The contribution of microsaccades and drifts in the maintenance of binocular steady fixation.

BACKGROUND: The eye performs three types of eye movements during fixation: fast microsaccades are interrupted by slow drift movements, and tremor is superimposed on the drifts. The contribution of the microsaccades and drifts in maintaining fixation has been discussed since the late 1950s. Initially, microsaccades were thought to correct the misalignment from the optimal fixation locus induced by the drift movements, a theory still postulated in more recent work. The present study aimed to uncover to what extent each fixation movement contributes to maintain steady binocular fixation. METHOD: Binocular fixation during a 40-s fixation task was recorded using an infrared recording technique for ten normal test persons. Start and end point of each microsaccade and drift were superimposed on a fixation map, and the distance to the preferred retinal location of fixation (PRL) was measured. RESULTS: It was found that 32.6% of the microsaccades corrected the previous drift movement towards the PRL, whereas 53.1% of the drifts corrected the endpoint of the previous microsaccade towards the PRL. The overall mean post-microsaccadic and mean post-drift distance to the PRL for the ten normal test persons were 0.46 degrees and 0.41 degrees , respectively; the difference was not statistically significant. Interindividually, the mean post-microsaccadic distance to the PRL ranged between 0.21 degrees and 0.91 degrees and the mean post-drift distance to the PRL ranged between 0.20 degrees and 0.72 degrees . CONCLUSION: Neither the endpoints of the microsaccades nor the drifts bring the visual line to coincide with the centre of the PRL. Consequently, it must be the eye movements performed during the drifts ("slow control") that keep the visual line in the centre of the foveola.

Fixation topography in normal test persons.

BACKGROUND: The eye is moved so that the object of interest falls on the central fovea, where the spatial resolution is highest. In the present study we quantified eye movements of normal test persons during steady fixation and characterized the fixation using a 3D fixation plot (X horizontal eye position, Y vertical eye position, Z time in each eye position). METHOD: Fixation eye movements were quantified binocularly in ten normal test persons during a 40-s fixation task using an infrared recording technique. RESULTS: The fixation plot was characterized by a single preferred fixation locus in 17 eyes. One eye had two distinctly separated preferred fixation locations and in two eyes the configuration of fixation plot was flat with no single identifiable locus of fixation. The fixation plots were elliptical along the horizontal meridian in 9 eyes, elliptical along the vertical meridian in 8 eyes, and round in 3 eyes. The fixation area (RAF95) ranged between 1418 and 14182 arcmin(2), and a significant positive correlation was found between RAF95 and the mean microsaccadic amplitude (p<0.001). CONCLUSION: The fixation plots are often characterized by a single preferred fixation locus but may also be almost flat with no identifiable location of fixation. The individual fixations patterns resembles the cone density contour plots as found in histological studies, and it may be speculated, that the shape of the fixation plot is determined by the cone density topography.

Binocular fixation topography in patients with diabetic macular oedema: possible implications for photocoagulation therapy (3rd revision).

BACKGROUND: During retinal photocoagulation for diabetic maculopathy, there is a potential risk of foveal burns, and laser scars may later enlarge to be sight-threatening when involving retinal areas previously used during fixation. Since the retinal area used during binocular steady fixation has been found to vary considerably in the normal test person and central fixation may be even further compromised in patients with diabetic maculopathy, the sight-threatening side effects could possibly be reduced by taking into account the fixation area individually. However, no study has described and quantified the retinal area of fixation binocularly in patients with clinically significant macular oedema (CSME). METHODS: Sixteen diabetic patients with CSME in one or both eyes were examined. Each examination included visual acuity testing (ETDRS charts), a standard eye examination, central retinal thickness assessment by optical coherent tomography, fluorescein angiography and binocular quantification of fixational eye movements using an infrared recording technique. RESULTS: A negative correlation was found between visual acuity and mean microsaccadic amplitude (R=0.48, p=0.009). The maximal retinal extension of the fixation area ranged between 1.0 degrees and 3.0 degrees , and in two eyes with CSME, this area was estimated to exceed 800 mum on the retinal plane. No correlation was found between retinal thickness and visual acuity, retinal area of fixation, maximal extension of the fixation area or mean microsaccadic amplitude. CONCLUSION: Large interindividual differences in quantitative measures of binocular fixational eye movements were found. The mean amplitude of fixational eye movements was not correlated to central retinal thickness, and fixation area could only partly be predicted by visual acuity. Two eyes with CSME had an estimated maximal extension of the fixation area exceeding the central 800 mum on the retinal plane; thus, the possible benefit of individualising central photocoagulation according to precise measures of fixation area needs to be investigated on a larger population.

Subthreshold micropulse diode laser treatment in diabetic macular oedema.

