Profound cardiac conduction delay predicts mortality in myotonic dystrophy type 1.

BACKGROUND: Myotonic dystrophy type 1 (DM1) is known to affect mainly the musculoskeletal system. Early mortality is related to respiratory disease and possibly additional cardiovascular complications. AIMS: To identify possible cardiovascular disturbances that could predict survival of DM1 patients. METHODS: We studied 30 DM1 patients (mean age 41 +/- 13.5 years, range 16-71, 15 women) who were cardiovascularly stable and compared them with 29 controls (mean age 55 +/- 7.8 years, range 42-66, 14 women) using electrocardiography (ECG) and conventional transthoracic echocardiography. The subgroup that survived a follow-up period of 17 years was re-examined using the same protocol. RESULTS: Of the 30 patients, 10 died of a documented respiratory cause and three of acute myocardial incidents. Compared with controls, left ventricular cavity size, corrected to body surface area, was slightly enlarged at end systole (P < 0.05) and hence fractional shortening was reduced (P < 0.01). Nine patients had first-degree heart block and 15 had a QRS duration >90 ms. Of all ECG and echocardiographic measurements, the sum of QRS duration + PR interval was the best predictor of mortality as shown by the area under the receiver operating characteristic curve of 85%, sensitivity of 70% and specificity of 84%. CONCLUSIONS: These findings suggest that silent cardiac dysfunction in DM1 patients may cause significant disturbances that over time result in serious complications. Regular follow-up of such patients with detailed electrical and mechanical cardiac assessment may suggest a need for early intervention that may avoid early mortality in some.

Long-term effect of the ICU-diary concept on quality of life after critical illness.

BACKGROUND: Critically ill patients often spend time in the intensive care unit (ICU) either unconscious or sedated. On recovery, they are often in a state of confusion with memory loss that may be associated with a longstanding reduction in health-related quality of life (QoL). We hypothesised that the ICU-diary concept could improve their QoL by filling in their memory gaps. METHODS: A non-randomised, prospective study in a non-academic eight-bedded general ICU. A group of patients (n=38) were selected to receive the ICU-diary concept (keeping a diary with photos while on the ICU plus a follow-up meeting) when a long and complicated course was expected. Health-related QoL at 6, 12, 24 and 36 months was compared with a group that did not receive the ICU-diary (n=224). The Medical Outcomes Study 36-Item Short-Form (SF-36) was used to measure health-related QoL. Multiple regression models adjusted for age, sex, illness severity, pre-existing disease and diagnostic category was used to analyse the effects of the ICU-diary concept at 6 months, and changes over time were analysed using repeated measures MANOVA. RESULTS: Crude and adjusted scores for two dimensions of SF-36 (general health and vitality) and the physical component summary score were significantly higher at 6 months in the ICU-diary group (P<0.05) and some of the effects remained during the 3-year follow-up period (P<0.05). CONCLUSION: The ICU-diary concept was associated with improved health-related QoL during the 3-year follow-up period after a critical illness. The effect of this intervention needs to be confirmed in a larger randomised study.

Blood-brain barrier penetration and in vivo activity of an NGF conjugate.

Nerve growth factor (NGF) is essential for the survival of both peripheral ganglion cells and central cholinergic neurons of the basal forebrain. The accelerated loss of central cholinergic neurons during Alzheimer's disease may be a determinant of dementia in these patients and may therefore suggest a therapeutic role for NGF. However, NGF does not significantly penetrate the blood-brain barrier, which makes its clinical utility dependent on invasive neurosurgical procedures. When conjugated to an antibody to the transferrin receptor, however, NGF crossed the blood-brain barrier after peripheral injection. This conjugated NGF increased the survival of both cholinergic and noncholinergic neurons of the medial septal nucleus that had been transplanted into the anterior chamber of the rat eye. This approach may prove useful for the treatment of Alzheimer's disease and other neurological disorders that are amenable to treatment by proteins that do not readily cross the blood-brain barrier.

Amyloid fibril composition is related to the phenotype of hereditary transthyretin V30M amyloidosis.

