Causes of anaemia other than acute blood loss and their clinical significance in dogs

Objectives : To identify the causes of anaemia, other than acute blood loss, in dogs and to determine whether severity of anaemia provides clues to the diagnosis. Methods : The veterinary medical database of the Veterinary Campus Hospital, Lyon was searched. Dogs with anaemia (packed cell volume <37%) were included and assigned to different disease groups. Dogs with acute blood loss were excluded. The case records were examined for weakness at presentation, the severity and regeneration of anaemia and the final diagnosis including tumour type if applicable. Results : The case records of 456 dogs with low packed cell volume were included. Cancer‐related anaemia and anaemia of inflammatory disease accounted for 33·1 and 28·5% of cases, respectively. Most dogs with cancer‐related anaemia had solid tumours (73%). The prevalence of immune‐mediated anaemia increased with severity of anaemia (5·3, 15·5, 41·2 and 56·2% for mild, moderate, severe and very severe anaemia, respectively), whereas the prevalence of anaemia of inflammatory disease decreased (36·7, 22·5, 2·9 and 0% for mild, moderate, severe and very severe anaemia, respectively). Clinical Significance : Anaemia of inflammatory disease and cancer‐related anaemia were the most frequently identified causes of anaemia in dogs. The percentage of dogs with immune‐mediated anaemia increased with anaemia severity, whereas the percentage of dogs with anaemia of inflammatory disease decreased with anaemia severity. Thus, severity of anaemia may provide clues to the diagnosis.     

Observational study of 14 cases of chronic pancreatitis in dogs

This study reports the clinical, clinicopathological and ultrasonographic findings from dogs with chronic pancreatitis (CP). Fourteen dogs with clinical signs consistent with CP and histological confirmation of the disease were evaluated. Abdominal ultrasound and clinical pathology results were recorded. Sensitivities of pancreatic enzymes for diagnosis of CP were calculated with two different cut-off values. The mean age of affected dogs was 9.1 years. Spaniels were the most common breed with CP, representing seven of the 14 dogs in this study. CP was histologically severe in nine cases. Most dogs showed chronic low-grade gastrointestinal signs and abdominal pain. Five dogs had exocrine pancreatic insufficiency and five dogs had diabetes mellitus. The sensitivity of elevated trypsin-like immunoreactivity for CP was 17 per cent. The sensitivities of canine pancreatic lipase immunoreactivity, lipase and amylase for CP were 44 to 67 per cent or 14 to 28 per cent depending on the cut-off value used. Cholesterol was elevated in 58 per cent of samples. Liver enzymes were often elevated. The pancreas appeared abnormal on 56 per cent of ultrasound examinations. Ten dogs had died by the end of the study period; only one case was due to CP.     

Idiopathic Eosinophilic Masses of the Gastrointestinal Tract in Dogs

Background: Eosinophilic inflammation of the gastrointestinal tract of dogs occurs in numerous disorders, typically resulting in diffuse intestinal thickening. Rarely, eosinophilic masses have been reported.
Objective: Describe a series of dogs with 1 or more idiopathic eosinophilic gastrointestinal masses (IEGM) to better characterize the clinical features, treatment, and prognosis.
Animals: Seven dogs with 1 or more gastrointestinal masses composed primarily of eosinophilic infiltrates for which no underlying cause was found.
Methods: Retrospective case series.
Results: Rottweilers and purebred, large breed dogs predominated. Dogs were middle-aged and typically had chronic signs of upper or lower gastrointestinal disease. Decreased appetite, vomiting, and evidence of gastrointestinal hemorrhage were present in the majority of cases. An abdominal or rectal mass was frequently noted on physical examination. Common laboratory abnormalities included peripheral eosinophilia, mature neutrophilia, hypoproteinemia, and hypocholesterolemia. The masses were histologically composed of moderate to severe eosinophilic infiltrates, which were often transmural and accompanied by fibrosis. All dogs treated with surgery alone died of complications of their disease. Treatment with corticosteroids and ivermectin improved clinical signs, caused resolution of eosinophilic infiltrates, and prolonged survival in most dogs treated medically.
Conclusions and Clinical Importance: These findings suggest that the prognosis for dogs with IEGM may be good when recognized and managed appropriately. When surgery is performed, medical treatment should also be added.     

