Intralesional cidofovir in severe juvenile respiratory papillomatosis.

UNLABELLED: Recurrent respiratory papillomatosis causes significant morbidity among affected children and usually requires frequent surgeries. We present a prospective case series including nine children at a Mexican tertiary referral center. All enrolled patients had severe disease that had required at least four surgical procedures, with a median of 6. Two children had tracheobronchial involvement, one had lung parenchymal disease, and one had a tracheostomy performed during his first surgery. OBJECTIVE: To assess the efficacy of intralesional cidofovir in lowering the surgery rate. STUDY DESIGN: Prospective case series. SETTING: Tertiary referral center in Mexico City. METHODS: Nine Mexican children with severe disease were enrolled. Intralesional cidofovir was applied after surgical debulking at a concentration of 5 mg/mL with a four to six week interval. RESULTS: Six of the nine patients had a notable decrease in the rate of surgeries, with three patients remaining disease-free with follow up ranging from 1.8 to 3.3 years. No patient demonstrated laboratory abnormalities. Two patients showed moderate and mild dysplasia on papilloma biopsy distinguished by a lack of epithelial maturation with no mitoses or cellular atypia. Two patients died several months after the last injection. CONCLUSIONS: Intralesional cidofovir appears to be effective in the treatment of recurrent respiratory papillomatosis, although further studies are required to determine its safety.

Risk factors for immune reconstitution inflammatory syndrome under combination antiretroviral therapy can be aetiology-specific.

In order to discriminate general from aetiology-specific risk factors for immune reconstitution inflammatory syndrome (IRIS), we followed up, during six months, 99 patients with advanced HIV infection commencing antiretroviral therapy (ART) without active opportunistic infections or evident inflammation. IRIS predictors were determined by univariate analysis using clinical data from 76 ART-responding patients either completing follow-up or developing IRIS, and by multivariate analysis of inflammation, disease progression and nutrition status variables. We identified 23 primary IRIS events (30.3%). Univariate predictors for all IRIS events were higher platelet counts and lower CD4/CD8 ratio, whereas subclinical inflammation was the multivariate predictor. Platelets, alkaline phosphatase levels and %CD8 T-cells in univariate analysis also predicted mycobacteria-associated IRIS independently, remaining elevated during follow-up. Herpesvirus IRIS was predicted by platelets and inflammation. Indicators of advanced HIV disease and subclinical inflammation jointly predict IRIS, and some are specific of the underlying microbial aetiology, possibly explaining previous reports.

Later onset of herpes zoster-associated immune reconstitution inflammatory syndrome.

OBJECTIVES: The aim of the study was to determine whether immune reconstitution inflammatory syndrome (IRIS) associated with herpes zoster occurs on a different time frame from other instances of IRIS. METHODS: Statistical analysis of onset times of herpes zoster-associated IRIS and other cases of IRIS was carried out in a retrospective cohort starting antiretroviral therapy at advanced stages of HIV infection. RESULTS: Herpes zoster-associated IRIS was significantly more frequent after the first 3 months of successful highly active antiretroviral therapy (HAART), than other instances of IRIS (IRIS associated with tuberculosis, Mycobacterium avium complex, Kaposi's sarcoma, etc.) which mainly occurred during the first 3 months of treatment. CONCLUSIONS: The characteristic onset time pattern of herpes zoster-associated IRIS, coincident with the second phase of immune recovery under HAART, suggests that the immune recovery events underlying herpes zoster-associated IRIS are different from those underlying other types of IRIS. Our findings may be useful in improving the follow-up of individuals who start HAART at an advanced stage of HIV infection.

Identification of oral candidosis, hairy leukoplakia and recurrent oral ulcers as distinct cases of immune reconstitution inflammatory syndrome.

Oral lesions such as candidosis, hairy leukoplakia (HL) and oral ulcers are strikingly absent in the numerous reports of immune reconstitution inflammatory syndrome (IRIS). To document oral manifestations attributable to immune reconstitution, we conducted a longitudinal follow-up of a cohort of HIV+ individuals starting highly active antiretroviral therapy (HAART) and completing oral pathology follow-up up to 12 weeks after treatment initiation. HIV-infected patients had oral examinations, CD4+ T-cell count and viral load determinations performed at baseline, and at weeks 4, 8 and 12 after HAART initiation. Among individuals with satisfactory viral response and recovery of > or =50 CD4+ T-cell/microL, eight patients complied with strict IRIS criteria: two developed clinical signs of oral candidosis (OC), two oral ulcers, three HL and one Kaposi's sarcoma. CD4+ T-cell counts at symptom onset suggested no remaining immune suppression. Our findings show that cases of OC, HL and recurrent ulcers can be instances of IRIS.

