Understanding dementia care pathways for policy development and service planning in Kenya.

BACKGROUND: In Kenya, there is lack of evidence on existing dementia care pathways, with minimal or no presentation for dementia-related symptoms in health care settings. Understanding the services available for people with dementia as well as how communities access the services could offer a practical pattern for policy makers to identify strategies that encourage early detection, care and support for people with dementia and their families. OBJECTIVES: To elucidate initial responses of individuals and their families to dementia and challenges encountered in help seeking through care pathways to inform dementia care-related policies and practice. METHODS: The Strengthening Responses to dementia in Developing Countries (STRiDE) Kenya team adapted case vignettes (brief hypothetical stories meant to elicit responses on how the characters would behave) developed by the entire STRiDE team. A total of 29 stakeholders were then asked to provide feedback on the completed vignettes and summarize a common pathway to dementia care in Kenya while using the proposed case vignettes. FINDINGS: We found four initial responses to dementia suspicion in Kenya where individuals:(i) Perceive symptoms as normal part of ageing, (ii) Consult a spiritual or traditional healer, (iii) Visit a private clinic or primary health care facilities, or (iv) No action taken. These were the first points within the care pathways which determined the care trajectory the person with dementia would follow. CONCLUSIONS: Identification of dementia care pathways could form a basis for improving the way communities perceive dementia etiology and establish standard pathways to care whilst ensuring that some pathways do not further pose an impediment to care and treatment for dementia.

Real-life experience in the treatment of solar urticaria: retrospective cohort study.

BACKGROUND: Solar urticaria (SU) is a rare photodermatosis causing a significant impact on patients' quality of life (QoL), and treatment is often challenging. AIM: To analyse clinical experience with a tailored stepwise therapeutic approach. METHODS: A retrospective cohort design was used. Patients with suspected SU underwent laboratory investigations and photoprovocation. Those with a high minimal urticaria dose (MUD) were treated with a single antihistamine (protocol 1), and those with a lower MUD received three types of antihistamines (protocol 2); both protocols included a leucotriene receptor antagonist (LRA). In cases of failure, treatment was switched to omalizumab at doses of < 300 mg/month with incremental dosage increases as necessary (monthly dose range, 150-600 mg/month). Symptom relief and photoprovocation under treatment were evaluated. RESULTS: In total, 30 patients (10 men, 20 women) were enrolled. Most (87%) were sensitive to visible light (1-70 J/cm2 ) with or without extension to ultraviolet A. Of the 30 patients, 23 opted for our stepwise approach: 22 achieved complete remission on protocols 1 or 2 (n = 17) or after switching to omalizumab (n = 5), and another patient achieved partial remission under omalizumab. There were no treatment-related severe adverse effects. CONCLUSIONS: Symptoms of SU can be well controlled by treatment with antihistamines and an LRA tailored to the degree of photosensitivity, followed by omalizumab in refractory cases. This has important implications for patient QoL.

Bromelain-based enzymatic debridement and minimal invasive modality (mim) care of deeply burned hands.

The objective was to critically review the data and assess the implications of NexoBrid [NexoBrid-NXB formerly Debrase Gel Dressing-DGD]a in the special field of deep hand burns. Detailed analysis of endpoints in the treatment of hand burn patients was conducted as part of a multi-center, open label, randomized, controlled two-arm study to evaluate the safety and efficacy of NXB enzymatic debridement, comparing it to the current standard of care (SOC). These results were compared to a large cohort of patients treated with NXB in a previous, single arm study. Thirty-one burned hands were treated with NXB and 41 hand burns were in the SOC group. In the NXB group, 4 out of 31 hand burns (12.9%) required some excisional debridement compared to 29 out of the 41 (70.7%) in the SOC group (p<0.0001). Mean percentage of burn wound area excised in the NXB group was 4.4 ± 13.1% compared to 52.0 ± 41.4% in the SOC group (p<0.0001). None of the NXB-treated hands required escharotomy compared to 4 out of the 41 (9.7%) in the SOC group. NXB enzymatic debridement demonstrated a statistically significant reduction in burn wound excision and auto-grafting compared to SOC, and seems to prevent the need for emergency escharotomy. a DGD is produced by MediWound and distributed under the name NexoBrid®.