Immune-based non-erosive inflammatory joint disease of the dog. 1. Canine systemic lupus erythematosus

The features of 13 dogs with systemic lupus erythematosus (SLE) are described. Canine SLE is a multisystemic disease characterized by autoimmunity and immune complex hypersensitivity. The presence of antinuclear antibody in the blood is an important diagnostic feature. All 13 cases had a non-erosive symmetrical polyarthritis. Autoimmune haemolytic anaemia was seen in five cases, thrombocytopenia in three, skin lesions in four; neurological involvement in one; and gastrointestinal signs in one. Treatment was with cytotoxic drugs(cyclophosphamide initially) and prednisolone.     

Mycoplasma canis and urogenital disease in dogs in Norway

Mycoplasmas identified as Mycoplasma canis were isolated from nine dogs with clinical signs of urogenital disease in Norway over a period of 20 months. Some of the dogs had been treated unsuccessfully with antibiotics, and three were euthanased as a result of severe persistent disease. Seven of the dogs had a urinary tract infection, one had chronic purulent epididymitis and one had chronic prostatitis. Overt haematuria was frequently observed among the dogs with cystitis. M canis was isolated in pure culture from seven of the dogs and in mixed culture from the other two. In three cases the mycoplasma was cultivated only from urinary sediment, and it was typically obtained in smaller numbers than would be considered indicative of a urinary tract infection. In contrast with most mycoplasmas, the M canis isolated from all the dogs grew on ordinary blood agar plates used for routine bacteriological cultivation. Specific mycoplasma media were not used and the presence of other Mycoplasma or Ureaplasma species cannot be excluded.     

Detection of Mycobacterium avium subspecies paratuberculosis-specific DNA by PCR in intestinal biopsies of dogs

Background: Mycobacterium avium subspecies paratuberculosis (MAP) is the cause of paratuberculosis. MAP infections have not been reliably detected in dogs, but a reemerging debate about the link between MAP and Crohn's disease has renewed interest about the occurrence of MAP in pets.
Hypothesis: This study was undertaken to examine canine intestinal biopsies for the presence of MAP-specific DNA.
Animals: Forty-two dogs with chronic vomiting, diarrhea, or both; and 14 dogs with no gastrointestinal disease.
Methods: All dogs with signs of gastrointestinal disease had a standard work-up for chronic gastrointestinal disease. Endoscopically obtained intestinal biopsies were submitted for histopathologic and molecular investigations. Biopsies were screened for MAP-specific DNA by 3 polymerase chain reaction (PCR) methods (nested, seminested, and triplex real-time PCR). Samples from control dogs were obtained during necropsy.
Results: Histopathology of the biopsies was indicative of inflammatory bowel disease (IBD) in 17 and neoplasia in 6 dogs. Six dogs showing nonspecific changes responded to diet and were classified as having food-responsive enteropathy. In 13 dogs a final diagnosis was not established. MAP-specific DNA was detected and confirmed by sequencing in 8 dogs (19%). These dogs were diagnosed with food-responsive enteropathy (n = 3), IBD (n = 2), and open diagnosis (n = 3). MAP-specific DNA was not detected in dogs with no gastrointestinal disease.
Conclusions and clinical importance: MAP-specific DNA was detected in approximately one fifth of dogs with chronic gastrointestinal disease and might play a role as a pathogenic agent. Apart from animal welfare, the zoonotic aspect warrants further studies addressing the viability of MAP organism in canine intestinal biopsies by culture.     

Comparison of clinical history and dermatologic findings in 29 dogs with severe eosinophilic dermatitis: a retrospective analysis