Three-yr follow-up of a type 1 diabetes mellitus patient with an islet xenotransplant.

In order to alleviate the shortage of human donors, the use of porcine islets of Langerhans for xenotransplantation in diabetic patients has been proposed as a solution. To overcome rejection, we have developed a procedure for protecting the islets by combining them with Sertoli cells and placing them in a novel subcutaneous device, that generates an autologous collagen covering. A type 1 diabetic woman was closely monitored for 10 months, and then transplanted in two devices with two months of difference and a third time after 22 months. Here we present a three-yr follow-up. The close monitoring induced a rapid decrease in exogenous insulin requirements, which stabilized between 19 and 28 IU/d for nine months. After transplantation, the requirements reduced further to below 6 IU/d and for some weeks she was insulin free. Glycosylated hemoglobin levels decreased concomitantly. Porcine insulin could be detected in the serum after a glucose challenge and insulin positive cells inside a removed device after two yr. No complications have arisen and no porcine endogenous retrovirus infection has been detected through PCR and RT-PCR. This case demonstrates the feasibility of using the xenotransplantation of porcine cells to alleviate metabolic complications and insulin requirements in type 1 diabetic patients.

Differential participation of the NBM in the acquisition and retrieval of conditioned taste aversion and Morris water maze.

Deficits in both learning and memory after lesions of the cholinergic basal forebrain, in particular the nucleus basalis magnocellularis (NBM), have been widely reported. However, the participation of the cholinergic system in either acquisition or retrieval of memory process is still unclear. In this study, we tested the possibility that excitotoxic lesions of the NBM affect either acquisition or retrieval of two tasks. In the first experiment, animals were trained for two conditioned taste aversion tasks using different flavors, saccharine and saline. The acquisition of the first task was before NBM lesions (to test retrieval) and the acquisition of the second task was after the lesions (to test acquisition). Accordingly, in the first part of the second experiment, animals were trained in the Morris water maze (MWM), lesioned and finally tested. In the final part of this experiment, another set of animals was lesioned, then trained in the MWM and finally tested. All animals were able to retrieve conditioned taste aversion (CTA) and MWM when learned before NBM lesions; however, lesions disrupted the acquisition of CTA and MWM. The results suggest that the NBM and cholinergic system may play an important role in acquisition but not during retrieval of aversive memories.

Redundant basal forebrain modulation in taste aversion memory formation.

Mnemonic deficits resulting from excitotoxic lesion of the basal forebrain have been classically attributed to the resulting depletion of cortical acetylcholine activity. It has been demonstrated that in spite of the strong cholinergic depletion after injections into the basal forebrain of the immunotoxin 192IgG-saporin, no detectable deficit can be found in the acquisition of several learning tasks, including conditioned taste aversion. Conversely, NMDA-induced lesions of the basal forebrain strongly impair taste aversion learning. In this study we show that 192IgG-saporin produces an efficient and selective cholinergic deafferentation of the rat neocortex but not the amygdala. Furthermore, a stronger relationship between severity of memory impairment after NMDA lesions and basoamygdaloid cholinergic deafferentation was found. Therefore, in a second experiment, we show that combining NMDA-induced lesions into the basolateral amygdala with 192IgG-saporin injections into the basal forebrain results in a strong disruption of taste aversion learning, whereas none of these treatments were by themselves capable of producing any detectable impairment in this learning task. The double lesion effect was only paralleled by simple NMDA lesions into the basal forebrain, suggesting that the learning deficits associated to excitotoxic lesions of the basal forebrain are the result of the simultaneous destruction of the corticopetal and basoamygdaloid interaction. A model is proposed, according to which the modulation of learning processes exerted by the basal forebrain can be redundantly performed by both the basocortical and basoamygdaloid pathway.

Long-term memory retrieval deficits of learned taste aversions are ameliorated by cortical fetal brain implants.

In this study, the effects that fetal brain implants have on the ability to retrieve the memory for a previously acquired conditioned taste aversion (CTA) in insular cortex (IC) lesioned rats were tested. Several groups of rats were trained for a CTA, were lesioned in the IC 4 days later, were implanted with different fetal cortical tissues, were treated or untreated with nerve growth factor (NGF), and then were tested for recall either 15 or 45 days later. Rats were then retrained and tested with a different taste and in the inhibitory avoidance (IA) task. All implanted animals recovered the retrieval of CTAs learned before IC lesions; however, only the homotopic IC implants at 45 days or NGF supplemented at 15 days induced recovery of the ability to learn CTA. The latter effect was also true for IA learning. The results suggest that the brain mechanisms for recovery of memory functions are different from those of learning abilities.

Differential effects of anterior and posterior insular cortex lesions on the acquisition of conditioned taste aversion and spatial learning.