BACKGROUND/AIM: Enlargement of laser scars after retinal argon laser photocoagulation can give rise to deterioration in visual acuity. Subthreshold micropulse diode laser may decrease this risk. The aim of this study was to compare the effectiveness of subthreshold micropulse diode laser (810 nm) and conventional argon laser (514 nm) photocoagulation for the treatment of clinically significant macular oedema in diabetic patients. METHODS: 23 eyes of 16 patients were randomised to either treatment. Follow up was conducted for a minimum of 5 months. Changes in visual acuity and macular oedema measured by optical coherence tomography were examined. RESULTS: Visual acuity remained stable in all treatment groups throughout the observation period. Changes in retinal thickness were small both foveally and perifoveally. In patients with focal macular oedema a significant reduction in retinal thickness (9% approximately -26 microm, p = 0.02) was seen foveally 3 months after diode laser photocoagulation. CONCLUSION: Subthreshold micropulse diode laser and conventional argon laser treatment showed an equally good effect on visual acuity. Subthreshold micropulse diode laser showed a stabilising or even improving effect on macular oedema. The combination of primary diode laser and supplementary argon laser might be particularly favourable in reducing diabetic macular oedema.

Binocular quantification and characterization of microsaccades.

BACKGROUND: The significance of microsaccades in the visual process has been discussed for more than 50 years. However, only a few studies have measured microsaccades binocularly, and detailed quantification and characterization of these small movements are needed in order to further understand their nature. METHOD: The amplitude, velocity, acceleration and direction of microsaccades were quantified binocularly in 10 normal test persons during a 40-s fixation task, using an infrared recording technique. RESULTS: All microsaccades for all test persons were performed simultaneously and individually with an almost identical amplitude in the right and left eye (a range of 0.003-0.042 deg between right and left eye mean values). The mean microsaccadic amplitude for the test persons was within a range of 0.223-1.079 deg. The directional difference between simultaneously-performed right and left eye microsaccades was less than 22.5 deg for 84.8% of the saccades, indicating that the majority of microsaccades are conjugated. Three different fixation patterns were identified and characterized: (1) a classic interplay between easily identified drifts and medium-sized microsaccades (mean amplitude range 0.328-0.413 deg); (2) long intersaccadic intervals (4-5 s) with almost absent drifts, followed by three or four large microsaccades (mean amplitude range 0.755-1.079 deg); and (3) low-amplitude drift movements interrupted by low-amplitude microsaccades (mean amplitude range 0.231-0.265 deg). CONCLUSION: Microsaccades are involuntary, predominantly conjugated, simultaneously performed, and of almost identical amplitude in the right and left eye, suggesting a central control mechanism for microsaccades at subcortical level.

Chemotherapy of malignant tumors--a self-defeating form of immunotherapy?

Chemotherapy of malignant diseases was introduced into clinical practice during the 1940's. The initial response rate to this type of therapy is high in patients with a variety of cancers but the survival rate is affected in only a few patients, mainly in women with choriocarcinoma. Despite intensive research, the percentage of survivors following chemotherapy, for example in patients with small-cell bronchogenic cancer, has remained almost constant during the last 2 decades. The objective of the present paper is to consider the likelihood of immune mechanisms being active both in the regression and again in the later progression of tumor growth observed during treatment with cytotoxic drugs. Such a dual role for immunity appears to be possible. In contrast to most malignant cells in solid tumors, the leucocytes and leukemia cells are highly sensitive to anti-cancer agents. Thereby the drugs become immunosuppressive at a level in serum lower than that required for a direct interference with the proliferative capacity of the cells in a solid tumor. Furthermore, the cytotoxic drugs selectively influence the immune system. In the first phase of treatment the drugs enhance the effect of T-killer cells relatively by reducing blocking activity in serum; the net result being a regression in the tumor volume. However, continued chemotherapy is inconvenient for cancer patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunotherapy in acute myelogeneous leukemia (AML)--a tool for maintaining remission?

Twelve trials of adjuvant immunotherapy in patients suffering from AML have been analyzed and compared to results from experimental studies. The analysis presents evidence suggesting that the immune response to leukemia cells exists in a state of balance; this appears to be regulated by the dose of antigen and the state of the cells used to immunize the patients. The injection of high doses of live allogeneic leukemia cells produced a significantly prolonged duration of the first remission in in AML patients. Immunization with high doses of irradiated and dead cells induced some prolongation of the remission phase and survival time, although the percentage of survivors after 3 years was not increased in these groups as compared to non-immunized patients. Immunization by the same route using a 100-fold lower amount of leukemia cells afforded no protection against relapse of the disease during the maintenance phase. A few patients even developed the relapse earlier than did patients treated with chemotherapy alone. Our understanding of the immune responses to malignant cells has increased considerably during the past 2 decades due to various observations. The results obtained with active immunotherapy of the AML patients during the same period agree well with experience from laboratory studies. Thus the results confirm the potential of an immunological interaction between the leukemia cells and the patient. Consequently, it seems likely that the addition of immunotherapy to the treatment of patients with AML might be effective and the tool for maintaining the phase of remission by up-to-date immunological engineering.

