Drug discovery and development for ageing: opportunities and challenges

The prevention and treatment of late-life dysfunction are the goals of most geriatricians and should be the primary target for discovery and development of new medicines for elderly people. However, the development of new medicines for elderly people will face a number of challenges that are not seen for other patient populations. The burdens of multiple chronic diseases, low physiological reserve and polypharmacy must result in new clinical trials in frail older people with a high expectation of safety and efficacy. The etiology of functional limitations in elderly people is complex and often ascribed to conditions that escape the traditional definition of disease. While our society urgently needs new treatments that can reduce the burden of physical decline among older persons, guidelines on how these treatments should be developed and tested are currently lacking, in part because a consensus has not yet been achieved regarding the identifiable target diseases. New potential indications included sarcopaenia, anorexia of ageing, frailty, mobility disability and reduced functional capacity secondary to hospitalization. The challenges to conducting clinical trials in the elderly should not offset the great opportunity for the development of new medicines to prevent or reverse age-associated changes in body composition and poor functional capacity in the elderly.     

A proposal for the classification and evaluation of fall detectors

Falls affect, each year, tens of million of elderly people throughout the world. It can have immediate lethal consequences but also causes many disabling fractures and dramatic psychological consequences which reduce the independence of the person. Falls in the elderly is thus a major public health problem. The “early” detection of fall consequently raises the interest of searchers, as most of elderly fallers cannot return to a standing position on their own following a fall. It is also an interesting scientific problem because it is an ill-defined process. The goals of this study were to classify various approaches used to detect the fall and to point out the difficulty to compare the results of these studies, as there is currently no common evaluation benchmark.     

Rehabilitation of the Aged

The rehabilitation needs and goals of older people differ in many respects from those of the young. In younger individuals a crippling condition may affect an otherwise healthy body, while in an older person it may be superimposed on other pre-existing degenerative diseases. Thus, in older patients the restorative or rehabilitative phase rarely can be separated from the phase of definitive medical treatment.The primary goal of rehabilitation of younger individuals is usually vocational. In the older group this goal or objective is, by and large, secondary. This does not minimize, however, the value of medical and social services in the rehabilitation of older persons. The simple ability to care for his own personal needs can do much to help the elderly disabled patient regain his dignity and self-respect and remove his fears of becoming a burden on his family or society.     

A mechanobiological model of orthodontic tooth movement

Orthodontic tooth movement is achieved by the process of repeated alveolar bone resorption on the pressure side and new bone formation on the tension side. In order to optimize orthodontic treatment, it is important to identify and study the biological processes involved. This article presents a mechanobiological model using partial differential equations to describe cell densities, growth factor concentrations, and matrix densities occurring during orthodontic tooth movement. We hypothesize that such a model can predict tooth movement based on the mechanobiological activity of cells in the PDL. The developed model consists of nine coupled non-linear partial differential equations, and two distinct signaling pathways were modeled: the RANKL–RANK–OPG pathway regulating the communication between osteoblasts and osteoclasts and the TGF-β pathway mediating the differentiation of mesenchymal stem cells into osteoblasts. The predicted concentrations and densities were qualitatively validated by comparing the results to experiments reported in the literature. In the current form, the model supports our hypothesis, as it is capable of conceptually simulating important features of the biological interactions in the alveolar bone—PDL complex during orthodontic tooth movement.     

Management of elderly patients with sustained hypertension.

OBJECTIVE--To assess the clinical benefits of treating hypertension in elderly patients and to derive practical guidelines regarding indications, goals, and forms of treatment. DESIGN--Review of six published randomised trials. RESULTS--Active treatment of hypertension in elderly patients was associated with significant improvements in several indices of cardiovascular morbidity and mortality, particularly the incidence of fatal and non-fatal strokes. On the basis of the trial data, combined systolic and diastolic hypertension was defined as a sustained systolic pressure greater than 160 mmHg and diastolic pressure greater than 90 mmHg. There is convincing evidence that efforts should be made to reduce both systolic and diastolic pressures to below these levels in patients up to the age of 80 years. Isolated systolic hypertension was defined as a systolic pressure greater than 160 mmHg in the presence of a diastolic pressure less than 90 mmHg. Two trials reported benefit from the treatment of isolated systolic hypertension in patients up to the age of 80, and further trials are underway to support or refute this recommendation. Diuretics have an established role in the management of hypertension in elderly patients; beta adrenoceptor antagonists have given variable results, and the benefits are less impressive than with diuretic based regimens. Newer agents show promise in the treatment of elderly patients, particularly in the presence of coexisting disease, but their effects on morbidity and mortality have not been evaluated in large randomised trials. CONCLUSIONS--Diuretics rather than beta blockers are the treatment of choice for patients with uncomplicated hypertension, but combinations of drugs may be required in as many as 50% of patients.     

