Factors that influence the provision of home-based rehabilitation services for people needing rehabilitation: a qualitative evidence synthesis.

BACKGROUND: To increase people's access to rehabilitation services, particularly in the context of the COVID-19 pandemic, we need to explore how the delivery of these services can be adapted. This includes the use of home-based rehabilitation and telerehabilitation. Home-based rehabilitation services may become frequently used options in the recovery process of patients, not only as a solution to accessibility barriers, but as a complement to the usual in-person inpatient rehabilitation provision. Telerehabilitation is also becoming more viable as the usability and availability of communication technologies improve. OBJECTIVES: To identify factors that influence the organisation and delivery of in-person home-based rehabilitation and home-based telerehabilitation for people needing rehabilitation. SEARCH METHODS: We searched PubMed, Global Health, the VHL Regional Portal, Epistemonikos, Health Systems Evidence, and EBM Reviews as well as preprints, regional repositories, and rehabilitation organisations websites for eligible studies, from database inception to search date in June 2022.  SELECTION CRITERIA: We included studies that used qualitative methods for data collection and analysis; and that explored patients, caregivers, healthcare providers and other stakeholders' experiences, perceptions and behaviours about the provision of in-person home-based rehabilitation and home-based telerehabilitation services responding to patients' needs in different phases of their health conditions.   DATA COLLECTION AND ANALYSIS: We used a purposive sampling approach and applied maximum variation sampling in a four-step sampling frame. We conducted a framework thematic analysis using the CFIR (Consolidated Framework for Implementation Research) framework as our starting point. We assessed our confidence in the findings using the GRADE-CERQual (Confidence in the Evidence from Reviews of Qualitative research) approach.  MAIN RESULTS: We included 223 studies in the review and sampled 53 of these for our analysis. Forty-five studies were conducted in high-income countries, and eight in low-and middle-income countries. Twenty studies addressed in-person home-based rehabilitation, 28 studies addressed home-based telerehabilitation services, and five studies addressed both modes of delivery. The studies mainly explored the perspectives of healthcare providers, patients with a range of different health conditions, and their informal caregivers and family members.  Based on our GRADE-CERQual assessments, we had high confidence in eight of the findings, and moderate confidence in five, indicating that it is highly likely or likely respectively that these findings are a reasonable representation of the phenomenon of interest. There were two findings with low confidence. High and moderate confidence findings Home-based rehabilitation services delivered in-person or through telerehabilitation  Patients experience home-based services as convenient and less disruptive of their everyday activities. Patients and providers also suggest that these services can encourage patients' self-management and can make them feel empowered about the rehabilitation process. But patients, family members, and providers describe privacy and confidentiality issues when services are provided at home. These include the increased privacy of being able to exercise at home but also the loss of privacy when one's home life is visible to others.  Patients and providers also describe other factors that can affect the success of home-based rehabilitation services. These include support from providers and family members, good communication with providers, the requirements made of patients and their surroundings, and the transition from hospital to home-based services. Telerehabilitation specifically Patients, family members and providers see telerehabilitation as an opportunity to make services more available. But providers point to practical problems when assessing whether patients are performing their exercises correctly. Providers and patients also describe interruptions from family members.  In addition, providers complain of a lack of equipment, infrastructure and maintenance and patients refer to usability issues and frustration with digital technology. Providers have different opinions about whether telerehabilitation is cost-efficient for them. But many patients see telerehabilitation as affordable and cost-saving if the equipment and infrastructure have been provided. Patients and providers suggest that telerehabilitation can change the nature of their relationship. For instance, some patients describe how telerehabilitation leads to easier and more relaxed communication. Other patients describe feeling abandoned when receiving telerehabilitation services.  Patients, family members and providers call for easy-to-use technologies and more training and support. They also suggest that at least some in-person sessions with the provider are necessary. They feel that telerehabilitation services alone can make it difficult to make meaningful connections. They also explain that some services need the provider's hands. Providers highlight the importance of personalising the services to each person's needs and circumstances. AUTHORS' CONCLUSIONS: This synthesis identified several factors that can influence the successful implementation of in-person home-based rehabilitation and telerehabilitation services. These included factors that facilitate implementation, but also factors that can challenge this process. Healthcare providers, program planners and policymakers might benefit from considering these factors when designing and implementing programmes.

