Oncology clinical trial disruption during the COVID-19 pandemic: a COVID-19 and cancer outcomes study.

BACKGROUND: COVID-19 disproportionately impacted patients with cancer as a result of direct infection, and delays in diagnosis and therapy. Oncological clinical trials are resource-intensive endeavors that could be particularly susceptible to disruption by the pandemic, but few studies have evaluated the impact of the pandemic on clinical trial conduct. PATIENTS AND METHODS: This prospective, multicenter study assesses the impact of the pandemic on therapeutic clinical trials at two large academic centers in the Northeastern United States between December 2019 and June 2021. The primary objective was to assess the enrollment on, accrual to, and activation of oncology therapeutic clinical trials during the pandemic using an institution-wide cohort of (i) new patient accruals to oncological trials, (ii) a manually curated cohort of patients with cancer, and (ii) a dataset of new trial activations. RESULTS: The institution-wide cohort included 4756 new patients enrolled to clinical trials from December 2019 to June 2021. A major decrease in the numbers of new patient accruals (-46%) was seen early in the pandemic, followed by a progressive recovery and return to higher-than-normal levels (+2.6%). A similar pattern (from -23.6% to +30.4%) was observed among 467 newly activated trials from June 2019 to June 2021. A more pronounced decline in new accruals was seen among academically sponsored trials (versus industry sponsored trials) (P < 0.05). In the manually curated cohort, which included 2361 patients with cancer, non-white patients tended to be more likely taken off trial in the early pandemic period (adjusted odds ratio: 2.60; 95% confidence interval 1.00-6.63), and substantial pandemic-related deviations were recorded. CONCLUSIONS: Substantial disruptions in clinical trial activities were observed early during the pandemic, with a gradual recovery during ensuing time periods, both from an enrollment and an activation standpoint. The observed decline was more prominent among academically sponsored trials, and racial disparities were seen among people taken off trial.

Experimental demonstration of a soft x-ray self-seeded free-electron laser.

The Linac Coherent Light Source has added a self-seeding capability to the soft x-ray range using a grating monochromator system. We report the demonstration of soft x-ray self-seeding with a measured resolving power of 2000-5000, wavelength stability of 10(-4), and an increase in peak brightness by a factor of 2-5 across the photon energy range of 500-1000 eV. By avoiding the need for a monochromator at the experimental station, the self-seeded beam can deliver as much as 50-fold higher brightness to users.

Pre-irradiation of mouse mammary gland stimulates cancer cell migration and development of lung metastases.

BACKGROUND: In most patients with breast cancer, radiotherapy induces inflammation that is characterised by an increase of promigratory factors in healthy tissues surrounding the tumour. However, their role in the emergence of the migration phenotype and formation of metastases is still unclear. METHODS: A single mammary gland of BALB/c mice was irradiated with four doses of 6 Gy given at a 24-h interval. After the last session of irradiation, treated and control mammary glands were either collected for quantification of promigratory and proinflammatory factors or were implanted with fluorescent ubiquitination-based cell cycle indicator (FUCCI)-expressing mouse mammary cancer D2A1 cells. The migration of cancer cells in the mammary glands was monitored by optical imaging. On day 21, mammary tumours and lungs were collected for histology analyses and the quantification of metastases. RESULTS: Pre-irradiation of the mammary gland increased by 1.8-fold the migration of cancer cells, by 2-fold the quantity of circulating cancer cells and by 2.4-fold the number of lung metastases. These adverse effects were associated with the induction of interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2). CONCLUSION: The emergence of the metastasis phenotype is believed to be associated with the accumulation of mutations in cancer cells. Our results suggest an alternative mechanism based on promigratory factors from irradiated mammary glands. In clinic, the efficiency of radiotherapy could be improved by anti-inflammatory agents that would prevent the stimulation of cancer cell migration induced by radiation.

The Ornaments of the Arma Veirana Early Mesolithic Infant Burial.

