anti-CD28-stimulated cytokine production patterns by peripheral blood mononuclear cells of 13 children with both asthma and diabetes, nine children with diabetes, 11 children with asthma and nine healthy children were assessed using cytometric bead assay. The spontaneous production of IFN-gamma, TNF-alpha and IL-10 by mononuclear cells in children with both asthma and diabetes was elevated compared to the other study groups (p=0.02, p=0.001 and p=0.04, respectively). Stimulation in vitro increased IL-10 secretion in solely diabetic (p=0.008), asthmatic (p=0.008) and healthy children (p=0.01), but not in children with both diseases (p=0.22). Children suffering from both diabetes and asthma display a unique cytokine secretion pattern, distinct from those of solely diabetic, asthmatic and healthy children. In particular, these children appear to have a defect in regulation of IL-10 secretion.     

Acute necrotic stomatitis (noma) associated with methicillin-resistant Staphylococcus aureus infection in a newly acquired rhesus macaque (Macaca mulatta)

Backgroud A newly acquired rhesus macaque was suffering from rapid destruction of the left cheek caused by necrotizing stomatitis. Methods To restore reconstructive surgery and intensive care with antibiotics, wound protection, wound healing agents, and debridement were applied. Results Staphylococcus aureus and Enterococcus faecalis were isolated from the culture of the lesion, and the antibiotic susceptibility test revealed methicillin‐resistant Staphylococcus aureus infection. Vancomycin and ampicillin‐sulbactam effectively treated the bacterial infections, and reconstructive surgery was performed once the infection was cleared. Topical application of recombinant human epidermal growth factor (rhEGF) was useful to treat exposed wound of the noma lesion. Conclusions Simian noma associated with methicillin‐resistant Staphylococcus aureus (MRSA) had not previously been reported in non‐human primates. Although noma associated with MRSA is hard to cure because of its rapid and destructive progress, the aggressive therapy used in this study led to the successful resolution of an acute necrotic stomatitis lesion in a rhesus macaque.     

Autoantibodies against bactericidal/permeability-increasing protein (BPI) in children with acute pneumonia

Antineutrophil cytoplasmic antibodies directed against bactericidal/permeability-increasing protein (BPI), an inhibitor of a lipopolysaccharide of gram-negative bacteria, are a common feature of chronic neutrophilic inflammatory processes such as cystic fibrosis. We investigated whether serum and salivary anti-BPI autoantibodies also appear in the course of acute pneumonia in 24 otherwise healthy children. Nine (38%) and four (17%) patients had detectable serum anti-BPI immunoglobulin G (IgG) (≥4 IU mL⁻¹) and IgA (ratio≥1.2), respectively, on the day of hospital admission (day 0). There was no increase in the rate of occurrence or the concentration of these antibodies in the convalescent sera obtained on day 30. The presence of anti-BPI IgG on admission did not correlate with inflammatory markers (peripheral white blood cell count, C-reactive protein) or temperature on admission. Also, salivary anti-BPI IgA, determined on days 0, 3–5 and 30, did not appear during the course of acute pneumonia. In summary, a substantial proportion of previously healthy children have pre-existing anti-BPI IgG autoantibodies. Acute neutrophilic infection, i.e. pneumonia, however, neither triggered the appearance of new antibodies nor boosted the concentrations of pre-existing ones. Thus, in typical acute pneumonia in children, autoantibodies directed against BPI may not have clinical significance.     

Cutting edge: vasoactive intestinal peptide (VIP) induces differentiation of Th17 cells with a distinctive cytokine profile

Immune cellular effects of vasoactive intestinal peptide (VIP) are transduced by VIP G protein-coupled receptors type 1 (VPAC1) and type 2 (VPAC2). We now show that VIP with TGFbeta stimulates the transformation of CD4 T cells to a distinctive type of Th17 cell that generates IL-17 but not IL-6 or IL-21. VIP induction of Th17 cells was higher in VPAC2 knockout mice than wild-type mice, suggesting that VPAC1 is the principal transducer. Compared with Th17 cells elicited by IL-6, those evoked by VIP were similar in the secretion of IL-17 and IL-22, but lacked IL-21 secretion. Suppression of VIP induction of Th17 cells by protein kinase A inhibitors and enhancement by pharmacologically increased cAMP supports a role for this signal. The ability of VIP-VPAC1 axis signals to evoke development of a novel type of Th17 cells demonstrates the unique specificity of neuroregulatory mechanisms in the immunological environment.     

