糖尿病及糖尿病心血管并发症患者肠道菌群的特征

【目的】比较2型糖尿病患者、糖尿病心血管并发症患者与健康人肠道菌群差异,分析肠道菌群与血糖、血脂等临床指标的关联,探讨肠道细菌在2型糖尿病、糖尿病心血管并发症发生、发展中的作用。【方法】招募健康人251例、糖尿病心血管并发症患者160例及糖尿病患者295例,三组各随机选取30例、30例和40例,进行血液生化指标分析和肠道菌群的宏基因组检测。【结果】与健康对照组比较,糖尿病心血管并发症组和2型糖尿病组血清丙氨酸氨基转移酶、碱性磷酸酶、甘油三酯、空腹血糖、胰岛素、糖化血红蛋白指标显著升高(P0.05);糖尿病患者组、糖尿病心血管并发症患者组的肠道菌群α-多样性明显降低,菌群发生改变。健康对照组中大部分优势菌属来自拟杆菌门和厚壁菌门,而糖尿病心血管并发症患者组和糖尿病患者组中大部分优势菌属则来自拟杆菌门、变形菌门和放线菌门。与健康对照组相比,糖尿病心血管并发症患者组和糖尿病患者组中,厚壁菌门比例明显下降,放线菌门和变形菌门比例明显上升。种水平上,空腹血糖与黏膜乳杆菌(Lactobacillus mucosae)、大肠埃希氏菌(Escherichia coli)、脆弱拟杆菌(Bacteroides fragilis)呈正相关,与细枝真杆菌(Eubacterium ramulus)、Roseburia inulinivorans、Roseburia hominis、挑剔真杆菌(Eubacterium eligens)、伶俐瘤胃球菌(Ruminococcus callidus)呈负相关;低密度脂蛋白胆固醇与嵴链球菌(Streptococcus cristatus)呈正相关,与Lachnospiraceae bacterium_6_1_63FAA和淀粉乳杆菌(Lactobacillus amylovorus)呈负相关;总胆固醇与血链球菌(Streptococcus sanguinis)呈正相关。【结论】2型糖尿病和糖尿病心血管并发症患者存在明显的糖脂代谢异常和肠道菌群失调,肠道菌群紊乱可能在糖尿病发病、进展过程中发挥重要作用。     

Prolactin and zinc in dialysis patients

The objectives of the present study were to investigate the frequencies of hyperprolactinemia and hypozincemia in patients undergoing hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD), the associations between blood levels of zinc (Zn²⁺) and hormones, and dietary zinc intake amount and its relation to zincemia. We studied 28 patients (14 HD and 14 CAPD) who had their blood levels of Zn²⁺, prolactin (PRL), parathyroid hormone (PTH), and gonadotropins (LH, FSH) evaluated. Thirteen patients had dietary nutrient amounts evaluated from a 3-d nutritional record. Hyperprolactinemia occurred in 29% patients (HD = CAPD), hypozincemia in 62% (20% HD and 42% CAPD), and low dietary Zn²⁺ intake in 90% of patients. No correlation among blood concentration of Zn²⁺ and PRL, PTH, LH, and FSH were observed in the two modalities of dialysis or between zincemia and Zn²⁺ ingestion. We concluded that the occurrence of hyperprolactinemia and hypozincemia were not related to dialysis modality and that zincemia did not reflect the observed low dietary intake of Zn²⁺.     

Immunodeficiency in cancer patients and immunorestoration

Summary Immunodepression in cancer patients appears to be a complex phenomenon with various possible mechanisms. Some explanations are reported according to the relationships between the host and the tumor; however, the causes of the impairment still remain unknown. Whatever the origins of the dysfunction may be, a better approach for a more efficient treatment would be to understand at which level the nature of the immunodeficiency arises and at which level the immunorestoration occurs.     

Helicobacter pylori-induced immunological responses in patients with duodenal ulcer and in patients with cardiomyopathies

