Construction and validation of a scoring system to predict resistance to chemotherapeutic drugs using gene expression profiles in canine lymphoma.

The present study aimed to verify the changes in the expression levels of 13 candidate genes associated with chemotherapy resistance and to construct a scoring system to predict resistance to these drugs. The expression levels of the 13 candidate genes were compared between 20 dogs with lymphoma that were sensitive to drugs used in CHOP-based protocol and 16 dogs with lymphoma that were resistant to these drugs. The expression levels of six genes; ASNS, CCR3, CALCA, FCER1A, LOC448801, and EDNRB were significantly different between the two groups. A scoring system to predict resistance to cyclophosphamide, doxorubicin and vincristine, which are used in CHOP-based protocol, was constructed based on expression levels of the six genes in these 36 dogs using logistic regression models. After internal validation, sensitivity and specificity of the scoring system were 0.759 and 0.853, respectively. External validation was conducted in another cohort of 33 dogs with lymphoma, and sensitivity and specificity of the scoring system were 0.800 and 0.696, respectively. In conclusion, this study identified six genes associated with resistance to drugs used in CHOP-based protocol in canine lymphoma and proposed a novel scoring system to predict resistance to these drugs. This system might be beneficial in selecting the most appropriate chemotherapy protocol for individual dogs with lymphoma.

[Two elderly patients with sarcoidosis and Sjögren's syndrome].

Two elderly patients with sarcoidosis complicated with Sjögren's syndrome are described. Case 1: A 70-year-old woman was admitted due to dry eyes. Histological examination of a minor salivary gland specimen revealed lymphocytic infiltration, which was compatible with Sjögren's syndrome. Because uveitis was demonstrated, transbronchial lung biopsy (TBLB) was performed, to confirm a diagnosis of lung sarcoidosis. Histological examination of TBLB showed non-caseating granulomas compatible with sarcoidosis. Case 2: A 70-year-old woman was admitted due to dyspnea on exercise and blurred vision. Two years previously, Sjögren's syndrome was diagnosed because of a positive Shirmer test and positive SS-A antibody. Result of ophthalmic examination were compatible with uveitis. Histological examination of TBLB showed non-caseating granulomas compatible with sarcoidosis. Certain similarities between sarcoidosis and Sjögren's syndrome in terms of immunological aspects have attracted attention. In the present manuscript, a possible relationship between the two diseases as well as the characteristics of elderly sarcoidosis are discussed.

Electrically stimulated induction of hsp70 gene expression in mouse astroglia and fibroblast cells.

Mouse astroglial cells, which were cultured on an electrode, were found responsive to an electric stimulation of sine wave potential in enhancing hsp70 mRNA resulting from an activation of hsp70 gene expression. On the basis of this finding, electrically responsive cells were established by transfecting mouse 3T3-L1 cells with a constructed plasmid encoding hsp70 promoter and the firefly luciferase gene. A stable cell line has been established through selection of heat-stimulated luciferase expression. A 1-h electric stimulation of the cells resulted in activation of luciferase expression, which was confirmed to produce an increase in light emission. The sequential pattern of the electrically stimulated expression of luciferase was found different from that of the heat stimulation. Furthermore, the promoter was activated depending on the potential and duration of the stimulation applied. Consequently, the electric stimulation has proven effective on activating hspP70 promoter. This cell line is feasible in expressing the gene of interest by electrical stimulation, which lead us to construct environment responsive cells in general.

[A clinical study of serum IgE concentrations in elderly patients with bronchial asthma and chronic obstructive pulmonary disease].

We tested the hypothesis that serum IgE concentrations may be influenced by the severity of respiratory symptoms, impairment of pulmonary functions, and smoking history in elderly patients with bronchial asthma and/or chronic obstructive pulmonary disease (COPD). A total of 325 elderly outpatients aged over 65 years were enrolled in the study: 112 (22 men, 90 women) with bronchial asthma (BA), 135 (118 men, 17 women) with COPD, and 78 (56 men, 22 women) with both COPD and asthma (COPD/BA). The mean ages for the 3 groups were 74.3,76.0 and 76.6 years, respectively; the age differential was not significant. As a group, the male subjects displayed higher serum IgE concentrations than the female subjects. Also, ex-smokers and current smokers showed higher serum IgE concentrations than patients who had never smoked, and patients in the BA group had higher serum IgE concentrations than those in the COPD or COPD/BA groups. Although serum IgE concentrations were increased in BA patients with decreased FEV1.0 levels, the reverse was observed in the COPD patients. Peripheral blood eosinophil counts for men and women were higher in the BA group than in the COPD group. A positive correlation between serum IgE concentration and eosinophil count was observed in the BA group. Although bronchial asthma and COPD in the elderly have been considered to be pathologically similar, the findings of our study suggested they are probably different in terms of serum IgE concentration, pulmonary function, and smoking history.

