Successful repeat therapy with rituximab for relapsed thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease that is treated successfully with therapeutic plasma exchange (TPE) and often with corticosteroids; however, almost one third of TTP patients have treatment failures that require either long-term TPEs or other adjunct therapies. Recent insights into the autoimmune-pathophysiology of this disease provide the rationale for immune-based therapies. Cumulative evidence suggests that rituximab, an anti-CD20 antibody that depletes B-cells temporarily, is an effective therapy in patients with refractory or relapsing TTP. We report here two patients with chronic relapsing TTP who were treated successfully with rituximab. However, both experienced TTP relapse following sustained and prolonged remissions for 21 and 37 months, respectively. They responded favorably with repeat therapy with rituximab. The benefits of rituximab treatment for refractory or relapsing TTP as well as in the prevention of recurrences are discussed.     

特应性皮炎瘙痒机制及相关治疗研究进展

特应性皮炎(atopic dermatitis, AD)是一种慢性复发性炎症性皮肤病, 慢性瘙痒是其特征性症状之一。AD瘙痒的发生机制复杂, 目前认为与皮肤屏障功能障碍、免疫调节异常及外界环境因素相关; 瘙痒-搔抓恶性循环可加重皮肤屏障的破坏、促进皮肤炎症反应及神经失调过程, 是AD瘙痒不易控制的原因之一。目前控制AD瘙痒的药物包括外用药物和系统药物, AD瘙痒机制的研究为其治疗提供了新靶点, 如IL-4、IL-13、IL-31、JAK、IL-33等。本文就AD瘙痒机制及相关治疗研究进展进行综述。     

Identification of Cofilin‐1 as a novel biomarker of atopic dermatitis using iTRAQ quantitative proteomics

BackgroundAtopic dermatitis (AD) is a chronic relapsing inflammatory skin condition; however, little is known about the pathogenesis and serum biomarker of this disease.MethodsIsobaric tagging for relative and absolute quantitation (iTRAQ) proteomic assay was adopted to identify and quantify the differentially expressed proteins (DEPs) in the serum of AD patients. Bioinformatic analysis, including GO, Reactome, GSEA, PPI, and ssGSEA analysis, were used to identified the enriched pathways, hub proteins and immune cells. The expression level and distribution of hub proteins were confirmed by ELISA and IHC.ResultsSixty‐six DEPs were identified with iTRAQ proteomic assay by analyzing serum from AD patients and normal subjects. GO and Reactome analysis shown the alternated pathway were mainly involved in immunity, oxidative stress, and actin cytoskeleton. The GSEA and PPI network analysis among the DEPs were carried out and identified Cofilin‐1 and profilin‐1 as the core components of this network. Additionally, the disruption of Th1/Th2/Th17 cell balance and the significantly reducing of Treg, MDSC, and γδT cells was also found in AD patients using the ssGSEA analysis. Further ELISA and IHC assay validated the significantly elevated expression of Cofilin‐1 in AD patients.ConclusionOur results suggested that Cofilin‐1 may serve as a novel biomarker for AD diagnosis.     

Role of splenectomy in patients with refractory or relapsed thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) was once uniformly fatal. Therapeutic plasma exchange in combination with immunosuppressive and anti-platelet agents, however, have resulted in improved survival rates of greater than 80% for patients with TTP. In spite of aggressive plasma exchange and adjuvant therapy, a number of TTP patients are refractory to treatment. In addition, up to 40% of TTP patients who initially respond to therapy eventually relapse. Alternative therapies such as splenectomy have been used with varying degrees of success in refractory and relapsing TTP patients. The usefulness of splenectomy in preventing relapse of TTP or treating those patients who are refractory to plasma exchange remains controversial. We present a single institution's experience with 14 patients who underwent splenectomy for refractory (six patients) or relapsed (eight patients) TTP since 1984. In both patient groups, splenectomy induced stable long-term remissions. Six of six (100%) patients who were refractory to plasma exchange, survived to be discharged from the hospital, apparently free of disease. Four of eight patients (50%) who had a splenectomy for relapsing TTP went into a complete remission and had no further relapses of their disease. Moreover, in relapsing patients who failed to experience long-term remission, the relapse rate after splenectomy was 0.3 events per patient year compared to 1.0 events per patient year prior to splenectomy. We conclude that splenectomy is a reasonable treatment option for TTP patients refractory to standard plasma exchange therapy or who have experienced multiple and/or complicated relapses. We believe this is the first series that demonstrates efficacy of splenectomy in plasma exchange-refractory TTP.     