Cardioprotective effect of des-Aspartate-angiotensin-I (DAA-I) on cytokine gene expression profile in ligation model of myocardial infarction

We investigate the influence of des-Aspartate-angiotensin-I (DAA-I) on the cytokine expression profile in a rodent model of myocardial infarction. Myocardial infarction model was created in female Wistar rats by coronary artery ligation. Animals were randomized to receive intravenously either a daily dose of 1.2 mug DAA-I/kg body weight (group 1; n = 60) or saline (group 2; n = 60) for 14 days after infarction. Heart function was assessed by echocardiography. Animals were euthanized at 1, 3, 7, 14 and 31 days. Morphometric analysis using tetrazolium chloride staining revealed that infarct size was reduced by 32.2% (p < 0.05) in group 1 after 14 days of DAA-I treatment. Left ventricular ejection fraction in group 1 improved significantly (73.4%) as compared to group 2 (47.7%; p < 0.001). Immunostaining for immune cells at the infarct site showed that CD8+ lymphocytes infiltration at the infarct site declined in group 1 (15 +/- 5 cells) as compared to group 2 (50 +/- 6 cells; p < 0.001). Infiltration of monocytes and macrophages remained high at day 14 in group 2 (126 +/- 40 cells) as compared to group 1 (49 +/- 11 cells; p = 0.006). Multiplex PCR was done for differential gene expression of various pro-inflammatory cytokines. IL-6, TNF-alpha, TGF-beta and GM-CSF expression were significantly down-regulated in the infarct, peri-infarct and contra-lateral zones of the left ventricle in group 1 as compared to group 2. IL-6, TGF-beta and GM-CSF expression started to decline from day 1 of DAA-I treatment while TNF-alpha expression only reduced after 7 days of DAA-I treatment. We conclude that DAA-I prevented infarct expansion through suppression of inflammatory cytokines and immune cell infiltration in the infarct region.     

Immunization of acute leukemic children with a live varicella vaccine (Oka strain)

A total of 52 acute leukemic children have been safely and effectively vaccinated with live varicella (Oka strain) vaccine given under close clinical and immunological observation. The incidence of zoster in the vaccinated children group was slightly less than that in the group that had experienced natural varicella.     

Occurrence of the African subgroup (Ia) of BK polyomavirus in younger Japanese children

BK polyomavirus (BKV) is ubiquitous among humans, usually infecting them asymptomatically during childhood. BKV persists in renal tissue of individuals and their progeny are excreted in urine, particularly in immunocompromised patients. JC virus, another human polyomavirus, has been considered to be transmitted from parents to children during prolonged cohabitation. However, BKV has been supposed to be transmitted not only within but also outside the family. In the present study, to clarify this possibility, we analyzed phylogenetically 35 BKV which were excreted in the urine by Japanese children and adults undergoing stem cell transplantation. Subtypes I, III and IV were detected in 15, two and one children and in 15, one and one adults, respectively. Among 15 subtype I isolates from children, three, four and eight belonged to subgroups Ia, Ib-1 and Ic, respectively. All the three children from whom Ia was detected were less than 9 years old. In contrast in the adults, three subtype I belonged to Ib-1 and the other 12 to Ic. These findings may reflect the recent transmission of BKV Ia strains to Japanese children.     