Tpeak-Tend, a novel electrocardiographic marker in cats with hypertrophic cardiomyopathy-a brief communication.

Hypertrophic cardiomyopathy (HCM) is the most common heart disease in feline species. ECG allows assessing parameters that can help in the diagnosis and risk stratification of conditions that occur secondary to this disease. This study aimed to evaluate electrocardiographic markers Tpte and Tpte/QT in leads I, II, III, aVR, aVL and aVF in control and HCM cats. Data were obtained from 63 domestic cats allocated in a Control (n = 40) and an HCM (n = 23) group. Tpte and Tpte/QT of all individuals were measured in all limb leads (I, II, III, aVR, aVL, aVF). We constructed ROC curves to evaluate the sensitivity and specificity of markers to identify HCM-affected cats. Logistic regression analysis was performed to assess the risks of cats having HCM based on Tpte indexes. Tpte in leads II (p < 0.01), aVR (p < 0.01), aVL (p < 0.01), and aVF (p < 0.01) had significantly higher results in the HCM group. Tpte/QT showed no statistical difference between groups in any of the derivations evaluated. A Tpte > 27.5ms in lead aVF showed an accuracy of 83.3% to identify individuals with HCM in our study. Univariable logistic regression reveals that cats with Tpte in aVR and aVF > 27.5ms and in aVL > 26.5ms had 1.28, 12 and 1.16 respectively, more chances of having HCM. The prolongation of Tpte may be a noninvasive electrocardiographic complementary tool to help differentiate patients with and without hypertrophic cardiomyopathy.

Mejoría del dolor, la función y la calidad de vida en dolor lumbar subagudo: ensayo clínico controlado con ejercicio vs. AINES / Improvement of pain, function and quality of life in subacute low back pain: controlled clinical trial with exercise vs. NSAIDs

Introducción. El dolor lumbar es una de las causas más frecuentes de consulta y discapacidad en pacientes, y según su evolución temporal se puede clasificar como agudo, subagudo y crónico. Objetivo. Estimar en pacientes con Dolor Lumbar Subagudo (DLS), la eficacia de un programa de ejercicio comparado con antiinflamatorios no esteroideos (AINES). Métodos. Se realizó un ensayo clínico controlado aleatorio, con enmascaramiento simple en 90 pacientes y DLS con o sin radiculopatía, 46 pacientes fueron asignados a un programa de ejercicio físico y 44 a tratamiento con AINES. El desenlace primario fue la mejoría del dolor y los secundarios mejoría en la función, calidad de vida, ausentismo laboral y depresión con seguimiento a 1, 3 y 6 meses. Resultados. Al mes, no se registró diferencias en el dolor entre los grupos de 8,16 (IC 95 % -2,19 a 18,51), sin embargo, en el grupo de ejercicios hubo una mejoría de 47,3 (SD: 19,8) a 28,8 (SD: 20,5), p <0,001, y en el grupo de AINES de 45,2 (SD: 22,6) a 34,9 (SD: 25,0), p = 0,018. Otras muestras de mejoría se observaron en la función medida por el Índice de Discapacidad de Oswestry (ODI), la cual mejoró al mes en el grupo de ejercicio (p<0,001), mientras,la función física también mejoró al mes en el grupo de ejercicio (p= 0,038). Otra mejoría se observó en el dolor, función y calidad de vida que se mantuvo a los 3 y 6 meses en ambos grupos. Finalmente, La recurrencia fue mayor en el grupo de AINES: 25,5 % vs. 7,1 % (p= 0,04) al mes; 25,5 % vs. 7,1 % (p= 0,04) y 20,5 % vs. 5 % (p= 0,04), a los 3 y 6 meses. Conclusión. El ejercicio supervisado fue más efectivo que los AINES para disminuir la discapacidad y las recurrencias y mejorar la función física en pacientes con DLS.

