A significant imbalance in mitosis versus apoptosis accelerates the growth rate of sessile serrated adenoma/polyps

Sessile serrated adenoma/polyps (SSA/Ps) of the colon are thought to be precursors of sporadic carcinomas. Although it is suggested that SSA/P may grow rapidly from the early stage, its cell kinetics remains obscure. To solve this problem, we analyzed the mitotic and apoptotic activity of normal crypts, microvesicular hyperplastic polyps (MVHPs), and tubular adenomas (TAs), using phospho-histone H3 and cleaved caspase 3 immunohistochemistry. The mitotic index for SSA/Ps (mean, 5.63) and TAs (6.98) was significantly higher than those for normal crypts (2.72) and MVHPs (2.86). Of all tested lesions, the apoptotic index was lowest for SSA/Ps (0.96; normal, 2.71; MVHPs, 2.62; TAs, 6.01) with statistically significant differences. The net growth ratio was close to 1.0 in normal crypts (1.07) while remaining low in MVHPs (1.06) and TAs (1.38), but was markedly elevated in SSA/Ps (7.32, P?<?0.01) due to the large imbalance between mitosis and apoptosis. As to apoptosis regulatory proteins, expression of anti-apoptotic Bcl-2 was significantly reduced or undetectable in MVHPs and SSA/Ps, while TAs showed stronger staining than normal crypts. Expression of pro-apoptotic Bax and its activators, Bim and Bad, was significantly reduced in MVHPs and SSA/Ps. We suggest that other complex mechanisms may act synergistically with Bax, Bim, or Bad deficiency to regulate apoptosis suppression in SSA/Ps.     

Characteristics of Japanese subjects who progress from normal to impaired glucose tolerance. Longitudinal study excluding changes in body weight

In this retrospective longitudinal study, we focused on the clinical characteristics of Japanese individuals with recent onset impaired glucose tolerance (IGT) who have been followed up for insulin secretory function and 75-gram oral glucose tolerance test (OGTT) for more than 3 years annually before they progressed from normal glucose tolerance (NGT) to IGT. Subjects whose body weight did not show significant change for the period were selected and labeled as either NGT (no change in OGTT over 3 years) or IGT (progressors from NGT to IGT) groups (n = 24, each). We compared the basal biochemical data and response of plasma glucose and serum insulin after OGTT of the two groups. In the IGT progressors, significant increase of plasma glucose at 30 to 120 minutes during OGTT and significant decrease of HDL-cholesterol were observed since 3 years before onset of IGT. In addition to increase of serum glucose and decrease of HDL-cholesterol, serum insulin at 120 minutes during OGTT were significantly and remarkably high at onset and 3 years before onset of IGT. Plasma glucose at 30-120 minutes and serum insulin level at 120 minutes after glucose load are potentially significant predictors of progression from NGT to IGT even in subjects who do not show increase of body weight.     

Prevalence,implication, and determinants of worsening renal function after surgery for congenital heart disease

Accumulating data in adults indicate the prognostic importance of worsening renal function (WRF) during treatment of acute heart failure. Venous congestion appears to play a dominant role in WRF; however, data regarding WRF in children with congenital heart disease (CHD) are limited. The present study was conducted to elucidate the prevalence and characteristics of WRF after surgery for CHD in children. We also tested our hypothesis that, similar to adult heart failure, venous congestion is an important determinant of WRF independent of cardiac output in this population. Fifty-five consecutive pediatric patients who underwent cardiovascular surgery for CHD were studied (median age 0.7 years; range 3 days to 17 years). The degree of WRF was assessed by the difference between the maximum levels of postoperative serum creatinine (Cr) and preoperative serum Cr. There was a high prevalence of WRF in the present cohort: an increase in Cr level was observed in 47 patients (85 %) and a Cr increase ≥0.3 mg/dL was seen in 23 (42 %). Importantly, WRF was significantly associated with a worse clinical outcome of a longer stay in the intensive care unit and hospital (both p < 0.05), even after controlling for age and operative factors. In addition, multivariate regression analysis revealed that central venous pressure, rather than cardiac output, was an independent determinant of WRF. Postoperative management to relieve venous congestion may help ameliorate or prevent WRF and thereby improve outcomes in patients with CHD.     

Clinical and genetic analysis in a family with familial renal glucosuria: Identification of an N101K mutation in the sodium–glucose cotransporter 2 encoded by a solute carrier family 5 member 2 gene

We report the identification of a mutation in the solute carrier family 5 member 2 (SLC5A2) gene, which encodes sodium–glucose cotransporter 2, in a family with familial renal glucosuria. The proband was a 26‐year‐old Japanese man referred to the diabetes division with repeated glucosuria without hyperglycemia. His mother, uncle and grandfather also had a history of glucosuria. A heterozygous missense mutation (c.303T>A:p.N101K) in SLC5A2 was identified in the patient and his mother, but not in 200 chromosomes from 100 healthy and unrelated individuals, or in 3,408 Japanese individuals in the Tohoku Medical Megabank. Furthermore, bioinformatics software predicted that this lesion would be pathogenic. We infer that the mutation led to clinically relevant sodium–glucose cotransporter 2 dysfunction. The patient showed no symptoms of hypoglycemia, but continuous glucose monitoring confirmed asymptomatic hypoglycemia.     

Association of sleep‐disordered breathing with decreased cognitive function among patients with dementia

Sleep is known to be essential for proper cognitive functioning. Sleep disturbance, especially respiratory disturbance during sleep, is a risk factor for the development of dementia. However, it is not known whether hypopnoea during sleep is related to severity of cognitive function in patients already diagnosed with dementia. Considering the high prevalence of sleep problems in aged people, it is important to determine if hypopnoea during sleep contributes to dementia. In addition, it would be desirable to develop a feasible method for objectively evaluating sleep in patients with dementia. For this purpose, a simple sleep recorder that employs single or dual bioparameter recording, which is defined as a type‐4 portable monitor, is suitable. In this study, a type‐4 sleep recorder was used to evaluate respiratory function during sleep in 111 patients with dementia, and data suggesting a possible relationship with cognitive function levels were examined. Multivariate logistic regression was used to investigate the association of severity of dementia with sleep‐disordered breathing, age, diabetes, dyslipidaemia and hypertension. It was found that the respiratory disturbance index was associated with severity of cognitive dysfunction in our subjects. Furthermore, patients younger than 80 years were more susceptible to lower cognitive function associated with sleep‐disordered breathing than patients 80 years old or over, because an increase in the respiratory disturbance index was associated with deteriorated cognitive function only in the former age group. These results suggest that proper treatment of sleep apnea is important for the preservation of cognitive function, especially in patients with early‐stage dementia.