Prosthetic Visual Acuity with the PRIMA System in Patients with Atrophic Age-related Macular Degeneration at 4 years follow-up.

Objective: To assess the efficacy and safety of the PRIMA subretinal neurostimulation system 48-months post-implantation for improving visual acuity (VA) in patients with geographic atrophy (GA) due to age-related macular degeneration (AMD) at 48-months post-implantation. Design: First-in-human clinical trial of the PRIMA subretinal prosthesis in patients with atrophic AMD, measuring best-corrected ETDRS VA (Clinicaltrials.gov NCT03333954). Subjects: Five patients with GA, no foveal light perception and VA of logMAR 1.3 to 1.7 in their worse-seeing "study" eye. Methods: In patients implanted with a subretinal photovoltaic neurostimulation array containing 378 pixels of 100 µm in size, the VA was measured with and without the PRIMA system using ETDRS charts at 1 meter. The system's external components: augmented reality glasses and pocket computer, provide image processing capabilities, including zoom. Main Outcome Measures: VA using ETDRS charts with and without the system. Light sensitivity in the central visual field, as measured by Octopus perimetry. Anatomical outcomes demonstrated by fundus photography and optical coherence tomography up to 48-months post-implantation. Results: All five subjects met the primary endpoint of light perception elicited by the implant in the scotoma area. In one patient the implant was incorrectly inserted into the choroid. One subject died 18-months post-implantation due to study-unrelated reason. ETDRS VA results for the remaining three subjects are reported herein. Without zoom, VA closely matched the pixel size of the implant: 1.17 ± 0.13 pixels, corresponding to mean logMAR 1.39, or Snellen 20/500, ranging from 20/438 to 20/565. Using zoom at 48 months, subjects improved their VA by 32 ETDRS letters versus baseline (SE 5.1) 95% CI[13.4,49.9], p<0.0001. Natural peripheral visual function in the treated eye did not decline after surgery compared to the fellow eye (p=0.08) during the 48 months follow-up period. Conclusions: Subretinal implantation of PRIMA in subjects with GA suffering from profound vision loss due to AMD is feasible and well tolerated, with no reduction of natural peripheral vision up to 48-months. Using prosthetic central vision through photovoltaic neurostimulation, patients reliably recognized letters and sequences of letters,and with zoom it provided a clinically meaningful improvement in VA of up to eight ETDRS lines.

The EIF4EBP3 translational repressor is a marker of CDC73 tumor suppressor haploinsufficiency in a parathyroid cancer syndrome.

Germline mutation of the tumor suppressor gene CDC73 confers susceptibility to the hyperparathyroidism-jaw tumor syndrome associated with a high risk of parathyroid malignancy. Inactivating CDC73 mutations have also been implicated in sporadic parathyroid cancer, but are rare in sporadic benign parathyroid tumors. The molecular pathways that distinguish malignant from benign parathyroid transformation remain elusive. We previously showed that a hypomorphic allele of hyrax (hyx), the Drosophila homolog of CDC73, rescues the loss-of-ventral-eye phenotype of lobe, encoding the fly homolog of Akt1s1/ PRAS40. We report now an interaction between hyx and Tor, a central regulator of cell growth and autophagy, and show that eukaryotic translation initiation factor 4E-binding protein (EIF4EBP), a translational repressor and effector of mammalian target of rapamycin (mTOR), is a conserved target of hyx/CDC73. Flies heterozygous for Tor and hyx, but not Mnn1, the homolog of the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor associated with benign parathyroid tumors, are starvation resistant with reduced basal levels of Thor/4E-BP. Human peripheral blood cell levels of EIF4EBP3 were reduced in patients with CDC73, but not MEN1, heterozygosity. Chromatin immunoprecipitation demonstrated occupancy of EIF4EBP3 by endogenous parafibromin. These results show that EIF4EBP3 is a peripheral marker of CDC73 function distinct from MEN1-regulated pathways, and suggest a model whereby starvation resistance and/or translational de-repression contributes to parathyroid malignant transformation.

[Postoperative course after uncomplicated tooth extractions in adults. Experiences in a university mouth disease and jaw surgery clinic]. / Het beloop na ongecompliceerde extracties bij volwassenen. Ervaringen in een universiteitskliniek mondziekten en kaakchirurgie.