[Clinical epidemiology of chronic obstructive pulmonary disease].

Chronic obstructive pulmonary disease (COPD) is more important as a cause of morbidity than as a cause of mortality but estimates of its frequency and distribution are inadequate and incomplete. According to annual report of World Health Organization, in 1998 there were estimated to be 52.2 millions deaths in the world, among them 2.9 millions were due to respiratory diseases and almost of them were COPD. Estimates of prevalence COPD vary depending on the diagnostic criteria used, the age and sex composition of the population, their exposure to cigarette smoke and possibly to other harmful environmental influences. In the present review, we discuss the problems arising in the data of morbidity and mortality of COPD in Japan.

Cerebrospinal fluid nitric oxide metabolites in painful diseases.

To elucidate the involvement of NO in pain transmission in humans, we measured NO metabolites (nitrite/nitrate) in the CSF of patients with painful diseases using an NO analyzer based on the Griess method. The nitrite/nitrate levels in patients with degenerative lumbar disease (DLD), but not those with fracture or appendicitis, were significantly higher than those in an age-matched control group. The duration of pain in the DLD group was much longer than that in the fracture or appendicitis group. The nitrite/nitrate levels in the middle-aged and elderly DLD patients depended on the duration of pain. These data probably suggest that the duration of pain is critical for the elevation in nitrite/nitrate levels.

[Interstitial pneumonitis associated with Sweet's syndrome in the elderly].

Sweet's syndrome occurring during the course of interstitial pneumonitis in a 70-year-old woman was encountered. She was admitted because of dyspnea on exercise, dry cough and interstitial shadow on chest x-ray. Lung biopsy, together with other findings confirmed interstitial pneumonitis. Five days after admission, genital ulcer and aphtha on the oral mucosa were detected and exudative erythema appeared on her right shoulder, chest and back. Histological examination of the skin lesions demonstrated numerous nutrophilic infiltration in the upper dermis, indicating Sweet's syndrome. The skin eruption rapidly disappeared on treatment with colchicine. Although six months after admission interstitial pneumonitis caused respiratory failure, treatment with prednisolone and cyclophosphamide was effective. Serological and immunological tests demonstrated hyper-gammaglobulinemia and positive reaction for anti SS-A antibody. Pathological examination of the lip revealed numerous lymphocyte infiltrates around the duct of the minor salivary gland, suggesting Sjögren's syndrome as the background disease of Sweet's syndrome and interstitial pneumonitis. This evidence indicating that even in elderly patients, skin lesions of Sweet's syndrome may reveal the background disease.

[An adult case of bacterial meningitis caused by penicillin-resistant Streptococcus pneumoniae with gene mutations of penicillin binding proteins].

A 62-year-old Japanese male developed acute bacterial meningitis. Administration of ABPC, CDZM, INH, and RFP was started. The causative bacteria was identified as penicillin-resistant Streptococcus pneumoniae (PRSP) 3 days later. We changed ABPC to PAPM/BP and the bacterial meningitis improved dramatically. Measurement of minimum inhibitory concentration (MIC) of the bacterial strain from CSF and blood showed that it is susceptible to PAPM/BP and RFP. Mechanism of drug resistance is considered to be gene mutations of penicillin binding protein (PBP) that decreases drug affinity to PBP. Recently penicillin resistance of Streptococcus pneumoniae has been found to be associated with mutations of pbp-2b, 1a genes and the cefem resistance of that is with those of pbp-2x, and 1a genes. By PCR (polymerase chain reaction) analysis we identified the mutations of pbp-1a, 2x, and 2b genes of the isolated strain of Streptococcus pneumoniae. We emphasize the importance of detection of pbp gene mutations for the diagnosis of PRSP infections.

Aspergillus endocarditis in a leukemia patient diagnosed by a PCR assay.

A patient in a blastic phase of chronic myelocytic leukemia developed multiple arterial emboli that originated from mitral valve vegetation. The diagnosis of infective endocarditis was not confirmed because blood cultures, serological assays and other examinations detected no pathogens. He died of intracranial hemorrhage after thrombolytic manipulation for embolization of the abdominal aorta and an autopsy was performed. Polymerase chain reaction analysis and Southern blot analysis of tissues from the mitral valve revealed Aspergillus species as the cause of the endocarditis, although none of the tissue specimens were culture-positive. These molecular analyses will be useful in the diagnosis of various types of Aspergillus infections.

