Immune response, accommodation, and tolerance to transplantation carbohydrate antigens

The carbohydrate antigens, blood groups A and B, and the alpha-gal epitope (Galalpha1-3Gal) are major risk factors in transplantation. Transplantation across ABO barriers may result in rejection by elicited anti-blood group antibodies, accommodation where elicited anti-blood group antibodies do not reject the graft, or tolerance where no anti-blood group antibodies are produced and the graft is not rejected. alpha1,3Galactosyltransferase knockout mice that lack alpha-gal epitopes but produce the anti-Gal antibody serve as a model for studying these immune responses. Knockout mice underwent transplantation heterotopically with wild-type mouse heart expressing alpha-gal epitopes and subsequently received lymphocytes including naive and memory anti-Gal B cells. The type of elicited immune response was found to be associated with the period that anti-Gal B cells were exposed to alpha-gal epitopes of the graft in the absence of T-cell help. Immediate T-cell help induced production of cytolytic anti-Gal antibodies that reject the graft, whereas delayed T-cell help induced production of accommodating anti-Gal antibodies. In the absence of T-cell help for prolonged periods, anti-Gal B cells exposed to alpha-gal epitopes were deleted, resulting in tolerance. Similar variations in the extent of T-cell help may determine the B-cell response to incompatible A or B antigens. The experimental model further suggests that active tolerance induction before transplantation may be achieved by gene therapy with autologous bone marrow cells or autologous lymphocytes manipulated to express the incompatible transplantation carbohydrate antigen by introduction of the corresponding glycosyltransferase gene into these cells.     

Impact of Carotid Artery Angioplasty and Stenting on Management of Recurrent Carotid Artery Stenosis

Citing the higher perioperative risk of redo carotid surgery, balloon angioplasty and stenting of the carotid artery (CAS) has been advocated for recurrent carotid stenosis (RCS). To examine the impact of CAS on the management and outcome of recurrent stenosis, a retrospective review of a prospectively compiled database was performed. From a registry of patients treated for carotid disease, 105 procedures were performed from 1992 to 2002 for RCS. For comparison, two study groups were examined. Time I consisted of 77 reoperations performed through 1998, before CAS was introduced at our institution. Time II included 12 reoperations and 16 CAS procedures performed for RCS from 1999 through 2002. Using perioperative stroke as a measure of outcome, the results for time II were poorer than for time I (7.2% vs. 5.2%, p = NS). Overall, the risk of perioperative stroke was the same for reoperation (5/89) and CAS (1/16) (5.6% vs. 6.3%, p = NS). Although not statistically significant, there was a trend toward a higher risk of perioperative stroke for patients treated with reoperation during the latter time period (8.3% vs. 5.2%, p = NS). This probably relates to the finding that during time II, CAS was most likely to be used in asymptomatic patients (68.6% vs. 41.7%, p = NS) with early (<3 years) RCS (87.5% vs. 41.7%, p = 0.01). No patient with asymptomatic, early RCS had a perioperative stroke with either surgery or CAS (0/35 cases, 0%). The presence of preoperative neurologic symptoms was significantly predictive of a perioperative stroke among all procedures performed for RCS (13.6% vs. 0%, p = 0.004). Contrary to suggestions that CAS might improve the management of RCS, a review of our data shows the overall risk of periprocedural stroke to be no better since CAS has become available. The bias for using CAS for asymptomatic myointimal hyperplastic lesions, and reoperation for frequently symptomatic late recurrent atherosclerotic disease, makes direct comparisons of the two techniques for treating RCS difficult. It is expected that the overall risk for redo carotid surgery will increase, as fewer low-risk patients will be receiving open procedures. However, the increased risk among symptomatic patients undergoing reoperation suggests that endovascular techniques should be investigated among this group of cases as well.Presented at the Twenty-eighth Annual Meeting of the Peripheral Vascular Surgery Society, Chicago, IL, June 7, 2003.     

