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Cyclic hematopoiesis (CH), also called cyclic neutropenia, is an inherited disorder known to occur in both humans and gray collie dogs. Previous reports have provided ample evidence to suggest that lymphocyte activity and regulatory mechanisms may be abnormal in CH. The present study examined the lymphocyte populations of several lymphoid compartments of gray collie dogs. The percentage of B lymphocytes in the lymph nodes of CH dogs was significantly increased whereas that of null lymphocytes was decreased. The percentage of T lymphocytes did not differ between CH and normal dogs, however, the proportions of T lymphocyte subpopulations were significantly different. The levels of T lymphocytes expressing IgGFc receptors (T gamma) in the thymus, lymph nodes, and peripheral blood were significantly increased; whereas the levels of T lymphocytes expressing IgMFc receptors (T mu) were significantly decreased. The percentage and absolute numbers of T gamma and T mu lymphocytes cycled in CH dogs. The percentage and absolute numbers of neutrophils were greatest when that of T gamma lymphocytes was reduced. The cycles of monocytes and T gamma lymphocytes occurred in close association and a linear relationship between the levels of these cells was observed both in terms of percentage (r = 0.62; P less than 0.01) and absolute number (r = 0.67; P less than 0.05). The percentage of T gamma and T mu lymphocytes were inversely correlated (r = -0.68; P less than 0.01).

Studies of neutrophil kinetics in neutropenic individuals, as well as clinical observations of variability in the occurrence of infection among patients with neutropenia, have suggested that blood neutrophil counts may not uniformly reflect the effective delivery of neutrophils to extravascular tissues where the cells perform their principal host defense functions. To evaluate this possibility we developed a sensitive, reproducible method of measuring the extravascular delivery of neutrophils to a normal mucosal site of neutrophil turnover. This method is based upon the quantification of neutrophils recoverable from saline mouth wash specimens. Twenty-five mL specimens, obtained in a controlled manner from neutropenic patients and normal subjects, were centrifuged and the sediments resuspended in 1.0 mL Hank's buffer with 2 micrograms acridine orange, incubated at 37 degrees C for 15 minutes, and then examined in a hemocytometer chamber by fluorescence microscopy. Neutrophils could be clearly distinguished by their characteristic fluorescence and were counted. With this method as few as 1,500 neutrophils were detected reliably in mouth wash specimens. Mucosal neutrophil counts varied less than 10% with repeated sampling of individual subjects over 5-day periods and were consistently greater than 1.3 X 10(5)/specimen in non-neutropenic individuals. Although profound neutropenia was generally reflected by lower than normal oral mucosal neutrophil counts, these counts were significantly higher in individuals with chronic severe neutropenia (blood neutrophils less than 300/mm3) than in patients with acute neutropenia of comparable severity that had developed following chemotherapy. Also, in individuals recovering from profound neutropenia, neutrophils usually reappeared earlier in mouth wash specimens than in blood, and oral mucosal neutrophil counts attained recovery levels more rapidly than did blood counts. This phenomenon was particularly evident in an individual with cyclic neutropenia. Moreover, mucosal neutrophils could occasionally be detected in profoundly neutropenic patients when neutrophils were not present in blood samples. These findings indicate that mucosal neutrophil counts in individuals with neutropenia provide information about the delivery of neutrophils to tissues that may not be apparent from blood neutrophil counts alone.

There is a large scale daily production of B lymphocytes within bone marrow of mammals, however until recently, little has been known about cellular interactions or humoral factors which normally regulate this process. Monoclonal antibodies to B lineage antigens of mice and humans now permit the detection and manipulation of B cell precursors which lack surface immunoglobulin. We have been using these with several culture techniques to identify factors which may be important in this process and have been particularly aided in our studies by materials from genetically defective animals and patients. The properties and possible target cells of two newly discovered cytokines will be summarized in this communication. An established tumor cell line is responsive to at least some of the factors which influence normal B cell precursors and it seems likely that a better understanding of such mechanisms will be instructive with respect to malignant cell proliferation and differentiation.