Personal ornaments are widely viewed as indicators of social identity and personhood. Ornaments are ubiquitous from the Late Pleistocene to the Holocene, but they are most often found as isolated objects within archaeological assemblages without direct evidence on how they were displayed. This article presents a detailed record of the ornaments found in direct association with an Early Mesolithic buried female infant discovered in 2017 at the site of Arma Veirana (Liguria, Italy). It uses microscopic, 3D, and positional analyses of the ornaments as well as a preliminary perforation experiment to document how they were perforated, used, and what led to their deposit as part of the infant's grave goods. This study provides important information on the use of beads in the Early Mesolithic, in general, as well as the relationship between beads and young subadults, in particular. The results of the study suggest that the beads were worn by members of the infant's community for a considerable period before they were sewn onto a sling, possibly used to keep the infant close to the parents while allowing their mobility, as seen in some modern forager groups. The baby was then likely buried in this sling to avoid reusing the beads that had failed to protect her or simply to create a lasting connection between the deceased infant and her community. Supplementary Information: The online version contains supplementary material available at 10.1007/s10816-022-09573-7.

Coloseminal vesicle fistula after low anterior resection: Report of a case and review of the literature.

INTRODUCTION: A rectoseminal vesicle fistula after a low anterior resection for rectal cancer is a rare complication despite their anatomic proximity. From a Medline search from 1966 to date, a total of twenty-one previous cases of coloseminal vesicle fistula have been reported. From these cases, eleven were a complication of laparoscopic low anterior resection for rectal cancer. DESCRIPTION OF THE CASE: This report presents the case of a 63-year-old patient who was readmitted to the hospital on the fifteenth postoperative day after his surgical intervention for fever, abdominal pain, dysuria and pneumaturia. A sinography with water-soluble contrast revealed a tract between the rectum and the seminal vesicle. The condition was treated conservatively with antibiotics, urinary catheter and a transanastomotic Malecot probe for abscess drainage. The fistula had completely recovered on postoperative day 71 and the patient is still symptoms free, six months after the complication developed. DISCUSSION: This case reinforces the presumed link between anastomotic leakage and rectoseminal vesicle fistula in cases of low anterior resection while reviewing and summarizing similar previously reported cases on the course of the disease, diagnostic procedures and treatment options. CONCLUSION: Seminal vesicle are susceptible to fistula in oncological resection of rectum. Both CT scan with water-soluble contrast or sinography are effective diagnostic examinations. Depending on the characteristics of the fistula, conservative approach may be adequate and benefits much less morbidities than the surgical options.

Quantitative trait loci mapping for cholesterol gallstones in AKR/J and C57L/J strains of mice.

Quantitative trait locus (QTL) mapping was used to locate genes that determine the difference in cholesterol gallstone disease between the gallstone-susceptible strain C57L/J and the gallstone-resistant strain AKR/J. Gallstone weight was determined in 231 male (AKR x C57L) F(1) x AKR backcross mice fed a lithogenic diet containing 1% cholesterol, 0.5% cholic acid, and 15% butterfat for 8 wk. Mice having no stones and mice having the largest stones were genotyped at approximately 20-cM intervals to find the loci determining cholesterol gallstone formation. The major locus, Lith1, mapped near D2Mit56 and was confirmed by constructing a congenic strain, AK. L-Lith1(s). Another locus, Lith2, mapped near D19Mit58 and was also confirmed by constructing a congenic strain AK.L-Lith2(s). Other suggestive, but not statistically significant, loci mapped to chromosomes 6, 7, 8, 10, and X. The identification of these Lith genes will elucidate the pathophysiology of cholesterol gallstone formation.

Role of the striatum, cerebellum and frontal lobes in the automatization of a repeated visuomotor sequence of movements.

Recently, Doyon et al. [20] demonstrated that lesions to both the striatum and to the cerebellum in humans produce a similar deficit in the learning of a repeated visuomotor sequence, which occurs late in the acquisition process. We now report the results of two experiments that were designed to examine whether this impairment was due to a lack of automatization of the repeating sequence of finger movements by using a dual-task paradigm and by testing for long-term retention of this skill. In Experiment 1, the performance of groups of patients with Parkinson's disease, or with damage to the cerebellum or to the frontal lobes, was compared to that of matched control subjects on the Repeated Sequence Test (primary task) and the Brooks' Matrices Test (secondary task). These two tests were administered concomitantly in both early and late learning phases of the visuomotor sequence. Overall, the groups did not differ in their ability to execute the primary task. By contrast, in accordance with the predictions, patients in Stages 2-3 of Parkinson's disease or with a cerebellar lesion failed to reveal the expected increase in performance on the secondary task seen with learning, suggesting that the latter groups of patients did not have access to the same level of residual cognitive resources to complete the matrices compared to controls. In Experiment 2, the same groups of patients and control subjects were retested again 10-18 months later. They were given four blocks of 100 trials each of the repeating sequence task, followed by a questionnaire and a self-generation task that measured their declarative knowledge of that sequence. The results revealed a long-term retention impairment only in patients who changed from Stage I to Stage II of the disease (suggesting further striatal degeneration) during the one-year interval, or who had a cerebellar lesion. By contrast, performance of the three clinical groups did not differ from controls on declarative memory tests. These findings suggest that both the striatum and the cerebellum participate to the automatization process during the late (slow) learning stage of a sequence of finger movements and that these structures also play a role in the neuronal mechanism subserving long-term retention of such a motor sequence behavior.