Swedish familial systemic amyloidosis with polyneuropathy (FAP) depends on a mutation leading to a methionine-for-valine substitution in transthyretin. The disease appears with different clinical manifestations, including age of onset and involvement of the heart. Liver transplantation is currently the only curative treatment, but progressive cardiomyopathy may occur post-transplant. Two amyloid deposition patterns have previously been described in the heart. In one, the amyloid consists partially of transthyretin fragments and is weakly stainable by Congo red, while in the other, only full-length molecules are found and the fibrils have a strong affinity for Congo red. The present study aimed to see whether these morphological and biochemical variations have clinical implications. Subcutaneous adipose tissue biopsies were taken from 33 patients with Val30Met FAP and examined by microscopy, electrophoresis and western blot. Clinical data included age, sex, duration of disease and echocardiographic determination of the interventricular septum (IVS) thickness. It was found that fibrils composed of only full-length transthyretin were associated with early age of onset (44.8 +/- 12.9 years), no clinical cardiac involvement and a strong affinity for Congo red. In contrast, presence of transthyretin fragments in the amyloid was associated with late age of onset (67.3 +/- 7.0 years), signs of cardiac involvement and weak Congo red staining. For each individual, the same molecular type of amyloid was found in different organs. This is the first report showing that variations in clinical appearance of familial ATTR amyloidosis are associated with specific structural differences in the amyloid fibrils, and therefore may have a molecular cause. The molecular type of amyloid can be determined from a subcutaneous fat tissue biopsy.

Do troponin and B-natriuretic peptide detect cardiomyopathy in transthyretin amyloidosis?

OBJECTIVES: Cardiomyopathy is a well known complication in familial amyloidotic polyneuropathy (FAP). Troponin T and B-natriuretic peptide (BNP) have been shown to be excellent markers for heart complications in AL-amyloidosis. The aim of the study was to investigate troponin T, troponin I and BNP as markers for myocardial damage and failure in FAP. DESIGN: Retrospective investigation of patients with FAP. SETTING: Tertiary referral centre. SUBJECTS: Twenty-nine patients who had been submitted for evaluation of FAP. INTERVENTIONS: Two-dimensional M-mode and Doppler echocardiography and strain echocardiographic examination. Measurement of Troponin T, troponin I and BNP. RESULTS: Troponin T was detectable in only three patients who all had abnormal interventricular septal (IVS) thickness. Troponin I was abnormal in six patients (21%), of which only two had an increased IVS thickness. The heart function was generally well preserved in the patients in spite of hypertrophy of the IVS in 14 patients. BNP was elevated in 22 patients (76%), and it correlated significantly with IVS thickness and basal septal strain. CONCLUSIONS: Transthyretin amyloid seems to be less harmful to myocytes than that of AL amyloid as evaluated by serum troponin T and I as well as by echocardiography. BNP appears to be a sensitive marker for cardiomyopathy in FAP, and could prove valuable for follow-up purposes as has been shown for AL-amyloidosis patients.

Evidence-based guidelines for the prevention of ventilator-associated pneumonia: results of a knowledge test among European intensive care nurses.

As part of a needs analysis preceding the development of an e-learning platform on infection prevention, European intensive care unit (ICU) nurses were subjected to a knowledge test on evidence-based guidelines for preventing ventilator-associated pneumonia (VAP). A validated multiple-choice questionnaire was distributed to 22 European countries between October 2006 and March 2007. Demographics included nationality, gender, ICU experience, number of ICU beds and acquisition of a specialised degree in intensive care. We collected 3329 questionnaires (response rate 69.1%). The average score was 45.1%. Fifty-five percent of respondents knew that the oral route is recommended for intubation; 35% knew that ventilator circuits should be changed for each new patient; 38% knew that heat and moisture exchangers were the recommended humidifier type, but only 21% knew that these should be changed once weekly; closed suctioning systems were recommended by 46%, and 18% knew that these must be changed for each new patient only; 51% and 57%, respectively, recognised that subglottic drainage and kinetic beds reduce VAP incidence. Most (85%) knew that semi-recumbent positioning prevents VAP. Professional seniority and number of ICU beds were shown to be independently associated with better test scores. Further research may determine whether low scores are related to a lack of knowledge, deficiencies in training, differences in what is regarded as good practice, and/or a lack of consistent policy.

