Prospects for the application of Müller glia and their derivatives in retinal regenerative therapies.

Neural cell death is the main feature of all retinal degenerative disorders that lead to blindness. Despite therapeutic advances, progression of retinal disease cannot always be prevented, and once neuronal cell damage occurs, visual loss cannot be reversed. Recent research in the stem cell field, and the identification of Müller glia with stem cell characteristics in the human eye, have provided hope for the use of these cells in retinal therapies to restore vision. Müller glial cells, which are the major structural cells of the retina, play a very important role in retinal homeostasis during health and disease. They are responsible for the spontaneous retinal regeneration observed in zebrafish and lower vertebrates during early postnatal life, and despite the presence of Müller glia with stem cell characteristics in the adult mammalian retina, there is no evidence that they promote regeneration in humans. Like many other stem cells and neurons derived from pluripotent stem cells, Müller glia with stem cell potential do not differentiate into retinal neurons or integrate into the retina when transplanted into the vitreous of experimental animals with retinal degeneration. However, despite their lack of integration, grafted Müller glia have been shown to induce partial restoration of visual function in spontaneous or induced experimental models of photoreceptor or retinal ganglion cell damage. This improvement in visual function observed after Müller cell transplantation has been ascribed to the release of neuroprotective factors that promote the repair and survival of damaged neurons. Due to the development and availability of pluripotent stem cell lines for therapeutic uses, derivation of Müller cells from retinal organoids formed by iPSC and ESC has provided more realistic prospects for the application of these cells to retinal therapies. Several opportunities for research in the regenerative field have also been unlocked in recent years due to a better understanding of the genomic and proteomic profiles of the developing and regenerating retina in zebrafish, providing the basis for further studies of the human retina. In addition, the increased interest on the nature and function of cellular organelle release and the characterization of molecular components of exosomes released by Müller glia, may help us to design new approaches that could be applied to the development of more effective treatments for retinal degenerative diseases.

Growth-fragmentation-coagulation equations with unbounded coagulation kernels.

In this paper, we prove the global in time solvability of the continuous growth-fragmentation-coagulation equation with unbounded coagulation kernels, in spaces of functions having finite moments of sufficiently high order. The main tool is the recently established result on moment regularization of the linear growth-fragmentation semigroup that allows us to consider coagulation kernels whose growth for large clusters is controlled by how good the regularization is, in a similar manner to the case when the semigroup is analytic. This article is part of the theme issue 'Semigroup applications everywhere'.

The older adult with diabetes: peripheral neuropathy and walking for health.

The rate at which older individuals are being diagnosed with diabetes is increasing. Therefore, the ability of older persons with diabetes to successfully age in place is of concern for health care professionals. Diabetic peripheral neuropathy can cause changes to the foot and ankle such as loss of protective sensation, joint dislocations and fractures, and formation of cracks and fissures. With special attention to their needs, practitioners can tell older people with diabetes that walking for health can be safe and without problems and can contribute to their ability to spend the rest of their lives in their own home.

Weight-Bearing Exercise and Foot Health in Native Americans.

Diabetes contributes to sensory peripheral neuropathy, which has been linked to lower limb abnormalities that raise the risk for foot ulcers and amputations. Because amputations are a reason for pain and hospitalization in those with diabetes, it is of critical importance to gain insight about prevention of ulcer development in this population. Although the American Diabetes Association (ADA) now recommends that individuals with neuropathy can engage in moderate-intensity weight-bearing activity (WBA), they must wear appropriate footwear and inspect their feet daily. The physical forces and inflammatory processes from WBA may contribute to plantar characteristics that lead to ulcers. The purpose of this study was to compare neuropathic status and foot characteristics in Native Americans according to WBA classification. The t tests for unequal sample sizes found that exercisers had more difficulty sensing baseline temperature than nonexercisers, except at the right foot (all p values < .05). By dividing groups into no/low risk and high risk for ulcer, a majority showed no/low risk according to touch and vibration sense. Exercisers demonstrated higher surface skin temperature gradients at the first metatarsal head, a plantar site where wounds tend to form. The more consistently exercisers performed, the higher the plan-tar pressures were at the right second (r = .24, p = .02) and third metatarsal heads (r = .26, p = .01). Findings from this investigation do not refute current ADA recommendations and further intervention studies are needed that are longitudinal and measures WBA more accurately.