To investigate the mechanisms of cyclic neutropenia, we studied the capacity of a patient's T lymphocytes (TLp) to interact with monocyte-macrophages from her normal HLA-identical sibling (MOb) in the elaboration of colony-stimulating activity (CSA). TLp obtained at the time of decreasing neutrophil counts, increased CSA elaboration (p less than 0.056) when incubated at a 1:1 ratio with MOb. Increasing the TLp to MOb ratios to 3:1 or 5:1 progressively decreased CSA. Also, lithium carbonate, which ordinarily prevents concanavalin A activation of suppressor TL, failed to do so, suggesting that preactivated suppressor TL were present in the patient while neutrophil levels were falling. In similar experiments performed while neutrophil levels were rising these activated suppressor TL were absent. These data suggest that some patients with cyclic neutropenia may have a cyclic increase in suppressor TL activity. As predicted by our in vitro experiments, lithium carbonate administration did not abrogate the first neutropenic cycle, but it did mitigate subsequent cycles.

A previously healthy woman developed severe, periodic neutropenia after ingestion of phenylbutazone. Oscillations in the monocyte count and hemoglobin concentrations also occurred. The neutropenic episodes were associated with severe bacterial infections requiring hospitalization. Lithium induced a transient interruption in the neutropenia, but continued use was ineffective. Prednisone in a dosage of 100 mg daily successfully interrupted the neutrophil cycling and prevented infection. The patient has remained in remission on 10 mg of prednisone on alternate days.

Granulocyte-macrophage progenitors (CFU-GM) from four patients with childhood onset cyclic neutropenia demonstrated abnormal in vitro proliferative responses to purified, recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) when examined in detailed dose-response studies. Marrow aspirate specimens were obtained for these studies from cyclic neutropenia patients (both during neutropenic nadirs and during recovery phases of cycles), from leukemia patients in remission who had received myelosuppressive chemotherapy, and from healthy normal volunteers. Nucleated marrow cells were then isolated by density-gradient centrifugation and cryopreserved to permit studies of CFU-GM from patients and controls to be carried out at the same time and in replicate. Maximum clonal growth of CFU-GM from normal subjects and from individuals recovering from drug-induced myelosuppression was elicited by 20-100 pmol/liter rhGM-CSF, and the CSF concentrations that induced half-maximal responses (ED50) were between 1.0 and 3.0 pmol/liter. In contrast, maximum growth of CFU-GM from the cyclic neutropenia patients required greater than or equal to 1.0 nmol/liter rhGM-CSF and ED50's were greater than 30.0 pmol/liter. These abnormalities in the GM-CSF responsive growth of myeloid progenitors were independent of cycle time and were most apparent with the predominantly neutrophilic 7-d CFU-GM. Moreover, differences in the growth of 14-d CFU-GM could be attributed mostly if not entirely to differences in the generation of neutrophilic colonies. These findings indicate that childhood onset cyclic neutropenia is associated with an underlying disturbance in the GM-CSF responsive growth of myeloid progenitors committed to neutrophilic differentiation.

INOUE, M., YAMADA, K., ISHIDA, Y., SHINOHARA, K., KANEKO, T. and MATSUMOTO, N. The Inhibitory Effect of Circulating Lymphocytes on Granulopoiesis in Human Cyclic Neutropenia in Vitro. Tohoku J. exp. Med., 1984, 143 (2), 213-220 - The effect of peripheral mononuclear cells (MNCs), lymphocytes and sera of a patient with typical cyclic neutropenia (CN) upon the normal colony forming unit in culture (CFU-C) growth was examined. MNCs and lymphocytes obtained during the recovery phase of the cycles inhibited CFU-C growth. In cntrast, these cells obtained during the neutropenic phase revealed no suppressive effect. Serum inhibitors of granulopoiesis were not detected at any time during the cycle. These findings suggest that MNCs, especially lymphocytes, may be one of the contributory factors for the development of CN in this case.

Cyclic hematopoiesis is a rare human disease for which a spontaneously occurring animal model was recognized in purebred collies in the 1960s. Initially the canine disease was called the “lethal gray syndrome” or the “silver-gray collie syndrome” because the affected collie puppies are born with gray coat color and they die prematurely. Dickson (1964) reported that the puppies die because of an absence of blood neutrophils with consequent infection. Lund et al. (1967) subsequently demonstrated that the dogs have cyclic neutropenia. In 1972, Dale et al. (1972a) reported that the reticulocytes, platelets, monocytes, eosinophils, and lymphocytes also fluctuate periodically and suggested that the name “cyclic hematopoiesis” more accurately describes this disorder.

A case of a boy with familial cyclic neutropenia and a large giant cell epulis is reported. The clinical management is described and the significance of the neutropenia in relation to subsequent infection of the epulis is discussed.