The interaction between the bacteria and the host is a key factor determining the clinical consequences of H. pylori infection. The immune system plays an important role in either promoting or preventing the disease. The mucosal production of TNF-alpha, IL-6, IL-8 and IL-10 and the CagA status were investigated in H. pylori-positive patients with duodenal ulcer (DU). The concentrations of these cytokines in gastric antral mucosal specimens from patients infected with H. pylori (n = 40) were determined by ELISA and compared with data on mucosal specimens from H. pylori-negative patients (n = 12). The local TNF-alpha, IL-6 and IL-8 concentrations in the antral biopsy samples were significantly higher (p < 0.001) in the patients infected with H. pylori than in the samples from the H. pylori-negative subjects. CagA positivity was demonstrated in 39 (97.5%) of the 40 patients with DU, and in 41 (70.7%) of H. pylori-positive (58 of 100) healthy blood donors. In complementary studies focusing on extragastric disease, it was found that 57% of patients with ischaemic heart disease were seropositive as concerns H. pylori, and 91% of them had antibodies against human heat shock protein 60, too. This study suggests that, besides the bacterial virulence factor, the host response of an increased mucosal production of inflammatory cytokines can be relevant to the gastric pathophysiology in H. pylori-induced DU. At the same time, in ischaemic heart diseases the role of autoimmune processes induced by H. pylori cannot be excluded.     

ABCB1 genotypes and haplotypes in patients with dementia and age-matched non-demented control patients

Amyloid β is an in vitro substrate for P-glycoprotein (P-gp), an efflux pump at the blood brain barrier (BBB). The Multi Drug Resistance (ABCB1) gene, encoding for P-gp, is highly polymorphic and this may result in a changed function of P-gp and may possibly interfere with the pathogenesis of Alzheimer's disease. This study investigates to what extent ABCB1 Single Nucleotide Polymorphisms (SNPs; C1236T in exon 12, G2677T/A in exon 21 and C3435T in exon 26) and inferred haplotypes exist in an elderly population and if these SNPs and haplotypes differ between patients with dementia and age-matched non-demented control patients. ABCB1 genotype, allele and haplotype frequencies were neither significantly different between patients with dementia and age-matched controls, nor between subgroups of different types of dementia nor age-matched controls. This study shows ABCB1 genotype frequencies to be comparable with described younger populations. To our knowledge this is the first study on ABCB1 genotypes in dementia. ABCB1 genotypes are presently not useful as a biomarker for dementia, as they were not significantly different between demented patients and age-matched control subjects.     

A new dental unit for both patients in wheelchairs and general patients

Objective: To develop a dental unit to accommodate both patients in wheelchairs and general patients, and to evaluate the acceptability of the new chair for patients and dentists. Design: To integrate a unit for patients in wheelchairs and a unit for general patients into a single dental unit. Results: (1) The newly developed dental unit could be used for both patients in wheelchairs and general patients and could be installed in nearly the same space as occupied by a conventional dental unit. (2) The dentists could take the home position because of the height‐adjusting and tilting mechanisms. (3) The patients could be treated with a sense of assurance because of the wheelchair immobilizer and the safety devices. (4) The dentists could perform patient treatment safely. (5) As patients did not need to be transferred from their wheelchairs, assistance was unnecessary. (6) From the questionnaires, both patients and dentists rated the newly developed dental unit favourable. Conclusions: The new dental unit for patients in wheelchairs and general patients permitted dentists to perform and patients to receive dental treatment safely and in a comfortable position. Also, as a single unit could be used for treatment of both types of patients, it required no extra space. Therefore, it has the potential to be installed in the clinics of general dental practitioners to treat both groups of patients.     

Post-proline cleaving enzyme in human cerebrospinal fluid from control patients and parkinsonian patients

PPCE activity was found in human CSF by using a HPLC-fluorescence method. PPCE activity in CSF from control patients without neurological diseases was 2.19 +/- 0.78 (mean +/- SD) pmole (hr)-1.(ml)-1. PPCE activity in CSF from patients with Parkinson's disease was significantly decreased while PPCE activity in serum did not change significantly.     

Cytokines correlate with age in healthy volunteers, dialysis patients and kidney-transplant patients

T-cell functions are currently used as biomarkers for the pharmacodynamic monitoring of immunosuppressive drugs or as disease biomarkers of inflammation/sepsis and organ rejection. In order to evaluate co-factors potentially influencing the expression of the immunological biomarkers, we explored T-cell proliferation, T-cell activation (CD25 and CD71 expressions) and intra-lymphocyte cytokine production (interleukin (IL)-2 and tumor necrosis factor (TNF)-α) in healthy volunteers, dialysis patients and stable kidney-transplant patients treated with standard immunosuppressive therapy, i.e. tacrolimus, mycophenolic acid with or without steroids. Age was positively correlated with TNF-α expression in all three patient populations, and with IL-2 expression in healthy volunteers and kidney-transplant patients. Further age was correlated with inhibition of lymphocyte proliferation in healthy volunteers and with the T-cell activation marker CD25 in kidney-transplant patients. In healthy volunteers lymphocyte proliferation was higher in woman as compared to men. Other biomarkers of T-cell function were independent of the gender. In the kidney-transplant patient group a significantly lower expression of all biomarkers of T-cell functions compared to healthy volunteers and dialysis patients. In dialysis patients we found significant increased IL-2 expression compared to healthy volunteers, while the other T-cell functions were not significantly different. Further time on dialysis had no effect on the level of biomarker expression. In conclusion we found decreased T-cell functions in kidney-transplant patients compared to healthy volunteers and dialysis patients, increased IL-2 expression in dialysis patients compared to healthy volunteers and in all three populations we found a correlation of age and intra-T-lymphocyte TNF-α expression.     