Distributional fixed-point equations for island nucleation in one dimension: a retrospective approach for capture-zone scaling.

The distributions of interisland gaps and captures zones for islands nucleated on a one-dimensional substrate during submonolayer deposition are considered using a novel retrospective view. This provides an alternative perspective on why scaling occurs in this continuously evolving system. Distributional fixed-point equations for the gaps are derived both with and without a mean-field approximation for nearest neighbor gap-size correlation. Solutions to the equations show that correct consideration of fragmentation bias justifies the mean-field approach, which can be extended to provide closed-from equations for the capture zones. Our results compare favorably to Monte Carlo data for both point and extended islands using a range of critical island size i=0,1,2,3. We also find satisfactory agreement with theoretical models based on more traditional fragmentation theory approaches.

Gap-size and capture-zone distributions in one-dimensional point-island nucleation and growth simulations: asymptotics and models.

The nucleation and growth of point islands during submonolayer deposition on a one-dimensional substrate is simulated for critical island size i=0,1,2,3. The small- and large-size asymptotics for the gap-size and capture-zone distributions (CZDs) are studied. Comparisons to theoretical predictions from fragmentation equation analyses are made, along with those from the recently proposed generalized Wigner surmise (GWS). We find that the simulation data can be fully understood in the framework provided by the fragmentation equations, while highlighting the theoretical areas that require further development. The GWS works well for the small-size CZD behavior, but completely fails to describe the large-size CZD asymptotics of the one-dimensional system.

Reliability and limitations of the durometer and PressureStat to measure plantar foot characteristics in Native Americans with diabetes.

Neuropathy with excessive weight-bearing activity may lead to foot changes that place it at risk for ulceration. Information about instruments to measure plantar skin hardness and pressures of the foot in adult Native Americans with diabetes is presented. Skin hardness was measured at 10 sites (plantar side of the hallux, third and fifth toes, first, third, and fifth metatarsal heads, medial and lateral midfoot, heel, and the dorsal aspect between the hallux and second toe) with a durometer. The PressureStat yielded data about barefoot, static pressures. The durometer was shown to be reliable (r = .62 to .91) at all sites of the foot except at the third and fifth toe, the medial midsection of both feet, and at the third metatarsal head and between the hallux and second toe, the dorsal aspect of the left foot. With four raters, concordance was found to be acceptable at the hallux, the third toe, the first, third, and fifth metatarsal heads and the heel (W = .61 to .86) for the PressureStat. Since most diabetic foot ulcers occur at the hallux, first, third, and fifth metatarsal heads, both the PressureStat and durometer may be reliable screening tools to determine the degree of risk.

Idiopathic thrombocytopenia in Cavalier King Charles Spaniels.

OBJECTIVE: To determine the prevalence of asymptomatic idiopathic macrothrombocytopenia in the population of Cavalier King Charles Spaniels (CKCS) in New South Wales (NSW) and to determine if it exhibits an autosomal recessive inheritance pattern. We also aimed to determine if significant differences existed when counting platelets manually, by auto analyser or by blood smear estimation in CKCS and mixed breed dogs. METHODS: Blood was collected from 172 dogs (152 CKCS and 20 mixed breed) and placed into sodium-citrate anticoagulant. Platelet counts were performed manually, by auto analyser and by blood smear estimates in CKCS and mixed breed dogs. Blood smears were also examined for platelet clumping and erythrocyte, leukocyte and platelet morphology. Pedigree analysis was performed to determine if an autosomal recessive inheritance pattern was supported. RESULTS: A statistically significant difference was found in platelet counts between CKCS and mixed breed dogs (P < 0.0001). CKCS had a platelet count that was 32% that of the controls (95% confidence interval, 28 to 37%). There was no significant difference between methods used to count platelets. Thirty percent of CKCS had macrothrombocytes. Pedigree analysis and examination of obtained and expected segregation ratios from 17 CKCS families supported an autosomal recessive pattern of Mendelian inheritance. CONCLUSIONS: A high prevalence of idiopathic macrothrombocytopenia exists in CKCS in NSW and automated or blood smear estimates are sufficient to count platelet numbers. Data supports an autosomal recessive inheritance pattern.