Introduction. Low back pain is one of the most frequent causes of consultation and disability in patients, and according to its temporal evolution it can be classified as acute, subacute and chronic. Objective. To estimate the efficacy of an exercise program compared to non-steroidal anti-inflammatory drugs (NSAIDs) in patients with subacute low back pain (LBP). Methods. A randomized, single-masked, controlled clinical trial was conducted in 90 patients and DLS with or without radiculopathy, 46 patients were assigned to a physical exercise program and 44 to NSAID treatment. The primary outcome was improvement in pain and the secondary outcomes were improvement in function, quality of life, work absenteeism and depression with follow-up at 1, 3 and 6 months. Results. At 1 month, there was no difference in pain between groups of 8.16 (95 % CI -2.19 to 18.51), however, in the exercise group there was an improvement from 47.3 (SD: 19.8) to 28.8 (SD: 20.5), p <0.001, and in the NSAID group from 45.2 (SD: 22.6) to 34.9 (SD: 25.0), p = 0.018. Other signs of improvement were seen in function as measured by the Oswestry Disability Index (ODI), which improved at 1 month in the exercise group (p<0.001), while physical function also improved at 1 month in the exercise group (p= 0.038). Another improvement was observed in pain, function and quality of life which was maintained at 3 and 6 months in both groups. Finally, recurrence was higher in the NSAID group: 25.5 % vs. 7.1 % (p= 0.04) at 1 month; 25.5 % (p= 0.04) at 1 month; 25.5 % (p= 0.038) in the exercise group (p= 0.038) at 1 month.

Adaptations for rehabilitation services during the COVID-19 pandemic proposed by scientific organizations and rehabilitation professionals.

OBJECTIVE: To describe adaptations in the provision of rehabilitation services proposed by scientific and professional rehabilitation organizations to avoid interruptions to patients rehabilitation process and delays in starting rehabilitation in patients with COVID-19. METHODS: A narrative review approach was used to identify the recommendations of scientific and professional organizations in the area of rehabilitation. A systematic search was performed in the main data-bases in 78 international and regional web portals of rehabilitation organizations. A total of 21 publications from these organizations were identified and selected. RESULTS: The results are presented in 4 categories: adequacy of inpatient services, including acute care services and intensive care unit for patients with and without COVID-19; adequacy of outpatient services, including home-based rehabilitation and tele-rehabilitation; recommendations to prevent the spread of COVID-19; and regulatory standards and positions during the COVID-19 pandemic expressed by organizations for protecting the rights of health workers and patients. CONCLUSION: Health systems around the world are rapidly learning from actions aimed at the reorganization of rehabilitation services for patients who are in the process of recovery from acute or chronic conditions, and the rapid response to the rehabilitation of survivors of COVID-19, as well as from efforts in the prevention of contagion of those providing the services.

Countries Response for People With Disabilities During the COVID-19 Pandemic.

