Sézary syndrome showing a stable clinical course for more than four years after oral administration of etoposide and methotrexate

A 62-year-old woman was admitted because of leukocytosis, systemic lymph node swelling and erythroderma. Laboratory data disclosed a WBC count of 15,600/microliter (CD4-positive cells: 91%). CD25 and HTLV-1 were negative. A skin biopsy revealed the involvement of T cells. These data and findings were consistent with a diagnosis of Sézary syndrome. Although the patient was treated with 2 courses of CHOP, the leukocyte count did not decrease. We then treated the patient orally with etoposide (25 mg/day) and methotrexate (10 mg/week), and this resulted in reduction of the leukocyte count and lymph node swelling, and amelioration of the erythroderma. As Sézary syndrome is an extremely rare disease, it is worthwhile reporting cases like the present one, where therapy was successful.     

NAD(P)H oxidase plays a crucial role in PDGF-induced proliferation of hepatic stellate cells

The proliferation of hepatic stellate cells (HSCs) is a critical step in hepatic fibrogenesis. Platelet-derived growth factor (PDGF) is the most potent mitogen for HSCs. We investigated the role of nonphagocytic NAD(P)H oxidase-derived reactive oxygen species (ROS) in PDGF-induced HSC proliferation. The human HSC line, LI-90 cells, murine primary-cultured HSCs, and PDGF-BB were used in this study. We examined the mechanism of PDGF-BB-induced HSC proliferation in relation to the role of a ROS scavenger and diphenylene iodonium, an inhibitor of NAD(P)H oxidase. We also measured ROS production with the aid of chemiluminescence. We showed that PDGF-BB induced proliferation of HSCs through the intracellular production of ROS. We also demonstrated that HSCs expressed key components of nonphagocytic NAD(P)H oxidase (p22phox, gp91phox, p47phox, and p67phox) at both the messenger RNA and protein levels. Diphenylene iodonium suppressed PDGF-BB-induced ROS production and HSC proliferation. Coincubation of H2O2 and PDGF-BB restored the proliferation of HSCs that was inhibited by diphenylene iodonium pretreatment. Phosphorylation of the mitogen-activated protein kinase (MAPK) family constitutes a signal transduction pathway of cell proliferation. Our data demonstrate that NAD(P)H oxidase-derived ROS induce HSC proliferation mainly through the phosphorylation of p38 MAPK. Moreover, an in vivo hepatic fibrosis model also supported the critical role of NAD(P)H oxidase in the activation and proliferation of HSCs. In conclusion, NAD(P)H oxidase is expressed in HSCs and produces ROS via activation of NAD(P)H oxidase in response to PDGF-BB. ROS further induce HSC proliferation through the phosphorylation of p38 MAPK.     

Angiotensin II plays an important role in maintaining blood pressure in postmenopausal women receiving hormone replacement therapy

BACKGROUND: We investigated the role of angiotensin (Ang) II in maintaining blood pressure (BP) by administering a small dose of candesartan, an Ang II type 1 receptor antagonist, in postmenopausal women receiving long-term hormone replacement therapy (HRT). METHODS: A single dose of 2 mg of candesartan was administered orally to 13 normotensive postmenopausal women receiving HRT (continuous combined conjugated estrogen and medroxyprogesterone acetate orally; HRT group) and 13 normotensive postmenopausal women not receiving HRT (control group). Both BP and heart rate (HR) were measured at baseline and at 1, 2, 3, 4, 5, and 6 h after administration. Plasma renin activity (PRA) and Ang I, Ang II, and bradykinin concentrations were measured at baseline and 4 h after the administration of candesartan. RESULTS: Candesartan lowered the BP and raised the HR in both groups. However, the decrease in BP was significantly greater in the HRT group than in the control group (P < .05), whereas no significant difference in the change in HR was observed between the two groups. In the HRT group, significant increases were found in PRA, Ang I, and Ang II (all P < .05) and a significant decrease in bradykinin (P < .01) with candesartan treatment. In the control group, candesartan as associated with an increase in PRA (P < .05) but not in Ang I, Ang II, or bradykinin. CONCLUSIONS: Based on our study results, Ang II plays an important role in maintaining BP in normotensive postmenopausal women receiving HRT. Maintenance of BP may be dependent on the balance between the hypertensive effect of Ang II and the hypotensive effect of bradykinin.     

Calcitonin gene-related peptide modulates adrenal hormones in conscious dogs.

The effects of a small dose (2 pmol/kg) of human calcitonin gene-related peptide I on plasma renin activity and hormones, including, aldosterone, ACTH, cortisol, AVP and ANH, were investigated in 14 conscious dogs. In addition, we studied the effects of calcitonin gene-related peptide on aldosterone secretion when it is stimulated by angiotensin II and ACTH. An intravenous bolus injection of 2 pmol/kg of calcitonin gene-related peptide raised plasma renin activity (by 216%, p less than 0.05), ACTH (by 85%, p less than 0.05), AVP (by 89%, p less than 0.05), and ANH (by 36%, p less than 0.05). Despite the elevation of plasma renin activity, aldosterone was decreased (by 52%, p less than 0.05). Cortisol did not change significantly. Infusion of 1 pmol.kg-1.min-1 of angiotensin II produced an elevation of aldosterone (by 186%, p less than 0.01), which was completely inhibited by pretreatment with an injection of 2 pmol/kg of calcitonin gene-related peptide. On the other hand, aldosterone secretion stimulated by ACTH was not altered significantly by pretreatment with an injection of 2 pmol/kg of calcitonin gene-related peptide. These results suggest that calcitonin gene-related peptide inhibits aldosterone secretion, especially when aldosterone is stimulated by angiotensin II. In addition, calcitonin gene-related peptide may be involved as an endocrine modulator in the physiological control of other several hormones closely related to the hemodynamics.     

