Intensive Therapy In Patients Research Articles

TREATMENT FOR ACUTE INTOXICATIONS WITH VENOMS: COBRA SNAKEBITES

Objective: to study the specific features of the clinical course of acute intoxications with venoms due to the bites of Naja (cobra) naja and Naja kaouthia and those of intensive therapy in patients with the severest forms of this condition. Subjects and methods. Two clinical cases of acute intoxications with venoms due to Naja naja and Naja kaouthia bites were examined. The specific features of their clinical picture over time, changes in clinical and biochemical indicators, blood gas composition, and acidbase balance, coagulogram readings, ECG and radiological findings were studied. Results. Acute intoxication with venoms due to serious cobrabites was found to be characterized by the development of toxicohypoxic encephalopathy, toxic myopathy with skeletal and respiratory muscle paresis to develop acute respiratory and cardiovascular failure, coagulopathy, and metabolic disorders. Specific therapy (with an anti-ophidic serum in one case) resulted in drastically worsening health conditions as fulminant acute respiratory distress syndrome. A package of intensive therapy measures should include actions based on general resuscitation approaches — maintenance of life support systems (breathing, blood circulation), anti-sensitizing therapy, correction of metabolic disturbances with substrate antihypoxants (cytofavin, reamberin), and antimicrobial therapy. Conclusion. In the severest acute intoxications due to cobra snakebites, specific therapy methods (with anti-ophidic serum) should be used with extreme caution and particular emphasis should be laid on the general resuscitation-based principles.

The streetlight effect--is there light at the end of the tunnel?

Autoimmune type 1 diabetes research and treatment are seemingly plagued with problems. Large and small, mostly well-thought out clinical studies and trials since the early 1980s have basically been negative. None of the treatments tested have reached clinical routine to replace current lifesaving insulin replacement therapy. A combination type of therapy to diminish the requirement for insulin is yet to be found. The chronic autoimmune disease at the time of clinical onset of type 1 diabetes has been the “winner” in all attempts made so far to stifle the disease process. The disease is also the “winner” over islet transplantation, a potential cure for diabetes. Islet transplantation research was drastically reduced after it was found that the so-called Edmonton protocol did not yield sustainable insulin independence despite short-term restoration of endogenous insulin production and glycemic stability (1). The Diabetes Control and Complications Trial (DCCT) study, well known to all, continues to underscore the importance of glucose control. The reduction in the risk of complications resulting from intensive therapy in patients with type 1 diabetes persisted at least for 4 years after the study was completed, despite increasing hyperglycemia (2). Notwithstanding progress in the overall diabetes management, we were all recently reminded of the fact that type 1 diabetes remains a deadly disease (3). Although mortality was the highest in patients with poorly controlled diabetes, it was reported that patients with type 1 diabetes with A1C of 6.9% or lower had a risk of death from any cause that was twice as high as the risk for matched control subjects (3). Against this background of an uphill battle, the current issue of Diabetes contains a Perspective by Battaglia and Atkinson entitled “The Streetlight Effect in Type 1 Diabetes” (4). In their Perspective, the authors put forward several remedies to …

Key elements of successful intensive therapy in patients with type 1 diabetes.

An intensified diabetes management approach (including increased education, monitoring, and contact with diabetes team) should be used for adolescents and also for younger children if glycaemic control is not achieved by insulin therapy. Treatment options may include increased frequency of injections (e.g. the patients on 2 bolus may require 3 or 4 bolus injections), change in the type of basal and/or bolus insulin depending on multiple times monitoring for adolescents and for younger children, and change to continuous subcutaneous insulin infusion pump therapy. Results of epidemiology of diabetes interventions and complications (EDIC) Research Group, where the Diabetes Control and Complications Trial patients were further followed up almost for a period of 7 years or more showed that intensive therapy significantly reduced and maintained glycated hemoglobin with relative risk reduction of microvascular complications in the intensive therapy group. In addition, intensive treatment reduced the risk of any cardiovascular disease (CVD) event by 42% and the risk of nonfatal myocardial infarction, stroke, or death from CVD by 57%. The reduction of microvascular and macrovascular events in the intensively-treated group persisted due to the “legacy effect” or “metabolic memory” of early intensive glycemic control. The main advantage of intensive insulin therapy is that it reduces the rate of diabetes complications, in the long run. Furthermore, it offers flexibility as the doses can be adjusted according to the activity and food consumed. The main disadvantage of intensive insulin therapy is the risk of hypoglycemia especially in type 1 diabetes mellitus and weight gain.