Precipitants of post-traumatic stress disorder following intensive care: a hypothesis generating study of diversity in care.

OBJECTIVE: This prospective observational study was designed to explore the relationships between post-traumatic stress disorder (PTSD), patients' memories of the intensive care unit (ICU) and sedation practices. DESIGN: Prospective multi-centre follow-up study out to 3 months after ICU discharge. SETTING: Two district general hospitals and three teaching hospitals across Europe. PATIENTS AND PARTICIPANTS: Two hundred and thirty-eight recovering, post-ventilated ICU patients. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Assessment of patients' memories of ICU was undertaken at 1-2 weeks post ICU discharge. Patients' psychological recovery was assessed by examining the level of PTSD-related symptoms and rate of PTSD by 3 months post ICU. The rate of defined PTSD was 9.2%, ranging from 3.2% to 14.8% in the different study ICUs. Independent of case mix and illness severity, the factors found to be related to the development of PTSD were recall of delusional memories, prolonged sedation, and physical restraint with no sedation. CONCLUSION: The development of PTSD following critical illness is associated with a number of different precipitating factors that are in part related to how patients are cared for within intensive care. This study raises the hypothesis that the impact of care within the ICU has an impact on subsequent psychological morbidity and therefore must be assessed in future studies looking at the way patients are sedated in the ICU and how physical restraint is used.

Repeated intratumoral administration of ONCOS-102 leads to systemic antitumor CD8+ T-cell response and robust cellular and transcriptional immune activation at tumor site in a patient with ovarian cancer.

Adenoviruses are excellent immunotherapeutic agents with a unique ability to prime and boost immune responses. Recombinant adenoviruses cause immunogenic cancer cell death and subsequent release of tumor antigens for antigen presenting cells, resulting in the priming of potent tumor-specific immunity. This effect may be further enhanced by immune-stimulating transgenes expressed by the virus. We report a case of a 38-year-old female with Stage 3 metastatic micropapillary serous carcinoma of the ovary. She was treated in a Phase I study with a granulocyte-macrophage colony stimulating factor (GMCSF)-expressing oncolytic adenovirus, Ad5/3-D24-GMCSF (ONCOS-102). The treatment resulted in progressive infiltration of CD8+ lymphocytes into the tumor and concomitant systemic induction of several tumor-specific CD8+ T-cell populations. The patient was alive at the latest follow up more than 20 months after initiation of the study.

Effects of ethanol on development of dorsal raphe transplants in oculo: a morphological and electrophysiological study.

The purpose of this project was to investigate ethanol influence on the development of serotonin-containing (5-HT) neurons of the dorsal raphe nucleus in rat. Fetal tissue of embryonic day 17 from the dorsal brainstem was grafted to the anterior chamber of the eye of adult albino rats. The experimental group was exposed to 16% ethanol in the drinking water, and the control group received water ad libitum. After 4 weeks, morphological and electrophysiological evaluations were performed. Immunohistochemical analysis showed that 5-HT-immunoreactive fibers from ethanol-treated transplants had a disturbed outgrowth pattern into the host iris as compared to the control group. Furthermore, the outgrowth area and axon bundle formation was significantly greater in the control group than in the ethanol group. Electrophysiological recordings revealed a dose-dependent biphasic effect of locally applied ethanol on transplanted monoaminergic neurons. Low doses of ethanol (0.5-3 mM) induced an increase in basal firing rate of control neurons, while higher doses (10-100 mM) caused inhibition. However, monoaminergic neurons in the ethanol group showed a decreased neuronal sensitivity to locally applied ethanol. The same dose of locally applied ethanol which produced an excitation of neuronal activity in the ethanol transplants produced an inhibition in the control grafts. The dose-response curve was shifted to the right. The present results suggest that chronic ethanol exposure during early development leads to altered axonal outgrowth from brainstem 5-HT neurons, as well as decreased sensitivity of these neurons to locally applied ethanol.

Carrier mediated delivery of NGF: alterations in basal forebrain neurons in aged rats revealed using antibodies against low and high affinity NGF receptors.