Diode laser thermal keratoplasty to correct hyperopia

PURPOSE: We investigated long-term efficacy, predictability, stability, and safety of diode laser thermal keratoplasty (DTK) to correct hyperopia. METHODS: DTK was performed on 24 eyes (18 patients). Eight eyes with high hyperopia (mean +4.75 +/- 0.63 D; range +3.50 to +5.50 D) received 12 pairs of coagulation spots at 6-mm and 7-mm treatment zone diameters; eight eyes with low hyperopia (mean +2.25 +/- 0.40 D; range +1.50 to +2.75 D) received eight coagulation spots at 8 mm, and eight eyes with low hyperopia (mean +1.50 +/- 0.46 D; range +1.25 to +2.25 D) were treated to induce mild myopia (-1.50 D) in the non-dominant eye for monovision using eight pairs of spots at 7 and 8-mm diameters. Minimum follow-up was 18 months. RESULTS: Mean decrease in cycloplegic refraction at 18 months was 5.00 +/- 0.38 D in the high hyperopia group, 1.75 +/- 0.19 D in the low hyperopia group, and 3.25 +/- 0.27 D in the presbyopia group. Mean increase in uncorrected visual acuity (UCVA) at 18 months was 8.125 +/- 2.1 Snellen lines in the high hyperopia group, 6.625 +/- 0.744 lines for low hyperopia; decrease of 1.00 +/- 1.85 line occurred in the presbyopia group. Near UCVA in the presbyopia group improved by 3.875 +/- 0.83 Jaeger lines. Best spectacle-corrected visual acuity (BSCVA) was restored by 3 months in all eyes. CONCLUSION: DTK was an effective and fairly safe procedure, with reasonable predictability and stability. Nomograms for laser energy level, treatment zone diameter, and number of spots need improvement.     

Latent inhibition and overswitching in schizophrenia

Attention disorders in schizophrenia are manifested in two different ways. On the one hand, the schizophrenia patient tends to keep a learned response even after it ceases to be relevant (perseveration). On the other hand, the schizophrenia patient tends to replace an adaptive response without being given a reason to do so (overswitching). In the present study, overswitching was investigated in relation to latent inhibition (LI), which is the normal ability to ignore nonrelevant stimuli. A new tool--the Combined Attention Test--was used for this purpose in a group of 41 unmedicated schizophrenia patients, divided into subgroups of patients with predominantly positive and negative symptoms, and 24 normal controls. The results show that positive schizophrenia patients, who exhibited high levels of overswitching, also revealed impaired LI, while the negative schizophrenia group, as well as normal controls, exhibited intact LI. These findings suggest that overswitching is a specific attention deficit in positive schizophrenia. We discuss the possibility that impaired LI is a consequence of overswitching and comment on the putative neurophysiology.     

Congenital hydrocephalus and continuous spike wave in slow-wave sleep--a common association?

Early-onset hydrocephalus was identified as the common denominator in 5 of 12 consecutive patients with Landau-Kleffner syndrome or continuous spike wave in slow-wave sleep who presented during the last 6 years. This association seems to be more common than expected, and the course of epileptic disease and outcome differs from that of previous reports. We present the clinical cases and discuss the possible connection between early hydrocephalus and epilepsy, especially continuous spike wave in slow-wave sleep. A retrospective analysis was undertaken of the clinical course and electroencephalographic (EEG) data before and after the development of continuous spike wave in slow-wave sleep in a group of five children with early-onset hydrocephalus identified in three epilepsy clinics in Israel. Landau-Kleffner syndrome or continuous spike wave in slow-wave sleep was identified in 12 patients during 6 years (1995-2000). Five patients had a history of early-onset hydrocephalus. Three patients had ventriculoperitoneal shunts; two of them were never shunted. Patients' seizures and continuous spike wave in slow-wave sleep epileptiform activity was resistant to appropriate anticonvulsant treatment. Pediatric neurologists and neurosurgeons should be aware of the association between continuous spike wave in slow-wave sleep and early-onset hydrocephalus. When a child with hydrocephalus presents with behavioral, cognitive, or motor deterioration, he or she should undergo sleep EEG in addition to investigation of shunt function. Our series demonstrated the presence of continuous spike wave in slow-wave sleep and localization-related epilepsy that did not originate from the shunt site. This group of patients is heterogeneous, and the exact trigger for continuous spike wave in slow-wave sleep development is still unclear.     

Bone strength in multiple sclerosis: cortical midtibial speed-of-sound assessment

It has been previously suggested that multiple sclerosis (MS) patients are at increased risk for osteoporosis due to reduced mobility, decreased exposure to sunlight and recurrent steroid treatment. In order to systematically evaluate bone strength we assessed 256 MS patients (171 females, 75 males) through quantitative ultrasound measurement of cortical bone. Tibial speed of sound (SOS, m/sec) was measured at midpoint of the tibial shaft using a Soundscan 2000 (Myriad Ultrasound Systems, Rehovot, Israel) and results were compared to age- and gender-matched population norms. T-score distribution in male MS patients was similar to normal population. In contrast, for female MS patients T-score distribution was significantly different from population norms, reflected by increased SOS in 30.4% (T-score intervals 1-2 and >2 above normal values; P=0.001), compared with 7.4% in controls. These findings held true for both female patients younger and older than 45 years of age. Increased neurological disability and specifically motor involvement were more frequent in female patients with increased SOS (P<0.05). Bone strength was preserved in MS patients. In a subgroup of female patients increased SOS was conceivably related to spasticity.     