阿尔茨海默患者面部情绪识别MRI研究进展

阿尔茨海默病(AD)是老年人常见神经退行性疾病,患者社会认知能力随疾病进展而下降。面部情绪识别(FER)是社会认知的重要组成部分,而AD患者FER受损。尽早发现、及时干预AD患者FER能力下降有助于改善患者生活质量。本文针对MRI研究AD患者FER进展进行综述。     

Autologous transplantation in relapsed and refractory Hodgkin's disease

The current data support the use of high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) as standard procedure for the majority of patients with Hodgkin's disease (HD) relapsing or progressing after combination chemotherapy. Prognostic factors reflecting unfavourable prognostic features of the disease as well as resistance to conventional salvage therapy have been identified. Preliminary data suggests a high efficacy of high-dose sequential chemotherapies in these patients. An ongoing randomized trial is comparing standard HDCT versus sequential HDCT in patients with relapsed HD.     

Alpha1-antitrypsin deficiency and inflammatory bowel diseases

OBJECTIVE: To evaluate a possible etiologic role of alpha1-antitrypsin deficiency (alpha1AD), most frequently caused by a Z allele mutation, in ulcerative colitis (UC) and Crohn disease (CD). PATIENTS AND METHODS: This retrospective study included 10 patients diagnosed with and/or treated for inflammatory bowel disease (IBD) between 1976 and 1997 and identified from the Mayo Clinic Medical Index System. All 10 patients had either alpha1AD and CD or alpha1AD and UC. The alpha1-antitrypsin (alpha1AT) types and levels were determined with isoelectric focusing testing. The allele types, representing genotypes, were designated PiZZ (or ZZ) for homozygotes and PiMZ (or MZ) for heterozygotes. RESULTS: Seven patients had UC: 4 were genotype ZZ and 3 MZ. Four of these 7 patients had emphysema, 2 had asthma, and 1 had chronic bronchitis. Five were cigarette smokers, but only 1 had smoked coincident with activity of her UC. Two of the UC patients never smoked, and 1 of these 2 had asthma. Three of the 10 patients had CD, 2 genotype ZZ and 1 MZ. Two of the 3 patients were long-term cigarette smokers, and both had emphysema. Nine of the 10 patients with UC and alpha1AD required surgery. CONCLUSIONS: The need for surgery in patients with UC and alpha1-AD may point to a unique phenotypic subgroup of patients with alpha1AD and severe UC. Further studies are required to substantiate the etiologic role of alpha1AD in IBD. Our observations, if confirmed by future studies, suggest that in patients with both IBD and chronic obstructive pulmonary disease, alpha1AD testing should be considered.     

Tick-borne disease

Tick-borne diseases in the United States include Rocky Mountain spotted fever, Lyme disease, ehrlichiosis, tularemia, babesiosis, Colorado tick fever, and relapsing fever. It is important for family physicians to consider these illnesses when patients present with influenza-like symptoms. A petechial rash initially affecting the palms and soles of the feet is associated with Rocky Mountain spotted fever, whereas erythema migrans (annular macule with central clearing) is associated with Lyme disease. Various other rashes or skin lesions accompanied by fever and influenza-like illness also may signal the presence of a tick-borne disease. Early, accurate diagnosis allows treatment that may help prevent significant morbidity and possible mortality. Because 24 to 48 hours of attachment to the host are required for infection to occur, early removal can help prevent disease. Treatment with doxycycline or tetracycline is indicated for Rocky Mountain spotted fever, Lyme disease, ehrlichiosis, and relapsing fever. In patients with clinical findings suggestive of tick-borne disease, treatment should not be delayed for laboratory confirmation. If no symptoms follow exposure to tick bites, empiric treatment is not indicated. The same tick may harbor different infectious pathogens and transmit several with one bite. Advising patients about prevention of tick bites, especially in the summer months, may help prevent exposure to dangerous vector-borne diseases.     