Inflammatory cerebrospinal fluid analysis in cats: clinical diagnosis and outcome.

The medical records of 62 cats with clinical signs of central nervous system disease and accompanying inflammatory cerebrospinal fluid (CSF) analysis were examined retrospectively to determine if signalment, clinical signs, CSF analysis and ancillary testing could accurately predict the type of central nervous system disease that was present. An inflammatory CSF was defined as one in which a total nucleated cell count was greater than 5 cells/microl or one in which the total nucleated cell count was normal but the nucleated cell differential count was abnormal. Sex, degree of CSF inflammation, neuroanatomical location and systemic signs provided little contributory information to the final diagnosis. In 63% of the cases a presumptive diagnosis could be made based on a combination of clinical signs, clinicopathological data and ancillary diagnostic tests. CSF analysis alone was useful only in the diagnosis of cats with feline infectious peritonitis, Cryptococcus species infection, lymphoma and trauma. Overall, despite extensive diagnostic evaluation, a specific diagnosis could not be made in 37% of cats. The prognosis for cats with inflammatory CSF was poor with 77% of cats surviving less than 1 year.

Tolerancia y seguridad de las formulas enterales hipercaloricas en la primera infancia / Tolerance and segurity of enteral hypercaloric formules in infants

Se evaluó la seguridad y la tolerancia de fórmulas pediátricas entérales con altas concentraciones de energía, comparándolas con una fórmula estándar. En este estudio abierto, aleatorio, multicéntrico, de fase III, se evaluaron niños de 1 a 6 años de edad que requerían alimentación por sonda para proporcionar al menos el 75 por ciento de sus requerimientos diarios de energía, durante 21 días. Los sujetos (n = 98) recibieron una fórmula de control, Pediasure (C: 1,0 kcal/ mL) o una fórmula experimental similar en su composición nutricional, pero con mayor densidad calórica (1,5 kcal/mL) con fibra (Ef) o sin fibra (E). Los sujetos regresaron a consultas semanales. En todos los grupos mejoraron los parámetros gastrointestinales (p<0,05). La ingestión de energía fue similar entre los grupos, pero se obtuvo con volúmenes más bajos (p< 0,0001) en EyEF, en comparación con C. El aumento de peso fue mayor (p>0,01) en E vs. C. El informe de efectos adversos fue similar entre los grupos. Las fórmulas hipercalóricas son una opción en los niños con restricción de líquidos o con requerimientos aumentados de energía o de fibra, sin comprometer la seguridad o la tolerancia

Spontaneous hepatic rupture in six cats with systemic amyloidosis.

Spontaneous hepatic rupture, secondary to the accumulation of hepatic amyloid, was diagnosed in six cats over a two-year period. Previous reports of feline hepatic amyloidosis have documented clusters of cases from breeding catteries. Most affected cats have been Siamese or a related breed and the disease is generally regarded as familial. In contrast, the cases presented here were sporadic, with relatives and other cats in the household not clinically affected. They included a Devon rex, a breed not previously reported with this condition, and a domestic shorthair. Clinical signs in three of these cases had, prior to referral, been misinterpreted as resulting from blunt trauma, immune-mediated haemolysis or a coagulopathy. Antemortem diagnostic features, including new data on the value of hepatic ultrasonography and fine-needle aspirate cytology, are reported. These cases illustrate how the course of this disease can vary between individuals and that, despite the dramatic underlying pathology, hepatic amyloidosis can present a diagnostic challenge and should be suspected in any young adult cat with consistent clinical signs, irrespective of breed or environment.

Polycythaemia and hypertension caused by renal artery stenosis.

A girl with failure to thrive and a haemoglobin of 140 g/l at 1.3 years died from a brain haemorrhage 2.5 years later. Renal artery stenosis had caused severe, chronic hypertension and increased erythropoietin secretion (haemoglobin 182 g/l). Blood pressure should be measured in all unwell children, including those failing to thrive.

Perirenal pseudocysts in 26 cats.