Le but était de réaliser une révision attentive des données et d'évaluer la place de Nexobrid (Nexobrid-NXB, précédemment Debrase Gel Dressing-DGD) dans l'indication particulière des brûlures profondes de la main. Une analyse détaillée des objectifs dans le traitement des brûlures de la main a été conduite en partie par une étude multicentrique, ouverte, randomisée, contrôlée avec 2 groupes pour évaluer la sécurité et l'efficacité de ce débridement enzymatique par rapport aux soins habituels (Standard of Care ou SOC). Ces résultats ont été comparés à une vaste cohorte de patients traités par NXB dans une étude précédente sur un seul groupe. 31 mains brûlées furent traitées par NXB et 41 dans le groupe SOC. Dans le groupe NXB, 4 sur 31 mains brûlées soit 12,9 % nécessitèrent une excision partielle, alors que 29 sur 41 dans le groupe SOC (70,7 %) (p < 0,0001). La moyenne des zones brûlées excisées dans le groupe NXB était de 4,4 (+ ou - 13,1 %) comparée aux 52,0 (+ ou - 41,4 % du groupe SOC) (p <0,0001). Aucune des mains traitées par NXB ont nécessité une excision totale, comparée à 4 sur 41 du groupe SOC (9,7 % du groupe). Le débridement enzymatique NXB montre une réduction statistiquement significative de l'indication d'excision avec autogreffe par rapport au groupe traité classiquement et semble prévenir la nécessité d'une escarrotomie en urgence.

Long-term drug administration in the adult zebrafish using oral gavage for cancer preclinical studies.

Zebrafish are a major model for chemical genetics, and most studies use embryos when investigating small molecules that cause interesting phenotypes or that can rescue disease models. Limited studies have dosed adults with small molecules by means of water-borne exposure or injection techniques. Challenges in the form of drug delivery-related trauma and anesthesia-related toxicity have excluded the adult zebrafish from long-term drug efficacy studies. Here, we introduce a novel anesthetic combination of MS-222 and isoflurane to an oral gavage technique for a non-toxic, non-invasive and long-term drug administration platform. As a proof of principle, we established drug efficacy of the FDA-approved BRAF(V600E) inhibitor, Vemurafenib, in adult zebrafish harboring BRAF(V600E) melanoma tumors. In the model, adult casper zebrafish intraperitoneally transplanted with a zebrafish melanoma cell line (ZMEL1) and exposed to daily sub-lethal dosing at 100 mg/kg of Vemurafenib for 2 weeks via oral gavage resulted in an average 65% decrease in tumor burden and a 15% mortality rate. In contrast, Vemurafenib-resistant ZMEL1 cell lines, generated in culture from low-dose drug exposure for 4 months, did not respond to the oral gavage treatment regimen. Similarly, this drug treatment regimen can be applied for treatment of primary melanoma tumors in the zebrafish. Taken together, we developed an effective long-term drug treatment system that will allow the adult zebrafish to be used to identify more effective anti-melanoma combination therapies and opens up possibilities for treating adult models of other diseases.

[Presentation of an assessment battery for visual mental imagery and visual perception]. / Normalisation d'une batterie d'évaluation de l'imagerie mentale visuelle et de la perception visuelle.

INTRODUCTION: The relationship between visual perception and visual mental imagery are at the center of a lively theoretical debate between those postulating common neurocognitive processes between perception and imagery and those who emphasize the differences between these two entities. Neuropsychology can make an important contribution to this debate, by assessing associations and dissociations between perceptual and imaginal deficits in patients with brain damage. However, currently there is no standardized test battery available for such assessments. MATERIAL AND METHODS: Here we present a battery of paper-and-pencil tests assessing different domains of visual mental imagery and visual perception abilities: object form and color, animals, orthographic material, numbers, faces, and space. We also explored the effects of age, educational level and gender on performance on a group of 103 participants free of neurological damage. RESULTS: The battery includes two parts: one composed of 14 tests assessing mental imagery and the second part composed of eight tests assessing the abilities of visual perception. We calculated the correlations between the tests, and found that, with the exception of orthographic material, there were generally poor correlations between imagery and perceptual tests. CONCLUSION: This result seems inconsistent with hypotheses postulating a strict correspondence between perceptual and imagery abilities.

Predicting drug susceptibility of non-small cell lung cancers based on genetic lesions.