Genome-wide search for linkage of bipolar affective disorders in a very large pedigree derived from a homogeneous population in quebec points to a locus of major effect on chromosome 12q23-q24.

We completed a genome-wide scan for susceptibility loci for bipolar affective disorders in families derived from a rather homogeneous population in the Province of Québec. The genetic homogeneity of this population stems from the migration of founding families into this relatively isolated area of Québec in the 1830s. A possible founder effect, combined with a prevalence of very large families, makes this population ideal for linkage studies. Genealogies for probands can be readily constructed from a population database of acts of baptism and marriage from the early 1830s up to the present time (the BALSAC register). We chose probands with a DSM III diagnosis of bipolar affective disorder and who may be grouped within large families having genealogical origins with the founding population of the Saguenay-Lac-St-Jean area. Living members (n approximately 120) of a very large pedigree were interviewed using the Structured Clinical Interview for DSM III (SCID I), SCID II, and with a family history questionnaire. A diagnostic panel evaluated multisource information (interview, medical records, family history) and pronounced best-estimate consensus diagnoses on all family members. Linkage, SimAPM, SimIBD, and sib-pair analyses have been performed with 332 microsatellite probes covering the entire genome at an average spacing of 11 cM. GENEHUNTER and haplotype analyses were performed on regions of interest. Analysis of a second large pedigree in the same regions of interest permitted confirmation of presumed linkages found in the region of chromosome 12q23-q24.

Role of glutathione in the beneficial effect of dietary restriction on bile formation in young, mature, and old rats.

We investigated the contribution of bile salts and glutathione (GSH) to the generation of bile flow in young, mature, and old female Sprague-Dawley rats, either fed ad libitum (AL) or subjected to a 40% dietary restriction (DR), which was supplemented or not with vitamins and minerals, starting from weaning. An age-related decline in bile flow was observed in the AL group. DR increased bile flow compared to age-matched AL rats, resulting in a twofold increase in the old animals. This was associated with a statistically significantly higher biliary GSH secretion rate and a moderate increase in the bile salt secretory rate. The apparent GSH-dependent flow was significantly increased in DR groups of all ages. Hepatic GSH concentration was closely related to the GSH secretion rate. These results indicate that the increase in biliary GSH content produced by DR is the major mediator of the increased bile flow, resulting in enhanced GSH and GSH-derived thiols supply to the intestinal lumen.

Reproducibility of 24-h energy expenditure and macronutrient oxidation rates in an indirect calorimeter.

The maintenance of weight and adipose tissue mass in humans appears to be related to a balance between the rates of oxidation and consumption of macronutrients; yet, little evidence is available on the reproducibility of 24-h macronutrient oxidation rates and how this relates to diet in the days preceding a chamber session. This study examined the reproducibility of 24-h macronutrient oxidation rates, 24-h energy expenditure (EE), and respiratory quotient (RQ) in 30 adults who ate their habitual diets before two 24-h whole body indirect calorimeter sessions. Results showed that the within-subject coefficients of variation (CVws) for 24-h EE and RQ were 2.8 and 2.6%, respectively. CVws for macronutrient oxidations ranged from approximately 15 to 25%. Means comparisons of 24-h EE, RQ, and macronutrient oxidation rates between sessions showed no significant differences, and all variables had significant positive intraclass correlation coefficients (P < 0.05). In conclusion, macronutrient oxidations all showed significant reproducibility for the group and a significant but lower reproducibility for individuals when habitual diet and activity preceded the experimental sessions.

Decreased biliary glutathione content is responsible for the decline in bile salt-independent flow induced by ethinyl estradiol in rats.