固定矫治对儿童口腔微生态环境的影响

固定矫治的放置,增加细菌粘附能力,从而改变口腔微生态环境。本文就固定矫治对儿童口腔内微生态环境变化如：菌斑生物膜的变化、致龋菌数量的改变、牙周致病菌的变化、唾液的性质和牙齿形态及结构等方面改变的研究进展作一综述。     

In vitro exposure of leukemic cells to low concentration Arabinosyl Cytosine: no evidence of differentiation inducing activity

Low dose Arabinosyl Cytosine (LD ARA-C) is widely used for treatment of acute non-lymphocytic leukemia (ANLL) and myelodysplastic syndrome (MDS) in the elderly, based on a favorable response rate and on the hypothesis that LD ARA-C can induce differentiation or maturation of leukemic cells. We investigated the effect of low concentration of ARA-C on the growth of marrow cells that were obtained from 6 cases of MDS and from 11 cases of ANLL by using the in vitro culture system for normal granulo-monocyte precursors (CFU-GM). At ARA-C concentrations equal to or higher than 1 ng/ml cell growth was inhibited in a dose-dependent manner. At ARA-C concentration of 0.1 ng/ml cell growth was slightly affected, but colony number and colony cell composition were identical to control cultures. This experiment did not support the hypothesis that ARA-C can induce leukemic cells to recover any normal growth patterns but confirmed that even very low ARA-C concentrations can inhibit or slow down leukemic cell proliferation.     

A double blind randomized controlled trial to evaluate the efficacy of green tea in gingivitis

Gingivitis is the most common form of oral disease especially among patients undergoing fixed orthodontic treatment. Green tea, which is extensively used in Asian countries, can help to improve the overall gingival health, which can be assessed by using the gingival indices. Evaluation of the effectiveness of green tea on the gingival health of patients undergoing Orthodontic treatment is of interest. 40 otherwise healthy patients undergoing fixed orthodontic treatment were randomly divided in two groups namely (1) study group and (2) control group. Gingival indices were scored for all the patients. Study group was given mouth rinse with green tea extract and control group was given placebo with no green tea extract. Gingival indices were measured for all the patients after 21 days. Mann Whitney U test and Wilcoxon test was used for statistical analysis. The gingival indices scoring in which the values before and after the use of mouthwash were compared. The p value was found to be statistically significant (p<0.05) in study group. But in control group statistical significant could not be reached.     

ATP depletion triggers acute myeloid leukemia differentiation through an ATR/Chk1 protein-dependent and p53 protein-independent pathway

Despite advances in oncology drug development, most commonly used cancer therapeutics exhibit serious adverse effects. Often the toxicities of chemotherapeutics are due to the induction of significant DNA damage that is necessary for their ability to kill cancer cells. In some clinical situations, the direct induction of significant cytotoxicity is not a requirement to meet clinical goals. For example, differentiation, growth arrest, and/or senescence is a valuable outcome in some cases. In fact, in the case of acute myeloid leukemia (AML), the use of the differentiation agent all-trans-retinoic acid (ATRA) has revolutionized the therapy for a subset of leukemia patients and led to a dramatic survival improvement. Remarkably, this therapeutic approach is possible even in many elderly patients, who would not be able to tolerate therapy with traditional cytotoxic chemotherapy. Because of the success of ATRA, there is widespread interest in identifying differentiation strategies that may be effective for the 90-95% of AML patients who do not clinically respond to ATRA. Utilizing an AML differentiation agent that is in development, we found that AML differentiation can be induced through ATP depletion and the subsequent activation of DNA damage signaling through an ATR/Chk1-dependent and p53-independent pathway. This study not only reveals mechanisms of AML differentiation but also suggests that further investigation is warranted to investigate the potential clinical use of low dose chemotherapeutics to induce differentiation instead of cytotoxicity. This therapeutic approach may be of particular benefit to patients, such as elderly AML patients, who often cannot tolerate traditional AML chemotherapy.     

Withholding and withdrawing life sustaining treatment from elderly people: towards formal guidelines.

Clinicians often decide either to withhold or to withdraw lifesaving treatment in elderly patients. Considerable disagreement exists about the circumstances in which such actions can be defended. Debates about the scarcity of resources in the NHS add urgency to the need to resolve this disagreement. Competent elderly patients have a legal and moral right to decide whether to receive life sustaining treatment. Such treatment should not be withheld or withdrawn on the basis of a patient''s age alone. Principles for making decisions about life sustaining treatment in incompetent elderly patients can be defended and should exist as written guidelines.     