Intensive Therapy of Patients with Acetic Acid Poisoning Complicated by Shock

Objective: to evaluate the efficiency of the elaborated intensive therapy policy for acute acetic acid poisoning complicated by exotoxic shock. Subjects and methods. The results of treatment were analyzed in 72 patients admitted in 2008—2012 with severe acute acetic acid poisoning complicated by exotoxic shock. The patients were divided into 2 groups: 1) combination therapy added by an improved intensive therapy complex; 2) conventional therapy. All the patients underwent comprehensive clinical and laboratory examination. Results and discussion. Group 1 versus the study group showed 1.7-, 2.0-, and 2.4- fold increases in the reduction of free hemoglobin levels 12, 24, and 48 hours after applying the improved complex of intensive therapy, respectively. In Group 1, hemodynamic and acidbase balance parameters recovered much faster and the incidence of acute renal failure and mortality rates were 2.1 and 2.0 times lower than those in the comparison group. Conclusion. Incorporation of the agents that correct volemic disorders and improve microcirculation into intensive therapy for acute acetic acid poisoning can considerably reduce the time of shock emergence, prevent acute renal failure, and decrease mortality rates.

Value of novel agents and intensive therapy for patients with multiple myeloma

We conducted a retrospective evaluation of response and survival for 293 patients with multiple myeloma treated since June 2000 with primary thalidomide- or bortezomib-based combinations, of whom 207 patients received intensive therapy supported by autologous blood stem cells within the first year. Survival times were calculated after a landmark of 1 year from start of therapy, so that subsequent median survival was 8.9 years for patients with CR, 4.9 years for those with PR and 0.6 year for patients with NR (P<0.001). Multivariate analyses confirmed CR or PR as the major favorable factors with less impact on prognosis for age or disease stage. Both novel agents and high-dose therapy (HDT) resulted in high frequencies of PR or CR, with early HDT useful for many patients with NR or PR in improving response status and subsequent survival.

Do patients with head and neck human papillomavirus-related carcinoma need a different treatment approach?

We congratulate Mizumachi and colleagues [1] on their assessment of ‘‘Improved survival of Japanese patients with human papillomavirus-positive oropharyngeal squamous cell carcinoma’’. However, we would like to raise several points regarding the necessity of less intensive therapy for patients with human papillomavirus (HPV)associated carcinoma. Numerous case series have established that HPV-positive oropharyngeal cancers have unique demographic and clinical characteristics [2, 3]. The prevalence of HPVrelated oropharyngeal carcinoma is rising in Western Europe and the USA. However, this correlation (as Mizumachi et al. have shown) has not been fully evaluated in Japan [1]. Indeed, HPV-positive tumor status is an important prognostic factor associated with a favorable outcome. However, the optimal treatment for HPV-positive head and neck squamous cell carcinoma is not yet defined. Moreover, quality of life (QoL) is receiving increasing attention as a criterion for the assessment of different treatment modalities [4]. Broglie et al. recently reported that patients treated by either surgery alone or surgery with adjuvant radiotherapy complained significantly less about troubles with dry mouth, teeth and senses compared to the non-surgically treated group. Moreover, HPV-positive patients appeared to have a better QoL independent of treatment strategy. Therefore, the authors consider that these patients could tolerate more intensive treatment without impairment of QoL [4]. Nevertheless, Lassen et al. [5] have recently reported that long-term morbidity was influenced neither by fractionation schedule nor by tumor HPV/p16 status in patients undergoing accelerated fractionated radiotherapy. In our opinion, although HPV-positive patients may have a better treatment tolerance, ‘‘less-intensive treatment’’ should be administered based on an understanding of the treatmentrelated risk factors that are independently associated with late swallowing complications (such as the volume of pharynx irradiated and radiation dose) [6, 7]. For example, patients with low volume stage III–IV disease (T1–2 and N1–2a/b) could be spared from aggressive multimodal treatment. It would therefore be interesting to corroborate these results in Japan too. Mizumachi et al. [1] have interestingly shown that patients in Japan with HPV-positive oropharyngeal cancers have a better prognosis than those with HPV-negative carcinomas. These results are consistent with those obtained in Europe and North America. However, to date there is insufficient data to justify a change in the treatment strategies for HPV-positive oropharyngeal cancer outside of clinical trials. From this point of view, these authors mention that HPV status should at least be included as a stratification factor into future randomized controlled trials to optimize the treatment of patients with this type of cancer in Japan [1]. J. Cacicedo Fernandez de Bobadilla (&) P. Bilbao Radiation Oncology Department, Cruces University Hospital, c/Plaza de Cruces s/n, 48903 Barakaldo, Vizcaya (Basque Country), Spain e-mail: jon.cacicedofernandezbobadilla@osakidetza.net