Characterizing Alzheimer's disease using a hypometabolic convergence index

This article introduces a hypometabolic convergence index (HCI) for the assessment of Alzheimer's disease (AD); compares it to other biological, cognitive and clinical measures; and demonstrates its promise to predict clinical decline in mild cognitive impairment (MCI) patients using data from the AD Neuroimaging Initiative (ADNI). The HCI is intended to reflect in a single measurement the extent to which the pattern and magnitude of cerebral hypometabolism in an individual's fluorodeoxyglucose positron emission tomography (FDG-PET) image correspond to that in probable AD patients, and is generated using a fully automated voxel-based image-analysis algorithm. HCIs, magnetic resonance imaging (MRI) hippocampal volume measurements, cerebrospinal fluid (CSF) assays, memory test scores, and clinical ratings were compared in 47 probable AD patients, 21 MCI patients who converted to probable AD within the next 18months, 76 MCI patients who did not, and 47 normal controls (NCs) in terms of their ability to characterize clinical disease severity and predict conversion rates from MCI to probable AD. HCIs were significantly different in the probable AD, MCI converter, MCI stable and NC groups (p=9e-17) and correlated with clinical disease severity. Using retrospectively characterized threshold criteria, MCI patients with either higher HCIs or smaller hippocampal volumes had the highest hazard ratios (HRs) for 18-month progression to probable AD (7.38 and 6.34, respectively), and those with both had an even higher HR (36.72). In conclusion, the HCI, alone or in combination with certain other biomarker measurements, has the potential to help characterize AD and predict subsequent rates of clinical decline. More generally, our conversion index strategy could be applied to a range of imaging modalities and voxel-based image-analysis algorithms.     

Efficacy study of galantamine in possible Alzheimer's disease with or without cerebrovascular disease and vascular dementia in Thai patients: a slow-titration regimen

The objective is to evaluate the efficacy of galantamine when a slow titration regimen is employed in Thai Alzheimer's disease (AD) patients with or without cerebrovascular disease and vascular dementia (VaD). A 6-month, multicentre, open-label, uncontrolled trial was undertaken in 75 AD patients. Eligible patients received an initial galantamine dose of 8 mg/day and escalated over 5-8 weeks to maintenance doses of 16 or 24 mg/day. Primary efficacy measures were AD Assessment Scale-cognitive subscale (ADAS-cog) and the Clinician's Interview-Based Impression of Change-Plus version (CIBIC-plus). The Behavioural Pathology in AD Rating Scale (BEHAVE AD), the AD Cooperative Study Activities of Daily Living Inventory and Pittsburgh Sleep Quality Index were the secondary efficacy variables. Analyses were based on the intent-to-treat population. Treatment with galantamine showed significant improvement in cognition on the ADAS-cog and CIBIC-plus at month 6. Galantamine showed favourable effects on activities of daily living. Behavioural symptoms and sleep quality were also significantly improved (p < 0.05). Galantamine was well tolerated. The adverse events were mild-to-moderate intensity. The most frequent adverse events commonly reported were nausea (16.4%), dizziness (9.6%) and vomiting (6.8%). The results of this study may be consistent with galantamine being an effective and safe treatment for mild-to-moderate AD patients with or without cerebrovascular disease and VaD. Flexible dose escalation of galantamine was well tolerated. The daily maintenance dose of galantamine was 16 mg/day, followed by a back up dose of 24 mg/day.     

Current concepts in the treatment of Alzheimer's disease.

The etiology of Alzheimer's disease (AD) is still unknown, and a definitive diagnosis of the disease can be determined only at autopsy or by brain biopsy. AD can be characterized by various structural changes, including cerebral cortical atrophy, neuronal loss, neuritic plaques, and neurofibrillary tangles. The primary defect involves reduced activity of choline acetyltransferase. Neurotransmitters, such as norepinephrine, serotonin, dopamine, and somatostatin, are also compromised. Treatment of AD requires maintenance of a consistent lifestyle and environment for the patient, as well as counseling and support for the patient's family. Medications, which have been effective in some patients, are primarily used to improve cognitive function and modify behavior. Cognitive medications such as tacrine hydrochloride and physostigmine have proven beneficial in some patients, while behavioral medications have been effective in the treatment of depression, aggression, agitation, and anxiety associated with AD. However, the side effect profile of each medication and its probable overall benefit to the individual patient should be evaluated before beginning therapy. Continued research in patients with AD is required to identify medications that will consistently ameliorate the memory loss associated with the disease.     