Taste- and odor-reactivity in elderly demented patients

Previous studies demonstrated that hedonically different chemical(taste or smell) stimuli induceinnate, inherited, differentialand distinct fixed reflectory motion features in the oral andfacial area. In the present study 20 elderly demented patients,suffering from ‘probable’ or ‘possible’Alzheimer's disease, and 20 normally functioning elderly subjectswere tested. The facial expressive behavioral reactions triggeredby a set of common gustatory and olfactory stimuli were videotaped.Both psychophysical and stimulus-dependent behavioral responseswere obtained from the control group, while for the dementedpatients only behavioral reactions were recorded. Results revealedthat: (i) severely demented elderly subjects displayed differentialand distinct orofacial responses indicating ‘acceptance’and ‘aversion’. These were found to be analogousto but less intense than those displayed by control age mates;(ii) the duration of responses induced by aversive tastes islonger than that triggered by pleasant or indifferent ones,for both groups; (iii) all gustatory and olfactory stimuli triggera longer lasting behavioral response in demented than in normalsubjects; and (iv) psychophysical and behavioral responses ofthe control subjects gave similar results for taste- and odor-hedonicsas well as for their intensity. This finding clearly indicatesthe validity of the alternative use of psychophysical and behavioraltesting procedures.     

Multicentric and localized tineas in immunocompromised patients

From the dermatological point of view, multifocal or multicentric tineas are widespread dermatophytic infections affecting two or more anatomical areas. In the immunosuppressed patient, these lesions are frequently atypical and the risk factors are not well established. The aims of this study were: to determine the risk factors associated to multicentric tinea in immunocompromised patients; to evaluate the immune response by trichophytin and candidin skin test, to determine the etiological agent and to quantify some serum interleukines. Thirty-six multicentric tinea and 37 localized tinea patients, both with immunocompromised factors, were included. By means of a questionnaire several risk factors were identified; the trichophytin and candidin skin test was evaluated after 48 hours. Mycological direct examination and culture were performed. The interleukins IL-2, IL-4, IL-10 and interferon gamma were quantified by ELISA. Statistical analysis was made by Chi-square, U Mann Whitney and logistic regression. In disseminated tinea patients a predominance of females (69%) versus localized tinea patients (30%) was observed. Prednisone, azathioprine and cyclophosphamide treatment was associated to multicentric tinea. Trichophytin was negative in all disseminated tinea patients and positive in only three localized tinea cases, candidin was positive in six and eight cases of multicentric and localized tinea respectively. Trichophyton rubrum was the most frequent etiological agent. No differences in interleukin concentrations were found. Female gender and some immunosuppressor treatments were associated with a high probability to develop multicentric tinea. In this study a defect in the cellular immune response was the possible explanation for the extensive reactions.     