Long-acting insulin analogues—are benefits worth the cost?

Controlled clinical trials have demonstrated a substantial reduction in all long-term complications of type 1 diabetes mellitus (T1DM) if an HbA1c level of <7% is achieved. Long-acting insulin analogues have now been developed; however, their role in the intensive therapy of patients with T1DM is debatable.

The impact factor analysis and prevention on insulin pump intensive therapyfor patients with hypoglycemia

[Objective]To investigate the factors and preventive measures of insulin pump treatment for the patients with hypoglycemia.[Methods]386 cases with insulin pump intensive therapy were admitted in our hospital from Octc ber 2008 to October 2011,they were randomly divided into control group (194 cases) and observation group (192cases),the observation group was treated with preventive measures while the control group was not given preventive measures,and the differences of the incidence of hypoglycemia in the two groups were observed.[Results]The incidence of hypoglycemia in the observation group was 8.85％ significantly lower than 1,that of the conrrol group (5.98％) (P＜ 0.05);in the impact factors,the incidence of the insulin pump and sports dietary in the observation group were 0％,significandy lower than 29.03％ and 32.26％ of the control group (P＜ 0.05); in the course of the disease and the combined factors of complications,there were no statistical differences between the two groups (P ＞ 0.05).[Conclusion]There are many factors affecting the incidences of hvpoglycemia,it should take targeted prevention measures in the clinical to avoid the unnecessary factors. Key words: Insulin pump; Hypoglycemia; Impact factors; Prevention