Background and Objectives: During the Coronavirus disease 19 (COVID-19) pandemic, isolation and prevention measures to reduce COVID-19 contagions are essential for the care of all people; these measures should comply with the principles of inclusion and accessibility for people with disabilities (PWD), with all kinds of deficiencies and levels of dependency. Thereby, the aim of this article is to present the measures adopted for PWD or people with rehabilitation needs, for containment, mitigation, or suppression of the SARS-CoV-2 virus in different countries of all continents and of all income levels. Methods: A narrative approach was used in this article. First, a broad search was carried out in the 193 member states of the UN, and then 98 countries that issued any document, report, or information related to disability and COVID-19 were selected. Finally, 32 countries were included in this article because they presented official information. We considered official sources, the information available in the government, or on the health ministry page of the country. In this way, the countries that presented information which did not correspond to an official source were excluded. The search was conducted in August 2020 and updated in March 2021. Results: First, the non-pharmacological general interventions for PWD included informative measures and general recommendations during the stay at home, isolation, and biosecurity measures, contagion prevention, detection of positive cases, mobilization measures, and measures implemented in institutions or residences of PWD. Second, we identified the economic and social benefits provided to PWD during the pandemic. Finally, we identified the measures taken by countries according to the type of impairment (visual, hearing, physical, mental, and cardiopulmonary impairment) during the COVID-19 pandemic. Conclusion: In response to the COVID-19 pandemic, only 50% of countries from the five world regions created and implemented specific measures for PWD to containment, mitigation, or suppression of the SARS-CoV-2 virus. There is very little specific information available about the measures to continue with the care of people with rehabilitation needs and the long-term follow-up of PWD, and for the prevention and response to violence, especially for women with disabilities.

Derechos de las personas con discapacidad en la pandemia por Covid-19. Síntesis rápida / The rights of people with disabilities in the Covid-19 pandemic Rapidreview

La pandemia por Coronavirus 2019 (Covid-19) ha profundizado las desigualdades preexistentes de las personas con discapacidad. Los afectados por Covid-19 se encuentran entre los grupos más vulnerables al ser uno de los grupos más excluidos de la sociedad. El objetivo del presente estudio esidentificarlas declaraciones y recomendaciones que las organizaciones supranacionales han emitido para garantizar los derechos de las personas con discapacidad en la actual pandemia. Se realizó una búsqueda amplia y sistemática; fueron consultadas 20 organizaciones y analizados 58 documentos en esta síntesis rápida. Los documentos encontrados fueron asignados en cuatro categorías dependiendo de su enfoque principal: principio de igualdad y no discriminación (25,8%), derecho al respeto de la dignidad inherente (10,3%), derecho a la accesibilidad (36,2%) y derecho a la salud (27,6%). Las organizaciones supranacionales hacen un llamado a los gobiernos a garantizar la protección y promoción de los derechos de las personas con discapacidad y a implementar medidas y estrategias razonables que aborden las necesidades especiales de esta población en la actual pandemia.

The Coronavirus 2019 (Covid-19) pandemic has deepened pre-existing inequalities for people with disabilities. Those affected by Covid-19 are among the most vulnerable groups as one of the most excluded groups in society. The objective of this study is to identify the declarations and recommendations that supranational organizations have issued to guarantee the rights of persons with disabilities in the current pandemic. A broad and systematic search was carried out; 20 organizations were consulted and 58 documents were analyzed in this rapid synthesis. The documents found were assigned into four categories depending on their main focus: principle of equality and non-discrimination (25.8%), right to respect for inherent dignity (10.3%), right to accessibility (36.2%) and right to health (27.6%). The supranational organizations call on governments to ensure the protection and promotion of the rights of persons with disabilities and to implement reasonable measures and strategies to address the special needs of this population in the current pandemic.

PANLAR Consensus Recommendations for the Management in Osteoarthritis of Hand, Hip, and Knee.

OBJECTIVE: The objective of this consensus is to update the recommendations for the treatment of hand, hip, and knee osteoarthritis (OA) by agreeing on key propositions relating to the management of hand, hip, and knee OA, by identifying and critically appraising research evidence for the effectiveness of the treatments and by generating recommendations based on a combination of the available evidence and expert opinion of 18 countries of America. METHODS: Recommendations were developed by a group of 48 specialists of rheumatologists, members of other medical disciplines (orthopedics and physiatrists), and three patients, one for each location of OA. A systematic review of existing articles, meta-analyses, and guidelines for the management of hand, hip, and knee OA published between 2008 and January 2014 was undertaken. The scores for Level of Evidence and Grade of Recommendation were proposed and fully consented within the committee based on The American Heart Association Evidence-Based Scoring System. The level of agreement was established through a variation of Delphi technique. RESULTS: Both "strong" and "conditional" recommendations are given for management of hand, hip, and knee OA and nonpharmacological, pharmacological, and surgical modalities of treatment are presented according to the different levels of agreement. CONCLUSIONS: These recommendations are based on the consensus of clinical experts from a wide range of disciplines taking available evidence into account while balancing the benefits and risks of nonpharmacological, pharmacological, and surgical treatment modalities, and incorporating their preferences and values. Different backgrounds in terms of patient education or drug availability in different countries were not evaluated but will be important.

