Blur adaptation: clinical and refractive considerations

The human visual system is amenable to a number of adaptive processes; one such process, or collection of processes, is the adaptation to blur. Blur adaptation can be observed as an improvement in vision under degraded conditions, and these changes occur relatively rapidly following exposure to blur. The potential important future directions of this research area and the clinical implications of blur adaptation are discussed.     

The efficacy and toxicity of immune checkpoint inhibitors in a real-world older patient population

ImportanceImmunotherapy has emerged as an effective treatment option for the management of advanced cancers. The effects of these immune checkpoint inhibitors in the older patient population has not been adequately assessed.ObjectiveTo understand the impact of aging on CTLA-4 and PDL-1 inhibitors efficacy and immune-related adverse events (irAE) in the context of real-world management of advanced solid cancers.Design, Setting, and ParticipantsThis retrospective study involved all non-study patients with histologically-confirmed metastatic or inoperable solid cancers receiving immunotherapy at Kingston Health Sciences Centre. We defined ‘older patient’ as age ≥ 75. All statistical analyses were conducted under SPSS IBM for Windows version 24.0.Main Outcomes and MeasuresStudy outcomes included immunotherapy treatment response, survival, as well as number, type, and severity of irAEs.ResultsOur study (N = 78) had 29 (37%) patients age <65, 26 (33%) patients age 65–74, and 23 (30%) patients age ≥75. Melanoma, non-small cell lung cancer, and renal cell carcinoma accounted for 70%, 22%, and 8% of the study population, respectively. Distributions of ipilimumab (32%), nivolumab (33%), and pembrolizumab (35%) were similar in the study. The response rates were 28%, 27%, and 39% in the age <65, age 64–74, age ≥75 groups, respectively (P = 0.585). Kaplan-Meier curve showed a median survival of 28 months (12.28–43.9, 95% CI) and 17 months (0–36.9, 95% CI) in the age <65 and age 64–74 groups, respectively; the estimated survival probability did not reach 50% in the age ≥75 group (P = 0.319). There were no statistically significant differences found in terms of irAEs, multiple irAEs, severity of grade 3 or higher, types of irAEs, and irAEs resolution status when comparing between different age groups.Conclusion and RelevanceOur results suggest that patients age ≥75 are able to gain as much benefit from immunotherapy as younger patients, without excess toxicity. Our findings suggest that single agent immunotherapy is generally well-tolerated across different age groups with no significant difference in the type, frequency or severity of irAEs. Future studies evaluating aging and combination immunotherapy are warranted.     

Treatment of the dumping syndrome with the somatostatin analogue SMS 201-995.

In six patients suffering from severe early dumping and six patients with late dumping after peptic ulcer surgery, the effect of the somatostatin analogue SMS 201-995 was compared with placebo. In early dumpers subcutaneous administration of 50 micrograms SMS 201-995 prior to meal ingestion induced a strong improvement of dumping symptoms as reflected by a decrease of the Sigstad dumping score from 12 +/- 2 during placebo to 5 +/- 2 (p less than 0.05). Furthermore, the postprandial increase of pulse rate was abolished; maximum pulse rate decreased from 85 +/- 7 beats/min to 67 +/- 7 beats/min (p less than 0.05). SMS 201-995 did not significantly affect postprandial changes in packed cell volume. In late dumpers 50 micrograms SMS 201-995 reduced peak plasma insulin after oral glucose from 173 +/- 16 mU/L during placebo to 35 +/- 9 mU/L during SMS 201-995 (p less than 0.05) and increased individual plasma glucose nadirs from 1.9 +/- 0.3 mmol/L to 7.5 +/- 3.3 mmol/L (p less than 0.01). Both in early and late dumpers SMS 201-995 improved postprandial expiratory breath hydrogen excretion indicating slowing of gastrointestinal hurry. SMS 201-995 is a powerful therapeutic agent for the management of patients suffering from the dumping syndrome after gastric surgery.     

Structural chromosome 1 aberrations in transitional cell carcinoma of the bladder: interphase cytogenetics combining a centromeric, telomeric, and library DNA probe.

Fluorescence in situ hybridization (FISH) was used to study numerical and structural chromosome 1 aberrations in interphase nuclei of transitional cell carcinomas (TCCs) of the urinary bladder. One of the characteristic numerical aberrations, as detected previously in low-grade noninvasive TCCs, included trisomy for chromosome 1 (A. H. N. Hopman et al., Cancer Res., 51: 644-651, 1991). We examined in more detail 22 cases with a centromeric (1q12) and a telomeric associated (1p36) DNA probe and with a library DNA probe from sorted human chromosome 1 in single- and double-target FISH procedures. All flow cytometrically determined DNA diploid TCCs (13 cases), which showed three spots for 1q12 (6 cases), had two spots for 1p36. Since the library DNA probe showed three separate domains in the nuclei of these cases, the additional copy for 1q12 could be explained as an extra chromosome 1p-, containing the 1q12 target. In the flow cytometrically determined DNA tetraploid/aneuploid tumors, the results were more complex. In 6 of 9 cases, we observed an overrepresentation of 1q12 as compared to 1p36, also suggesting the presence of extra copies of 1p- chromosomes. The results of the present study demonstrate the utility of the FISH method to assess structural chromosome aberrations in interphase nuclei of solid tumors.     