The records of 68 adult patients, referred to a Department of Oral and Maxillofacial Surgery for extraction of one or more teeth, have been studied with regard to the complexity of the treatment and the postoperative course. In 11 patients surgical removal had to be performed, while in the remaining 57 patients treatment consisted of simple extractions. Forty-six patients of these 57 patients returned a questionnaire about postoperative problems and use of analgesics. These patients were divided into two groups, one consisting of 17 healthy patients without any medical disorder and/or use of drugs, and a second consisting of 29 medically compromised patients. The postoperative course did not differ between both groups. Four patients (1 healthy, 3 medically compromised) experienced postoperative complaints during more than 6 days. Remarkably, the number of patients who experienced pain but did not use analgesics was considerably higher in the healthy group (29%) compared with the medically compromised group (7%). On the other hand, medically compromised patients more often experienced pain in spite of the use of analgesics (52%) than healthy patients (41%). No differences in wound healing after simple tooth extractions were observed between healthy and medically compromised patients.

Risk factors associated with lung cancer in Hong Kong.

The purpose of this study was to investigate the risk factors associated with lung cancer in Hong Kong. Three hundred and thirty-one histologically or cytologically proven consecutive cases of lung cancer and the same number of in- and out-patients without cancer matched for age and sex were recruited for this study using a detailed questionnaire completed by a trained interviewer. Smoking was the most important risk factor associated with lung cancer but the attributable risk (AR) was estimated to be 45.8% in men and 6.2% in women, considerably lower compared with those estimated in early 1980s. In addition, among women, exposure to environmental tobacco smoke (ETS) at work+/-at home and lack of education, were independent risk factors for lung cancer with adjusted odds ratio (OR) 3.60, (95% confidence interval (CI) 1.52-8.51) and OR 2.41 (95% CI 1.27-4.55), respectively. Among men, exposure to insecticide/pesticide/herbicide, ETS exposure at work or at home, and a family history of lung cancer and were independent risk factors with adjusted OR 3.29 (95% CI 1.22-8.9, OR 2.43, 95% CI 1.24-4.76 and OR 2.37, 95% CI 1.43-3.94, respectively). Exposure to incense burning and frying pan fumes were not significant risk factors in both sexes. A moderate or high consumption of fat in the diet was associated with increased risk in men but decreased risk in women. The results of this study suggested that as the prevalence of smoking declined, the influence of smoking as a risk factor for lung cancer decreased even further. Moreover, the contribution of other environmental, occupational and socioeconomic factors may be more apparent as etiological factors for lung cancer in a population with relatively high lung cancer incidence but low AR from active smoking.

Strategy for the treatment of noncompliant hypertensive hemodialysis patients.

Hypertensive hemodialysis patients noncompliant for their medications do not benefit from pharmacologic advances in the treatment of high blood pressure, and increase their already high risk of cardiovascular complications. The medical staff often becomes frustrated by severe hypertension in those who refuse to take medicines at home, drink excessive fluids, miss multiple dialysis sessions and sign-off dialysis early. In addition to addressing the psychosocial, financial, educational and substance abuse problems which contribute to noncompliance, we have developed a medication strategy to serve as an at least interim means of lowering blood pressure. Antihypertensive agents which have long half-lives in renal failure (lisinopril) and/or are intrinsically long acting (transdermal clonidine and amlodipine) were administered on dialysis days by the unit personnel to those patients who did not or would not take that or any dose on their own. The lisinopril and amlodipine were assured to have been taken on at least the dialysis days (thrice weekly), and the clonidine patch replaced weekly. Sixteen patients were thus treated when they failed to reliably self-administer medications. They had a significant decline in the predialysis systolic pressure of 15 mm Hg (175 +/- 6 to 160 +/- 5 mm Hg), diastolic of 12 mm Hg (103 +/- 3 to 91 +/- 3 mm Hg), and mean pressure of 13 mm Hg (127 +/- 4 to 114 +/- 4 mm Hg). There was an improvement in post-dialysis bood pressures, with the mean pressure declining 13 mm Hg from 110 +/- 4 to 97 +/- 4 mm Hg. Many individuals had erratic blood pressure control, having intermittently missed dialysis and hence unit-administered medicine, as well as continued fluid or drug abuse. The patients had uniformly excellent acceptance of this regimen, even spontaneously requesting it, and had no appreciable adverse effects. In summary while noncompliance is being addressed by the entire medical team, dialysis unit administration of long-acting medicines helps many hypertensive dialysis patients who would otherwise be at increased risk for severe cardiovascular complications.