Glutathione appears to be a major osmotic factor in the generation of bile salt-independent flow (BSIF). This study was designed to investigate its importance in the pathology of 17-alpha-ethinyl estradiol (EE)-induced cholestasis. Five-day EE treatment at the dose level of 5 mg/kg/day significantly decreased bile flow (57% of controls) and biliary glutathione secretion. Evaluation of the contribution of bile salt dependent flow (BSDF), glutathione dependent flow (GSDF) and the bile flow generated independently of both bile salts and glutathione (BS-GSIF) revealed that EE decreased all portions of the flow (63, 44 and 52% of control values, respectively). At 4 and 20 h after a single administration of the same EE dose, a significant diminution of bile flow was noted (decreases of 17 and 29%, respectively) in association with a significant fall in biliary glutathione content. Under these conditions, BSDF and BS-GSIF were not modified (98 and 112% of control BSDF values, respectively; 96 and 99% of control BS-GSIF values, respectively) while GSDF was decreased markedly, representing 65 and 50% of control values. Biliary glutathione secretion was diminished without modification of liver and blood glutathione concentration or redox status following single EE dose whereas, after 5 days of EE treatment, a significant increase in liver glutathione was observed, suggesting that EE may interfere with the glutathione secretory process. This study demonstrates that EE rapidly alters biliary glutathione content, leading to a marked decline in GSDF. This reduction may explain the decrease in BSIF produced by EE at the outset of cholestasis.

Origin and diffusion of the myotonic dystrophy gene in the Saguenay region (Quebec).

A very high prevalence (approximately 1/475 in 1985) of myotonic dystrophy (Steinert disease) is observed in the Saguenay region, which is located in the north-east part of the Province of Quebec. For various reasons, however, the literature on the subject generally associates a high degree of selective disadvantage with this gene, which seems to contradict the Saguenay data. Using a computerized regional population register, we have reconstituted patients' genealogies and family biographies. We have thus been able to study the origin of the gene and to compare the demographic behavior of patients and controls. On the whole, patients seem to be very little disadvantaged compared to controls, in terms of reproduction as well as of geographical and occupational mobility.

Dietary cholestyramine reduces ochratoxin A-induced nephrotoxicity in the rat by decreasing plasma levels and enhancing fecal excretion of the toxin.

Ochratoxin A (OTA) is a mycotoxin that may contaminate animal feed (oat, barley, and rye) and food (wheat, rice, coffee, beer, pig meat), leading to major health problems (e.g., nephropathy) in several animal species including humans. Several methods have been tested to reduce the toxicity of OTA in animals but with limited success. In rats, the effect of cholestyramine (CHA), a bile acid-binding resin, was investigated on OTA-induced nephrotoxicity and bioavailability. Animals were fed semisynthetic diets containing two levels of OTA: 1 or 3 ppm. At each level of OTA, the diets were enriched with 0.1, 1, and 5% of CHA. The results showed that CHA decreased the concentration of OTA in plasma. At 1 and 3 ppm of OTA in the diet, CHA is effective at a level of 0.1% and 5%, respectively. The excretion of OTA and its metabolites (ochratoxin alpha and hydroxylated ochratoxin A) in bile and urine was also decreased by addition of 5% CHA in the diet. This was associated with an increase of OTA excretion in feces. Enzymuria and renal morphology revealed that dietary CHA can decrease OTA-induced nephrotoxicity, probably by reducing renal exposure to the toxin. In conclusion, CHA can reduce OTA concentrations in plasma as well as reducing nephrotoxicity, which may be attributed to a decrease of bioavailability and/or enterohepatic circulation of the toxin.

Predictors of reduction and cessation of drinking in community-dwelling men: results from the normative aging study.

As part of a longitudinal study of health and aging, the conditions and motivational factors that prospectively predicted either cessation or reduction in alcohol consumption were compared. Data were from 1,517 community-dwelling men who in 1973 (Time 1) and 1982 (Time 2) completed mailed questionnaires about their drinking behaviors. Time 2 quitters (n = 62) had consumed no alcohol for at least the 6 months before that survey; reducers (n = 255) had decreased their yearly alcohol consumption by at least one-half. Compared to 971 controls, quitters reported more drinking problems at Time 1; reducers reported higher consumption at Time 1, which was the only factor predictive of subsequent reduction (p less than .001). Regression analyses considering contextual-motivational factors for drinking showed that at Time 1 quitters were less likely than controls to have consumed alcohol during evenings out (p = .008), in family-home settings (p = .013), or for salutary reasons (p = .084); conversely, they were more likely to have consumed alcohol to reduce negative affect (p = .011). Reducers cited more social-situational reasons for curtailing drinking; quitters cited more personal reasons related to health and alcohol effects. These findings indicate that in a community sample of men, problematic drinking behaviors tend to predict subsequent abstention rather than reduced drinking.