OBJECTIVE: To evaluate clinical features, anatomical location, nature of pseudocyst fluid, results of surgical treatment and links with underlying renal disease in cats with perirenal pseudocysts. DESIGN: A retrospective study of 26 affected cats, including 8 treated surgically. RESULTS: Nineteen (73%) affected cats were male. The median age was 11 years. Most presented for abdominal enlargement and had varying degrees of renal dysfunction on presentation. Thirteen cats (50%) had bilateral pseudocysts. The pseudocyst fluid was a transudate or modified transudate in all cases. All surgically treated cats had subcapsular perirenal pseudocysts. Associated renal lesions were identified in all cats that had renal biopsies or detailed ultrasonographic examinations. Surgery relieved clinical signs but did not stop progression of renal disease. Cats survived a median of 9 months after surgery and survival was correlated statistically to degree of azotaemia at presentation. Percutaneous drainage of pseudocysts was ineffective in controlling long-term fluid accumulation. CONCLUSIONS: Subcapsular perirenal pseudocysts are formed in cats by accumulation of transudate between the capsule and parenchyma of the kidney as a result of underlying parenchymal disease. Pseudocyst formation can occur at variable stages of renal dysfunction. Resection of the pseudocyst wall is usually effective in eliminating signs but does not stop progression of renal disease. The prognosis for cats with pseudocyst formation is related to the degree of renal dysfunction at time of diagnosis.

Plasma cortisol concentrations in normal dogs given hydrocortisone sodium succinate.

OBJECTIVE: To evaluate the effects on plasma cortisol concentration of a continuous infusion of a readily available steroid with equipotent glucocorticoid and mineralocorticoid effects. PROCEDURE: Plasma cortisol concentrations were measured before and regularly after hydrocortisone sodium succinate was administered as a continuous intravenous infusion over 6 h at 0.32 and 0.65 mg kg-1 h-1 to 12 healthy dogs weighing 12 to 22 kg. RESULTS: The infusion at both does rates produced significant and stable increases in plasma cortisol concentrations. The plateau concentrations produced by the large and small doeses were respectively above and below plasma cortisol concentrations likely to provide adequate glucocorticoid and mineralocorticoid activity in stressed dogs with significantly decreased adrenal function. CONCLUSION: This paper presents information regarding the changes in plasma cortisol concentrations in 12 normal dogs given an hydrocortisone sodium succinate infusion at two dose rates. The marked and continuous increase in plasma cortisol concentrations suggests a continuous HSS infusion may be a possible alternative to desoxycorticosterone acetate and dexamethasone in the treatment of acute adrenal dysfunction.

Metabolic and inflammatory responses after laparoscopic and open inguinal hernia repair.

A prospective comparison of metabolic and inflammatory responses after laparoscopic and open inguinal hernia operations was undertaken. There were 10 patients in each group. Plasma levels of cortisol, growth hormone, prolactin, C-reactive protein (CRP) and interleukin-6 (IL-6) were measured preoperatively and at fixed intervals up to 120 h postoperatively. In vitro, endotoxin stimulated whole blood tumour necrosis factor alpha (TNF alpha) was measured in preoperative and 24 h postoperative blood samples. Changes in the plasma levels of cortisol, growth hormone and prolactin showed no statistically significant difference between the groups. No significant change in IL-6 levels were recorded in any group. Changes in CRP levels were significantly higher (P < 0.006) in open hernia patients. Endotoxin stimulated TNF alpha production was suppressed in both groups. The degree of suppression in open hernia patients was significantly higher (P < 0.005). This study has shown that both these operations produce similar stress responses. However, open hernia operation results in a higher acute phase response and induces a greater endotoxin tolerance.

A study of the quality of perinatal autopsy in the former northern region. The Northern Perinatal Mortality Survey Steering Group.

OBJECTIVE: To assess the quality of perinatal autopsy. DESIGN: Review of all reports of post mortem examinations carried out following perinatal deaths from January 1994 to June 1994. POPULATION: Former Northern Region of England. METHODS: Assessment of post mortem reports concerning their content and interpretation, the assessment carried out by panel comprising a pathologist, obstetrician and paediatrician. RESULTS: Reports were available for all 104 cases where post mortem examinations had been undertaken, of which 53 (51%) met the minimum standards for such autopsies proposed by the Royal College of Pathologists. Interpretative comments were judged to be adequate in 51 (49%). CONCLUSIONS: The quality of perinatal autopsies is frequently poor. Improvement requires increased awareness of the potential value of the autopsy, and more consultation between pathologists, obstetricians and paediatricians.

