Restraint use among nursing home residents: cross‐sectional study and prospective cohort study

Aims and objectives. To investigate (1) the prevalence of physical restraints and psychoactive medication, (2) newly administered physical restraints, frequency of application of the devices and frequency of psychoactive medication on demand during 12‐month follow‐up and (3) characteristics associated with restraint use in nursing homes. Background. High quality data on restraint use in German nursing homes are lacking so far. Such information is the basis for interventions to achieve a restraint‐free care. Design. Cross‐sectional study and prospective cohort study. Setting and subjects. Thirty nursing homes with 2367 residents in Hamburg, Germany. Methods. External investigators obtained prevalence of physical restraints by direct observation on three occasions on one day, psychoactive drugs were extracted from residents’ records and prospective data were documented by nurses. Results. Residents’ mean age was 86 years, 81% were female. Prevalence of residents with at least one physical restraint was 26·2% [95% confidence interval (CI) 21·3–31·1]. Centre prevalence ranged from 4·4 to 58·9%. Bedrails were most often used (in 24·5% of residents), fixed tables, belts and other restraints were rare. Prevalence of residents with at least one psychoactive drug was 52·4% (95% CI 48·7–56·1). The proportion of residents with at least one physical restraint after the first observation week of 26·3% (21·3–31·3) cumulated to 39·5% (33·3–45·7) at the end of follow‐up (10·4 SD 3·3 months). The relative frequency of observation days with at least one device ranged from 4·9–64·8% between centres. No characteristic was found to explain centre differences. Conclusions. The frequency of physical restraints and psychoactive drugs in German nursing homes is substantial. Pronounced centre variation suggests that standard care is possible without restraints. Relevance to clinical practice. Effective restraint minimisation approaches are urgently warranted. An evidence‐based guideline may overcome centre differences towards a restraint‐free nursing home care.     

Phenotype variability in spinocerebellar ataxia type 2: A longitudinal family survey and a case featuring an unusual benign course of disease

We report a 67 years old female patient out of a multigenerational family with spinocerebellar ataxia type 2 (SCA2) with an unusually benign course of disease. Although all SCA2 gene carriers have by now developed the predominant gait ataxia and brainstem oculomotor dysfunction, the index patient presented with a very mild course of disease, scoring only six points on the Scale for the Assessment and Rating of Ataxia after a disease duration of 13 years. Otherwise, intragenerational variability within family members such as the age at onset of disease and the course of disease was low. Reinvestigation of the genetic background variables in the SCA2 gene carrier reported here showed 27 repeats in the normal allele and 37 noninterrupted repeats in the abnormal allele. Interestingly, this patient has been taking lithium‐carbonate over more than 30 years because of psychotic depression. Although anecdotic, this SCA2 case may provide promising insights into possible disease modifying mechanisms in SCA2. © 2009 Movement Disorder Society     

Identification of μ‐ and κ‐opioid receptors as potential targets to regulate parasympathetic,sympathetic, and sensory neurons within rat intracardiac ganglia

Recent interest has been focused on the opioid regulation of heart performance; however, specific allocation of opioid receptors to the parasympathetic, sympathetic, and sensory innervations of the heart is scarce. Therefore, the present study aimed to characterize such specific target sites for opioids in intracardiac ganglia, which act as a complex network for the integration of the heart's neuronal in‐ and output. Tissue samples from rat heart atria were subjected to RT‐PCR, Western blot, radioligand‐binding, and double immunofluorescence confocal analysis of μ (M)‐ and κ (K)‐opioid receptors (ORs) with the neuronal markers vesicular acetylcholine transporter (VAChT), tyrosine hydroxylase (TH), calcitonin gene‐related peptide (CGRP), and substance P (SP). Our results demonstrated MOR‐ and KOR‐specific mRNA, receptor protein, and selective membrane ligand binding. By using immunofluorescence confocal microscopy, MOR and KOR immunoreactivity were colocalized with VAChT in large‐diameter parasympathetic principal neurons, with TH‐immunoreactive small intensely fluorescent (SIF) cells, and on nearby TH‐IR varicose terminals. In addition, MOR and KOR immunoreactivity were identified on CGRP‐ and SP‐IR sensory neurons throughout intracardiac ganglia and atrial myocardium. Our findings show that MOR and KOR are expressed as mRNA and translated into specific receptor proteins on cardiac parasympathetic, sympathetic, and sensory neurons as potential binding sites for opioids. Thus, they may well play a role within the complex network for the integration of the heart's neuronal in‐ and output. J. Comp. Neurol. 518:3836–3847, 2010. © 2010 Wiley‐Liss, Inc.     

A novel missense mutation in a neonate with nonketotic hyperglycinemia

Nonketotic hyperglycinemia (OMIM #605899), also known as glycine encephalopathy, is an autosomal recessive disorder of glycine metabolism caused by a defect in the glycine cleavage system. A term neonate developed progressive lethargy, muscular hypotonia, and respiratory insufficiency on day 2 after birth, but no overt clinical seizures. Amplitude-integrated electroencephalography indicated a continuous burst-suppression pattern. The diagnosis of nonketotic hyperglycinemia was made biochemically and was confirmed by genetic studies, which revealed two missense mutations (one not previously described) within the glycine decarboxylase gene, GLDC. Nonketotic hyperglycinemia should be incorporated into the differential diagnosis of neonatal hypotonia, to avoid an erroneous diagnosis of sepsis or hypoxic ischemic injury. Amplitude-integrated electroencephalography may be helpful in the initial assessment of severely sick and hypotonic neonates without overt clinical seizures, and may direct further diagnostic evaluation.     