Personalized Medical Treatment of Patients With Acromegaly: A Review

Acromegaly is associated with significant morbidity and mortality if it is not appropriately treated. In addition to insulin-like growth factor 1 and growth hormone normalization as well as tumor shrinkage, the treatment goals include relieving symptoms, managing complications, and improving patients’ quality of life. Surgical resection is a first-line treatment option for most patients, with few being pretreated preoperatively with medications. Somatostatin receptor ligands (SRLs), injectable and, more recently, oral capsules, have been the cornerstone of first-line medical therapy for persistent disease. However, several factors, including sparsely granulated adenomas, absent or low somatostatin receptor status, T2-hyperintensity imaging, young age, and aryl hydrocarbon receptor-interacting protein mutations, can predict first-generation SRL resistance. Patients with these characteristics may be better candidates for the growth hormone receptor antagonist pegvisomant, or in cases of large tumors, the second-generation SRL pasireotide. Combination therapy should be further pursued in patients who remain biochemically uncontrolled or have a high remnant tumor after monotherapy. An efficacious and cost-effective pegvisomant dose-sparing effect of SRLs when used in combination has been demonstrated. With such a wide array of medical treatment options, it is becoming increasingly important to tailor treatment to patients’ unique characteristics and preferences, with a goal of personalizing management to achieve high-quality outcomes.     

The somatopause: to treat or not to treat?

There is much evidence that some aspects of ageing are similar to those observed in selective hormone deficiencies during adulthood. Replacement therapy in hypogonadism and/or growth hormone (GH) deficiency in adulthood is very successful in reversing the related clinical symptomatology. However, preliminary studies of GH treatment in the normal elderly have been largely disappointing: an increase in muscle mass is only accompanied by improved muscle strength if exercise is also increased during this period. No real benefit of GH therapy, additional to that of exercise, has been reported. Epidemiological studies indicate a relationship between high-normal insulin-like growth factor-I levels and cancer development. No definitive answers can presently be given regarding the safety of long-term GH therapy in otherwise healthy individuals during the somatopause.     

吸烟对老年克罗恩病的影响

目的探讨吸烟对老年人克罗恩病的影响。方法回顾性分析1995年1月～2011年8月在我院住院的老年克罗恩病患者87例的临床资料,分为吸烟组及无烟组,比较两组并发症（肠梗阻、肠穿孔）发生率、手术治疗率及复发率。结果吸烟组并发症的发生率、手术治疗率、复发率均明显高于无烟组。结论吸烟可增加老年克罗恩病患者并发症、手术治疗及复发的风险,建议老年克罗恩病患者戒烟是必要的。     

Treating dyslipidemia in the elderly

PURPOSE OF REVIEW: The treatment of dyslipidemia has been dynamic over the past several years. Of special importance is the impact of recent clinical trial data on management strategies of dyslipidemia in the elderly. People 65 years and older are living longer and are the fastest growing subset of the US population, necessitating more attention to chronic disease conditions that manifest in this age group. This review addresses guidelines of lipid management, discusses data that support their use, and examines the benefits of lipid-lowering therapy in the elderly with attention to the chronic conditions that are common in this population. RECENT FINDINGS: Clinical trials completed since the publication of the 2001 National Cholesterol Education Program (NCEP) Adult Treatment Panel III guidelines support the use of lipid-lowering therapy in the elderly population. Lipid-lowering therapy has not only proven to be generally safe in the elderly, but has also proven effective in helping manage the chronic disease conditions that are common in this age group. SUMMARY: The elderly segment of our population continues to grow. Along with this growth in population is a growth in incidence of cardiovascular disease, the metabolic syndrome, chronic kidney disease, cerebrovascular disease, and diabetes mellitus. There is no known panacea for managing these chronic disease conditions; however, lipid-lowering therapy has been shown to prevent or delay the progression of these diseases and the mortality and morbidity that accompanies them.     