Somatic genetic alterations in cancers have been linked with response to targeted therapeutics by creation of specific dependency on activated oncogenic signaling pathways. However, no tools currently exist to systematically connect such genetic lesions to therapeutic vulnerability. We have therefore developed a genomics approach to identify lesions associated with therapeutically relevant oncogene dependency. Using integrated genomic profiling, we have demonstrated that the genomes of a large panel of human non-small cell lung cancer (NSCLC) cell lines are highly representative of those of primary NSCLC tumors. Using cell-based compound screening coupled with diverse computational approaches to integrate orthogonal genomic and biochemical data sets, we identified molecular and genomic predictors of therapeutic response to clinically relevant compounds. Using this approach, we showed that v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations confer enhanced Hsp90 dependency and validated this finding in mice with KRAS-driven lung adenocarcinoma, as these mice exhibited dramatic tumor regression when treated with an Hsp90 inhibitor. In addition, we found that cells with copy number enhancement of v-abl Abelson murine leukemia viral oncogene homolog 2 (ABL2) and ephrin receptor kinase and v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) (SRC) kinase family genes were exquisitely sensitive to treatment with the SRC/ABL inhibitor dasatinib, both in vitro and when it xenografted into mice. Thus, genomically annotated cell-line collections may help translate cancer genomics information into clinical practice by defining critical pathway dependencies amenable to therapeutic inhibition.

Striatal degeneration impairs language learning: evidence from Huntington's disease.

Although the role of the striatum in language processing is still largely unclear, a number of recent proposals have outlined its specific contribution. Different studies report evidence converging to a picture where the striatum may be involved in those aspects of rule-application requiring non-automatized behaviour. This is the main characteristic of the earliest phases of language acquisition that require the online detection of distant dependencies and the creation of syntactic categories by means of rule learning. Learning of sequences and categorization processes in non-language domains has been known to require striatal recruitment. Thus, we hypothesized that the striatum should play a prominent role in the extraction of rules in learning a language. We studied 13 pre-symptomatic gene-carriers and 22 early stage patients of Huntington's disease (pre-HD), both characterized by a progressive degeneration of the striatum and 21 late stage patients Huntington's disease (18 stage II, two stage III and one stage IV) where cortical degeneration accompanies striatal degeneration. When presented with a simplified artificial language where words and rules could be extracted, early stage Huntington's disease patients (stage I) were impaired in the learning test, demonstrating a greater impairment in rule than word learning compared to the 20 age- and education-matched controls. Huntington's disease patients at later stages were impaired both on word and rule learning. While spared in their overall performance, gene-carriers having learned a set of abstract artificial language rules were then impaired in the transfer of those rules to similar artificial language structures. The correlation analyses among several neuropsychological tests assessing executive function showed that rule learning correlated with tests requiring working memory and attentional control, while word learning correlated with a test involving episodic memory. These learning impairments significantly correlated with the bicaudate ratio. The overall results support striatal involvement in rule extraction from speech and suggest that language acquisition requires several aspects of memory and executive functions for word and rule learning.

Covert processing of faces in prosopagnosia is restricted to facial expressions: evidence from cross-modal bias.

We present a single case study of a brain-damaged patient, AD, suffering from visual face and object agnosia, with impaired visual perception and preserved mental imagery. She is severely impaired in all aspects of overt recognition of faces as well as in covert recognition of familiar faces. She shows a complete loss of processing facial expressions in recognition as well as in matching tasks. Nevertheless, when presented with a task where face and voice expressions were presented concurrently, there was a clear impact of face expressions on her ratings of the voice. The cross-modal paradigm used here and validated previously with normal subjects (de Gelder & Vroomen, 1995, 2000), appears as a useful tool in investigating spared covert face processing in a neuropsychological perspective, especially with prosopagnosic patients. These findings are discussed against the background of different models of the covert recognition of face expressions.

Multiple-domain dissociation between impaired visual perception and preserved mental imagery in a patient with bilateral extrastriate lesions.

A brain-damaged patient is described whose pattern of performance provides insight into both the functional mechanisms and the neural structures involved in visual mental imagery. The patient became severely agnosic, alexic, achromatopsic and prosopagnosic following bilateral brain lesions in the temporo-occipital cortex. However, her mental imagery for the same visual entities that she could not perceive was perfectly preserved. This clear-cut dissociation held across all the major domains of high-level vision: object recognition, reading, colour and face processing. Our findings, together with other reports on domain-specific dissociations and functional brain imaging studies, provide evidence to support the view that visual perception and visual mental imagery are subserved by independent functional mechanisms, which do not share the same cortical implementation. In particular, our results suggest that mental imagery abilities need not be mediated by early visual cortices.