Treatment of Diffuse Large B-Cell Lymphomas

Abstract 2684 Introduction:diffuse Large B-cell lymphoma (DLBCL) are aggressive but potentially curable with multi-agent chemotherapy. The R-CHOP regimen is standard therapy for treatment of DLBCL patients. Whereas attempts to improve outcome with more intensive chemotherapy failed to show additional benefit. Aims:to set the indications to standard or intensive therapy in patients with nodal DLBCL and to evaluate the efficiency of modified protocol NHL-BFM-90 in adult patients. Patients and methods:139 patients with newly diagnosed nodal DLBCL were included in the study since January 2002 till December 2010. The diagnosis was established according to the criteria of the WHO classification. Diagnostic methods include neck, thorax, abdomen and pelvis CT scan, tumor biopsy bilateral bone marrow (BM) biopsy, lumbal puncture, MRT or scintigraphy of bones. Bone marrow involvement was found in 18 cases and confirmed by immunohistochemistry. Bulky disease, direct invasion to adjacent organs, III-IV stage according Ann-Arbor and increased level LDH were considered as the unfavorable prognostic factors. The patients were stratified into 2 groups: the first group with unfavorable prognostic factors (86 patients), the second group without unfavorable prognostic factors (53 patients). Median age in the first group was 53 years. There were 46 men and 40 women. The level of LDH was elevated in the 61 patients. III-IV stage without involvement of BM was diagnosed in the 35 patients, IV stage with BM involvement-in the 18 patients, bulky disease and direct invasion to adjacent organs-in the 33 patients. Median age in the second group was 55 years. There were 28 men and 25 women. All patients in the first group received intensive therapy by modified protocol NHL-BFM-90. The patients in the second group received chemotherapy CHOP-21(n=28) or R-CHOP-21 (n=25). The program NHL-BFM-90 was modified: the dose of methotrexate was 1,5 g/m2 for 12 hours and adriamycin 25 mg/m2 was infused in 1–2 days of course AA. All patients treated with this protocol gave written informed consent. We made spleneectomy to all the patients of splenic DLBCL before chemotherapy (n=20). The estimation of the chemotherapy efficiency was carried out according to the criteria of the International Working Group: rate of complete remissions (CR), overall (OS) and relapse-free (RFS) survival. The data were analyzed with SAS statistical package program. Statistical significance of the difference in the survival curves for two groups was calculated with Log-rank Test. Results:64 patients in the first group (74,4%) and 53 patients (100%) in the second group achieved CR. 5-year OS and RFS were 65% and 86% in the first group 96% and 100% in the second group, accordingly. In the first group the best results were obtained in patients without BM involvement. 5-year OS was 84% in these patients comparing 12% in patients with BM involvement–figure 1 (Log-Rank Test=0,0001). The rate of CR and OS were the same in CHOP-21 group and R-CHOP-21 group–figure 2 (Log-Rank Test=0,8). [Display omitted] [Display omitted] Conclusion:The stated unfavorable prognostic factors allowed to stratify patients into prognostic groups. Modified program NHL-BFM-90 is effective treatment for adult patients with DLBCL with unfavorable prognostic factors. The concordant of BM involvement is the most strict prognostic factor. Disclosures:No relevant conflicts of interest to declare.

Changes of high sensitive-C reactive protein and cardiac troponin I levels in patients with type 2 diabetes during glucose-lowering therapy

Objective To compare the changes of high sensitive-C reactive protein (hs-CRP) and cardiac troponin Ⅰ ( cTn Ⅰ ) levels before and after intensive therapy in patients with type 2 diabetes,and to find out the reasonable glucose-lowering rate.Methods One hundred and thirty-two cases of type 2 diabetes( T2DM group) and 135 cases of type 2 diabetes with coronary heart disease( T2DM+CHD group) received intensive therapy.After testing hs-CRP and cTn Ⅰ levels,the variations were analyzed.Results The ranges of the change in cTn Ⅰ and hs-CRP levels were different under four glucose-lowering rates in the T2DM+CHD group( P＜0.05 ).cTn Ⅰ and hs-CRP levels were higher than those before intensive therapy in the T2DM+CHD group with glucose-lowering rate greater than 4.0mmol· L-1 · d-1.The other two subgroups with glucose-lowering rate less than 4.0 mmol· L-1 · d-1 showed decreased cTn Ⅰ and hs-CRP levels.While at the end of 3 months follow-up,cTn Ⅰ and hs-CRP levels were all significantly lower than those before intensive therapy in four subgroups ( P＜0.05 ).Conclusions The increase of cardiovascular events after intensive therapy may be due to excessively fast glucose-lowering rate.The reasonable glucose-lowering rate for patients with type 2 diabetes should depend on whether there is accompanying coronary heart disease.For type 2 diabetes with coronary heart disease,excessively fast glucose-lowering rate could lead to acute rise ofcTn Ⅰ and hs-CRP levels,which causes myocardial injury.The mechanism of myocardial injury resulted from excessively fast glucose-lowering rate may be due to activation of the inflammatory pathway.In type 2 diabetes with coronary heart disease,long-term good control of blood glucose could alleviate inflammatory response and cardiac damage resulted from excessively fast glucose-lowering rate. Key words: Diabetes mellitus, type 2; Coronary disease; Glucose-lowering rate; Troponin Ⅰ ; High sensitive-C reactive protein