Fostering in an African rodent, Saccostomus campestris (Cricetidae)

Fostering was studied in females of an African rodent Saccostomus campestris , the pouched mouse, which, contrary to most other rodents, is a solitary species. Females will only tolerate their own offspring and other adults are viciously attacked at all times except during the short period of pro-oestrus, when a male will be temporarily accepted.
Alien pups (n = 857) of different age-groups (0–30 days) were introduced to lactating females (n = 191) with their own pups (n = 1053) of different age-groups (0–20 days) over a period of three years. The total number of pups per female was made up to 10 (e.g. 7 own + 3 alien or 4 own + 6 alien).
The 'foster mother' readily accepted and successfully reared alien pups provided they were less than 21 days of age when introduced. Weaned alien pups, introduced when 25 or 30 days old, were viciously attacked by the foster mother and had to be removed, althoughin the breeding colony, pups that were allowed to remain with their mother after weaning were not attacked. It appears that up to weaning-age, female Saccostomus campestris may not distinguish between may not distinguis between their own and alien offspring, but rather between suckling and weaned pups.     

Prevalence of GSTT1, GSTM1 and NQO1 (609C>T) in Filipino children with ALL (acute lymphoblastic leukaemia)

In the present paper, we examined the incidence of polymorphic genes involved with the detoxification of exogenous chemicals, including carcinogens, namely GSTT1 (glutathione transferase theta1), GSTM1 (glutathione transferase mu1) and NQO1 (NAD(P)H:quinone oxidoreductase 1) in 60 Filipino paediatric patients with ALL (acute lymphoblastic leukaemia). We found a significantly high incidence of the GSTM1 null genotype in ALL children (71.7%) compared with 51.7% in the control group of children (P<0.05). The GSTT1 null genotype was observed in 35.0% and 33.3% of the ALL cases and the control subjects respectively, with no significant difference. Screening for NQO1 (609C>T) mutant alleles showed a high incidence of the NQO1 C/C genotype (NQO1 homozygous wild-type allele genotype) in 60.0% of ALL cases and was significantly higher than in the control group (23.3%) (P<0.01). These GSTM1 null and NQO1 wild-type genotypes are independently associated with the risk of ALL in Filipino patients. When these two genotypes, GSTM1 null and NQO1 C/C, were combined, the hazard rate for childhood leukaemia was significantly increased (P<0.001). We also noticed that the incidences of GSTM1 null mutations and the NQO1 C/C genotype were significantly higher among Filipinos. These findings suggest a possible role of the GSTM1 null and NQO1 C/C genotypes in the susceptibility of paediatric ALL cases in the Philippines.     

Cranial computertomography in children with acute lymphatic leukemia (ALL) and non Hodgkin-lymphoma (NHL) after different methods of CNS-treatment

42 children with acute lymphatic leukemia (ALL) or non-Hodgkin lymphoma (NHL) were subjected to cranial computer tomography (CT). 4 groups were formed according to CNS therapy. Group 1: 18 children in complete first remission after CNS prophylaxis with intrathecal 198 Au-colloid and methotrexate were examined between 3 1/2 and 7 1/3 years after beginning of therapy. 15 patients had normal computer tomograms, only 3 children had slight anomalies. The quantitative assessment of the computer tomograms yielded normal results for all 18 children. Group 2: 8 children were examined before CNS prophylaxis. 1 child had a connatal septum pellucidum cyst, 4 children had no anomalies and 3 children slight anomalies. The deviations from normal in groups 1 and 2 should be physiological variations. Group 3: 6 children were examined between 10 months and 8 1/4 years after termination of prophylactic CNS-irradiation (18-22.5 Gy) in combination with intrathecal methotrexate. Normal findings were obtained for 2 patients only. The other children had distinct cortical, subcortical or cerebellar atrophies and calcification of stem ganglia. Neurological complications had temporarily appeared in one child after skull irradiation. Group 4: A CT was made of 10 children during or after meningosis leukemia. The children who had received 198 Au-colloid for CNS prophylaxis yielded no pathological CT results. Distinct cortical, subcortical and cerebellar atrophies or calcification of stem ganglia were found in children after one or two CNS irradiations. These CT investigations confirm the results published by other authors, i.e. that owing to an irradiation--cytostatic therapy of the children's brains CNS lesions can be found in the CT. Their prognosis can only be determined by longterm observations. CNS prophylaxis by means of intrathecal 198 Au-colloid and methotrexate does not lead to any pathological CT anomalies.