The medical records and histopathological sections of 29 dogs diagnosed with a unique eosinophilic dermatitis resembling Wells' syndrome were reviewed in an attempt to elucidate the pathogenesis of this syndrome. The medical records were reviewed for information on dermatological lesion appearance, systemic signs in other organ systems, clinical analyte abnormalities, and drug therapy. Histological sections of dogs with moderate to severe eosinophilic dermatitis without folliculitis and furunculosis were reviewed and evaluated for the presence of collagen flame figures. Three categories of patients were found. Category 1 consisted of 17 dogs treated for vomiting and/or diarrhoea (often haematochezia or haematemesis) prior (mean: 4.6 days) to the onset of skin lesions. Fourteen category 1 dogs had erythematous lesions (macules, papules or plaques) that were most pronounced on the abdomen. Sixteen of the 17 dogs received multiple classes of drugs, and 59% were hypoalbuminemic. Category 2 consisted of five dogs that had skin lesions and gastrointestinal signs at presentation and four of these dogs were hypoalbuminemic. Category 3 included seven dogs without enteric illness. A positive drug score was found in six category 1 dogs and one each from categories 2 and 3. Eighteen cases had eosinophilic dermatitis without flame figures, seven cases had early flame figures and four had well-developed flame figures. These changes did not correlate with the categories of clinical presentation. More than 50% of the dogs developed eosinophilic dermatitis following treatment for severe gastrointestinal disease. The authors propose that this represents a unique syndrome that may have causal drug association.     

Clinical laboratory evaluation of deep mycotic diseases in dogs

A retrospective study of 27 dogs with deep mycoses was conducted to evaluate the usefulness of initial laboratory results in determining a diagnosis. Fifteen cases of disseminated blastomycosis, five cases of disseminated histoplasmosis and seven cases of gastrointestinal phycomycosis were studied. Haematologic results consistent with a chronic inflammatory disease (mild to moderate anaemia and moderate to marked monocytosis) were common findings in blastomycosis and phycomycosis. Cases of histoplasmosis were characterized by a more severe anaemia with a neutrophilia and left shift. The severe anaemia present in three out of five (3/5) dogs with histoplasmosis was apparently due to myelophthisis and intravascular erythrocyte fragmentation. Coagulation function tests and/or the haemograms suggested the presence of microangiopathic haemolysis in four dogs with histoplasmosis. Clinical chemistry results in blastomycosis and phycomycosis were usually unremarkable. Hepatic lesions in histoplasmosis were suggested by increases in serum alkaline phosphatase and decreases in serum albumin. Cytology was frequently diagnostic for blastomycosis (11/13 cases) and histoplasmosis (3/4 cases) but was inconsistent in phycomycosis (1/3 cases).     

Severe gastrointestinal bleeding secondary to lornoxicam in the dog

Six dogs with lornoxicam induced severe gastrointestinal bleeding are described. The ingested dose ranged between 0.5 - 5.1?mg/kg BW (median 0.63?mg/kg BW). The severity of the bloodloss anemia was moderate to severe with PCV values ranging between 12 - 27 % (median 16 %) and serum albumin concentrations between 12 - 22 g/l (median 16 g/l). One dog had evidence of chronic thrombocytopathia over 13 days and clinicopathologic findings of gastrointestinal bleeding over 55 days. None of the dogs developed kidney injuries. The clinical condition required transfusion of blood products in 5 of 6 cases. One dog with a perforated duodenal ulcer and septic peritonitis survived until discharge but had to be euthanized later on due to recrudescent clinical signs (hematemesis, melena). The median length of hospitalisation was 12 days (5 - 14). No correlation was seen between the ingested dose and severity of clinical signs. Lornoxicam ingestion leads to severe and longlasting gastrointestinal bleeding in the dog and requires immediate intensive therapy.     

Relationship of disease progression and plasma histamine concentrations in 11 dogs with mast cell tumors

Plasma histamine concentrations (PHCs) were measured serially over 9 months or until death in 11 dogs with mast cell tumors (MCTs). Eight dogs had grossly visible disease and the other 3 dogs had microscopic disease. Initial PHCs in the dogs with gross disease were significantly higher than PHCs in healthy dogs (median, 0.73 ng/mL and 0.19 ng/mL respectively; P < .009), whereas initial PHCs in dogs with microscopic disease showed no difference from controls. Seven dogs subsequently had progressive increases in PHC, and developed hyperhistaminemia (median, 14.0 ng/mL; range, 5.11-30.1 ng/nL). These 7 dogs died from MCTs, and 1 had general weakness with rapid lysis of a large tumor burden after radiation therapy. PHCs of the other 4 dogs were less than 1 ng/mL during the study. These 4 dogs were still alive with adequate control of the tumor at the conclusion of the study. Four of the 11 dogs initially had gastrointestinal (G1) signs, which abated soon after administration of histamine-2 (H-2) blockers. No significant difference was found between PHCs in dogs with GI signs and those without GI signs (median, 0.86 ng/mL and 0.35 ng/mL. respectively). Thereafter, 7 dogs had serious GI complications for which H-2 blocker therapy was ineffective. PHCs in these 7 dogs were extremely high (median, 12.2 ng/mL; range, 3.42-30.1 ng/nL). Results of this study demonsrated that PHC was one factor related to disease progression, and indicated that marked hyperhistaminemia was associated with the GI signs refractory to H-2 blocker therapy in dogs with MCTs.     