The distribution of low and high affinity nerve growth factor (NGF) receptors was investigated in the basal forebrain during aging and NGF treatment. A peripheral administration model for NGF was utilized. NGF was conjugated to a transferrin receptor antibody (OX-26-NGF), and this conjugate was injected into the tail vein of aged Fischer 344 male rats (24 months) twice weekly for 5 weeks (equivalent to 50 microg of NGF/injection). Controls were injected with a non-conjugated mixture of OX-26 and NGF. The aged rats treated with conjugate showed a significant increase in cell size of p75- and trkA-immunoreactive neurons in the medial septal nucleus and vertical limb of the diagonal band as compared to controls. A significant increase in cell size of trkA-immunoreactive neurons was also observed in the horizontal limb of the diagonal band in rats treated with conjugate. Rats treated with conjugate also showed a significant increase in overall staining density for p75 and trkA antibodies in the medial septal nucleus as compared to controls. A significant increase in staining density of p75-immunoreactive structures was also observed in the vertical and horizontal limbs of the diagonal band. Therefore, treatment with OX-26-NGF conjugate has regional effects on both the low and high affinity NGF receptors in terms of cell body size and staining density in the basal forebrain of aged rats. The current findings support the idea that this delivery system might be useful in therapeutic approaches involving the delivery of neurotrophic factors and other large molecules into the brain.

A non-invasive system for delivering neural growth factors across the blood-brain barrier: a review.

Intraventricular administration of nerve growth factor (NGF) in rats has been shown to reduce age-related atrophy of central cholinergic neurons and the accompanying memory impairment, as well as protect these neurons against a variety of perturbations. Since neurotrophins do not pass the blood-brain barrier (BBB) in significant amounts, a non-invasive delivery system for this group of therapeutic molecules needs to be developed. We have utilized a carrier system, consisting of NGF covalently linked to an anti-transferrin receptor antibody (OX-26), to transport biologically active NGF across the BBB. The biological activity of this carrier system was tested using in vitro bioassays and intraocular transplants; we were able to demonstrate that cholinergic markers in both developing and aged intraocular septal grafts were enhanced by intravenous delivery of the OX-26-NGF conjugate. In subsequent experiments, aged (24 months old) Fischer 344 rats received intravenous injections of the OX-26-NGF conjugate for 6 weeks, resulting in a significant improvement in spatial learning in previously impaired rats, but disrupting the learning ability of previously unimpaired rats. Neuroanatomical analyses showed that OX-26-NGF conjugate treatment resulted in a significant increase in cholinergic cell size as well as an upregulation of both low and high affinity NGF receptors in the medial septal region of rats initially impaired in spatial learning. Finally, OX-26-NGF was able to protect striatal cholinergic neurons against excitotoxicity and basal forebrain cholinergic neurons from degeneration associated with chemically-induced loss of target neurons. These results indicate the potential utility of the transferrin receptor antibody delivery system for treatment of neurodegenerative disorders with neurotrophic substances.

Impact of autonomic neuropathy on circulatory instability during liver transplantation for familial amyloidotic polyneuropathy.

BACKGROUND: Circulatory instability with severe hypotension frequently complicates liver transplantation in patients with familial amyloidotic polyneuropathy. Autonomic dysfunction is found early in the course of the disease by analysis of beat-to-beat heart rate variability (HRV). The aim of the present study was to investigate the impact of autonomic neuropathy on intraoperative circulatory instability during liver transplantation for familial amyloidotic polyneuropathy. METHODS: Twenty-two patients were evaluated at the Department of Medicine, Umea University Hospital, by spectral analysis of HRV and later received liver transplants at Huddinge University Hospital. The low-and high-frequency bands obtained by spectral analysis of HRV in the supine and upright positions, respectively, were used as representative of sympathetic and parasympathetic activity. Circulatory instability during transplantation was defined as a fall in systolic arterial blood pressure below 70 mmHg for more than 5 min during the preanhepatic phase. RESULTS: Both arrhythmia preventing spectral analysis of HRV and a sympathetic variability peak below 2.5 mHz2 were significantly more common among patients with intraoperative circulatory instability (P=0.03 and 0. 004, respectively). A diminished increase in pulse rate when tilting the patients from the supine to the upright position was also more pronounced among patients with circulatory instability (P<0.05). CONCLUSIONS: The majority of patients who will develop circulatory instability with a pronounced fall in arterial blood pressure can be identified by Poincare plots of R-R intervals and spectral analysis of HRV. A low sympathetic peak or arrhythmia precluding spectral analysis of HRV is significantly related to operative circulatory instability.