老年患者腹部手术后胃瘫综合征的诊治思考

目的:探讨老年患者腹部手术后胃瘫的病因、临床特点、诊断和治疗原则。方法:对9例老年患者腹部手术后胃瘫的临床资料进行回顾性分析。结果:9例老年患者依据临床表现、上消化道造影和胃镜检查确诊为术后胃瘫。经非手术治疗11-47d后,9例均治愈。结论:老年患者胃瘫是由多种因素引起的,通过上消化道造影及胃镜检查可以明确诊断,治疗上采取以营养支持为主的非手术综合治疗,一般均可治愈。     

Lipids,oxidized lipids,oxidation-specific epitopes,and Age-related Macular Degeneration

Age-related Macular Degeneration (AMD) is the leading cause of blindness among the elderly in western societies. While antioxidant micronutrient treatment is available for intermediate non-neovascular disease, and effective anti-vascular endothelial growth factor treatment is available for neovascular disease, treatment for early AMD is lacking due to an incomplete understanding of the early molecular events. The role of lipids, which accumulate in the macula, and their oxidation, has emerged as an important factor in disease development. These oxidized lipids can either directly contribute to tissue injury or react with amine on proteins to form oxidation-specific epitopes, which can induce an innate immune response. If inadequately neutralized, the inflammatory response from these epitopes can incite tissue injury during disease development. This review explores how the accumulation of lipids, their oxidation, and the ensuing inflammatory response might contribute to the pathogenesis of AMD. This article is part of a Special Issue entitled: Lipid modification and lipid peroxidation products in innate immunity and inflammation edited by Christoph J. Binder .     

正畸治疗上颌尖牙埋伏阻生38例的临床分析

目的:探讨正畸导萌治疗上颌尖牙埋伏阻生的临床效果。方法:对38例上颌尖牙埋伏阻生患者的临床资料进行回顾性分析,总结正畸导萌治疗上颌尖牙埋伏阻生的临床效果。结果:经过17-25个月(平均20个月)的正畸治疗,38例上颌埋伏阻生尖牙均完全萌出纳入到正常牙列中,牙齿及牙周组织未见异常,牙齿排列整齐且咬合关系良好,临床效果令人满意。结论:正畸配合外科手术导萌可有效避免上颌尖牙因埋伏阻生而拔除给患者带来的美观和功能上的缺憾,是一种有效治疗上颌尖牙埋伏阻生的方法。     

Success of dental implants in elderly people--a literature review

Implant-supported dentures seem particularly appropriate for the predicament of being elderly and becoming edentulous. The aim of this article was to review the literature on success of dental implants in elderly people. The results of two studies suggested that the treatment with implants can be considered safe and predictable for older as well as for younger patients. Three studies found no increased implant failure-rate in patients with a compromised medical status. Four studies revealed high success-rates of dental implants among groups of elderly people. Within the limitations of this review of the literature it can be concluded that old age does not seem to represent a factor of major prognostic significance in treatment with dental implants.     

Simulation of bone remodelling in orthodontic treatment

Orthodontic treatments not only displace irregular teeth but also induce responses in surrounding bone tissues. Bone remodelling is regarded as the regulatory mechanism triggered by mechanical loading. This study was aimed at investigating the effect of orthodontic loading on both tooth movement and neighbouring bone density distribution. A set of computational algorithms incorporating both external and internal remodelling mechanisms was implemented into a patient-specific 3D finite element (FE) model to investigate and analyse orthodontic treatment under four typical modes of orthodontic loading. The consequence of orthodontic treatment was reproduced numerically by using this FE-based technique. The results indicated that the diverse modes of orthodontic loading would result in different magnitudes of tooth movement and particular morphology of bone density distribution. It is illuminated that the newly developed algorithms may replicate the clinical situation more closely compared with the previous proposed method.     

DHEA enhances effects of weight training on muscle mass and strength in elderly women and men

The plasma levels of dehydroepiandrosterone (DHEA) and its sulfated form (DHEAS) decline approximately 80% between the ages of 25 and 75 yr. Muscle mass and strength also decrease with aging. Published data on the effects of DHEA replacement on muscle mass and strength are conflicting. The goals of this study were to determine whether DHEA replacement increases muscle mass and strength and/or enhances the effects of heavy resistance exercise in elderly women and men. We conducted a randomized, double-blind, placebo-controlled study of the effects of 10 mo of DHEA replacement therapy with the addition of weightlifting exercise training during the last 4 mo of the study (DHEA + exercise group, n = 29; placebo + exercise group, n = 27). DHEA alone for 6 mo did not significantly increase strength or thigh muscle volume. However, DHEA therapy potentiated the effect of 4 mo of weightlifting training on muscle strength, evaluated by means of one-repetition maximum measurement and Cybex dynamometry, and on thigh muscle volume, measured by magnetic resonance imaging. Serum insulin-like growth factor concentration increased in response to DHEA replacement. This study provides evidence that DHEA replacement has the beneficial effect of enhancing the increases in muscle mass and strength induced by heavy resistance exercise in elderly individuals.