Chronic active hepatitis in 26 Doberman pinschers

Chronic active hepatitis with increased hepatic copper concentration was diagnosed in 25 female and 1 male Doberman Pinscher dogs. Common clinical signs included polyuria/polydipsia, weight loss, anorexia, icterus, and ascites. Increased liver enzyme activities and abnormal liver function test results were the most consistent clinicopathologic changes. The dogs were assigned to 3 groups on the basis of clinical course of the disease. Group 1 dogs (n = 12) had clinical signs of advanced liver failure and died within one week. Group 2 dogs (n = 7) had less severe clinical signs of liver disease and died within one month. Group 3 dogs (n = 5) did not have clinical signs of illness or had mild clinical signs of liver disease and died 1 to 42 months after initial evaluation. One dog could not be reevaluated and another dog was alive 3 months after initial examination. Treatments consisted of supportive care for dogs in group 1, and dietary manipulations and corticosteroids for dogs in groups 2 and 3. The association of increased liver copper concentration and chronic active hepatitis is not known.     

Risk factors associated with outcome in dogs with tetanus: 38 cases (1987-2005)

OBJECTIVE: To assess the clinical course of disease and risk factors associated with outcome in dogs with tetanus. DESIGN: Retrospective case series. ANIMALS: 38 dogs with tetanus. PROCEDURES: Data were collected from medical records of dogs with tetanus, including signalment; wound characteristics; initial clinical signs; severity of worst clinical signs; time to wound management, antimicrobial treatment, and antitoxin administration; and 28-day survival rate. Statistical analyses were performed to evaluate relationships between the potentially predictive variables and disease progression and outcome. RESULTS: The 28-day survival rate was 77% (among 35 uncensored dogs). The most common initial clinical signs in affected dogs were ocular (n = 18) and facial (11) abnormalities. Nineteen dogs progressed to recumbency with severe muscle spasms, and 14 dogs had high or low heart rate or blood pressure values. Eight dogs died or were euthanized because of complications of tetanus. There was a significant association between younger age and development of more severe clinical signs. Furthermore, a significant inverse relationship between development of severe clinical signs and survival was identified. There was no association between earlier initiation of wound management, antimicrobial administration, or antitoxin administration and either progression of signs or 28-day survival rate. Wound type was not associated with 28-day survival rate. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that younger dogs with tetanus may be more likely to develop severe clinical signs. The prognosis for survival in dogs with tetanus is good if abnormalities in heart rate or blood pressure values do not develop.     

Doppler ultrasonographic changes in the canine kidney during normovolaemic anaemia

The haemodynamics of the canine left renal artery (LRA) and interlobar artery (ILA) were evaluated in eleven fasted, healthy, conscious beagles with severe acute (haematocrit [Hct] 16%), moderate chronic (Hct 26%) and mild chronic (Hct 34%) normovolaemic anaemia using Doppler ultrasound. Heart rate, peak systolic velocity (PSV), end diastolic velocity (EDV), time-averaged mean velocity (TAVmean), pulsatility index (PI) and resistive index (RI) were recorded. Doppler values in the dogs following the induction of anaemia states were compared with corresponding values in the same dogs prior to the induction of anaemia. Left renal artery mean PSV, mean PI and mean RI were significantly higher and the mean EDV was significantly lower in severe acute anaemia. No significant change was seen in mean values of the same parameters in moderate or mild chronic anaemia. There was no significant change in TAVmean of the LRA or mean PI and mean RI of the ILA in any grade of anaemia. Acute, severe normovolaemic anaemia significantly altered LRA Doppler parameters in resting dogs without influencing those of the ILA. Moderate or mild chronic anaemia had no effect on any renal Doppler parameter.     