Contaminated collection media as a cause of pseudoinfection.

Following the appearance of positive Gram's stains from sterile surgical cases, an investigation was begun. Nonviable but stainable bacteria were found in the gel-based transport media. The use of a cause-and-effect diagram helped to show the numerous items that affected the problem.

Effects of age and GDNF on noradrenergic innervation of the hippocampal formation: studies from intraocular grafts.

Recent studies have suggested that factors in the target tissue influence the degree of plasticity and regeneration following aging and/or specific insults. We have investigated whether young or aged targets differ in their noradrenergic innervation from fetal locus coeruleus (LC) neurons, and also if a specific growth factor, glial cell line-derived neurotrophic factor (GDNF) can affect this innervation pattern. Tissue pieces of fetal brainstem and young (3 months) or old (18 months) iris tissue were transplanted simultaneously into the anterior chamber of the eye of adult hosts. We found that aged iris transplants became innervated to a significantly lesser degree by the cografted LC neurons than young iris transplants. Fetal hippocampal tissue was then grafted to adult hosts, and a fetal brainstem graft containing LC neurons was placed adjacent to the first graft, either at 3 or 21 months post-grafting. Thus, old/young chimeras of the noradrenergic coeruleo-hippocampal pathway were created. Aged hippocampal grafts received a much less dense innervation from co-grafted LC neurons than young hippocampal grafts. Tyrosine hydroxylase-positive-immunoreactive innervation was only found in the outskirts of aged grafts, while the young hippocampal grafts contained an even innervation pattern. The innervation density of hippocampal grafts was significantly enhanced by GDNF treatment. These findings demonstrate that target-derived factors may regulate neuronal plasticity, and that the age of the target is more important for innervation properties than the age of the neuron innervating a particular target.

Use of a personal diary written on the ICU during critical illness.

OBJECTIVE: To explore the use of a diary as an aid in debriefing patients and relatives following critical illness. DESIGN: Observation study. SETTING: Intensive care unit of a 500-bed hospital. PATIENTS AND PARTICIPANTS: Fifty-one critically ill patients and their relatives. METHOD: A daily account of the patient's progress was written in everyday language by nursing staff, photographs were added as necessary. The booklet was given to the patient or a relative at a follow-up appointment 2 weeks after discharge from the unit. A standard questionnaire was mailed 6 months later, responses were analyzed by an independent observer. MEASUREMENTS AND RESULTS: All diaries had been read by survivors (n = 41) or relatives (n = 10), 51% of the diaries had been read more than 10 times. Comments in the questionnaires were graded as very positive (39%), positive (28%) and neutral (33%). CONCLUSIONS: A detailed narrative of the patient's stay is a useful tool in the debriefing process following intensive care.

A selective group of dopaminergic neurons express Nurr1 in the adult mouse brain.

Nurr1, an orphan receptor of the nuclear receptor superfamily, is widely expressed in the central nervous system (CNS) including brain regions where dopaminergic neurons are abundant. Recent analyses of Nurr1 null mutant mice have shown that Nurr1 is essential for the development and survival of midbrain dopaminergic neurons. However, other dopaminergic neuronal populations do not seem to be affected by ablation of the Nurr1 gene. The purpose of the present study was to investigate the degree of co-existence of Nurr1 mRNA and tyrosine hydroxylase (TH) immunoreactivity in the brain of adult mice to better characterize the selective effects of Nurr1 on catecholaminergic neurons. Our results indicate that the majority of TH-immunoreactive neurons in the substantia nigra (SN; 96%), ventral tegmental area (VTA; 95%), retrorubral field (91%), olfactory bulb (85%), linear nucleus raphe (91%) and central grey (61%) express Nurr1. In contrast, dopaminergic cells of the paraventricular and periventricular hypothalamic nucleus showed only a few Nurr1/TH double labeled neurons, while TH-immunoreactive neurons in the arcuate nucleus and zona incerta did not express Nurr1 mRNA. Nurr1 expression was also excluded from (nor)adrenergic neurons of the brainstem. In conclusion, Nurr1 transcripts were not found in all CNS catecholaminergic neurons. Nurr1 expression was confined to periglomerular and midbrain dopaminergic neurons. These results suggest that within the adult mouse brain, Nurr1 may participate in dopaminergic functions of the olfactory bulb and midbrain.