Reversible pressure deformation of a thermophilic cytochrome P450 enzyme (CYP119) and its active-site mutants.

The pressure stability of the thermophilic CYP119 from Sulfolobus solfataricus and its active-site Thr213 and Thr214 mutants was investigated. At 20 degrees C and pH 6.5, the protein undergoes a reversible P450-to-P420 inactivation with a midpoint at 380 MPa and a reaction volume change of -28 mL/mol. The volume of activation of the process was -9.5 mL/mol. The inactivation transition was retarded, and the absolute reaction volume was decreased by increasing temperature or by mutations that decrease the size of the active-site cavity. High pressure affected the tryptophan fluorescence yield, which decreased by about 37% at 480 MPa. The effect was reversible and suggested considerable contraction of the protein. Aerobic decomposition of iron-aryl complexes of the CYP119 T213A mutant under increasing hydrostatic pressure resulted in variation of the N-arylprotoporphyrin-IX regioisomer (N(B):N(A):N(C):N(D)) adduct pattern from 39:47:07:07 at 0.1 MPa to 23:36:14:27 at 400 MPa. Preincubation of the protein at 400 MPa followed by complex formation and decomposition gave the same regioisomer distribution as untreated protein. The results indicate that the protein is reversibly inactivated by pressure, in contrast to the irreversible inactivation of P450(cam) and other P450 enzymes, and that this inactivation process is modulated by changes in the active-site cavity dimensions.

Crystal structure of a thermophilic cytochrome P450 from the archaeon Sulfolobus solfataricus.

The structure of the first P450 identified in Archaea, CYP119 from Sulfolobus solfataricus, has been solved in two different crystal forms that differ by the ligand (imidazole or 4-phenylimidazole) coordinated to the heme iron. A comparison of the two structures reveals an unprecedented rearrangement of the active site to adapt to the different size and shape of ligands bound to the heme iron. These changes involve unraveling of the F helix C-terminal segment to extend a loop structure connecting the F and G helices, allowing the longer loop to dip down into the active site and interact with the smaller imidazole ligand. A comparison of CYP119 with P450cam and P450eryF indicates an extensive clustering of aromatic residues may provide the structural basis for the enhanced thermal stability of CYP119. An additional feature of the 4-phenylimidazole-bound structure is a zinc ion tetrahedrally bound by symmetry-related His and Glu residues.

The active site of the thermophilic CYP119 from Sulfolobus solfataricus.

CYP119 from Sulfolobus solfataricus, the first thermophilic cytochrome P450, is stable at up to 85 degrees C. UV-visible and resonance Raman show the enzyme is in the low spin state and only modestly shifts to the high spin state at higher temperatures. Styrene only causes a small spin state shift, but T(1) NMR studies confirm that styrene is bound in the active site. CYP119 catalyzes the H(2)O(2)-dependent epoxidation of styrene, cis-beta-methylstyrene, and cis-stilbene with retention of stereochemistry. This catalytic activity is stable to preincubation at 80 degrees C for 90 min. Site-specific mutagenesis shows that Thr-213 is catalytically important and Thr-214 helps to control the iron spin state. Topological analysis by reaction with aryldiazenes shows that Thr-213 lies above pyrrole rings A and B and is close to the iron atom, whereas Thr-214 is some distance away. CYP119 is very slowly reduced by putidaredoxin and putidaredoxin reductase, but these proteins support catalytic turnover of the Thr-214 mutants. Protein melting curves indicate that the thermal stability of CYP119 does not depend on the iron spin state or the active site architecture defined by the threonine residues. Independence of thermal stability from active site structural factors should facilitate the engineering of novel thermostable catalysts.

Protein control of the formation and decomposition of the CYP119 and CYP101 aryl-iron complexes.