Splenic Infarction in 16 Dogs: A Retrospective Study

Sixteen dogs with splenic infarction due to causes other than splenic torsion were identified. Dogs with splenic infarction often had multiple concurrent diseases, and surgical management of splenic infarction was associated with high mortality. Splenic infarction occurred in dogs with hypercoagulable conditions associated with liver disease, renal disease, and hyperadrenocorticism, or as a consequence of uniform splenomegaly, neoplasia, or thrombosis associated with cardiovascular disease. Clinical signs and common laboratory findings generally reflected the underlying disease process. A variety of splenic abnormalities were detected by abdominal ultrasound in 15 dogs, with the ventral extremity of the spleen being most often abnormal. Four dogs were euthanized or died because of the presence of severe systemic disease, whereas 12 dogs underwent laparotomy. Complete splenectomy was performed in 9 dogs and partial splenectomy was performed in 2 dogs. Seven dogs died in the immediate postoperative period, 3 required chronic veterinary care, and 2 had uncomplicated long-term recoveries. Splenic infarction should be regarded as a sign of altered blood flow and coagulation, rather than as a primary disease, and surgical management should be reserved for patients with life-threatening complications such as hemoabdomen or sepsis.     

Autoimmune haemolytic anaemia in dogs

The clinical, haematological and immunological findings in 24 dogs with Coombs' positive haemolytic anaemia are described; 33% were Old English Sheepdogs. Dogs with intravascular haemolysis had a shorter history of illnesses, more severe clinical signs including vomiting, jaundice and fever, and had a poor survival rate compared to dogs with extravascular haemolysis. The anaemia was severe and regenerative in 18 dogs, and was characterised by spherocytosis and microscopic red cell agglutination, with leukocytosis. Serum IgG levels were elevated in 20 dogs, and changes in IgM, IgA, C3 and C4 were found. Antinuclear antibody was also demonstrated in 13 dogs, of which 7 were Old English Sheepdogs. It is suggested that a distinct multisystem autoimmune syndrome exists within the local Old English Sheepdog population.     

Serial monitoring of clinical, haematological and immunological parameters in canine autoimmune haemolytic anaemia

Clinical, haematological and immunological data are presented from 14 dogs with autoimmune haemolytic anaemia (AIHA) serially monitored for up to 945 days after initial presentation. At the time of diagnosis, all dogs had severe anaemia (mean packed cell volume [PCV] 17.6±7.1 per cent) with leucocytosis in seven cases and thrombocytopenia in four dogs. The Coombs' test was positive in all cases. Immunoglobulin G (IgG) autoantibody alone was identified in eight cases, a combination of IgG and IgM autoantibodies was recognised in three cases, and in two dogs only IgM autoantibody was recorded (complement fixing in one of these dogs). All dogs were treated with immunosuppressive doses of corticosteroids and some animals also received cyclophosphamide (four cases), azathio-prine (two cases), blood transfusion (four cases) or underwent splenectomy (two cases). Two dogs died during the initial episode of AIHA. In 12 dogs, the anaemia was resolved by an average of 36.3 ±16.0 days after initial presentation, but autoantibody titre often persisted after clinical improvement and normalisation of PCV. Four dogs had a clinical relapse 67 to 170 days after initial presentation and one of these dogs subsequently died from thromboembolic disease. One dog developed lymphocytic thyroiditis and serum antinuclear antibody at day 691 after initial presentation, and two cases developed disease consistent with autoimmune thrombocytopenia (AITP) at 365 and 618 days post initial presentation. In one of these dogs, AITP was concurrent with multicentric lymphoma. No correlation was recorded between haematological and immunological parameters at presentation and subsequent response to therapy or long-term clinical behaviour.     

Canine monocytic ehrlichiosis presenting as acute blindness 36 months after importation into the UK

A four-year-old Labrador retriever developed sudden-onset blindness, associated with bilateral uveitis, intraocular haemorrhage and retinal detachment. It had been imported into the UK from Sardinia 36 months before presentation. Haematological abnormalities included non-regenerative anaemia, thrombocytopenia and neutropenia. Serum and urine protein electrophoresis demonstrated a monoclonal gammopathy. An immunofluorescent antibody test for Ehrlichia canis was positive, with a titre of 1:320, confirming a diagnosis of chronic monocytic ehrlichiosis. This case highlights how the prolonged subclinical phase of monocytic ehrlichiosis could enable infected dogs to enter the UK without signs of disease. Chronic monocytic ehrlichiosis should be considered in dogs which have been imported from E canis-endemic countries and present with bleeding disorders and gammopathy, even if signs develop many years after importation.     