Serum ionic fluoride levels in haemodialysis and continuous ambulatory peritoneal dialysis patients

High serum fluoride (F-) in patients with chronic renal failure (CRF) and end-stage renal disease (ESRD) is associated with risk of renal osteodystrophy and other bone changes. This study was done to determine F- in normal healthy controls and patients with ESRD on haemodialysis (HD) or peritoneal dialysis (PD). Seventeen healthy controls (12 males, 5 females) and 39 ESRD patients on dialysis (17 males, 22 females) were recruited in the study in a community with 47.4 +/- 3.28 microM/l (range 44-51 microM/l) of F- content in drinking water. Control subjects showed a mean serum F- concentration of 1.08 +/- 0.350 microM/l. Males in control group showed slightly higher F- levels (1.15 +/- 0.334, range 0.55-1.9 microM/l) than females (0.92 +/- 0.370, range 0.6-1.5 microM/l). Mean serum F- concentration did not correlate significantly with age and sex among control subjects, whereas such correlation was observed in patients with ESRD on dialysis. Mean serum F- concentration was significantly higher in patients on dialysis (2.67 +/- 1.09, range 0.8-5.2 microM/l) than normal controls. When grouped according to sex, the mean serum F- concentration in males (3.05 +/- 1.04, range 1.8-5.2 microM/l) was significantly higher than females (2.38 +/- 1.08, range 0.8-5.2 microM/l). When patients were grouped according to age, it was observed that F- concentration was significantly higher in patients with age groups 21-70 (2.86 +/- 1.05) than those with age group 13-20 years (1.42 +/- 0.531). Thus F- concentration correlated with age and sex, being higher in males and above 20 years. Despite appreciable clearance of F- (39-90%) across the peritoneum, patients on CAPD showed higher serum F- concentration than those on HD (3.1 +/- 1.97 vs 2.5 +/- 1.137 microM/l). Of the total 39 patients on dialysis 39% had their serum F- concentration above 3.0 microM/l, posing the risk of renal osteodystrophy.      

Andrology: Application of different in-situ hybridization detection methods for human sperm analysis

The detection of some types of aneuploidy in human spermatozoacan be based on the use of the fluorescence in-situ hybridizationtechnique (FISH). One of the crucial steps for FISH is to achievea proper decondensation and denaturation of the DNA in the specimen,so as to obtain efficient hybridization results. However, afterDNA decondensation the morphology of sperm heads is partly distortedand the majority of the tails is lost. This situation leadsto problems in the distinction between disomic and diploid spermatozoa,as well as between abnormal spermatozoa and somatic cells. Double-and triple-target FISH can partly solve this discriminationproblem. To improve these procedures we adapted the steps ofdecondensation and visualization of the single sperm cells.Firstly, DNA decondensation with 25 mM dithiothreitol in 1 MTris at pH 9.5 resulted in sperm cells with intact morphologyof both the head and the tail, and allowed efficient single-,double- and triple-target ISH to be performed. Secondly, weapplied a novel detection method, based on enzyme immunocyto-chemicalreactions, with coloured precipitation products. Thirdly, thisISH procedure was combined with Diff-Quik staining and bright-fieldmicroscopy. This absorption method has the advantage of a permanentsignal, and the adapted cytoplasmic staining of the sperm plasmamembrane allows the visualization of the outline of the singlespermatozoon. Using this approach, therefore, it is possibleto discriminate between disomic, diploid and abnormal spermatozoa,somatic cells and spermatozoa that overlap, because the morphologyof the cells is not distorted and the tails of the spermatozoaare intact and properly visualized.     

Numerical chromosome 1, 7, 9, and 11 aberrations in bladder cancer detected by in situ hybridization

Forty transitional cell carcinomas of the human urinary bladder (TCCs) were examined for numerical aberrations of chromosomes 1, 7, 9, and 11 by in situ hybridization using chromosome-specific probes. Our interphase cytogenetic study of 24 low-grade, noninvasive TCCs, which were near-diploid by flow cytometry, showed a numerical aberration for at least 1 of these chromosomes in 14 of these cases. Most strikingly, a monosomy for chromosome 9 was found in 9 of 24 low-grade TCCs. A trisomy for chromosomes 1, 7, and 11 was detected in 5, 2, and 1 case(s), respectively. In 1 case a monosomy for chromosome 1 was detected by in situ hybridization. Monosomy for chromosome 9 was the only detected numerical change in 5 low-grade TCC cases. Examination of 16 invasive TCCs showed extra copies for chromosomes 1 and 7 in 7 flow cytometrically diploid cases with numerical chromosome aberrations; also, loss of chromosome 9 was detected. In 5 invasive and 2 noninvasive aneuploid/tetraploid TCCs a profound imbalance between the different chromosomes was found. In 5 of these cases an evident underrepresentation of chromosome 9 in comparison to chromosomes 1, 7, and 11 was detected. This underrepresentation of chromosome 9 in diploid, as well as aneuploid, TCCs, and in some cases the constant ratio between this chromosome and the other chromosomes, may be explained by a process of tetraploidization. Therefore, loss of chromosome 9 may be one of the primary genetic events in TCC oncogenesis, with secondary events, such as tetraploidization, correlated to tumor progression. Our results show that in situ hybridization can be routinely used to study important cytogenetic changes which occur during the development of a malignant disease.