CYP119, the first thermophilic P450 enzyme, reacts much more slowly than CYP101 (P450cam) with aryldiazenes to give sigma-bonded aryl-iron complexes. The CYP119 complexes are stable anaerobically at 80 degrees C but are readily oxidized by O2 to give the N-arylprotoporphyrin IX regioisomers. The aryl shift can also be initiated in the absence of O2 by K3Fe(CN)6. In contrast, the corresponding CYP101 complexes are insensitive to O2 but decompose at temperatures above 50 degrees C owing to denaturation of the protein. The rate of the CYP119 aryl shift is decreased by electron-withdrawing substituents, with rho = -1.50 for both the O2- and K3Fe(CN)6-dependent reactions. A similar dependence (rho = -0.90) is observed for the K3Fe(CN)6-dependent CYP101 shift. The enthalpies and entropies of activation suggest that the CYP119 and CYP101 K3Fe(CN)6-mediated reactions are similar, but the CYP119 O2-dependent reaction proceeds via a different transition state. In all cases, the rate-determining step is oxidation of the aryl-iron complex. The temperature dependence of the O2- and K3Fe(CN)6-dependent CYP119 shifts provides evidence for temperature-dependent equilibration of two active site conformations. The oxygen sensitivity of the CYP119 aryl-iron complexes, and the temperature dependence of their rearrangement, reflect the unique active site properties of this thermophilic P450 enzyme.

Birthplace and yield of nipple aspirate fluid in Chinese women.

The different rates of breast cancer found between Chinese women in Asia compared with Chinese-born women in the United States suggest that dietary and environmental factors may be of etiological significance. We evaluated the proportion of 480 premenopausal Chinese women who yielded nipple aspirate fluid (NAF) by birthplace in Asia versus the United States and by reproductive and other risk factors. Birthplace was used as a surrogate for presumed differences in exposures during gestation, childhood, and adolescence that might influence yield of NAF in premenopausal women. In United States-born Chinese women compared with Asia-born Chinese women, the proportion yielding NAF was 44 of 95 (46.3%) versus 120 of 385 (31.2%), respectively. The relative risk of yield of NAF in United States-born women compared with Asia-born women was odds ratio = 2.37 (95% confidence interval, 1.26-4.47). Independent positive associations of NAF yield were also found with history of parity and breast feeding, cerumen phenotype, and a negative association with ever use of oral contraceptives. These findings support the hypothesis that early environmental exposures may have long-lasting physiological effects discernible in the breast glands of adult women.

Improved nutrition after the detection and treatment of occult gastroparesis in nondiabetic dialysis patients.

Malnutrition in dialysis patients is of multifactorial etiology and is associated with greatly increased morbidity and mortality. A low serum albumin level is one of the most powerful predictors of death and may persist despite optimization of the dialysis prescription. We retrospectively reviewed our experience in improving nutrition in nondiabetic patients with unexplained hypoalbuminemia. Using radionuclide solid-phase gastric emptying scans, we identified 6 patients who had occult gastroparesis. These patients (one on hemodialysis and five on peritoneal dialysis) were then treated with prokinetic medications (erythromycin elixir or metoclopramide) selected on the basis of their effectiveness in improving the scanning results after being given intravenously. Gastric emptying half-times improved from a median of 122 minutes (range, 95 to >300 minutes; normal, < or = 90 minutes) to 12 +/- 2 minutes (mean +/- SEM). The serum albumin increased from 3.3 +/- 0.04 g/dL to 3.7 +/- 0.08 g/dL at 3 months, with every patient's value higher than 3.5 g/dL. This improvement was statistically significant (P = 0.008) over the 5-month period of observation, which encompassed the 2 months before and 3 months after treatment. There was a linear improvement (P = 0.008) that showed a quadratic trend (P = 0.078) for a plateau at the final sampling point. The serum blood urea nitrogen, creatinine, and hematocrit levels remained unchanged (P > 0.1). We conclude that gastric emptying scans are valuable in identifying occult gastroparesis in high-risk patients and can guide the selection of prokinetic therapy, which may significantly increase serum albumin levels.

Low whole blood and erythrocyte levels of glutathione in hemodialysis and peritoneal dialysis patients.