Dependence on antigen dose and timing in the immune response of C3H mice to malignant ascites cells.

This study presents evidence suggesting that the immune response to malignant ascites cells exists in some state of balance, which seems to be regulated by the dose of antigen and the time used for immunization. Injection s.c. of high doses of tumour cells weekly for 5 weeks afforded protection against a subsequent i.p. tumour graft. Immunization by the same route with a 100-fold lesser amount of the tumour also induced immunity, but along with factors able to abrogate the effect of this immunity. These tumour-specific factors were able to reduce the binding to the cell membrane of specific antibodies detectable in the indirect immunofluorescence test and to protect the tumour cells against complement-dependent cytotoxic activity present in the tumour fluid. The factors interacted with protein A at pH 8.0, suggesting that they share properties with immunoglobulins. The factors eluted in the same fractions as IgG from Sephadex G-200 and showed high affinity for membrane associated antigens.

Immunological enhancement induced by gastrointestinal immunization of mice pretreated with cyclophosphamide.

The present study suggests that pretreatment of mice with cyclophosphamide (CPA) not only suppresses the intestinal immune response to malignant ascites cells but alters the character of the response. Non-treated animals were sensitized by intestinal immunization while CPA-treated animals showed enhanced tumour growth. Sera from enhanced mice contained factors which at the tumor cell membrane were able to interfere with the binding of antibodies detectable by immunofluorescence technique. These factors might be immunoglobins with similarities to IgG, but bound to antigen they were undetectable by the fluorescence method. Enhanced mice were found to be immunologically hyporesponsive to the challenging tumor graft as evidenced by a delay in the immune response to the graft.

Is cyclophosphamide self-defeating as an antitumor agents?

The study shows inhibition of the antitumor effect of cyclophosphamide (CPA) on mammary carcinomas growing in mice prior-immunized by intragastric inoculations of the tumor. Immunization with tumor cells through this route produces under certain conditions factors able to modulate the antigenic determinants on tumor cells. The possibility that the antigenicity of tumor cells might be an important factor in obtaining successful therapy with CPA is proposed.

Serological response to intracaecal injections of antigenic mouse tumour cells.

Immunofluorescence studies of sera from mice with induced enhancement of tumour growth demonstrated that these sera contained factors ("interfering factors") which in an apparently competitive manner interfered with the subsequent binding of specific antibodies to antigenic sites on the tumour-cell membrane. The factors were tumour-specific but lacked some of the immunoglobulin determinants. They could not be detected by polyvalent FITC-antimouse gamma-globulin. Interfering factors did not seem to be related to IgA or IgE. They were demonstrable in sera from tumour-free animals without growing tumours, thus differing from the tumour-specific "blocking factors".

Enhancement of tumour growth in two syngeneic C3H murine systems by immunization via the intracaecal route.

Over the past 70 years many experiments have been designed to promote tumour growth. These studies were all carried out in allogeneic tumour systems or by artificially influencing the immunization process. In the present study, the growth of syngeneic mammary tumour cells was enhanced by prior immunization via the intracaecal route. Such induced enhancement could be transferred to untreated animals by serum or by spleen cells. Tumour growth was also enhanced in another syngeneic system by immunization via the intestinal route with frozen-thawed ascites tumour cells. The result is in direct contrast to that obtained by similar immunization with live cells, which affords protection against a later challenge.

The influence of salicyl-azo-sulfapyridine on the immune response to antigenic tumour cells inoculated into the coecal lumen of C3H mice.

Pretreatment of C3H mice with salicyl-azo-sulfapyridine (SASP) was found to increase the susceptibility of the intestine to malignant ascites cells inoculated into the coecal lumen. The response to intestinal immunization was radically changed by prior treatment of mice with SASP. In non-treated animals protection against a subsequent graft followed the intracoecal inoculation of ascites tumour cells. By prior treatment of the mice with SASP the protective immune response was suppressed and some of the treated animals showed enhanced tumour growth of the challenging graft. The immunological enhancement induced in SASP-treated animals was transferable by spleen cells to untreated mice. In sera from SASP-treated and intestinally immunized animals were found factors which in a competitive manner interfered with the binding of antibodies to antigenic sites on the tumour cell membrane. It is proposed that treatment with SASP modifies the intestinal immunity by suppressing antibody production and increasing production of antigen-specific factors lacking some of the immunoglobulin determinants.