Mechanical ventilation in patients with most severe forms of influenza a H1N1

Pandemic of A H1N1 influenza is noted for its rapid spreading and life-threatening consequences like acute respiratory distress syndrome (ARDS) which requires mechanical ventilation (MV) and intensive therapy (IT).The aim of the study was to determine the significance of mechanical ventilation application in the presence of comorbidities on the outcome of the disease and patients with severe forms of acute influenza caused by A H1N1 virus. Five patients with acute respiratory failure caused by A H1N1 influenza that required MV were included in the study. Course and outcome of the treatment were monitored in relation to age and sex of the patients, concomitant diseases, time of influenza beginning, a time of admittance in an intensive care unit, a time of an endotracheal intubation and MV beginning, MV duration and occurrence of secondary infections. Three patients were on a very prolonged MV (39, 43 and 20 days, respectively) and they all survived. Two patients with a significantly shorter duration of MV (14 and 12 days, respectively) died because of a very severe clinical course and concomitant diseases. Unexpectedly, we found a positive correlation between duration of MV and survival although two patients, who were on MV for the longest period of time (43 and 39 days, respectively), developed, as a complication, secondary bacterial pneumonia. Intensive therapy of patients with ARDS due to A H1N1 influenza virus requires MV which should be carried out according to guidelines of international expert forums. That is in accordance with our unexpected observation on negative correlation between duration of MV and fatal outcome. Intensive treatment of these patients, specially MV, can be very prolonged and, therefore, requires specialized teams of anesthesiologists, separate, isolated intensive therapy units and high level of medical staff protection, as was the case in this study, so no member of medical staff was infected.

Experience in Clinical Application of Perftorane for Intensive Therapy in Patients with Severe Combined Injuries Resulted from Explosion in Coal-Mine

Twenty victims with severe combined injuries caused by explosion in the coal-mine were included into the study. The components of such injuries were barotrauma, mechanical injury, skin and inhalation burns, carbon oxide poisoning intensified by syndrome of mutual aggravation. The ultimate cause of death was the affection of oxygen transport system. Temporary substitution of affected blood - lung system with oxygenated perftorane enabled to decrease considerably the lethality rate in miners with negative and doubtful survival prognosis. Efficacy of perftorane inclusion into intensive therapy was stipulated by its chemical inertness owing to which it can transport oxygen under conditions of blood poisoning by carbon oxide and unfit for breathing atmosphere in the mine after explosion.

Role of Advanced Glycation End Products (AGEs) and Oxidative Stress in Diabetic Retinopathy

Diabetic retinopathy is a common and potentially devastating microvascular complication in diabetes and is a leading cause of acquired blindness among the people of occupational age. However, current therapeutic options for the treatment of sight-threatening proliferative diabetic retinopathy such as photocoagulation and vitrectomy are limited by considerable side effects and far from satisfactory. Therefore, to develop novel therapeutic strategies that specifically target diabetic retinopathy is actually desired for most of the patients with diabetes. Chronic hyperglycemia is a major initiator of diabetic retinopathy. However, recent clinical study has substantiated the concept of 'hyperglycemic memory' in the pathogenesis of diabetic retinopathy. Indeed, the Diabetes Control and Complications Trial-Epidemiology of Diabetes Interventions and Complications (DCCT-EDIC) Research, has revealed that the reduction in the risk of progressive retinopathy resulting from intensive therapy in patients with type 1 diabetes persisted for at least several years after the DCCT trial, despite increasing hyperglycemia. These findings suggest a long-term beneficial influence of early metabolic control on clinical outcomes in type 1 diabetic patients. Among various biochemical pathways implicated in the pathogenesis of diabetic retinopathy, the process of formation and accumulation of advanced glycation end products (AGEs) and their mode of action are most compatible with the theory 'hyperglycemic memory'. Further, there is a growing body of evidence that AGEs-RAGE (receptor for AGEs) interaction-mediated oxidative stress generation plays an important role in diabetic retinopathy. This article summarizes the role of AGEs and oxidative stress in the development and progression of diabetic retinopathy and the therapeutic interventions that could prevent this devastating disorder. We also discuss here the pathological crosstalk between the AGEs-RAGE and the renin-angiotensin system in diabetic retinopathy and a potential clinical utility of telmisartan, an angiotensin II type 1 receptor blocker with peroxisome proliferator-activated receptor-gamma-modulating activity.