Abnormality of left ventricular sympathetic nervous function assessed by (123)I-metaiodobenzylguanidine imaging in patients with COPD

BACKGROUND: Cardiac and systemic autonomic nervous function may be impaired in patients with COPD. Few reports, however, have described sympathetic nervous function of the left ventricle (LV) in COPD patients. STUDY OBJECTIVE: To assess the LV sympathetic nervous function in patients with COPD using (123)I-metaiodobenzylguanidine (MIBG) imaging of the heart. DESIGN: Prospective comparison of (123)I-MIBG imaging results in COPD patients and normal subjects. PARTICIPANTS: Twenty-eight patients with COPD without manifest right ventricular overload and 7 volunteers without cardiopulmonary disease (control subjects). MEASUREMENTS: (123)I-MIBG imaging results and plasma norepinephrine concentration were compared between the COPD and control groups. In the COPD group, pulmonary function tests were performed and all subjects were interviewed about their symptoms. RESULTS: (123)I-MIBG uptake, assessed as the cardiac to mediastinal activity ratio in the delayed image, was significantly lower in the COPD group than in the control group (p < 0.05). (123)I-MIBG turnover, expressed as the washout rate (WR) of (123)I-MIBG from 15 to 240 min, was significantly higher in the COPD group than in the control group (p < 0.01). In the COPD group, patients with dyspnea showed lower cardiac to mediastinal activity ratios and higher WRs compared with patients who had mild dyspnea. The WR correlated negatively with the vital capacity/predicted value ratio, correlated negatively with the maximal voluntary ventilation volume/predicted value ratio, and correlated positively with the residual volume/total lung capacity ratio in the COPD group. The plasma norepinephrine concentration in COPD patients was higher than that in the control subjects. CONCLUSION: Patients with COPD have significant sympathetic nervous impairment of the LV myocardium as a result of generalized sympathetic overactivity.     

Evaluation of the relationship between linezolid exposure and hyponatremia

IntroductionAims of this study were (a) to assess the development ratio of hyponatremia during treatment with linezolid and (b) to evaluate the relationship between the risk of hyponatremia and linezolid exposure and patient background.MethodClinical data including linezolid serum concentrations and serum sodium values were collected at Toyama University Hospital and Kyorin University Hospital. Data from 89 patients were used for the analysis, and a nadir serum sodium level ≤130 mmol/L during the treatment with linezolid was defined as hyponatremia. Mann-Whitney's U test was used to evaluate the effects of the area under the time-concentration curve (AUC) of linezolid at the nadir sodium level, clinical characteristics (e.g. laboratory data), and baseline serum sodium levels on the development of hyponatremia.ResultsThe hyponatremia was occurred in 21 of 89 patients (23.6%). Data are compared for baseline and nadir serum sodium levels of patients with and without hyponatremia. In both groups, nadir serum sodium levels were significantly different from those of the baseline values (P < 0.05). The values of AUC_0-12, accumulated AUC, baseline serum sodium levels and age were significantly different between patients with and without hyponatremia (P < 0.05).ConclusionsLinezolid exposure, age, and baseline sodium levels were detected as the risk factors for linezolid-related hyponatremia. Our findings suggest that regular monitoring of serum sodium levels is desirable during treatment with linezolid, especially for the elderly and patients with low serum sodium levels before the start of linezolid administration.     

Sleep disordered breathing in patients with chronic obstructive pulmonary disease

Sleep-related disordered breathing (SDB) and its influence on desaturation were examined in stable COPD patients with waking SpO2 > 90%. With respiratory inductance plethysmography, thoracic-abdominal respiratory movements for all events with more than 4% desaturation were analyzed in 26 patients. Types of SDB were confirmed by full polysomnography. Irregular breathing induced desaturation, while stable respiration continued during some desaturation events. Three types of altered ventilation were observed: hypoventilation, paradoxical movement and periodic breathing. An unusual type of paradoxical movement, with normal airflow despite progressive desaturation, was observed in REM sleep. Patients were divided into desaturation (15 patients) and non-desaturation (11 patients) groups. Daytime arterial blood gas, lung function values, and 6-min walking distance did not differ. Awake, mode, maximum and minimum nocturnal SpO2 were lower in the desaturation group. SDB-induced desaturation events in the desaturation group were more frequent (9.2+/-3.5 vs. 1.8+/-2.2 times), a greater SpO2 decrease (11.4+/-7.1% vs. 5.2+/-2.1%) and longer duration (73.2+/-34.8 vs. 18.8+/-39.0 min). Patterns of SDB in the desaturation group were hypoventilation (74.4+/-23.4%), paradoxical movement (10.2+/-14.5%), periodic breathing (12.1+/-18.3%) and unclassified (5.8+/-11.2%). These results reveal that lower SpO2 and SDB influence nocturnal desaturation in stable COPD patients.