ERG and VER recordings were carried out in patients suffering from a so-called periodic disease (periodic fever, paroxismal peritonitis, cyclic neutropenia, intermittent arthralgia etc.). Electrodiagnostic findings were normal in cases with normal eye functions, irrespective of the presence of eyeground changes. Neuro-uveitis and neuro-retinopathy in ERG and even more in VER provide pathologic signs. Changes became discernible during the attacks and in the state of cessation.

In vitro studies have been done on haematopoietic cells from a patient with cyclic neutropenia characterized by severe depression of blood neutrophil levels every 21 days. Serial blood counts reveal periodic fluctuations in neutrophils, monocytes and reticulocytes. Agar culture of marrow cells shows normal concentration of colony forming cells. The percentage of colony forming cells in S phase is highly increased during profound neutropenia and normal during the recovery phase relating the granulocyte production to the peripheral neutrophil level. Studies of ingestion rate, bactericidal activity, lactate production and glucose oxidation during phagocytosis in isolated granulocytes show normal results. Also the ingestion rate in isolated monocytes is normal. Serial karyotype analyses of marrow cells during the neutrophil cycle display a normal pattern. Serum myeloperoxidase levels vary inversely with the peripheral neutrophil count indicating increased granulopoietic activity during profound neutropenia, which might be associated with non effective granulopoiesis during profound neutropenia, leading to a lack of granulocyte reserves in the marrow.

Human cyclic neutropenia is a distinctive disorder of unknown cause characterized by regularly recurrent episodes of profound neutropenia, which have a periodicity of about 3 weeks. This periodicity remains constant and is remarkably consistent among patients. Although blood elements other than neutrophils are nt depleted, essentially all patients experience a cycling of monocyte counts with monocyte cycles of the same length as but reciprocal to neutrophil cycles. Cycling of platelet and reticulocyte numbers also may occur. Patients experience a clinical syndrome of recurrent illness characterized by malaise, fever, aphthous stomatitis, and cervical adenopathy. Incidental infections may occur with neutropenia but respond readily to antibiotics. The clinical course is benign compared with others conditions in which similar degrees of neutropenia occur. The only life-threatening complication encountered during long-term follow-up of patients was the occurrence of spontaneous peritonitis, segmental bowel necrosis, and septicemia which required surgical intervention. Most patients develop the disease in childhood, but a significant number of patients develop the disease in adulthood as an apparently acquired condition. The disease occurs equally in both sexes and is familial in some. Studies of marrow morphology, myelopoiesis, and neotrophil kinetics have shown that cyclic neutropenia is primarily a disease of abnormally regulated neutrophil production. The judicious use of antibiotics, careful oral and dental care, and patient education are the mainstays of management. Alternate-day corticosteroids have been used successfully to abate the recurrent signs and symptoms, and in one patient the disease was gradually corrected by alternate day prednisolone. Human cyclic neutropenia is of special investigative interest because clarification of this disease may contribute greatly to an understanding of the normal control of myelopoiesis.

The role of gram-negative bacteria in the pathogenesis of necrotizing enterocolitis has been stressed. We describe a 21-year-old woman with chronic neutropenia with cyclic fluctuations who died of necrotizing enterocolitis due to Clostridium septicum. Seven patients with cyclic neutropenia and necrotizing enterocolitis have been described in the literature and in each case in which bacteriologic data were reported, a Clostridial infection was documented. Patients with cyclic neutropenia should be treated with antibiotics effective against Clostridial species when abdominal symptoms complicate neutropenic periods.

Recurrent skin and mucous membrane infections, occurring at regular intervals, should alert the clinician to the possibility of an unusual hematologic disorder known as cyclic or periodic neutropenia. This disease is characterized by a cyclic depression of neutrophils, occurring at intervals of 12 to 30 days (average 21 days) lasting from 5 to 8 days and accompanied by fever, malaise, and infections occurring in the skin and mucous membranes. The neutrophils in the peripheral blood regularly fall to low levels or disappear at this time. Between the periods of depression, the neutrophils increase but seldom rise to above 50% of the total. The leukocyte count is usually in the low normal range (4,000 to 5,000). The literature describing this rare disorder will be reviewed in this paper, and three cases will be reported. These cases are of particular interest, since a long period of observation (10 and

Summary. An analogue model of human granulopoiesis incorporating feedback control is presented which is less restricted than previous models. The model simulates kinetic data from human DF32 P and 3H-thymidine labelling experiments, and the data obtained by Morley & Stohlman in mice (1970) following destruction of four-fifths of the marrow. Support for King-Smith & Morley's (1970) suggestion that cyclic neutropenia may be a stem cell defect is forthcoming, but only after the addition of a further negative feedback loop simulating a granulocyte‘chalone’ or a considerable reduction in the time required for precursor cell division. The value of the model in the interpretation and design of kinetic studies, particularly in the non-steady state, is discussed.