Cristalurias medicamentosas en el laboratorio de urgencias: reporte de dos casos / Drug induced crystalluria in the emergency laboratory: report of two cases

Ciertos fármacos que son excretados en orina, como los antibióticos, pueden formar cristales cuando la dosis empleadas son elevadas, la diuresis se encuentra disminuida o el pH de la orina es ácido. Los eventos de cristaluria medicamentosa son poco frecuentes y pueden ser cuadros asintomáticos e incluso originar fallos renales agudos. En este reporte se describen dos casos: una mujer de 26 años con cristaluria de ampicilina y una niña de 8 años con cristaluria de amoxicilina, registrados en el laboratorio de urgencias del Hospital Central del Instituto de Previsión Social. El análisis del sedimento fue realizado empleando microscopía óptica, luego los cristales fueron sometidos a microscopía de polarización y espectrofotometría infrarroja logrando la identificación exacta de la naturaleza química de los cristales. Este es el primer reporte de cristaluria medicamentosa del país y pone de manifiesto la importancia del trabajo colaborativo entre instituciones del estado.

Certain drugs that are excreted in the urine, including antibiotics, could induce theformation of crystals when the dose used is high, the diuresis is low or the pH of the urine isacid. The events of drug induced crystalluria are rare and could be asymptomatic or couldcause acute renal failure. In this report, we describe two cases: One of a 26-year-oldwoman with ampiciline crystalluria and a 8-year-old child with amoxiciline crystalluria, bothregistered at the Emergency Laboratory of the Central Hospital of the Instituto de PrevisionSocial. The analysis of the urinary sediment was made by conventional microscopy, andthen the crystals were studied by polarized light microscopy and infrared spectroscopyachieving the exact identification of the chemical nature of the crystals. This is the firstreport of drug induced crystalluria in the country and shows the importance of thecolaborative work between state institutions.

Preditores de prováveis transtornos mentais comuns (TMC) em prostitutas utilizando o Self-Reporting Questionnaire / Predictors of probable common mental disorders (CMD) in sex workers using the Self-Reporting Questionnaire

Objetivo Avaliar a prevalência de prováveis transtornos mentais comuns (TMC) e os fatores associados em um grupo de prostitutas de Minas Gerais. Métodos Estudo transversal utilizando o Self-Reporting Questionnaire (SRQ-20) em mulheres cadastradas na Associação de Prostitutas de Minas Gerais (Aprosmig). Avaliaram-se características sociodemográficas e aspectos do trabalho na prostituição. Teste do qui-quadrado foi empregado na análise de associação entre variáveis categóricas sociodemográficas e a presença de prováveis TMC. A análise dos fatores associados à presença de prováveis TMC foi realizada por meio de modelo de regressão logística. Resultados Foram entrevistadas 216 prostitutas. A prevalência global de prováveis TMC foi de 57,9%, mais observada em mulheres com baixa escolaridade, história de violência física e ingresso precoce na prostituição. Conclusão Os resultados deste estudo mostraram que a prevalência de prováveis TMC entre prostitutas foi superior à observada na população geral, indicando a necessidade de melhorar os cuidados com a saúde dessas mulheres. .