Advanced Glycation End Products (AGEs) and Cardiovascular Disease (CVD) in Diabetes

Accelerated atherosclerosis and microvascular complications are perhaps the leading cause of coronary heart disease, blindness and renal failure, which could account for disabilities and high mortality rates in patients with diabetes. Several mechanisms including endothelial cell damage, platelet activation and aggregation, hypercoagulability, and impaired fibrinolysis are involved in the pathogenesis of thrombogenic diathesis in diabetes. However, the underlying molecular mechanism is not fully elucidated. A recent clinical study, the Diabetes Control and Complications Trial-Epidemiology of Diabetes Interventions and Complications (DCCT-EDIC) Research, has revealed that the reduction in the risk of progressive retinopathy and nephropathy resulting from intensive therapy in patients with type 1 diabetes persist for at least several years, despite increasing hyperglycemia. In addition, intensive therapy during the DCCT also reduced the risk of cardiovascular events by about 50 % in type 1 diabetic patients 11 years after the end of the trial. These clinical studies strongly suggest that so-called 'hyperglycemic memory' causes chronic abnormalities in diabetic vessels that are not easily reversed, even by subsequent, relatively good control of blood glucose. Among various biochemical pathways implicated in diabetic vascular complications, the process of formation and accumulation of advanced glycation end products (AGEs) and their mode of action are most compatible with the theory 'hyperglycemic memory'. In this review, we discuss the role of AGEs in thrombogenic abnormalities in diabetes, especially focusing on the deleterious effects of these macroproteins on endothelial cell function, platelet activation and aggregation, coagulation and fibrinolytic systems.

Cost-effectiveness of postremission intensive therapy in patients with acute leukemia

We assessed the cost-effectiveness of high-dose arabinoside (HiDAC)-based and allogeneic stem-cell transplantation (alloSCT)-based therapy in patients with acute leukemia. We analyzed the outcome, cost and cost-effectiveness of 106 patients treated from January 1994 to January 2002 [94 acute myelogenous leukemia (AML)/12 acute lymphoblastic leukemia (ALL)]. Forty-two young patients at either intermediate or unknown cytogenetic risk received postremission intensive therapy (24 HiDAC-based/18 alloSCT-based therapy). After a median follow-up of 50 months, the estimated 7-year overall survival for the HiDAC-based group showed a tendency to be higher than the alloSCT-based group (48% versus 28%, P = 0.1452). The HiDAC-based group spent a significantly lower total cost ($US51,857 versus 75,474, P = 0.004) than the alloSCT-based group. Cost-effectiveness analysis showed that the mean cost per year of life saved for the HiDAC-based group is considerably less expensive than the alloSCT-based group ($US11,224 versus 21,564). The reduced total cost for the HiDAC-based group originated from lower cost in room fees, medication, laboratory and procedure, but not in blood transfusion and professional manpower fees. For the postremission therapy in young AML patients at either intermediate or unknown cytogenetic risk, cost-effectiveness of HiDAC-based therapy compares favorably with that of alloSCT-based therapy, which deserves further clinical trials.

Cost Effectiveness of Post-Remission Intensive Therapy in Patients with Acute Leukemia.