Nasopharyngeal cryptococcosis.

Naturally occurring cryptococcosis in five cats, a dog and a koala is described. Involvement of the nasopharynx was documented in all patients, and nasopharyngeal mass lesions accounted for the major presenting complaints in four. Signs referable to nasopharyngeal disease included snoring, stertor, inspiratory dyspnoea and aerophagia. Diagnoses were made by caudal rhinoscopy using a retroverted flexible endoscope, vigorous orthograde flushing with saline, or at necropsy. Concurrent cryptococcal rhinitis was present in all cases, although involvement appeared limited to the caudal nasal cavity in most cases. Typical signs of nasal cavity disease, such as sneezing and nasal discharge, were often absent. Treatment of nasopharyngeal cryptococcosis should include physical dislodgement or debulking of lesion(s) to provide immediate alleviation of upper airway obstruction, followed by systemic antifungal therapy to eliminate residual infection from the nasal cavity. Infections caused by Cryptococcus neoformans var gattii accounted for a disproportionately large number of these cases.

Expression of cytokine messenger RNA after heart transplantation: relationship with rejection and serum cytokines.

Different groups of cytokines may initiate or inhibit the rejection process. We used the polymerase chain reaction to study the expression of cytokine mRNA for interleukin (IL)-2, -4, -6 and -10, tumor necrosis factor-alpha, and interferon-gamma in 187 biopsy specimens from 24 human cardiac transplant recipients 5-555 days after transplantation. Cytokine levels in the serum were also measured. Cytokine mRNA was detected in 38.5% of biopsy specimens. IL-10 mRNA was detected more frequently with mild or absent rejection (11.6% in grades 0 and 1 - vs. 1.4% in grades 2 and 3, P=0.01). Up to 90 days after transplantation, IL-2 mRNA was detected more frequently with moderate rejection (13% in grades 2 and 3 vs. 0% in grades 0 and 1, P=0.076), and IL-4 mRNA was detected more frequently with mild or absent rejection (16% in grades 0 and 1 - vs. 0% in grades 2 and 3, P=0.061). More than 90 days after transplantation, IL-2 mRNA was detected more frequently with mild or absent rejection (10% in grades 0 and 1 vs. 0% in grades 2 and 3, P=0.078). Serum IL-4 levels corresponding to biopsy specimens positive for IL-4 mRNA were higher than those corresponding to specimens negative for IL-4 mRNA (59 pg/ml vs. 32 pg/ml medians, P=0.028). Our results suggest that IL-10 and possibly IL-4 (T helper 2 cytokines) may suppress graft rejection, whereas IL-2 (T helper 1 cytokine) may promote cellular rejection. In addition, cytokine profiles may change with length of time after transplantation. The association of elevated serum levels of IL-4 with increased expression of intragraft IL-4 mRNA may suggest release of this cytokine from the graft into the circulation.

Serum cytokines in human heart transplant recipients. Is there a relationship to rejection?

Cytokines are important in the pathogenesis of allograft rejection. Some studies have suggested a positive relationship between serum levels of cytokines and rejection, so this study was designed to investigate the presence of a range of cytokines in a large cohort of cardiac transplant recipients. We used enzyme linked immunosorbent assays (ELISA) to examine sequential serum samples from 28 consecutive heart transplant recipients; length of follow up varied between 2 and 566 days (median 357 days). Serum levels of IL-2, 4, 6, 10, TNF-alpha, and IFN-gamma were measured. We compared these results with detailed data on patients' clinical courses, including histological rejection, infection, and therapeutic use of antithymocyte globulin (ATG). No significant relationship was found between rejection and serum cytokine levels for samples taken more than 30 days after transplantation. Prior to this cytokine levels were significantly disturbed by the use of cytolytic therapy for induction immunosuppression. Serum cytokine levels sometimes showed peaks that appeared to be related to rejection, or occasionally to infection, but these relationships were not consistent. Serum TNF-alpha and IL-6 were consistently elevated within a few days of administration of ATG. We conclude that there is no systematic relationship between serum cytokine levels and histological rejection or infection in cardiac transplant recipients.