Cellular mRNA expression of the transcription factor NGFI-B suggests a gene regulatory role in striatal opiate-peptide neurons.

Previous studies have shown that NGFI-B mRNA is highly expressed in the adult striatum. In the present study we analyzed the anatomical distribution of NGFI-B mRNA within this brain region as well as the degree of co-existence of NGFI-B with different striatal markers in the adult brain. NGFI-B mRNA levels were found to be significantly higher within the dorsomedial portion of the striatum as compared to the ventrolateral striatum. This distribution pattern was maintained throughout the rostro--caudal axis of the striatum. Double in situ hybridization studies showed that striatal NGFI-B mRNA colocalized with a subset of preproenkephalin and prodynorphin positive spiny neurons within the dorsomedial striatum; 22--28% of all opiate-peptide positive cells co-expressed NGFI-B mRNA. NGFI-B did not colocalize with striatal aspiny interneurons expressing choline acetyl transferase mRNA or those containing the calcium-binding protein parvalbumin. The pattern of NGFI-B mRNA expression within different striatal spiny projecting neurons suggests that this transcription factor may have a direct effect on the function of different striatal efferent pathways.

Arthritis hand function test: inter-rater reliability among self-trained raters.

OBJECTIVE: The purpose of this project was to examine the inter-rater reliability of the Arthritis Hand Function Test (AHFT), a new instrument for measuring hand strength and dexterity in adults with arthritis. METHODS: Six occupational therapists (two at each of three sites) trained themselves as AHFT administrators using the test manual and training videotape. They recruited 30 adult subjects (10 at each site) with rheumatoid arthritis or osteoarthritis affecting the hands. There were 21 women and 9 men in the sample (mean age, 57.5 years; average time since diagnosis, 14.8 years). Subjects were tested twice, once by each rater from that site. RESULTS: Inter-rater reliability ranged from 0.45 to 0.99 (Pearson r). Because subjects were tested twice, AHFT scores were examined for an order effect. Although scores on all strength items declined by the second test session, and improved for all dexterity items, only the aggregate applied dexterity score showed significant change across all three sites (P = 0.002, 0.001, and 0.031, respectively). CONCLUSIONS: These results suggest the AHFT is a reliable instrument for measuring hand strength and dexterity that requires minimal training on the part of occupational therapist raters.

Chronic achilles paratenonitis with tendinosis: an experimental model in the rabbit.

An experimental model for inducing chronic Achilles paratenonitis with tendinosis in the rabbit is presented. Thirteen rabbits were exercised in a kicking machine producing passive flexions and extensions of the ankle joint. Active contractions of the triceps surae muscles were induced by electric stimulation via surface electrodes. The animals were exercised for 5 to 6 weeks, with a rate of 150 flexions and extensions per minute for 2 h, three times a week. Light microscopic examination showed degenerative changes of the tendon, and increased number of capillaries, infiltrates of inflammatory cells, edema, and fibrosis in the paratenon. We conclude that chronic Achilles paratenonitis with tendinosis can be experimentally induced in a standardized manner in rabbits.

Technetium-99m pyrophosphate single-photon emission computed tomography of the heart in familial amyloid polyneuropathy.

A patient with familial amyloid polyneuropathy and congestive heart failure underwent myocardial imaging using technetium-99m pyrophosphate. Planar scintigraphy showed an intense, diffuse biventricular uptake of the radiotracer. Single-photon emission computed tomography demonstrated an unevenly distributed uptake of the isotope. The greatest activity corresponded to regions with marked echocardiographic changes. Emission tomography may aid in assessing the degree and distribution of the infiltrative lesions in cardiac amyloidosis.