Fasting and differential chemotherapy protection in patients

Chronic calorie restriction has been known for decades to prevent or retard cancer growth, but its weight-loss effect and the potential problems associated with combining it with chemotherapy have prevented its clinical application. Based on the discovery in model organisms that short term starvation (STS or fasting) causes a rapid switch of cells to a protected mode, we described a fasting-based intervention that causes remarkable changes in the levels of glucose, IGF-I and many other proteins and molecules and is capable of protecting mammalian cells and mice from various toxins, including chemotherapy. Because oncogenes prevent the cellular switch to this stress resistance mode, starvation for 48 hours or longer protects normal yeast and mammalian cells and mice but not cancer cells from chemotherapy, an effect we termed Differential Stress Resistance (DSR). In a recent article, ten patients who fasted in combination with chemotherapy, reported that fasting was not only feasible and safe but caused a reduction in a wide range of side effects accompanied by an apparently normal and possibly augmented chemotherapy efficacy. Together with the remarkable results observed in animals, these data provide preliminary evidence in support of the human application of this fundamental biogerontology finding, particularly for terminal patients receiving chemotherapy. Here we briefly discuss the basic, pre-clinical and clinical studies on fasting and cancer therapy.Key words: fasting, cancer, chemotherapy, calorie restriction, stress resistanceAfter decades of slow progress in the identification of treatments effective on a wide range of malignancies, cancer treatment is now turning to personalized therapies based in part on pharmacogenomics. By contrast, aging research is moving in the opposite direction by searching for common ways to prevent, postpone and treat a wide range of age-related diseases, based on the modulation of genetic pathways that are conserved from yeast to mammals.¹ In fact, it may be a solid evolutionary and comparative biology-foundation, which makes this ambitious goal of biogerontologists a realistic or at least a promising one. On the other hand, the progress of biogerontology is viewed by many clinicians as too fundamental and far from translational applications. In most cases, it is not clear how aging research will be translated into FDA approved drugs or treatments that have effects that are superior to those already available or being developed. For example, it is not clear how the long-term 20–30% reduction in calorie intake (dietary restriction, DR) that we and many others before us have shown to be effective in extending the life span of model organisms will make humans live longer or healthier.^1–3 Furthermore, despite the fact that long-term DR was confirmed to reduce cancer and cardiovascular disease in monkeys⁴ and to be effective in preventing obesity, type 2 diabetes, inflammation, hypertension and atherosclerosis, as indicated by the early results in humans studies,⁵ it is highly unlikely to be adopted in its more extreme and effective version by even a small portion of the population. For example, the 20 to 40% chronic reduction in daily calorie intake shown to be effective in retarding cancer growth in mice would not be feasible for cancer therapy for multiple reasons: (1) the effects of chronic DR in patients with a clinically evident tumor is expected to delay but not stop the progression of the disease^6–8 and this delay may only occur for a portion of the malignancies,⁹ (2) although weight loss and cachexia in the early stages of treatment are less prevalent than commonly thought,^10–12 the ∼15% loss of BMI and ∼30% long-term loss of body fat caused by a moderate (20%) calorie restriction¹³ may be tolerated by only a very small portion of cancer patients receiving treatment, (3) Because this long-term restriction is accompanied by delayed wound healing and immunologic impairment in rodents,^1,14,15 it is not clear what risks it may impose on cancer patients receiving treatment.¹⁶ Our studies of DSR, which were triggered by our fundamental findings that switching yeast cells to water protected them against a wide range of toxins, started as a way to address these concerns but also as an attempt to achieve a much more potent therapeutic effect than that achieved by DR.^17,18 Because starvation-induced protection can increase many fold when combined with modulation of pro-aging pathways and since it is in principle blocked by the expression of any oncogene, it has the potential to provide a method to allow common chemotherapy to selectively kill cancer cells, independently of the type of cancer.^19–21 The DSR experiments in mammals were also based on our hypothesis that stress resistance and aging regulatory pathways were conserved from yeast to mammals.We found that fasting for 48 or more hours or in vitro starvation conditions that mimic fasting protected mice and/or normal cells but not cancer cells from various chemotherapy drugs and other deleterious agents.²¹ This effect was shown to depend in part on the reduction of circulating IGF-I and glucose levels.^21,22 Although a differential regulation of cell division in normal and cancer cells^23,24 is likely to contribute to DSR, much of it appears to be dependent on protective systems which are normally maintained in an inactive or low activity state even in non-dividing cells.^1,25 In fact, in non-dividing yeast and mice, deficiencies in glucose or IGF-I signaling that match those observed after starvation promote resistance to doxorubicin, a chemotherapy drug that specifically targets muscle cells in the heart.^21,22As expected, many clinicians were skeptical of our hypothesis that cancer treatment could be improved not by a “magic bullet” but by a “not so magic DSR shield” as underlined by Leonard Saltz, an oncologist at Memorial Sloan-Kettering Cancer Center: “Would I be enthusiastic about enrolling my patients in a trial where they''re asked not to eat for 2.5 days? No.”²⁶ However, ten oncologists did allow their patients, suffering from malignancies ranging from stage II breast cancer to stage IV esophageal, prostate and lung malignancies to undergo a 48–140 hours pre-chemotherapy and a 5–56 hours post chemotherapy water-only fast. The six patients who received chemotherapy with or without fasting reported a reduction in fatigue, weakness and gastrointestinal side effects while fasting²⁷ (Fig. 1). A trend for a reduction of many additional side effects was also reported by the group of patients who always fasted before chemotherapy.²⁷ In those patients whose cancer progression was assessed, chemotherapy was effective and in some cases it was highly effective.²⁷ A clinical trial sponsored by the V-Foundation for Cancer Research, aimed at testing the safety and efficacy of a 24 hour fast in combination with chemotherapy, is in its safety stage. Because it was originally limited to patients diagnosed with bladder cancer the clinical trial progressed slowly. However, its recent expansion to include patients receiving platinum-based chemotherapy (breast, ovarian, lung cancer), is expected to expedite it. Conclusive results for the effect of a 3–4 day fast on chemotherapy-dependent side effects and possibly therapeutic index are not expected to become available for several years. Even if a more modest effect than the 1,000-fold differential protection against oxidative stress and chemotherapy observed in normal and cancer-like yeast cells was achieved in humans, this method could result in long-term survival for many patients with metastatic cancers, particularly those in which malignant cells have not acquired multidrug resistance.Open in a separate windowFigure 1Average self-reported severity of symptoms in patients that have received chemotherapy with or without fasting.     