Central nervous system sarcoidosis

The presenting features, clinical course and outcome of 19 patients with a diagnosis of CNS sarcoidosis are described. In two-thirds of the patients the initial features of sarcoidosis were neurological; half of them had an acute monophasic illness and half a chronic progressive or relapsing course. A favourable outcome was recorded unexpectedly during a study period of one to 16 years for two-thirds of the patients. The course of the disease in four patients suggested multiple sclerosis thus emphasising the importance of considering the possibility of CNS sarcoidosis in patients with suspected demyelinating disease.     

Discrimination between Alzheimer dementia and controls by automated analysis of multicenter FDG PET

A new diagnostic indicator of FDG PET scan abnormality, based on age-adjusted t statistics and an automated voxel-based procedure, is presented and validated in a large data set comprising 110 normal controls and 395 patients with probable Alzheimer's disease (AD) that were studied in eight participating centers. The effect of differences in spatial resolution of PET scanners was minimized effectively by filtering and masking. In controls FDG uptake declined significantly with age in anterior cingulate and frontolateral perisylvian cortex. In patients with probable AD decline of FDG uptake in posterior cingulate, temporoparietal, and prefrontal association cortex was related to dementia severity. These effects were clearly distinct from age effects in controls, suggesting that the disease process of AD is not related to normal aging. Women with probable AD had significantly more frontal metabolic impairment than men. The new indicator of metabolic abnormality in AD-related regions provided 93% sensitivity and specificity for distinction of mild to moderate probable AD from normals, and 84% sensitivity at 93% specificity for detection of very mild probable AD (defined by Mini Mental Score 24 or better). All regions related to AD severity were already affected in very mild AD, suggesting that all vulnerable areas are affected to a similar degree already at disease onset. Ventromedial frontal cortex was also abnormal. In conclusion, automated analysis of multicenter FDG PET is feasible, provides insights into AD pathophysiology, and can be used potentially as a sensitive biomarker for early AD diagnosis.     

Altered kallikrein 7 and 10 concentrations in cerebrospinal fluid of patients with Alzheimer's disease and frontotemporal dementia

BACKGROUND: The role of various proteases in the pathogenesis of Alzheimer's disease is well documented. Recently, many members of the human tissue kallikrein family, a group of 15 secreted serine proteases, were found to be highly expressed in the central nervous system (CNS). Some of these enzymes can be measured in cerebrospinal fluid (CSF) by using ELISA-type methodologies. METHODS: We quantified various kallikreins in CSF of 20 patients with Alzheimer's disease (AD), 16 patients with frontotemporal dementia (FTD), and 15 controls. We then correlated the levels of various kallikreins with presence of AD or FTD. Among all kallikreins measured, detectable levels in CSF were identified for kallikreins hK6, hK7, and hK10. Other tested kallikreins (hK5, hK8, hK11, and hK13) were unmeasurable. The most notable differences between kallikrein levels in CSF and the three groups of subjects were seen between controls and FTD patients for hK6 (decrease in FTD; P = 0.017), controls and FTD patients for hK7 (decrease in FTD; P < 0.001), and controls and AD patients for hK7 (decrease in AD; P = 0.019). In addition, significant differences were seen between FTD patients or control subjects and patients with AD patients for hK10 (increase in AD; P < 0.02). Approximately half of the AD patients had CSF hK10 levels that were higher than all patients with FTD except one and all control subjects except two. Various kallikrein concentrations in CSF were correlated, the strongest correlation seen between hK6 and hK7 (r(s) = 0.58). We also observed a statistically significant association between decreasing hK7 concentration in CSF and possession of one or two ApoE4 alleles (P = 0.014). CONCLUSIONS: We demonstrate for the first time significant alterations of hK6, hK7, and hK10 concentration in CSF of patients with AD and FTD. Notably, all three kallikreins (hK6, hK7, and hK10) are decreased in CSF of FTD patients and hK10 is increased in CSF of AD patients, in comparison to control subjects. The possible connection between these enzymes and the pathogenesis and progression of AD and FTD needs to be further investigated.     