Background: We assessed the cost-effectiveness of high dose arabinoside (HiDAC)-based and allogeneic stem cell transplantation (alloSCT)-based therapy in patients with acute leukemia.Patients and Methods: We analyzed the outcome, cost and cost-effectiveness of 106 patients treated between 01/94 and 01/02 (94 AML/12 ALL). Forty-two young patients at either intermediate or unknown cytogenetic risk received post-remission intensive therapy (24 HiDAC-based / 18 alloSCT-based therapy).Results: After a median follow-up of 50 months, the estimated 7 year overall survival for the HiDAC-based group showed a tendency to be higher than the alloSCT-based group (48% versus 28%; p=0.1452). HiDAC-base group spent a significantly lower total cost (USD 51,857 versus 75,474; p=0.004) than the alloSCT-based group. Cost-effectiveness analysis showed that the mean cost per year of life saved for the HiDAC-based group is considerably less expensive than the alloSCT-based group (USD 11,224 versus 21,564). The reduced total cost for the HiDAC-based group originated from lower cost in room fees, medication, laboratory and procedure, but not in blood transfusion and professional man-power fees.Conclusion: HiDAC therapy as initial post-remission intensive therapy is a cost-effective approach in AML patients at either intermediate or unknown cytogenetic risk, which deserves further prospective clinical study to address this issue.

Role of Advanced Glycation End Products (AGEs) in Thrombogenic Abnormalities in Diabetes

Accelerated atherosclerosis and microvascular complications are perhaps the leading cause of coronary heart disease, blindness and renal failure, which could account for disabilities and high mortality rates in patients with diabetes. Several thrombogenic abnormalities have been shown to play a central role in the pathogenesis of these devastating complications. However, the molecular mechanism for thrombogenic diathesis in diabetes is not fully elucidated. A recent clinical study, the Diabetes Control and Complications Trial-Epidemiology of Diabetes Interventions and Complications (DCCT-EDIC) Research, has revealed that the reduction in the risk of progressive retinopathy and nephropathy resulting from intensive therapy in patients with type 1 diabetes persist for at least several years, despite increasing hyperglycemia. Further, intensive therapy during the DCCT resulted in decreased progression of carotid intima-media thickness six years after the end of the trial as well. These clinical studies strongly suggest that so-called 'hyperglycemic memory' causes chronic abnormalities in diabetic vessels that are not easily reversed, even by subsequent, relatively good control of blood glucose. Among various biochemical pathways activated under diabetes, the process of formation and accumulation of advanced glycation end products (AGEs) and their mode of action are most compatible with the theory 'hyperglycemic memory'. In this review, we discuss the role of AGEs in thrombogenic abnormalities in diabetes.

Effect of Intensive Glycemic Control on Levels of Markers of Inflammation in Type 1 Diabetes Mellitus in the Diabetes Control and Complications Trial

Type 1 diabetes mellitus is associated with an increased risk of cardiovascular disease (CVD) that is not fully explained by conventional risk factors. The Diabetes Control and Complications Trial (DCCT) showed that intensive diabetes therapy reduced levels of LDL cholesterol and triglycerides but increased the risk of major weight gain, which might adversely affect CVD risk. The present study examined the effect of intensive therapy on levels of several markers of inflammation that have been linked to risk of CVD. We measured levels of inflammatory biomarkers in stored baseline and 3-year follow-up serum specimens from a random sample of 385 participants in the DCCT, a multicenter trial in which 1441 subjects aged 13 to 39 years with type 1 diabetes mellitus were randomized to intensive or conventional diabetes treatment. The markers included high-sensitivity C-reactive protein (hsCRP), soluble intercellular adhesion molecule type 1 (sICAM-1), soluble vascular cell adhesion molecule type 1 (sVCAM-1), and the 55-kDa soluble tumor necrosis factor-alpha receptor 1 (sTNF-R1). We examined the effect of intensive therapy on the change in levels of the inflammatory markers. In unadjusted analyses, levels of hsCRP and sTNF-R1 increased in both treatment groups after 3 years of follow-up, with no significant difference between groups for hsCRP (P=0.53) but with a greater increase of sTNF-R1 in the intensive therapy group (P=0.002). In contrast, mean levels of sICAM-1 and sVCAM-1 decreased among participants assigned to intensive therapy, whereas they did not change among those in the conventional treatment group (P=0.03 for sICAM-1; P=0.03 for sVCAM-1). After adjustment for baseline levels and other factors, intensive therapy remained associated with a significant decrease in sICAM-1 (P=0.02) and an increase in sTNF-R1 (P=0.03). For hsCRP, there was a significant interaction between the top third of weight gain and treatment assignment (P=0.03). In subgroup analyses among subjects undergoing intensive therapy, hsCRP levels increased among those who gained the most weight, whereas it decreased among those in the bottom third of weight gain (P=0.0004). Intensive therapy in patients with type 1 diabetes mellitus reduced levels of sICAM-1 and increased levels of sTNF-R1 and of hsCRP among those who gained weight. These data demonstrate that the effect of intensive therapy on inflammation is complex and, to the extent that hsCRP is a risk factor, suggest that the risk of atherosclerosis among diabetic patients may be influenced by the degree of weight gain while undergoing intensive therapy.