A case of silent 21-hydroxylase deficiency with persistent adrenal insufficiency after removal of an adrenal incidentaloma.

A case of an adrenal incidentaloma in a 57-year-old man with silent 21-hydroxylase deficiency is reported. Abdominal computed tomography revealed a right adrenal tumour of 6cm in diameter. There was no evidence of adrenal hormone excess. However, after surgical removal of the adrenal tumour, the patient developed acute adrenal insufficiency. Adrenocortical function has remained low ever since surgery. Pathological examination of the tumour revealed a cortical adenoma. On the basis of increased plasma renin activity and serum 17 alpha-hydroxyprogesterone concentration and decreased 21-hydroxylase activity of the adenoma tissue, the patient was diagnosed as having systemic 21-hydroxylase deficiency. There are two possible mechanisms for the persistent adrenal insufficiency; first the residual left adrenal gland may have been originally hypo-functioning for some reason and, second, the left gland may have lost the ability to regenerate following prolonged suppression by the adenoma. In cases of adrenal incidentalomas with 21-hydroxylase deficiency, the indications for surgical removal should be carefully considered.

DNA analysis of two patients with a non-fluorescent Y chromosome.

Results of DNA study on two patients of gonadal dysgenesis with a 45,X/46,X,Ynf (non-fluorescent Y chromosome) karyotype are described. In one patient who developed gonadoblastoma, all 12 loci on the non-fluorescent part of Yq were detected. Another patient did not have gonadoblastoma at 20 years, and only the proximal 6 loci out of 12 were detected.

[Acute autonomic and sensory neuropathy associated with galactorrhea-amenorrhea syndrome and intractable anorexia].

Acute autonomic and sensory neuropathy (AASN), one subtype of acute pandysautonomia, in which dorsal root ganglia and autonomic ganglia are involved is uncommon. Little is so far known on central nervous system involvement in AASN. In the present paper we described a rare case of AASN associated with the central nervous system manifestations such as galactorrhea-amenorrhea syndrome and intractable anorexia. A 30-year-old woman rapidly developed burning pain and numbness in her arms and legs as well as orthostatic syncope. She had severe anorexia and no no menstruation from onset. On physical examination, she was emaciated. There was marked orthostatic hypotension with tachycardia. Skin was dry. Moderate galactorrhea was detected. Neurological examination showed prominent paresthesia and dullness of superficial sensation, predominantly to pinprick and thermal stimuli, segmentally over the neck, occipital scalp, and extremities. Deep sensation was intact. She had no weakness or ataxia. Deep tendon reflexes were almost normal. NCV and SEP were normal, while EEG was abnormal. Sural nerve biopsy demonstrated axonal degeneration with the loss of myelinated, predominantly in small-caliber fibers, and unmyelinated fibers. The levels of HVA and MHPG in CSF were decreased. The autonomic nervous function tests revealed postganglionic dysfunction. alpha-adrenergic system was predominantly impaired, while beta-adrenergic system was relatively preserved. The endocrinological studies demonstrated mild or moderate elevation of PRL basal value and hyper-response of PRL and LH for TRH and LH-RH loading test, which suggested disorder of the hypothalamo-hypophysial system. Cranial MRI showed moderate dilatation of the 3rd ventricle.(ABSTRACT TRUNCATED AT 250 WORDS)

[Subacute sensory neuropathy manifestated by tonic pupils associated with small cell carcinoma of the lung].

Only a few cases of carcinomatous neuropathy with tonic pupils have been reported. In the present paper we described a 53-year-old woman with subacute sensory neuropathy who had presented with bilateral tonic pupils. She noticed numbness over the medial aspect of the left thigh in March, 1988, and then developed dysesthesia over the left forearm and hand, mild weakness of left upper and lower extremities and urinary disturbance. Neurological symptoms were subacutely progressive and she was bed-ridden in May. She was admitted to our hospital in June, 1988. On examination, she had body-weight loss of 6 kg during the last six months and general status was otherwise unremarkable. She had anisocoria; the left pupil was larger in daylight than the right, while smaller in dim light. The left pupil scarcely reacted to light, but promptly constricted to near vision. The right pupil constricted normally to light and near vision. An instillation of 0.0625% pilocarpine solution showed supersensitive response of both pupils. An instillation of 1.25% epinephrine solution demonstrated mild dilation of both pupils. Thus, it was conceivable that she had postganglionic ciliary nerve damage characteristic of tonic pupil as well as the lesion of sympathetic nerve innervating pupillary dilator. She had severe sensory ataxia and pseudoathetosis of the hands. Weakness was mild to moderate in extremities. Almost all deep tendon reflexes were absent. All modalities of sensation, particularly on deep sense, were severely involved with sea-level-type distribution below Th7, and over C2 to C3 regions on the left side.(ABSTRACT TRUNCATED AT 250 WORDS)