Determination of ovulation time in bitches based on teasing, vaginal cytology, and elisa for progesterone.

The estrous cycle of 16 mature mongrel female dogs was monitored to evaluate the accuracy of teasing, vaginal cytology and quantitative ELISA progesterone assay to determine ovulation. The dogs were presented to male, and blood samples and vaginal swabs were taken daily during proestrus and estrus. Selected serum samples collected during estrus were assayed for endogenous LH by radioimmunoassay (RIA). Plasma samples collected during proestrus and estrus were assayed for progesterone with a commercially available ELISA kit. Ovulation was considered to take place 48 h after the preovulatory LH peak. Vaginal cytology smears were stained with Wright's stain and evaluated for the percentage of superficial squamous cells. Day 1 of diestrus (Day 1) was defined as a drop of 20% or more in the total number of superficial cells. Two standard curves (linear and best fitted curves) commonly used with ELISA were compared together and with the RIA progesterone assay. Ovulation was estimated to occur when progesterone concentration was 4.9 +/- 1.0 ng/ml (mean +/- SD, n = 15), with a range of 3.4 to 6.6 ng/ml. Based on vaginal cytology, ovulation took place 6.9 +/- 1.6 d (n = 15) after 80% of the squamous cells were superficial and 6.8 +/- 1.4 d (n = 16) before Day 1. Ovulation took place 2.1 +/- 3.9 d (n=11) after the first day of standing estrus and 8.8 +/- 1.5 d (n = 10) before the last day of receptivity. The two standard curves were found parallel to each other and to the RIA progesterone assay. Based on the results of the present study, ELISA progesterone assay and determination of the first day of estrus by vaginal cytology are reliable methods for predicting ovulation, whereas the last day of receptivity as determined by teasing and Day 1 as determined by vaginal cytology are reliable methods to retrospectively estimate ovulation time.

Seasonality and variability of the interestrous interval in the bitch.

Records from two breeding colonies (A and B) located near each other were analyzed for this experiment. Colony A consisted of 19 bitches (8 Maltese, 5 Yorkshire, 3 Lhasa Apso, and 3 Bouvier des Flandres), while Colony B consisted of 48 Beagle bitches. A total of 126 interestrous intervals (141 estrous cycles) from Colony A were reviewed to quantitate the variability of the interestrous interval. Analysis of variance showed that the degree of variation of the estrous cycle length within bitches (65%) was about twice the degree of variation of means of the estrous cycle length among bitches (35%). It was found that the estrous cycle length is extremely variable, and it cannot be used to predict the next estrus in a single bitch, although some bitches were very consistent. The seasonal and monthly distribution of estrous cycles throughout the year was also analyzed from bitches kept in Colonies A and B for a total of 210 estrous cycles. The data were collected over a four-year period. A seasonal pattern was observed when the cumulative distributions over years were analyzed. A higher frequency of estrous cycles was observed during winter and summer. This seasonality pattern was not observed when individual years were analyzed separately. However, the overall probability that an estrus would occur at any month of the year was the same for each month (1/12) when cumulative distribution over years were analyzed.

Estrus induction in the bitch using a combination diethylstilbestrol and FSH-P.

The purpose of the study was to induce estrus and ovulation in normal bitches using a combination of diethylstilbestrol (DES) and follicle stimulating hormone of porcine pituitary origin (FSH-P). Thirteen mature mongrel female dogs were divided into two groups, the first group was treated for estrus induction during late anestrus and the second group during mid-anestrus. The dogs were monitored by teasing, vaginal cytology, and hormonal assay during the induced (n=13) and the previous spontaneous estrous cycle (n=9). Six of eight and three of five bitches came into standing estrus in the first and second group, respectively. Of the bitches that came into estrus, three conceived in the first group and one in the second. The average induced litter size was 7.0 versus 7.5 for the colony. Based on vaginal cytology the induced proestrus and estrus lasted 1.7 (0 to 3) and 12.9 (4 to 24) d, respectively, while the spontaneous proestrus and estrus lasted 5.8 (0-17) and 12.8 (9-15) d, respectively. Progesterone profiles were similar between the induced and spontaneous estrous cycles, although the progesterone peak was higher during the spontaneous cycle. The preovulatory luteinizing hormone (LH) surge was observed in only one induced estrous cycle. Modest results were obtained with this therapy. However, the litter sizes were normal and the induced cycles were very similar to the physiologic ones. No side effects were seen with the oral form of DES.