Dialysis patients are reported to have impaired antioxidant mechanisms, including those involving glutathione-dependent enzymes. This study used high-performance liquid chromatography assays that directly measure total (oxidized + reduced) glutathione and its precursor cysteine (CYS) to compare the whole blood of hemodialysis (prehemodialysis and posthemodialysis) and peritoneal dialysis patients to that of blood donors with no known kidney disease (n=20 in each group). The levels in erythrocytes were calculated from that data (as nmol/g hemoglobin) because these cells are the major compartment of blood glutathione and their survival may be shortened by oxidant damage. Both dialysis groups had significantly (P=0.0001) higher CYS levels in the plasma compartment than the controls (251 nmol/mL), with prehemodialysis levels (432 nmol/mL) being greater than peritoneal dialysis levels (334 nmol/mL). Hemodialysis acutely lowered CYS levels (215 nmol/mL) below those of controls. Expressed per milliliter whole blood, both dialysis groups had significantly (P=0.0001) lower glutathione levels than controls (1,276 nmol/mL), with prehemodialysis and peritoneal dialysis levels being similar (778 and 912 nmol/mL). Values increased prehemodialysis to posthemodialysis, consistent with hemoconcentration. Expressed per gram hemoglobin, the dialysis groups had significantly (P < 0.015) lower glutathione levels than the controls (8,938 nmol/g hemoglobin), with similar prehemodialysis, posthemodialysis, and peritoneal dialysis values (7,207, 7,315, and 7,915 nmol/g hemoglobin, respectively). In summary, hemodialysis and peritoneal dialysis patients are at increased risk from oxidative stress due to glutathione deficiency in whole blood and erythrocytes.

Dietary and lifestyle correlates of passive smoking in Hong Kong, Japan, Sweden, and the U.S.A.

From epidemiologic studies in several countries, passive smoking has been associated with increased risk for lung cancer, respiratory diseases, and coronary heart disease. Since the relative risks derived from those studies are weak, i.e. relative risk less than two, we investigated whether poorer diets and less healthy lifestyles might act as confounders and be correlated with having a smoking husband on a cross-cultural basis. Characteristics of never-smoked wives with or without smoking husbands were compared between 530 women from Hong Kong, 13,047 from Japan, 87 from Sweden, and 144 from the U.S. In all four sites, wives with smoking husbands generally ate less healthy diets. They had a tendency to eat more fried food but less fruit than wives with nonsmoking husbands. Other healthy traits, e.g. avoiding obesity, dietary cholesterol and alcohol, or taking vitamins and participating in preventive screening were also less prevalent among wives with smoking husbands. These patterns suggest that never-smoked wives with smoking husbands tend to share the same less healthy dietary traits characteristic of smokers, and to have dietary habits associated with increased risk for lung cancer and heart disease in their societies. These results emphasize the need to take into account the potential confounding effects of diet and lifestyle in studies evaluating the health effects of passive smoking, especially since it is known that the current prevalence rates of smoking among men is indirectly associated with social class and education in affluent urban societies.

Diet and lung cancer 20+ years later: more questions than answers?

A critical review of epidemiological studies on diet and lung cancer over the last 20+ years has not provided overwhelming evidence that higher consumption of vegetables, fruit, low-fat/low-cholesterol foods or such micronutrients as carotenoids, selenium and vitamins A, C or E is associated with reduced lung cancer risk. Results from case-control studies have been more positive, with about one half showing fruit and vegetables or their associated micronutrients to be associated with reduced risk. However, most results from cohort and serum micronutrient studies, which avoid the problems of inaccurate accounting of diet and recall bias, were statistically insignificant. Moreover, although most studies were conducted on white male smokers in North America and Europe, the few studies which found significant contrary trends were among subjects of different backgrounds, i.e., black American males and Chinese women in China. Since male smokers vs. nonsmokers in Europe, North America and Japan have been shown in other studies to be lower consumers of fruit/vegetables, and less likely to pursue "perceived healthier lifestyles," the possibility that some of the epidemiological findings on diet and lung cancer are artifactually due to inadequate adjustment for behavioral correlates of smoking and health seekers in a particular society must be considered. This is especially true with recent chemoprevention trials showing higher lung cancer incidence and deaths among consumers of beta-carotene supplements vs. placebo.

An ecological study of trends in cancer incidence and dietary changes in Hong Kong.

Cancer incidence rates from the Hong Kong Cancer Registry show significant increases in lung and colon cancers and decreases in nasopharyngeal cancer in both sexes from 1973 to 1992. Moreover, cervical cancer and male esophageal cancer have declined significantly, and changes in the trends of cancer of the following sites were of borderline significance: decreasing male laryngeal and female esophageal cancers and increasing prostate and female breast cancers. These changes have occurred along with dietary shifts in the population, from a diet predominantly of rice and small portions of meat, vegetables, and fish to one with larger portions of all foods but rice and eggs. The latter data were gathered from six government household surveys from 1963-64 to 1994-95. By combining the two data sets, correlation coefficients were calculated for per capita consumption patterns of eight foods (rice, pork, beef, poultry, saltwater fish, freshwater fish, fresh vegetables, and eggs) and cancer incidence data of the same year or 10 years later. Higher meat intakes were significantly and positively correlated with cancers of the colon, rectum, prostate, and female breast. The correlations also suggested that current diets were more influential than diets a decade before for cancers of the lung, esophagus, rectum, and prostate. Cancers of the nasopharynx and colon were significantly correlated with current and past diets. These results support the hypothesis that intakes of meat and its associated fat are risk factors for colon, rectal, prostate, and female breast cancers.