Objective To evaluate the prevalence of common mental disorders (CMD) and associated factors in a group of prostitutes in Minas Gerais. Methods Cross-sectional study using the Self-Reporting Questionnaire (SRQ-20) in women enrolled in the Association of Prostitutes of Minas Gerais (Aprosmig). We assessed sociodemographic characteristics and aspects of work in prostitution. Chi-square test was used to analyze the association between categorical sociodemographic variables and the presence of CMD. Analysis of factors associated with the presence of CMD was performed using logistic regression model. Results We interviewed 216 prostitutes. The overall prevalence of CMD was 57.9%, more seen in women with low education, history of physical violence and early entry into prostitution. Conclusion The results of this study showed that the prevalence of CMD among sex workers was higher than that observed in the general population, indicating the need to improve health care of these women. .

Gz- and not Gi-proteins are coupled to pre-junctional µ-opioid receptors in bovine airways.

We investigated the signal transmission pathway by which activation of µ-opioid receptors attenuates acetylcholine (ACh) release in bovine trachealis. Electrical stimulation (ES)-induced [(3)H]-ACh release was determined in bovine tracheal smooth muscle strips pre-incubated with either the Gi-protein inhibitor pertussis toxin (PTX, 500 ng/ml and 1 µg/ml) or the Gz-protein specific inhibitor arachidonic acid (AA, 10(-6)M and 10(-5)M) and then treated with DAMGO (D-Ala(2),N-MePhe(4),Gly-ol(5)-enkephalin) 10(-5)M. Indomethacin 10(-5)M was used to block AA cascade. The inhibitory effect of DAMGO on ES-induced [(3)H]-ACh release was PTX-insensitive, but, by contrast, ablated by AA in a concentration-dependent manner. AA 10(-5)M alone reduced [(3)H]-ACh release, an effect that was prevented by iberiotoxin 10(-7)M, suggesting an involvement of Ca(2+)-activated K(+)-channels. Western blot analysis consistently showed immunoreactive bands against a specific antibody anti-Gz-α subunit at ∼40 kDa, consistent with the presence of Gz-protein. The present findings suggest that in isolated bovine trachealis, activation of µ-opioid receptors inhibits ACh-release through a signal transmission pathway involving Gz-protein rather than Gi-protein.

Iodoacetic acid, but not sodium iodate, creates an inducible swine model of photoreceptor damage.

Our purpose was to find a method to create a large animal model of inducible photoreceptor damage. To this end, we tested in domestic swine the efficacy of two chemical toxins, known to create photoreceptor damage in other species: Iodoacetic Acid (IAA) and Sodium Iodate (NaIO(3)). Intravenous (IV) administration of NaIO(3) up to 90 mg/kg had no effect on retinal function and 110 mg/kg was lethal. IV administration of IAA (5-20 mg/kg) produced concentration-dependent changes in visual function as measured by full-field and multi-focal electroretinograms (ffERG and mfERG), and 30 mg/kg IAA was lethal. The IAA-induced effects measured at two weeks were stable through eight weeks post-injection, the last time point investigated. IAA at 7.5, 10, and 12 mg/kg produce a concentration-dependent reduction in both ffERG b-wave and mfERG N1-P1 amplitudes compared to baseline at all post-injection times. Comparisons of dark- and light-adapted ffERG b-wave amplitudes show a more significant loss of rod relative to cone function. The fundus of swine treated with ≥10 mg/kg IAA was abnormal with thinner retinal vessels and pale optic discs, and we found no evidence of bone spicule formation. Histological evaluations show concentration-dependent outer retinal damage that correlates with functional changes. We conclude that NaIO(3,) is not an effective toxin in swine. In contrast, IAA can be used to create a rapidly inducible, selective, stable and concentration-dependent model of photoreceptor damage in swine retina. Because of these attributes this large animal model of controlled photoreceptor damage should be useful in the investigation of treatments to replace damaged photoreceptors.

Decreased visual function after patchy loss of retinal pigment epithelium induced by low-dose sodium iodate.