Because of their rarity, or because they are overlooked, disregarded or mistaken for other conditions, little attention has been paid to certain peculiar, benign syndromes which last several days and recur for years at remarkably regular, short intervals. In naming them the adjectives periodic, cyclic, rhythmic, episodic, relapsing, paroxysmal, recurrent and intermittent are used interchangeably before the noun indicating the outstanding characteristic, as noted in the title and in the references. In this paper, studies of 6 patients with periodic diseases, three featured chiefly by fever and abdominal pain, one by neutropenia, one by arthralgia and one by myasthenia, are reported and compared with those of similar and different periodic diseases which have been noted by others. Each causes, periods of temporary disability, which recur for years with predictable accuracy and uniformity. Since all 6 patients are under observation, the duration and outcome of their ailments cannot be stated. PERIODIC

A B S T R A C T 12 grey collie dogs had cyclic neutropenia with the neutropenia recurring at 11.8+0.1-day intervals. The recovery from neutropenia was accompanied by a single wave of myeloid proliferation, an increase in marrow myeloid-labeling indices, and an increase in serum muramidase levels. After recovery from neutropenia during the period when blood neutrophils (PMN) were normal or increased, marrow myeloid precursors became scarce. The decline in marrow precursors and marrow PMN reserves heralded the recurrence of neutropenia. Neither diisopropyl fluorophosphate (DF32P) leukokinetic studies nor the rate of development of neutropenia suggested shortened PMN survival as a mechanism for the neutropenia. These studies indicate that the cyclic neutropenia is due to a regularly recurring failure in PMN production.

There are a number of disorders which recur with remarkably regular periodicity over many years without affecting the general health otherwise. In different persons the episodes are characterized by different features, which allow an arrangement of the disorders accordingly into four groups as periodic fever, periodic abdominalgia (benign paroxysmal peritonitis), periodic (cyclic) neutropenia and periodic (intermittent) arthralgia. 1 The name periodic disease was proposed to embrance the conditions in a newly established symptomcomplex, but it appears that periodicity of disease was known to the ancients and was ascribed to the influence of solar and lunar cycles. 2 Knowledge of its cause has not progressed much further. Infectious, allergic, endocrinologic, epileptic or migrainous influences have been held responsible; however, as Mead 3 wrote apropos of the subject in 1704, "and thus far the foundation was good, but when a false theory happened to be joined to true observation, this did considerably

Microscopie changes in tissues of 8 dogs with the gray collie syndrome (GCS) and in 5 related non-gray dogs were described. Three of the GCS dogs died as neonates, 2 as puppies, and 3 (treated clinically) as adults. Clinical signs of disease were abnormal hair pigmentation, cyclic neutropenia, diarrhea, lameness, and chronic ulceration of oral and genital mucosa. Lesions included lymphoid atrophy, amyloidosis, enteritis, aseptic bone necrosis, and acute and chronic purulent inflammation of several organs. Abnormalities in serum included decreased albumin and increased γ- and α-globulin. Electron microscopy of the spleen revealed amyloid fibers deposited chiefly at the periphery of the splenic follicles and within the central artery. Tissues from non-gray related dogs were normal except for laminar malacia of the motor areas of the cerebral cortex in 3 of these dogs which probably resulted from ischemia due to epileptiform seizures.

The kinetics of granulopoiesis and neutrophils was studied in a case of cyclic neutropenia using labeling techniques (3HTDR, 3H-DFP) combined with serial quantitative evaluations of the granulopoietic cells. It was demonstrated that the oscillation of the neutrophil count was caused by rhythmic fluctuations of the neutrophil production rate due to periodic changes in the proliferation activity of granulopoiesis. The results could be interpreted as indicating pathological regulation of granulopoiesis.