P-glycoprotein polymorphism in hypo- and hyper-thyroidism patients

P-glycoprotein (Pgp) is encoded by the multidrug resistance gene (MDR1) in humans and is the product of MDR1. It is expressed in various tissues and is related to drug distribution in intestinal erythrocytes, capillary endotel of brain, proximal tubules cells of kidneys and liver canalicular cells. Expression of Pgp is affected by Pgp polymorphism, and exon 26 C3435T polymorphism is the most common one. It has been thought that expression of Pgp is high in C-allele subjects and this situation is responsible for the resistance against some drugs and substances. Pgp may have a role in the distribution of thyroid hormones, drugs used for hypo- and hyperthyroidism and the resistance occurred. For this purpose possible relationship between T and C alleles and frequency of Pgp polymorphism as well as thyroid hormone distribution in patients with hypo- and hyperthyroidism was investigated. Thirty five hyperthyroidism patients diagnosed as Graves’ disease, 78 hypothyroidism patients diagnosed as Hashimoto’s thyroiditis and 100 healthy volunteers were included in the study. According to the results obtained no statistically significant difference was found in Pgp C3435T polymorphism between hypo- and hyperthyroidism patients. In addition, the serum free T3 levels of hyperthyroidism patients with C alleles was higher than those of subjects with T alleles. No statistically significant difference was seen in the CC, CT and TT genotype frequencies between the patients and control groups. In conclusion, it seems that Pgp polymorphism is not a predictor factor for the occurrence of hypo- and hyperthyroidism. There is a significant relationship between Pgp and the elevated serum free T3 levels of hyperthyroidism patients, and further research will help understand this situation.     

Clinical and electrophysiologic findings in dialysis patients

The aim of this study was to quantitatively determine the electrophysiologic changes occurring in the peripheral nerves and muscles in patients with chronic renal failure (CRF) treated with haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD), and to determine which electrophysiologic parameters are most commonly abnormal in uraemic patients. We investigated the relationship between the parameters of neurography and quantitative electromyography (QEMG) and clinical findings.The study included 42 patients with CRF (30 on HD and 12 on CAPD). Nerve conduction studies (NCSs) of the median, ulnar, tibial, peroneal, and sural nerves, and QEMG of the tibialis anterior and biceps brachii muscles were performed.We found axonal and/or demyelinating polyneuropathies in 97.6% of the patients (100% of HD and 91.7% of CAPD patients), but were not able to verify any significant differences between the HD and CAPD patients using NCS or QEMG. Median, ulnar, sural sensory nerve action potential (SNAP) amplitudes, peroneal CV and F-latency were the most common abnormal parameters in sensory and motor NCSs, respectively. The clinical findings only correlated with the parameters of neurography, and not with the parameters of QEMG. Sural SNAP amplitudes, peroneal and tibial CVs, F-latencies also correlated with the severity of the clinical findings in these patients, suggesting that these parameters can be used in follow up studies in these patients.In this study, most of the uraemic patients were found to have already mild or moderate neuropathies in which the objective clinical signs might be absent, even if they have some clinical symptoms. NCS showed abnormality indicating polyneuropathy in 24 out of 25 patients with clinical neuropathy signs and in 17 out of 17 patients with no clinical signs. Thus, in subclinical conditions NCS is useful to detect the abnormalities in peripheral nerves of the ureamic patients under chronic dialysis.