PURPOSE: To correlate damage to the retinal pigment epithelium (RPE) with decreased visual function after the systemic administration of sodium iodate (NaIO(3)). METHODS: Damage was produced in mice by injection of 15, 25, or 35 mg/kg NaIO(3). Visual function was assessed with the cued water maze (WM) behavioral test and the optokinetic reflex (OKR) measurement at different times after injection. Autofluorescence in whole eye flatmounts was quantified, and hematoxylin and eosin staining of paraffin sections was performed to assess changes in the outer retina. RESULTS: After 15 mg/kg NaIO(3), cued WM test results were normal, whereas OKR measurements were significantly decreased at all times. Focal RPE loss began on day 21, but no significant damage to the outer nuclear layer was observed. After 25 mg/kg NaIO(3), the cued WM test was transitionally reduced and the OKR measurement again decreased at all times. Large areas of RPE loss occurred on day 14 with a reduced outer nuclear layer on the same day. With 35 mg/kg NaIO(3), the cued WM test was reduced beginning on day 14 with complete obliteration of the OKR beginning on day 3, large areas of RPE loss on the same day, and a reduced outer nuclear layer on day 7. CONCLUSIONS: Stable, patchy RPE loss was observed with a low concentration of NaIO(3). The OKR measurement showed changes in visual function earlier than the cued WM test and before histologic findings were observed.

Abscisic acid activates the murine microglial cell line N9 through the second messenger cyclic ADP-ribose.

Abscisic acid (ABA) is a phytohormone regulating important functions in higher plants, notably responses to abiotic stress. Recently, chemical or physical stimulation of human granulocytes was shown to induce production and release of endogenous ABA, which activates specific cell functions. Here we provide evidence that ABA stimulates several functional activities of the murine microglial cell line N9 (NO and tumor necrosis factor-alpha production, cell migration) through the second messenger cyclic ADP-ribose and an increase of intracellular calcium. ABA production and release occur in N9 cells stimulated with bacterial lipopolysaccharide, phorbol myristate acetate, the chemoattractant peptide f-MLP, or beta-amyloid, the primary plaque component in Alzheimer disease. Finally, ABA priming stimulates N9 cell migration toward beta-amyloid. These results indicate that ABA is a pro-inflammatory hormone inducing autocrine microglial activation, potentially representing a new target for anti-inflammatory therapies aimed at limiting microglia-induced tissue damage in the central nervous system.

Long-term cellular and regional specificity of the photoreceptor toxin, iodoacetic acid (IAA), in the rabbit retina.

This study investigated the anatomical consequences of a photoreceptor toxin, iodoacetic acid (IAA), in the rabbit retina. Retinae were examined 2 weeks, 1, 3, and 6 months after systemic IAA injection. The retinae were processed using standard histological methods to assess the gross morphology and topographical distribution of damage, and by immunohistochemistry to examine specific cell populations in the retina. Degeneration was restricted to the photoreceptors and was most common in the ventral retina and visual streak. In damaged regions, the outer nuclear layer was reduced in thickness or eliminated entirely, with a concomitant loss of immunoreactivity for rhodopsin. However, the magnitude of the effect varied between animals with the same IAA dose and survival time, suggesting individual differences in the bioavailability of the toxin. In all eyes, the inner retina remained intact, as judged by the thickness of the inner nuclear layer, and by the pattern of immunoreactivity for protein kinase C-alpha (rod bipolar cells) and calbindin D-28 (horizontal cells). Müller cell stalks became immunoreactive for glial fibrillary acidic protein (GFAP) even in IAA-treated retinae that had no signs of cell loss, indicating a response of the retina to the toxin. However, no marked hypertrophy or proliferation of Müller cells was observed with either GFAP or vimentin immunohistochemistry. Thus the selective, long lasting damage to the photoreceptors produced by this toxin did not lead to a reorganization of the surviving cells, at least with survival as long as 6 months, in contrast to the remodeling of the inner retina that is observed in inherited retinal degenerations such as retinitis pigmentosa and retinal injuries such as retinal detachment.