A B S T R A C T Two grey collie dogs had regular cyclic fluctuations in the number of all formed elements of the blood. The period lengths for all elements for an individual dog were the same, but the pattern of fluctuation for each element was distinctive. Normal dogs lacked periodic fluctuations. The patterns of day-to-day variation in the normal dogs counts were consistent with a first-order autoregressive process of serial dependence (i.e., each observation of the series depends on the last preceding observation and no others). The grey collie counts showed the same pattern of serial dependence after the component of the over-all variability due to cyclic oscillation was removed. These data suggest that a defect of hematopoietic regulation at the stem cell level leads to periodic interruptions of production of all hematopoietic elements and accounts for the cycles seen in the peripheral blood counts.

Human cyclic neutropenia is characterized by severe depression of blood neutrophil levels approximately every 21 days. To investigate the mechanism of cyclic neutropenia four patients were studied with daily complete blood counts, serial bone marrow examinations, marrow reserve testing, serum muramidase determinations, DF(22)P granulocytokinetic studies, and, in one patient, in vivo [(3)H]TdR labeling. Periodogram analysis of the serial blood counts in the latter patient and visual inspection of multiple cycles in the others revealed periodic fluctuations in the levels of blood neutrophils, monocytes, lymphocytes, reticulocytes, and platelets. Rhythmic changes in the morphologic and radioisotopic studies as well as the marrow reserve tests and muramidase measurements were consonant with a mechanism of periodic failure of marrow production rather than peripheral destruction. Human cyclic neutropenia is analogous to cyclic neutropenia in the grey collie dog and may be viewed as the consequence of cyclic hematopoiesis.

Çocukluk çağında ateş etyolojisinin tam olarak aydınlatılamadığı durumlarda ‘periyodik ateş sendromları’ düşünülmelidir.PFAPA sendromu, Hiper IgD sendromu, Tümör nekroz faktörü ile ilişkili periyodik sendrom TRAPS , Ailesel soğuk ürtikeri, Muckle-Wells sendromu, Ailevi Akdeniz Ateşi FMF ve Siklik Nötropeni bu sendromları oluşturmaktadır. Bu hastalıklarotoimmun etyoloji veya infeksiyon olmadan sistemik inflamasyon ataklarıyla karakterizedir. Tekrarlayan ateş atakları olanbir çocukla karşılaşan hekimlerin bu hastalıklara özgü bazı ipuçlarından yararlanarak tanı koymaları mümkündür. Kliniktablo oldukça iyi tanımlanmasına karşın hastalığa özgü laboratuvar bulgularının olmayışı tanıyı güçleştirmektedir. Bu yazıda bu hastalıklardan bahsedilmektedir, When common infectious agents and other causes of fever such as neoplastic and rheumatologic diseases, immune deficiencies, various endocrinologic and metabolic disorders are differentiated, periodic fever syndromes must be brought inmind in recurrent fever attacks of childhood. Among periodic fever syndromes PFAPA, hyper-IgD syndrome, tumor necrosis factor receptor-associated periodic syndrome TRAPS , familial cold urticaria, Muckle-Wells syndromes, familial Mediterranean fever and cyclic neutropenia are well described. Although clinical findings are clear enough , as there is no specific test for these diseases, it is sometimes hard to diagnose. Hereby, we rewieved these diseases which may cause recurrent fever attacks in children

We have described a case of cyclic neutropenia and pregnancy. Although many such cases exist, we believe this is the first time the association has been documented. In this patient, pregnancy had a mitigating effect on the symptoms caused by cyclic neutropenia.

Transplantation of normal bone marrow cells to a gray collie dog with cyclic neutropenia resulted in normal granulocytopoiesis. The finding suggests that cyclic neutropenia occurs because the hematopoietic stem cells are defective. Because of the similarity of human and canine cyclic neutropenia, it also suggests that the human disease may be curable by marrow transplantation.

The urinary activities for bone marrow colony formation were measured on consecutive 24-hour urine samples from two gray collie dogs with cyclic neutropenia and from two normal collies. The activity varied cyclically in the gray collies with a peak activity developing during the neutropenic phase, which antecedes the return of blood neutrophils. The activity fell to undetectable levels after the blood neutrophil counts returned to the normal range. The urine of normal dogs showed no activity. Since the dogs with cyclic neutropenia have been shown to have periodic hematopoiesis, these data suggest a regulatory hormonal role for the substance measured by this assay.