Protective effect of topical iodine containing anti-inflammatory drugs against sulfur mustard-induced skin lesions

Previous studies have shown the antidotal efficacy of topical iodine at 15 and 30 min post-exposure to sulfur mustard (SM). Here we demonstrate efficacy at longer intervals (20, 30, 45, and 60 min, respectively, for data) using an improved topical povidone-iodine preparation termed N66, which contains steroidal and non-steroidal anti-inflammatory agents. In the mouse, N66 reduced severity of ear edema by 43, 47, 44, and 36%; ear epidermal ulceration by 74, 58, 45, and 58%; and epidermal necrosis by 54, 34, 26, and 31% at the respective time points. A similar effect was observed with encrustation. The healing marker, grade of acanthotic area, showed dramatic increases of 39.6-, 25.3-, 20.9-, and 22-fold. Severity of the dermal parameters, acute inflammation and dermal necrosis, was reduced by 63, 34, 34, and 38% and 80, 54, 54, and 59%, respectively. In guinea pig skin, topical treatment with N66 45 min post-exposure reduced the SM-induced ulceration area by 75%. The histological parameters subepidermal microblister formation, epidermal ulceration, epidermal necrosis, and encrustation were reduced by 63, 61, 41, and 41%, respectively. The healing marker, grade of acanthotic area, was elevated by 73%. N66 induced a statistically significant reduction in two dermal markers for tissue damage: acute inflammation (33%) and dermal necrosis (48%). Reduced skin damage was also observed in areas adjacent the treated sites. The pharmacologically active components of N66 showed additive effect. These findings suggest that the povidone-iodine preparation combined with anti-inflammatory agents functions as a potent antidote against skin lesions induced by SM at relatively long intervals between exposure and treatment.Part of this work was presented at the 41st Annual Meeting of the American Society of Toxicology, Nashville, TN, March 17–21, 2002.     

Local and non-local deficits in amblyopia: acuity and spatial interactions

Amblyopic vision is thought to be limited by abnormal long-range spatial interactions, but their exact mode of action and relationship to the main amblyopic deficit in visual acuity is largely unknown. We studied this relationship in a group (N=59) of anisometropic (N=21) and strabismic (or combined, N=38) subjects, using (1) a single and multi-pattern (crowded) computerized static Tumbling-E test with scaled spacing of two pattern widths (TeVA), in addition to an optotype (ETDRS chart) acuity test (VA) and (2) contrast detection of Gabor patches with lateral flankers (lateral masking) along the horizontal and vertical axes as well as in collinear and parallel configurations. By correlating the different measures of visual acuity and contrast suppression, we found that (1) the VA of the strabismic subjects could be decomposed into two uncorrelated components measured in TeVA: acuity for isolated patterns and acuity reduction due to flanking patterns. The latter comprised over 60% of the VA magnitude, on the average and accounted for over 50% of its variance. In contrast, a slight reduction in acuity was found in the anisometropic subjects, and the acuity for a single pattern could account for 70% of the VA variance. (2) The lateral suppression (contrast threshold elevation) in a parallel configuration along the horizontal axis was correlated with the VA (R2=0.7), as well as with the crowding effect (TeVA elevation, R2=0.5) for the strabismic group. Some correlation with the VA was also found for the collinear configuration in the anisometropic group, but less suppression and no correlation were found for all the vertical configurations in all the groups. The results indicate the existence of a specific non-local component of the strabismic deficit, in addition to the local acuity deficit in all amblyopia types. This deficit might reflect long-range lateral inhibition, or alternatively, an inaccurate and scattered top-down attentional selection mechanism.     

Therapeutic vaccination for closed head injury

Closed head injury often has a devastating outcome, partly because the insult, like other injuries to the central nervous system (CNS), triggers self-destructive processes. During studies of the response to other CNS insults, it was unexpectedly discovered that the immune system, if well controlled, provides protection against self-destructive activities. Here we show that in mice with closed head injury, the immune system plays a key role in the spontaneous recovery. Strain-related differences were observed in the ability to harness a T cell-dependent protective mechanism against the effects of the injury. We further show that the trauma-induced deficit could be reduced, both functionally and anatomically, by post-traumatic vaccination with Cop-1, a synthetic copolymer used to treat patients with multiple sclerosis and found (using a different treatment protocol) to effectively counteract the loss of neurons caused by axonal injury or glutamate-induced toxicity. We suggest that a compound such as Cop-1 can be safely developed as a therapeutic vaccine to boost the body's immune repair mechanisms, thereby providing multifactorial protection against the consequences of brain trauma.