Confabulation following rupture of posterior communicating artery.

In this study we report a patient, MG, who following rupture of left posterior communicating artery exhibited an amnesic-confabulatory syndrome. Neuropsychological examination showed severe impairment on episodic memory tasks, which were marred by florid but plausible and semantically appropriate confabulation. Performance on tasks involving various kinds of semantic knowledge was normal or only mildly impaired. Performance on tasks traditionally considered sensitive to frontal dysfunction was severely impaired with the exception of Cognitive Estimates where MG's performance was completely normal. There was no evidence of structural (CT scan) or metabolic (SPECT) damage to the frontal lobe. It is argued that tasks traditionally considered sensitive to frontal dysfunction are not specifically implemented by cognitive resources based on frontal structures. MG's confabulation is discussed in terms of a possible disruption of cognitive functions involved in the control of the subjective experience of feeling of remembering.

Cultured adult rabbit myocytes: effect of adding supplements to the medium, and response to isoprenaline.

INTRODUCTION: The aims of this study were to investigate: (1) the effect of supplementing the culture medium on preservation of L-type calcium channel current (1Ca,L) in adult rabbit ventricular myocytes cultured for 4 days; and (2) preservation of the ICa,L response in cultured myocytes to the beta-adrenergic agonist isoprenaline. METHODS AND RESULTS: Adult rabbit myocytes were cultured on laminin-pretreated glass coverslips. The basic, serum-free culture medium was supplemented with 2 mM L-carnitine, 5 mM creatine, and 5 mM taurine. Myocytes were whole cell patch-clamped, and the L-type Ca channel current was recorded selectively as Ba flux (IBa,L) via the channels. IBa,L density (i.e., IBa,L amplitude normalized to membrane capacitance) in myocytes maintained in supplemented medium did not change significantly during culture (P > 0.1). By comparison, IBa,L density in myocytes cultured in nonsupplemented medium declined by 36% after 24 hours in culture (day 1) and then recovered by the fourth day (day 4). There was no significant difference in the response to isoprenaline of acutely isolated myocytes and 4-day cultured myocytes. Isoprenaline 100 nM increased peak IBa,L by 149% +/- 32% (mean +/- SEM) in acutely isolated myocytes (n = 4 cells), and by 224% +/- 60% (n = 6 cells) and 159% +/- 24% (n = 8 cells) in day 1 and 4 cultured myocytes, respectively. CONCLUSIONS: Supplemented medium improved IBa,L density in cultured myocytes. beta-Adrenergic receptors and intracellular messenger pathways appear to remain intact in adult rabbit myocytes cultured for up to 4 days.

Preserved imagery for colours in a patient with cerebral achromatopsia.

We report the case of a patient who, after sequential bilateral strokes in the occipital regions sparing the primary visual cortex, developed a severe deficit of colour perception. At variance with other reports of acquired achromatopsic patients, she showed a perfectly vivid visual imagery for colours. These findings, together with similar data in domains other than colour processing, challenge the theories which posit that the same cognitive processes are involved in both the perception and the retrieval from memory of a given stimulus.

Hypothalamic expression of a novel gene product, VGF: immunocytochemical analysis.