Evaluation of endoscopically obtained duodenal biopsy samples from cats and dogs in an adapter-modified Ussing chamber

This study was conducted to evaluate an adapter-modified Ussing chamber for assessment of transport physiology in endoscopically obtained duodenal biopsies from healthy cats and dogs, as well as dogs with chronic enteropathies. 17 duodenal biopsies from five cats and 51 duodenal biopsies from 13 dogs were obtained. Samples were transferred into an adapter-modified Ussing chamber and sequentially exposed to various absorbagogues and secretagogues. Overall, 78.6% of duodenal samples obtained from cats responded to at least one compound. In duodenal biopsies obtained from dogs, the rate of overall response ranged from 87.5% (healthy individuals; n = 8), to 63.6% (animals exhibiting clinical signs of gastrointestinal disease and histopathological unremarkable duodenum; n = 15), and 32.1% (animals exhibiting clinical signs of gastrointestinal diseases and moderate to severe histopathological lesions; n = 28). Detailed information regarding the magnitude and duration of the response are provided. The adapter-modified Ussing chamber enables investigation of the absorptive and secretory capacity of endoscopically obtained duodenal biopsies from cats and dogs and has the potential to become a valuable research tool. The response of samples was correlated with histopathological findings.     

Neurologic dysfunction in hypothyroid, hyperlipidemic Labrador Retrievers

BACKGROUND: Hypothyroidism has been associated with a variety of neurologic signs, but the mechanism for this association is not completely understood. Hypothyroidism also is associated with hyperlipidemia that predisposes to atherosclerosis, increased blood viscosity, and thromboembolic events. OBJECTIVE: The objective is to characterize neurologic signs potentially associated with hyperlipidemia and atherosclerosis in canine hypothyroidism. ANIMALS: This study used dogs referred to North Carolina State University Veterinary Teaching Hospital for evaluation of neurologic signs. MATERIALS AND METHODS: A retrospective study was conducted in which medical records of dogs with neurologic signs and a diagnosis of hypothyroidism and hyperlipidemia were reviewed. Details of the history, presenting signs, results of routine blood tests, thyroid tests, cerebrospinal fluid (CSF) analysis and diagnostic imaging, and response to therapy were compiled. RESULTS: Three Labrador Retrievers and one Labrador Retriever cross fit the inclusion criteria. All dogs were hypothyroid and severely hyperlipidemic. Neurologic signs included tetraparesis, central and peripheral vestibular signs, facial paralysis, and paraparesis. Two dogs had an acute history and rapid resolution of signs consistent with an infarct, the presence of which was confirmed in 1 of the dogs by magnetic resonance imaging. Two dogs had chronic histories of cranial neuropathies and paraparesis. One of these dogs had evidence of iliac thrombosis and atherosclerosis on ultrasound examination. All dogs improved with thyroid hormone supplementation. CLINICAL RELEVANCE: Labrador Retrievers may be predisposed to the development of severe hyperlipidemia in association with hypothyroidism. One possible consequence of severe hyperlipidemia is the development of neurologic signs due to atherosclerosis and thromboembolic events.     

Inherited copper toxicosis in the Bedlington terrier: a report of two clinical cases

The clinical signs, laboratory findings and pathological changes are described in two cases of inherited copper toxicosis in the Bedlington terrier. The first case presented with acute signs of depression, vomiting, anorexia, weight loss and jaundice while the second case followed a more chronic course with less severe clinical signs which included weight loss and ascites. Both dogs had elevated circulating levels of alanine aminotransferase (ALT), however other haematological and biochemical parameters, while reflecting liver involvement, varied between the two cases. Chemical analysis of the liver revealed elevated copper levels in both cases (951·7 and 1093·4 μg/g wet weight respectively; normal less than 150 μg/g). These levels, however, are less than some affected but asymptomatic Bedlington terriers. Pathologically the first case had micronodular cirrhosis, while the second had focal hepatitis with fibrosis. Both dogs showed vacuolation of the white matter in the cerebrum, cerebellum, midbrain and medulla. Attention is drawn to the similarities and differences between copper toxicosis in the Bedlington terrier and Wilson's disease in man.