Long-lived antitumor CD8+ lymphocytes for adoptive therapy generated using an artificial antigen-presenting cell.

PURPOSE: Antitumor lymphocytes can be generated ex vivo unencumbered by immunoregulation found in vivo. Adoptive transfer of these cells is a promising therapeutic modality that could establish long-term antitumor immunity. However, the widespread use of adoptive therapy has been hampered by the difficulty of consistently generating potent antitumor lymphocytes in a timely manner for every patient. To overcome this, we sought to establish a clinical grade culture system that can reproducibly generate antigen-specific cytotoxic T lymphocytes (CTL). EXPERIMENTAL DESIGN: We created an off-the-shelf, standardized, and renewable artificial antigen-presenting cell (aAPC) line that coexpresses HLA class I, CD54, CD58, CD80, and the dendritic cell maturation marker CD83. We tested the ability of aAPC to generate tumor antigen-specific CTL under optimal culture conditions. The number, phenotype, effector function, and in vitro longevity of generated CTL were determined. RESULTS: Stimulation of CD8(+) T cells with peptide-pulsed aAPC generated large numbers of functional CTL that recognized a variety of tumor antigens. These CTLs, which possess a phenotype consistent with in vivo persistence, survived ex vivo for prolonged periods of time. Clinical grade aAPC(33), produced under current Good Manufacturing Practices guidelines, generated sufficient numbers of CTL within a short period of time. These CTL specifically lysed a variety of melanoma tumor lines naturally expressing a target melanoma antigen. Furthermore, antitumor CTL were easily generated in all melanoma patients examined. CONCLUSIONS: With clinical grade aAPC(33) in hand, we are now poised for clinical translation of ex vivo generated antitumor CTL for adoptive cell transfer.     

Genetic animal models for retinal degeneration

Inherited retinal degenerations are a common cause of blindness in Western countries. A mechanism for most retinal degenerations is still unknown; hence, a suitable treatment for most of these diseases has yet to be found. Before one can rationally design a treatment, it is necessary to understand the pathway from a gene mutation to the phenotype in patients. Animal models are crucial to understand this process and to develop a treatment. Some naturally occurring animal models are known. However, over the past few years, transgenic engineering has allowed the generation of a rapidly growing number of animal models. In this review, we give an overview of the broad variety of genetic animal models for retinal degeneration.     

Induction of autoimmune diabetes through insulin (but not GAD65) DNA vaccination in nonobese diabetic and in RIP-B7.1 mice

Insulin has been used to modify T-cell autoimmunity in experimental models of type 1 diabetes. In a large clinical trial, the effect of insulin to prevent type 1 diabetes is currently investigated. We here show that insulin can adversely trigger autoimmune diabetes in two mouse models of type 1 diabetes, using intramuscular DNA vaccination for antigen administration. In female nonobese diabetic (NOD) mice, diabetes development was enhanced after preproinsulin (ppIns) DNA treatment, and natural diabetes resistance in male NOD mice was diminished by ppIns DNA vaccination. In contrast, GAD65 DNA conferred partial diabetes protection, and empty DNA plasmid was without effect. In RIP-B7.1 C57BL/6 mice (expressing the T-cell costimulatory molecule B7.1 in pancreatic beta-cells), autoimmune diabetes occurred in 70% of animals after ppIns vaccination, whereas diabetes did not develop spontaneously in RIP-B7.1 mice or after GAD65 or control DNA treatment. Diabetes was characterized by diffuse CD4(+)CD8(+) T-cell infiltration of pancreatic islets and severe insulin deficiency, and ppIns, proinsulin, and insulin DNA were equally effective for disease induction. Our work provides a new model of experimental autoimmune diabetes suitable to study mechanisms and outcomes of insulin-specific T-cell reactivity. In antigen-based prevention of type 1 diabetes, diabetes acceleration should be considered as a potential adverse result.     

Detection of MDM2 alterations in cultured human hepatocytes treated with 17beta-estradiol or 17alpha-ethinylestradiol

BACKGROUND: Preneoplastic and neoplastic lesions of the liver are suspected to arise as a result of estrogen treatment. Here we present the first report on the modulational effects of the steroids 17beta-estradiol (E2) and 17alpha-ethinylestradiol (EE2) on oncogene MDM2 in human hepatocytes. MATERIALS AND METHODS: Collagen-embedded cultures of hepatocytes stimulated with different E2/EE2 concentrations were analyzed by immunocytochemistry, RT-PCR and sequencing for MDM2 protein/mRNA expression, MDM2 mRNA splicing and MDM2 gene mutation. RESULTS: The hepatocytes responded to stimulation with steroid E2/EE2 concentrations from 1-100 nmol/l with the overexpression of MDM2 protein while non-stimulated cells were negative. Stimulation with 1 nmol/l E2 and 10-100 nmol/l EE2 induced MDM2 splicing variants. Hepatocytes treated with 100 nmol/l E2 contained full-length MDM2 mRNA carrying a new type of MDM2 gene mutation. Unstimulated hepatocytes revealed neither mRNA splicing nor alteration of the MDM2 genes. CONCLUSION: The data show that steroid hormones are involved in the induction of MDM2 alterations in benign human hepatocytes. We speculate that some of the alterations may influence MDM2 function, thus possibly favouring genesis of liver changes.