VGF is the designation for a new 712 amino acid protein, regulated by nerve growth factor (NGF) in PC12 cells, that has not been previously described in the CNS. Northern blot analysis with a nick-translated VGF cDNA probe revealed a single band of mRNA in the brain with a molecular weight identical to that found in PC12 cells. The current paper presents a series of immunocytochemical studies of VGF expression with a focus on the hypothalamus. Two different antisera were raised against nonoverlapping amino acid sequences of a bacterial-expressed protein from the VGF gene cloned from PC12 cells. VGF immunoreactivity is strongly expressed in the rat suprachiasmatic nucleus (SCN), particularly in the dorsomedial part of the nucleus. The administration of colchicine to block axonal transport facilitates detection of the VGF immunoreactivity also in the ventrolateral suprachiasmatic nucleus. This protein appears to be the first one of limited neuronal distribution which is found in both dorsomedial SCN and ventrolateral SCN. Immunostaining of serial 1 micron SCN sections reveals co-localization of VGF in cells which also contain vasopressin or vasoactive intestinal polypeptide. Weaker immunoreactivity is also found in the magnocellular paraventricular and supraoptic nuclei, where the VGF immunoreactivity co-localizes with oxytocin or vasopressin. Mutant Brattleboro rats which do not express vasopressin showed strong VGF immunoreactivity both in the dorsomedial SCN and in cells of the magnocellular neuronal systems, including cells which normally express vasopressin. When axonal transport of the protein is blocked by colchicine, VGF-immunoreactive cells in the hypothalamic arcuate, parvocellular paraventricular, and tuberomammillary nuclei can also be detected, in addition to weakly immunoreactive scattered cells in the hippocampus, amygdala, thalamus, and cortex. VGF immunoreactivity is strong in the axonal projections of SCN and weak in the axons of the paraventricular and supraoptic nuclei. With ultrastructural studies, VGF immunoreactivity is found in presynaptic boutons in the SCN and in axons in the neurohypophysis. Weak axonal staining is present in some regions of the hypothalamus and in the external and internal zones of the median eminence. Immunoreactivity is absent from the intermediate lobe of the hypophysis. In neonatal rats strong VGF immunoreactivity is found throughout the SCN at postnatal day 4 but not in the adjacent hypothalamus. VGF immunoreactivity is also seen in other areas of the brain in neonatal rats, including the lateral geniculate nucleus; while the staining in the dorsal lateral geniculate disappears in the adult, that in the intergeniculate leaflet, a visual center which projects to the SCN, remains.(ABSTRACT TRUNCATED AT 400 WORDS)

Deep heat in the treatment of inflammatory joint disease.

There is now a growing body of clinical evidence suggesting a therapeutic approach to cancer and prostatic hypertrophy by using hyperthermia. It is proposed that such a hyperthermic modality can produce thermal synovectomy in inflammatory arthritis. Heating the joint cavity up to 42 deg C can inhibit the enzymatic effect of collagenase, oxygenase, and other enzymes playing a role in the inflammatory process. If this hypothesis is correct, therapeutic intervention using hyperthermia may offer hope for the treatment of isolated inflammatory joint diseases.

Intestinal permeability and inflammation in rheumatoid arthritis: effects of non-steroidal anti-inflammatory drugs.

The suggestion that the intestinal mucosa may be abnormally permeable and a site of absorption of antigens in rheumatoid arthritis was tested by the use of a 51Cr-EDTA (edetic acid) absorption test. 24 patients with rheumatoid arthritis excreted significantly more 51Cr-EDTA than did 34 controls. Intestinal permeability was normal in untreated patients but almost invariably abnormal in patients treated with non-steroidal anti-inflammatory drugs. Studies in patients with osteoarthritis showed that the permeability abnormalities were due to an effect of NSAIDs on both the proximal and the distal intestine and that the effect was systemically mediated. Indium-111-labelled leucocyte scans showed ileocaecal inflammation in 6 of 9 patients on or recently on NSAIDs. Although increased intestinal permeability does not seem to be important in the pathogenesis of rheumatoid arthritis, the administration of NSAIDs may lead to loss of intestinal integrity, thus facilitating antigenic absorption and perhaps contributing to persistence of the disease.

Absorption of 51chromium-labeled ethylenediaminetetraacetate in inflammatory bowel disease.

Intestinal permeability was assessed in patients with inflammatory bowel disease by measuring the urine excretion of 51chromium-labeled ethylenediaminetetraacetate over periods up to 24 h after oral administration. Twenty-eight control subjects and 10 patients with ulcerative colitis excreted less than 2.6% of the test dose in 24 h. Ten patients with small bowel Crohn's disease excreted 3.3%-14.0%, and 10 of 11 patients with ileocolonic involvement had increased excretion. At the same time, 5 of 11 patients with Crohn's colitis were clearly outside the normal range, suggesting small bowel involvement. The 24-h urine excretion of 51chromium-labeled ethyl-enediaminetetraacetate after oral administration appears to be a sensitive, noninvasive test for assessing small intestinal integrity, and may be a valuable adjuvant in the differential diagnosis of inflammatory bowel disease.