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.     

Cutoff value of 1 h, 50 g glucose challenge test for screening of gestational diabetes mellitus in a Japanese population

A total of 2651 consecutive native Japanese women who underwent a glucose challenge test (GCT) were retrospectively investigated. GCT was performed between 24 and 27 weeks of gestation; each subject received a 50 g oral glucose load without regard to the fasting or fed state, followed by a determination of 1 h venous plasma glucose level. Women demonstrating GCT exceeding 130 mg/dl received a 75 g, 2 h oral glucose tolerance test to determine whether or not they had gestational diabetes mellitus (GDM). All women with GDM were treated with a strict diabetic protocol including insulin therapy. Forty-nine (1.8%) women were diagnosed to have GDM. The receiver-operator characteristic curve identified a GCT finding above 140 mg/dl as the cutoff value for detecting GDM, which showed a sensitivity and specificity of 96 and 76%, respectively. Our results suggest that the cutoff value of a 50 g GCT is 140 mg/dl to identify pregnancies with GDM in a Japanese population.     

Targeting oncogenic interleukin‐7 receptor signalling with N‐acetylcysteine in T cell acute lymphoblastic leukaemia

Activating mutations of the interleukin‐7 receptor (IL7R) occur in approximately 10% of patients with T cell acute lymphoblastic leukaemia (T‐ALL). Most mutations generate a cysteine at the transmembrane domain leading to receptor homodimerization through disulfide bond formation and ligand‐independent activation of STAT5. We hypothesized that the reducing agent N‐acetylcysteine (NAC), a well‐tolerated drug used widely in clinical practice to treat acetaminophen overdose, would reduce disulfide bond formation, and inhibit mutant IL7R‐mediated oncogenic signalling. We found that treatment with NAC disrupted IL7R homodimerization in IL7R‐mutant DND‐41 cells as assessed by non‐reducing Western blot, as well as in a luciferase complementation assay. NAC led to STAT5 dephosphorylation and cell apoptosis at clinically achievable concentrations in DND‐41 cells, and Ba/F3 cells transformed by an IL7R‐mutant construct containing a cysteine insertion. The apoptotic effects of NAC could be rescued in part by a constitutively active allele of STAT5. Despite using doses lower than those tolerated in humans, NAC treatment significantly inhibited the progression of human DND‐41 cells engrafted in immunodeficient mice. Thus, targeting leukaemogenic IL7R homodimerization with NAC offers a potentially effective and feasible therapeutic strategy that warrants testing in patients with T‐ALL.     

Alteration of the Intestinal Environment by Lubiprostone Is Associated with Amelioration of Adenine-Induced CKD

The accumulation of uremic toxins is involved in the progression of CKD. Various uremic toxins are derived from gut microbiota, and an imbalance of gut microbiota or dysbiosis is related to renal failure. However, the pathophysiologic mechanisms underlying the relationship between the gut microbiota and renal failure are still obscure. Using an adenine-induced renal failure mouse model, we evaluated the effects of the ClC-2 chloride channel activator lubiprostone (commonly used for the treatment of constipation) on CKD. Oral administration of lubiprostone (500 µg/kg per day) changed the fecal and intestinal properties in mice with renal failure. Additionally, lubiprostone treatment reduced the elevated BUN and protected against tubulointerstitial damage, renal fibrosis, and inflammation. Gut microbiome analysis of 16S rRNA genes in the renal failure mice showed that lubiprostone treatment altered their microbial composition, especially the recovery of the levels of the Lactobacillaceae family and Prevotella genus, which were significantly reduced in the renal failure mice. Furthermore, capillary electrophoresis–mass spectrometry-based metabolome analysis showed that lubiprostone treatment decreased the plasma level of uremic toxins, such as indoxyl sulfate and hippurate, which are derived from gut microbiota, and a more recently discovered uremic toxin, trans-aconitate. These results suggest that lubiprostone ameliorates the progression of CKD and the accumulation of uremic toxins by improving the gut microbiota and intestinal environment.     

A father and son with Turcot's syndrome: Evidence for autosomal dominant inheritance

Typical Turcot's syndrome is characterized by the association of a brain glioma together with multiple colonic polyposis, in which the number of polypoid lesions is small and the association of colonic cancer occurs at a younger age than in familial adenomatous polyposis. We describe a family in which both the father and his son presented with typical Turcot's syndrome without parental consanguinity. This is the first report of a family that is considered to follow an autosomal dominant inheritance. After reviewing 25 documented cases in which the average age of death was 20.3 years old, it was learned that the major cause of death was brain tumor (76 percent) and the minor cause was colon cancer (16 percent). Patients were very young and, therefore, unlikely to have produced a child before their death. These facts seem to support the theory that Turcot's syndrome is an autosomal dominant disorder.     

Hepatic Circulation and Hepatic Oxygen Consumption in Alcoholic and Nonalcoholic Fatty Liver

The purpose of this study was to determine the differences in hepatic circulation and oxygen consumption in two groups: those with nonalcoholic obesity-related fatty live and those with alcoholic fatty liver. Although the histological degree of fatty infiltration was equal in the two groups, the delta Er569-650, as an index of the regional liver blood flow estimated by spectrophotometric method, was significantly lower in alcoholic fatty liver than in nonalcoholic fatty liver, and the in vivo hepatic oxygen consumption (VO2), also determined by hepatic reflectance spectrophotometry during peritoneoscopy, tended to be lower in alcoholic fatty liver than in nonalcoholic fatty liver. The oxygen saturation of hemoglobin in local liver blood (SO2) was, however, significantly higher in alcoholic fatty liver than in nonalcoholic fatty liver. These results suggest that an increase in oxygen extraction to maintain oxygen consumption, which was indicated by the lowering of the SO2, was not found in alcoholic fatty liver, in spite of a reduction of oxygen supply to the liver. It is concluded that the impairment of hepatic circulation and hepatic oxygen consumption was more serious in alcoholic fatty liver than in nonalcoholic fatty liver, possibly contributing to a different prognosis for the two forms of fatty liver.     

Disseminated tuberculosis following reduced-intensity cord blood transplantation for adult patients with hematological diseases

Allogeneic hematopoietic stem cell transplantation (allo-SCT) recipients are prone to infections. The incidences of mycobacterial infections after allo-SCT in several case series vary from less than 0.1-5.5%. However, no study has been published on tuberculosis following unrelated cord blood transplantation (UCBT). We retrospectively reviewed medical records of 113 adult patients with a median age of 54 years who underwent reduced-intensity UCBT (RI-UCBT) at Toranomon Hospital from March 2002 to May 2004. Mycobacterium tuberculosis infections were diagnosed in three patients (2.7%), of these two patients developed primary infection and one patient developed reactivation of latent tuberculosis. The interval between RI-UCBT and the diagnosis of tuberculosis was 34, 41 and 61 days. All the patients had disseminated disease at diagnosis. Histological examination showed the lack of granuloma in caseous necrosis. Combination antituberculous treatments showed limited efficacy, and two patients died immediately after diagnosis. M. tuberculosis caused life-threatening illness, rapidly progressing in RI-UCBT recipients. The lack of granuloma in caseous necrosis suggests the impaired T-cell function in early post transplant phase of RI-UCBT. We should consider M. tuberculosis in the differential diagnoses of fever of unknown source after RI-UCBT.