Clinical outcomes with intensive therapy for patients with primary resistant multiple myeloma.

Clinical outcomes were evaluated in 89 consecutive patients with multiple myeloma that had not responded to dexamethasone-based primary therapy, who received early intensive therapy supported by autologous stem cell transplantation. Results were compared with those of 45 comparable patients who refused or were unable to receive intensive treatment for socioeconomic reasons. Following high-dose therapy, the response rate was 69% including 16% with CR. Survival of 14 patients with CR (median >7.0 years) was significantly longer than those of 47 patients with PR (median 4.5 years) or of 28 patients who remained NR (median 2.2 years). CR occurred in 43% of patients with serum myeloma protein <1.5 gm/dl, in contrast to 7% of those with higher values, a finding similar to that observed previously for patients consolidated in PR. No prognostic factor was associated with PR and, in view of the high frequencies of PR or CR, all patients with primary resistant myeloma should be considered for early intensive therapy. The limited improvement of lifespan and disease-free survival for those in PR indicated the need for further treatment to achieve CR, the major surrogate marker for long survival.

Inhibition of protein kinase C might be harmful to diabetic retinopathy

Selective loss of retinal pericytes is the earliest histopathological hallmark in diabetic retinopathy. Various structural and functional abnormalities in diabetic retinas are the consequent of the loss of pericytes. Therefore, elucidating the molecular mechanisms for pericyte loss and targeting this characteristics change in early diabetic retinopathy may help to slow the development and progression of sight-threatening retinopathy in diabetes. Protein kinase C (PKC) inhibition has been used in therapeutic trials intended to reduce the incidence of proliferative diabetic retinopathy. However, we speculate that it is likely to do more harm than good in diabetic retinopathy because PKC inhibition augments pro-apoptotic effects of high glucose on cultured retinal pericytes. In the DCCT-Epidemiology of Diabetes Interventions and Complications Research, the reduction in the risk of progressive retinopathy resulting from intensive therapy in patients with type 1 diabetes persisted for at least four years, despite increasing hyperglycemia. These clinical studies strongly suggest that so-called ‘hyperglycemic memory’ causes vascular damage in diabetic retinopathy. Glucose react non-enzymatically with the amino groups of proteins to initiate a complex series of rearrangement and dehydration reactions to produce a class of irreversibly cross-linked, fluorescent moieties, termed advanced glycation end products (AGEs). The formation and accumulation of AGEs progress at an extremely accelerated rate in diabetic retinas, and these products have been implicated in the pathogenesis of loss of pericytes in diabetic retinopathy. The nature of AGEs is most compatible with the theory of ‘hyperglycemic memory’ as well. We hypothesize here that PKC inhibition is likely to do harm in diabetic retinopathy, while inhibition of AGE formation might be a promising therapeutic strategy for treatment of this devastating complication.