In this study, we evaluated the effects of NMDA-induced lesions in different sites of the insular cortex of the rat on the acquisition of conditioned taste aversion and spatial learning in the Morris water maze. The lesions were produced by bilateral microinjections of NMDA in the insular cortex at +3.7 mm (Anterior group), +1.7 mm (Central group), and -0.3 mm (Posterior group) anteroposterior from bregma. The results showed that the central and posterior, but not the anterior, lesions disrupted the acquisition of water maze learning as measured by the high latency to reach the target. In contrast, the conditioned taste aversion learning was disrupted by lesions in the central but not in the anterior or posterior insular cortex. These data confirm functional heterogeneity of the insular cortex and demonstrate that the more caudal parts are only necessary for acquisition of the water maze task, while the central insular cortex is crucial for the acquisition of both the conditioned taste aversion learning and the Morris water maze.

Insular cortex lesions impair the acquisition of conditioned immunosuppression.

Conditioned immunosuppression can be readily obtained in animals by associating a taste with an immunosuppressive drug. On subsequent exposure to the conditioned taste, the animals show an attenuated immune response and also exhibit a conditioned taste aversion. It has been established that insular cortex lesions disrupt the acquisition of conditioned taste aversion. The effect of NMDA-induced lesions in either the insular cortex or the parietal cortex of male Wistar rats was evaluated in the acquisition of conditioned immunosuppression in two experiments. Unlesioned control rats showed the conditioned immunosuppressive response after reexposure to the taste, as indicated by lower hemagglutinating titers to sheep red blood cells in the first experiment and by a decreased IgM production to ovalbumin, measured by ELISA, in the second experiment. Insular cortex-lesioned rats did not show the conditioned immunosuppression in either experiment, while parietal cortex lesions and the sham-lesioned animals presented a clear decrease of hemagglutinating titer and a low IgM production. The insular cortex lesions did not affect the normal immune response, showing normal hemagglutinating titers and IgM production when compared to nonconditioned controls. The immunosuppressive action of cyclophosphamide also remained unaltered. In conclusion, these results show that the insular cortex is essential for the acquisition of conditioned immunosuppression.

Differential recovery of inhibitory avoidance learning by striatal, cortical, and mesencephalic fetal grafts.

Four groups of male Wistar rats showing disrupted inhibitory avoidance conditioning due to striatal lesions were studied. Three groups received striatal, cortical, or ventral mesencephalic brain grafts and the fourth group remained as a lesioned control. Sixty days postgraft the animals were retrained in an inhibitory avoidance task. The striatal-grafted animals were the only group that significantly improved in the ability to acquire the inhibitory avoidance task. Acetylcholinesterase histochemistry revealed positive patches of cells in the striatal grafts. Cortical grafts showed less reactivity, without patches. Immunocytochemical analyses for tyrosine hydroxylase revealed positive cell reactivity in the mesencephalic grafts and few positive fibers were detected in the border between the striatal grafts and the host tissue. These results demonstrate that striatal but not cortical or mesencephalic brain grafts can promote the restoration of the ability to acquire an inhibitory avoidance task and suggest that the acetylcholine tissue content is involved in the behavioral recovery.

Graft-induced recovery of inhibitory avoidance conditioning in striatal lesioned rats is related to choline acetyltransferase activity.

Four groups of male Wistar rats showing disrupted inhibitory avoidance conditioning due to striatal lesions received either striatal or ventral mesencephalic brain grafts. Two additional non-lesioned groups were used as controls. Half of the groups was retrained in an inhibitory avoidance task at fifteen days postgraft and the other half at sixty days postgraft. Those animals receiving striatal grafts significantly improved their ability to acquire the inhibitory avoidance task at fifteen and sixty days postgraft, as opposed to those receiving mesencephalic grafts, which did not show behavioral recovery. Choline acetyltransferase and glutamate decarboxylase activities, as well as dopamine content, were measured in the grafted tissue. Striatal grafts showed levels of choline acetyltransferase activity similar to the control group. Moreover, a positive correlation was found between the choline acetyltransferase activity and the behavioral recovery. In contrast, both glutamate decarboxylase activity and dopamine levels were significantly lower in striatal and in mesencephalic grafts, as compared to the controls. These results show that striatal but not mesencephalic grafts can promote the restoration of the ability to acquire an inhibitory avoidance task even at early stages (15 days) of the development of the grafts. The results also suggest that acetylcholine plays an important role in behavioral recovery.

Perception of static orientation in a constant gravitoinertial environment.

The illusions associated with the perception of static tilt in various specific force environments have been reviewed and then classified in such a way that a simple perceptual model could be developed to account for the experimental data. The fundamental conclusion to be drawn from this model is that these illusions can be accounted for by a simple non-linear transformation of the information primarily from the saccule.