A 2 year old M and a 10 year old F with 21-day cycles of neutropenia and apthous stomatitis were studied. Bone marrow aspirates at the cycles' nadir showed a maturation arrest at the myelocyte stage. In vitro bone marrow culture in agar documented quantitatively normal colony formation with rare colonies of neutrophils (PMN). Serial liquid suspension cultures (Marbrook chamber) yielded cell counts which were in the normal range or higher than companion control cultures. CN PMN maturation was defective early in culture; some mature PMNs appeared after 7 days and persisted for up to 25 days. Plasma, obtained from normal donors and from those given typhoid vaccine and plasmaphoresed 1 hour later, was assayed for CSA, using normal and CN bone marrow. Only plasma which stimulated normal marrow promoted PMN maturation in CN marrow in vitro. In vivo, administration of plasma containing CSA increased PMN production and ameliorated the clinical symptoms of neutropenia. It is concluded that one type of CN involves a maturation defect of PMNs, which may be altered in vitro and in vivo by plasma containing CSA. Supported by Grant 5-M01-RR00199.

THERE are several well-described, although not necessarily distinct, febrile, noninfectious, recurrent illnesses with normal-intervening intervals as follows: intermittent hydrarthrosis, familial Mediterranean fever (FMF), cyclic neutropenia (cyclic hematopoiesis), and periodic hypothalamic discharge. Although many of these disorders have been recognized for years, they are often misdiagnosed and frequently are discovered only after long and difficult diagnostic evaluation.1No specific origins characterize these disorders, and effective drug therapy is available for only two of these disorders: colchicine for FMF2and prednisone for cyclic neutropenia.3We report a case of recurrent fever and neutropenia that responded to therapy with lithium carbonate. The control of human body temperature is complicated and has recently been reviewed.4In patients with recurrent fevers, the following causes might be found: abnormal production or release of endogenous pyrogen from host phagocytic cells; abnormalities of the hypothalamic thermoregulatory center's response to endogenous pyrogen; or abnormalities of

Cyclic neutropenia was first reported by Leale1in 1910. In 1946, Reimann and de Berardinis2collected 13 cases from the literature, reported 1 of their own, and briefly abstracted two others which were previously unpublished. One of the latter is reported here in more detail. Thirteen case reports3other than the 16 summarized by Reimann and de Berardinis have appeared in the literature. In none of these has there been any evidence of this entity appearing in more than one member of the family. The subject of this report is two cases of cyclic neutropenia occurring at a young age in a father and daughter. Report of Cases Case 1.— A boy was first seen in 1941 at the age of 14 years. His family stated that he had had furunculosis at the age of 6 weeks and bronchopneumonia at 18 months. Since the age of 2

To the Editor : In the article entitled "Hypogammaglobulinemia in a Young Girl" by Taggis et al. in the July issue of theAmerican Journal of Diseases of Childrenthe authors suggested that their patient represented an unclassified category of hypogammaglobulinemia. They differentiated this type from the congenital form by occurrence in young girls as well as boys, hyperplasia of lymphoid tissue, absence of leukocytosis in the presence of infection, splenomegaly frequently, and γ-globulin levels which tended to be somewhat higher. The authors further suggested that a young female we reported in 1957 might fall into this unclassified category. Our patient, however, lacks certain of the authors' differentiating characteristics. This child has had a conspicuous lack of lymphadenopathy—in fact, during a skin biopsy the surgeon was unable to find an available node in the axillary space for biopsy. Although she has had cyclic neutropenia, at times she has had marked leukocytosis—during

It has been reported that normal monocytes kill S. aureus as effectively as do PMN but patients with congenital neutropenia (CN) have increased number of circulating monocytes in the presence of uncontrolled infection. Therefore, we have compared the metabolic and bactericidal responses of CN monocytes from 2 such patients, the monocytes from 2 patients with cyclic neutropenia, patients with chronic infection, to the PMN from normals and patients with chronic infection, to the PMN from normals and patients with acute infections. At a bacteria to phagocyte ratio of 2–3:1 in an in vitro system which measured the combined effect of uptake and intracellular killing of S. aureus, PMNs consistently killed about 95% of the inoculum during 2 hours. In contrast, monocytes from all patients failed to diminsh the number of bacteria during the incubation. PMNs initiated ingestion sooner, took up S. aureus or zymosan particles faster, and ingested more bacteria or particles than did monocytes. Furthermore, despite a brisk respiratory burst, pentose shunt stimulation and hydrogen peroixde production by monocytes, there was less iodintion of bacteria by monocytes than PMN. Granule myeloperoxidase was significantly less in monocytes (163 ± 47) from all patients compared to PMN (390 ± 10). Cell associated bactericidal activity by monocytes was markedly diminshed compared to PMN (390 ± 10). Cell associated bactericidal activity by monocytes was markedly diminshed compared to PMN. These studies show that monocytes from patients with neutropenic syndromes function similarly to monocytes from children with subacute infection. Such monocytes are less bactericidal than PMN because of the combination of decreased phagocytic capacity and lower activity of the intracellular mechanisms related to peroxidation of bacteria.