Effect of blood on susceptibility to Staphylococcal endophthalmitis.

PURPOSE: The authors examined the effect of blood on susceptibility to experimental endophthalmitis. METHODS: Forty rabbits received an injection of 5-25 colony-forming units of Staphylococcus epidermidis into the vitreous of the right eye. Twenty of these same eyes received a subsequent intravitreal injection of 0.2 mL blood while the remaining 20 received an intravitreal injection of 0.2 mL of a salt solution. All eyes were examined daily for signs of endophthalmitis. Vitreous cultures were obtained on day 2 from 30 of the 40 rabbits. Twenty rabbits were assigned for culture and euthanasia at day 5 and those remaining were cultured and killed at day 7. RESULTS: In rabbits with blood and bacteria, 10 of 15 (67%) were culture positive at 2 days, compared to 2 of 15 (13%) that received salt solution and bacteria (P < 0.01). At days 5 and 7 there was no statistically significant difference in culture results. However, inflammatory scores were significantly higher at days 3-7 in rabbits with blood compared to those with salt solution (P

Cyclic ADP-ribose is a second messenger in the lipopolysaccharide-stimulated activation of murine N9 microglial cell line.

Lipopolysaccharide, the main component of the cell wall of Gram-negative bacteria, is known to activate microglial cells following its interaction with the CD14/Toll-like receptor complex (TLR-4). The activation pathway triggered by lipopolysaccharide in microglia involves enhanced basal levels of intracellular calcium ([Ca2+]i) and terminates with increased generation of cytokines/chemokines and nitric oxide. Here we demonstrate that in lipopolysaccharide-stimulated murine N9 microglial cells, cyclic ADP-ribose, a universal and potent Ca2+ mobiliser generated from NAD+ by ADP-ribosyl cyclases (ADPRC), behaves as a second messenger in the cell activation pathway. Lipopolysaccharide induced phosphorylation, mediated by multiple protein kinases, of the mammalian ADPRC CD38, which resulted in significantly enhanced ADPRC activity and in a 1.7-fold increase in the concentration of intracellular cyclic ADP-ribose. This event was paralleled by doubling of the basal [Ca2+]i levels, which was largely prevented by the cyclic ADP-ribose antagonists 8-Br-cyclic ADP-ribose and ryanodine (by 75% and 88%, respectively). Both antagonists inhibited, although incompletely, functional events downstream of the lipopolysaccharide-induced microglia-activating pathway, i.e. expression of inducible nitric oxide synthase, overproduction and release of nitric oxide and of tumor necrosis factor alpha. The identification of cyclic ADP-ribose as a key signal metabolite in the complex cascade of events triggered by lipopolysaccharide and eventually leading to enhanced generation of pro-inflammatory molecules may suggest a new therapeutic target for treatment of neurodegenerative diseases related to microglia activation.

ADP-ribosyl cyclases generate two unusual adenine homodinucleotides with cytotoxic activity on mammalian cells.

ADP-ribosyl cyclases are ubiquitous enzymes responsible for synthesis from NAD(+) of the intracellular calcium-releasing signal molecules cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP(+)). Here, we show that cyclases from lower and higher Metazoa also synthesize three adenylic dinucleotides from cADPR and adenine: diadenosine diphosphate and two isomers thereof. These dinucleotides are present and metabolized in mammalian cells and affect intracellular calcium and cell proliferation. The diadenosine diphosphate isomers are naturally occurring nucleotides containing an N-glycosidic bond different from the usual C1'-N9. The identification of these members of the family of NAD(+)-derived, calcium-active nucleotides opens new areas of investigation into their functional cooperation with cADPR and NAADP(+) and into their involvement in the physiology and pathology of calcium-controlled cell functions.