Diet as a confounder of the association between air pollution and female lung cancer: Hong Kong studies on exposures to environmental tobacco smoke, incense, and cooking fumes as examples.

Chinese females in Hong Kong, where only about a third of the lung cancer cases can be attributed to a history of active smoking, have a world age-standardized lung cancer incidence rate of 32.6 per 100 000, which is among the highest in the world. Trends in Hong Kong's female lung cancer mortality also indicate a tripling in mortality rates from 1961 to 1990. The characteristically high Chinese female lung cancer incidence among nonsmokers is also found among overseas Chinese communities in Singapore and Hawaii. To help elucidate the role of ingested and inhaled substances in the etiology of lung cancer, four epidemiological studies have been conducted in Hong Kong over the last 15 years: (1) a retrospective study of 200 cases and 200 neighbourhood controls, (2) a cross-sectional study measuring personal exposures to nitrogen dioxide among 362 children and their mothers, (3) a site monitoring study of 33 homes measuring airborne carcinogens, and (4) a telephone survey of 500 women on their dietary habits and exposure to air pollutants. Selected data from each study were drawn to evaluate exposures to three major air pollutants (environmental tobacco smoke, incense, and cooking fumes), their relationship with lung cancer risk, and their association with dietary habits. Generally in this population, nutritionally poorer diets were characterized by higher consumption of alcohol and preserved/cured foods, whereas better diets were characterized by higher intakes of fresh fruits, vegetables, and fish. For environmental tobacco smoke, exposure was only moderately high in Hong Kong (36% have current smokers at home), lung cancer risk was equivocal with exposure, and it was associated with poorer diets among wives with smoking husbands. Incense was identified as a major source of exposure to nitrogen dioxide and airborne carcinogens, but it had no effect on lung cancer risk among nonsmokers and significantly reduced risk (trend, P-value = 0.01) among smokers, even after adjusting for smoking. The last finding may be explained by the relatively better diets among smoking women who burned incense versus those who did not. Although about 94% of the Chinese women cook on a regular basis, and the cooking fires were associated with increased airborne carcinogens, nonsmoking women who cooked for more than 25 years had a 60% reduction in lung cancer risk and the trend was highly significant (P < 0.001). Again, this unexpected finding may be due to the confounding effects of diet. Female controls who cooked for more than 25 years had a poorer diet than those who cooked for shorter durations. These three examples were chosen to illustrate the complexities of assessing air pollution exposure, and understanding the behavioral and dietary dynamics underlying lung cancer risk assessments. Our conclusion is that diet can be an important confounding factor affecting lung cancer risk estimates from air pollution exposures among Chinese women living in an affluent urban environment.

Distinct mutational spectrum of the p53 gene in lung cancers from Chinese women in Hong Kong.

Accumulating evidence suggests that the p53 gene is a good target for molecular epidemiological studies to search for risk factors in carcinogenic events. The lung cancer incidence for females in Hong Kong is unusually high, ranking among the highest in the world despite a low percentage with a history of smoking. To gain insights into possible etiological risk factors responsible for this high incidence, we examined p53 mutations in 35 lung cancer specimens from Chinese females living in Hong Kong and compared them with 35 matched cases from Japanese women as well as previously reported p53 mutations in the world literature. p53 mutations in exons 5-8 were present in 20 and 31% of the Hong Kong and Japanese cases, respectively. Notably, single-base deletions within runs of identical bases were observed in 3 (43%) of the 7 mutations in the Hong Kong cases, in contrast to the absence of such mutations in the controls and the extreme scarcity in the literature, suggesting that distinct environmental and/or genetic factor(s) might be involved. Although the frequent occurrence of characteristic single-base deletions could be a reflection of mutator mutations leading to inefficient mismatch repair of slipped strand mispairings, none of the lung cancer specimens exhibited such microsatellite instabilities.