To the Editor:— The reply to the query (193:752, 1965) about a possible relationship between cyclic neutropenia and recurrent pancreatitis needs amendation and amplification. If the episodes of neutropenia recur at three-week intervals as in most other instances, the condition is better termed "periodic myelodysplasia." Examples of periodic pancreatitis recurrent at similar intervals were described in theJournal of the Indian Medical Profession(9:4189, 1962) and inPeriodic Diseases, (Philadelphia: F. A. Davis Co., 1963). Hence, there is reason to believe that there is a relationship. Evidence indicates that overlapping of features, their concurrence, or transition occurs among various periodic disorders. Furthermore, Gilsdorf et al report a central nervous system influence on experimentally produced pancreatitis (abstracted,JAMA188:447, 1964). Theoretically, hypothalamic excitation provokes periodic disorders (Ann NY Acad Sci117:589, 1964).

Cyclic or periodic neutropenia is an unusual disorder characterized by malaise, fever, oral ulceration with scarring, gingivitis, periodontitis, and disappearance of neutrophils from the blood and bone marrow at approximately 21-day intervals. Frequently, but by no means constantly, other findings include the periodic occurrence of sialorrhea, abdominalgia, headache, arthralgia, cutaneous infections, and conjunctivitis. 34 Less than 25 well-documented cases in which oral manifestations are mentioned 1-25 are available for study, although an additional number may have been reported under such titles as periadenitis mucosa necrotica recurrens, Sutton's disease, recurring scarring painful aphthae, ulcus neuroticum mucosae oris, chronic aphthae, painful mouth ulceration, etc. Although a periodic recurrent history suggesting cyclic neutropenia has been noted in several cases described under these headings, definitive blood studies were not carried out. Clinical investigation of the etiology of cyclic neutropenia has been futile. Hormonal factors, long suspected as being responsible for the disease, have been

Cyclic neutropenia is a rare disease characterized by the regular disappearance of neutrohils from the circulating blood at approximately 21-day intervals. The neutropenic phase of the cycle is generally associated with clinical manifestations of fever, malaise, and the appearance of ulcers in the oral mucous membranes. Other symptoms, which are not common to all the patients, include intermittent arthralgia, abdominal pain, sore throat, lymphadenitis, headache, ischiorectal infections, mental depression, conjunctivitis, and cutaneous ulcers. To date only 23 well-documented cases have been reported in the literature. A summary of these cases is presented in Table 1. The neutrophils in the peripheral blood regularly fall to extremely low levels and often disappear for several days during each cycle. Between attacks the neutrophils may rise to nearly normal levels, but in most of the reported cases the neutrophil count is always somewhat lower than normal and seldom exceeds 50% of the differential count.

Cyclic neutropenia, or periodic neutropenia as Reimann has recently termed it, is a rare hematological disorder of unknown etiology and is characterized by severe neutropenia or agranulocytosis recurring at approximately 21 day intervals. The neutropenic phase, which lasts for from five to eight days, is usually accompanied by mild fever and localized, superficial infections of the skin or mucous membranes. Sometimes the infection is so severe that it simulates acute agranulocytosis, while, at other times, infection may be minimal or even absent. These symptoms always subside as the neutrophils rise to normal levels during the recovery periods. This sequence of events continues for years without impairing the general health of the person. Accurate recognition of this type of neutropenia is of great importance because it implies a favorable prognosis and because the disorder must be differentiated from acute and chronic types of neutropenia, both idiopathic and secondary, in which a

Marshall Syndrome or PFAPA is an inflammatory periodic disease characterized by periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis. Restless, headache, abdominal pain, vomiting, hepatosplenomegaly and arthralgia are less common symptoms seeing in this disease. The diagnosis is established on the basis of clinical criteria that require the presence of a recurrent fever of early onset (