Effect of storage temperature, cooling rates and two different semen extenders on canine spermatozoal motility.

Ejaculates were collected form three mixed-breed male dogs daily for 3 d. The semen was diluted in either a nonfat dried milk solid-glucose (NFDMS-G) or egg yolk citrate (EYC) extender at a concentration of 25 x 10(6) sperm/ml. The diluted samples were exposed to three different storage temperatures (35, 22 and 4 degrees C). Three cooling rates (-1.0, -0.3 and -0.1 degrees C/min) were also investigated at the lowest storage temperature (4 degrees C). The semen was evaluated for total motility, progressive motility and velocity at 0, 6, 12, 24, 48, 72, 96 and 120 h after collection by two independent observers. Interactions between extenders, temperatures and time after collection were found for each of the variables. Nonfat dried milk solid-glucose diluent was superior to EYC (P<0.05) in preservating sperm motility parameters that were evaluated for most of the observations. The evaluated sperm motility parameters were also significantly superior (P<0.05) in semen stored at 4 degrees C than at 35 or 22 degrees C for most of the observations. The progressive motility and velocity of sperm in semen cooled at 4 degrees C in NFDMS-G were higher (P<0.05) at the fast and medium cooling rates (-1.0 and -0.3 degrees C) than at the slow cooling rate (-0.1 degrees C/min) at 24 and 72 h, and at 48 h, respectively. In conclusion, the present study suggests that canine spermatozoal motility is well preserved when a NFDMS-glucose extender is added to the semen and the semen is cooled at a medium or fast rate to a storage temperature of 4 degrees C. Additional studies are needed to evaluate the fertility of semen stored in this manner.

Control of FSH, follicular development and estrus synchronization in the mare with steroid-free follicular fluid.

Twenty-two pony mares were used in a project designed to determine the effectiveness of different treatments in controlling FSH, follicular development and synchronization of estrus and ovulation. Mares in Group 1 (n=8) received daily oral altrenogest (0.044 mg/kg); those in Group 2 (n=7) received daily altrenogest (0.044 g/kg) and, during the last 4 days of treatment they received steroid-free follicular fluid, (15 cc) intravenously (I.V.) two times a day; Mares in Group 3 (n=7) received daily intramuscular (I.M.) injections of progesterone (80 mg) and estradiol valerate (7 mg). All treatments lasted for 10 days, at the end of which prostaglandin (PgF(2)alpha, 10 mg) was administered. Sexual behavior, follicular development and FSH concentrations were monitor daily. Concentrations of FSH in Group 2 mares, were not significantly different (P>0.05) from those of Group 1 until the mares in Group 2 were treated with follicular fluid (P<0.05). Concentrations of FSH in Group 3 mares, were significantly lower than those of Groups 1 and 2 (P<0.05) until the mares in Group 2 were treated with steroid-free follicular fluid. At this point there was no significant difference between groups 2 and 3 (P>0.05). Steroid-free follicular fluid appears to induce atresia in larger follicles (>11 mm), and the initiation of new follicular wave. The combination of progesterone and estradiol valerate appears to delay follicular growth and not to induce atresia, since larger follicles (>11 mm) continued to grow after treatment. Both treatments (groups 2 and 3) resulted in ovulations within 5 days period. The treatment in Group 1 did not have any effect on FSH or follicular development and ovulations were dispersed through a 9-day period. We concluded that steroid-free follicular fluid offers a new possibility to synchronize ovulation in the mare by controlling FSH and follicular development.

Fertility in couples heterozygous for the tyrosinemia gene in Saguenay Lac-St-Jean.

A case-control study of 84 couples from Saguenay-Lac-St-Jean, jointly heterozygous for the tyrosinemia gene, was done to determine whether the birth of an homozygous child affected their fertility rates. The mean number of children born to tyrosinemia and control couples between 1940 and 1986 was not different (p greater than 0.05). The knowledge that tyrosinemia was an autosomal recessive disorder, with risk of recurrence in these families, did not appear to modify reproductive behaviour. Fertility fell significantly in both the tyrosinemia and control families in the period of observation. This change reflects the decline in fertility of French Canadians in general during this period.