Dermatology for the internist: optimal diagnosis and management of atopic dermatitis

Internists are front-line health care providers that commonly provide the first encounter to patients for dermatological conditions, especially atopic dermatitis (AD). Internists need to be comfortable with managing mild-moderate AD in their practices. Criteria and guidelines established in dermatology literature are available to help the general practitioner diagnose and treat AD. AD is a systemic disease associated with multiple cutaneous and extra-cutaneous comorbidities that warrant screening by internists, especially mental health conditions. Environmental factors may play a role in the development or worsening of AD; however, there is currently no strong evidence to guide specific population- or clinic-based interventions for their avoidance. While food allergies are common in AD patients, the role of food allergens as an exacerbating factor for AD is controversial. Before starting any dietary modifications, careful evaluation should be performed by an allergist. If the patient is not well-controlled despite adequate topical therapies or is experiencing severe/worsening disease, early referral to dermatology is warranted to rule out confounding diagnoses and/or escalation to systemic therapies. Finally, it is important to recognise the racial disparities present in AD and address these when formulating treatment plans.

Key messages:

• Confounding dermatoses, either instead of or in addition to AD, should be considered in treatment-refractory AD, and the appropriate workup may be initiated while awaiting dermatology referral.
• AD patients have multiple cutaneous and extra-cutaneous comorbidities that warrant screening by internists, especially mental health conditions.

     

Serum anti-amyloid-beta antibodies and Alzheimer's disease in elderly Korean patients

Alzheimer's disease (AD) is characterized by the deposition of senile plaques and neurofibrillary tangles in the brain. The presence of the amyloid-beta (Abeta) peptide in senile plaques seems to play a central role in the neuropathology of AD. Diagnosis of AD involves neuropsychological examinations or magnetic resonance imaging and, to date, a specific diagnostic marker indicating AD has not been found. This study analysed anti-Abeta antibodies from the serum of 153 patients with AD using an enzyme-linked immunosorbent assay method. The levels of anti-Abeta antibody from patients in the control group (n=193) were compared with those of patients with AD. Our results showed a significantly lower anti-Abeta antibody level in patients with AD than in the control group. These results showed that the anti-Abeta antibody level in serum could potentially be used to diagnose the presence of AD.     

Blood smear analysis in babesiosis, ehrlichiosis, relapsing fever, malaria, and Chagas disease

Blood smear analysis is especially useful for diagnosing five infectious diseases: babesiosis, ehrlichiosis, relapsing fever due to Borrelia infection, malaria, and American trypanosomiasis (Chagas disease). It should be performed in patients with persistent or recurring fever or in those who have traveled to the developing world or who have a history of tick exposure, especially if accompanied by hemolytic anemia, thrombocytopenia, or hepatosplenomegaly.     

Nursing management of the patient with Alzheimer's disease

Alzheimer's disease (AD) is a progressive, degenerative, debilitating illness that affects all races and both sexes. In 2002 the numbers of women over the age of 90 years with AD were higher compared with men of the same age group (Office for National Statistics (ONS), 2004). Although there are no data identifying the number of women suffering from AD compared with men, it could be concluded from these data (ONS, 2004) that more women than men suffer from AD. The number of individuals suffering from AD is increasing as people are living longer. Analysis of postmortem brain tissue in patients with AD has identified senile plaques in the hippocampal region, neurofibrillary tangles in the brain cells and also a decline in levels of acetylcholine in the brain. There is no known cure for the illness and therefore patients will ultimately require constant care in the community or in special units in residential homes. The National Service Framework for Long-Term Conditions (Department of Health, 2005) gives clear guidelines for healthcare providers in caring for these patients.     

早老性痴呆和血管性痴呆的核素影像学显像特点

目的通过SPECT显像半定量法来进行Alzheimer’s病(AD)和血管性痴呆(VD)的早期诊断和鉴别诊断。方法AD组25例,VD组21例,正常对照组15例,通过Tc-99m-ECD脑显像SPECT显像,运用大脑皮质与小脑ROIs区比值来进行半定量分析。结果AD病人与正常对照组比较,双侧额叶、双侧后颞顶部,大脑皮质/小脑比值存在高度显著差异(P<0.05),其它二叶无明显差异。而VD病人的放射性比呈非对称性、局灶性放射性降低。结论SPECT半定量分析结果提示双侧额叶及后颞顶部的血流灌注降低是诊断AD的主要特征。结合SPECT和CT、MRI,有助于痴呆的诊断与鉴别诊断。