High prevalence of proliferative retinopathy in diabetic patients with low pancreatic B-cell capacity.

A retrospective study on the role of pancreatic B-cell insulin secretory capacity in the development of proliferative diabetic retinopathy was performed in 160 diabetic patients with a duration of diabetes of more than 10 years (mean 19.5 +/- 7.9 years). Pancreatic B-cell insulin secretory capacity was assessed in terms of the quantity of C-peptide excreted into urine per day (24-h urinary C-peptide). When the patients were divided into three groups according to the quantity of 24-h urinary C-peptide (group I, C-peptide less than 30 micrograms, n = 49; group II, 30 micrograms less than or equal to C-peptide less than 80 micrograms, n = 76; and group III, C-peptide greater than or equal to 80 micrograms, n = 35), the prevalence of proliferative diabetic retinopathy was much higher in group I (26.5%) than in group II (5.3%) or group III (2.9%). The incidence of proliferative diabetic retinopathy during the follow-up period (mean 9.8 +/- 4.8 years) was also highest in group I (20.0%, 2.7%, and 2.9% in groups I, II, and III, respectively). Other factors which might affect the development of proliferative diabetic retinopathy, including duration of diabetes and past glycemic control, were comparable in these three groups. In contrast, a division of the patients according to glycemic control revealed a strong correlation between glycemic control and background diabetic retinopathy whereas no such correlation was apparent with proliferative diabetic retinopathy. These data are consistent with the view that low pancreatic B-cell insulin secretory capacity may be a risk factor for the development of proliferative diabetic retinopathy.

Deletion of a single chromosome band 4q26 in a malformed girl: exclusion of Rieger syndrome associated gene(s) from the 4q26 segment.

We report a malformed girl with a single chromosome band deletion of 4q26 in peripheral lymphocytes. This patient is the fourth case reported with an interstitial deletion involving 4q26 and has the smallest deletion of those reported. Deletion mapping indicates that psychomotor retardation, coloboma, prominent forehead, epicanthus, broad based nose, and broad, thin upper lip are associated with monosomy 4q26, and that gene(s) associated with Rieger syndrome can be excluded from the 4q26 segment.

Deletion (13)(q13q14.3) with retinoblastoma: confirmation and extension of a recognisable pattern of clinical features in retinoblastoma patients with 13q deletion.

A girl with retinoblastoma and a del(13)(q13q14.3) is presented. This case helps to confirm and extend our previous observations regarding a recognisable facial pattern in retinoblastoma patients with 13q deletion involving 13q14 and its adjacent segments.

Mitotic figures of glial fibrillary acidic protein-positive cells in the periphery of human brain abscess.

It has been unclear until now as to whether human astrocytes proliferate through mitosis or through amitosis, and little attention has been paid to the biological meaning of glial cell division. We examined an autopsy case of a 53-year-old man who died of brain abscesses and have found GFAP-positive mitotic cells in the zone between the abscess cavity and the reactive gliosis. The results suggest that human normal astrocytes which act in response to the brain abscess proliferate the process of mitosis, and become reactive to repair the lesions.

Problems of trace elements and vitamins during long-term total parenteral nutrition: a case report of idiopathic intestinal pseudo-obstruction.

An 8-year-old girl with chronic idiopathic intestinal pseudo-obstruction (CIIP), who is the first case of CIIP in Japan, has been receiving total parenteral nutrition (TPN) for more than 6 years. During this time, she experienced deficiencies of copper, zinc, vitamin A, vitamin B12, folic acid, and biotin, and an excess of vitamin A; she exhibited a series of signs and symptoms due to these deficiencies and vitamin A overdosage. Nevertheless, careful monitoring of serum levels of trace elements and vitamins and appropriate therapy have almost solved these problems. She has achieved normal physical and mental development and goes to school, while receiving home parenteral nutrition with an ambulatory infusion system.