Effects of ENU dosage on mouse strains.

The germline supermutagen, N-ethyl-N-nitrosourea (ENU), has a variety of effects on mice. ENU is a toxin and carcinogen as well as a mutagen, and strains differ in their susceptibility to its effects. Therefore, it is necessary to determine an appropriate mutagenic, non-toxic dose of ENU for strains that are to be used in experiments. In order to provide some guidance, we have compiled data from a number of laboratories that have exposed male mice from inbred and non-inbred strains or their F(1) hybrids to ENU. The results show that most F(1) hybrid animals tolerate ENU well, but that inbred strains of mice vary in their longevity and in their ability to recover fertility after treatment with ENU.

Differential response of mouse male germ-cell stages to radiation-induced specific-locus and dominant mutations.

In an attempt to provide a systematic assessment of the frequency and nature of mutations induced in successive stages of spermato- and spermiogenesis, X-irradiated male mice were re-mated at weekly intervals, and large samples of progeny, observed from birth onward, were scored and genetically tested for recessive mutations at seven specific loci and for externally recognizable dominant mutations. Productivity findings provided a rough measure of induced dominant-lethal frequencies. A qualitative assessment of specific-locus mutations (which include deletions and other rearrangements) was made on the basis of homozygosity test results, as well as from information derived from more recent complementation studies and molecular analyses. Both recessive and dominant visibles revealed clear distinctions between spermatogonia and postspermatogonial stages. In addition, differences for both of these endpoints, as well as for presumed dominant lethals, were found among various postspermatogonial stages. It may be concluded that radiation produces its maximum rates of genetic damage in germ-cell stages ranging from midpachytene spermatocytes through early spermatids, a pattern unlike any of those that have been defined for chemicals; further, the frequency peaks for radiation are lower and broader. The difference between post-stem-cell stages overall and stem-cell spermatogonia was smaller than is generally found with chemicals, not only with respect to the frequency but also the nature of mutations.

The role of ultrasonography and inferior vena cava filter placement in high-risk trauma patients.

Undetected lower-extremity deep-vein thrombosis (LEDVT) in the trauma patient can lead to significant morbidity and mortality. The purpose of this study was to: 1) evaluate the role of ultrasonography in the early detection of LEDVT in high-risk trauma patients; 2) identify prognostic indicators that predict LEDVT; and 3) evaluate the efficacy of selected inferior vena cava (IVC) filter placement in the prevention of pulmonary emboli. From October 1993 through December 1994, all adult multiple-trauma patients admitted to the Trauma Service who required prolonged bed rest (>3 days) or sustained a lower-extremity, pelvic, or spinal fracture with paralysis were prospectively studied with serial physical examinations and lower-extremity venous ultrasounds within 72 hours of admission and then weekly until discharge. Two hundred twenty-eight patients were entered into the study. Thirty-nine patients (17%) developed ultrasound evidence of LEDVT; of these, only seven (18%) were evident on physical examination. This allowed 32 patients (82%) with unsuspected LEDVT to receive earlier definitive therapy. Multivariate logistic regression analysis of LEDVT with various predictors found age, hospital length of stay, and lower-extremity trauma to be significant predictors of LEDVT (P < 0.05). Twenty-nine patients (74%) had immediate IVC filter placement upon ultrasound identification of proximal LEDVT. None of these patients developed pulmonary emboli. Ten patients (26%) with a LEDVT were treated with systemic anticoagulation alone. One of these patients sustained a fatal pulmonary embolus. In a historic control group of 234 high-risk trauma patients admitted in the 14 months prior to implementing screening ultrasounds, six patients sustained pulmonary emboli (P < 0.05). Screening ultrasounds combined with selective placement of IVC filters play an important role in reducing the morbidity and mortality associated with LEDVT in high-risk trauma patients.

Serum amylase and lipase in the evaluation of acute abdominal pain.

The purpose of this study was to determine 1) the incidence and magnitude of elevation in admission serum amylase and lipase levels in extrapancreatic etiologies of acute abdominal pain, and 2) the test most closely associated with the diagnosis of acute pancreatitis. Serum amylase and lipase levels were obtained in 306 patients admitted for evaluation of acute abdominal pain. Patients were categorized by anatomic location of identified pathology. Logistic regression analysis was used to compare the enzyme levels between patient groups and to determine the correlation between elevation in serum amylase and lipase. Twenty-seven (13%) of 208 patients with an extrapancreatic etiology of acute abdominal pain demonstrated an elevated admission serum amylase level with a maximum value of 385 units (U)/L (normal range 30-110 U/L). Twenty-six (12.5%) of these 208 patients had an elevated admission serum lipase value with a maximum of 3685 U/L (normal range 5-208 U/L). Of 48 patients with abdominal pain resulting from acute pancreatitis, admission serum amylase ranged from 30 to 7680 U/L and lipase ranged from 5 to 90,654 U/L. Both serum amylase and lipase elevations were positively associated with a correct diagnosis of acute pancreatitis (P < 0.001) with diagnostic efficiencies of 91 and 94 per cent, respectively. A close correlation between elevation of admission serum amylase and lipase was observed (r = 0.87) in both extrapancreatic and pancreatic disease processes. Serum amylase and lipase levels may be elevated in nonpancreatic disease processes of the abdomen. Significant elevations (greater than three times upper limit of normal) in either enzyme are uncommon in these disorders. The strong correlation between elevations in the two serum enzymes in both pancreatic and extrapancreatic etiologies of abdominal pain makes them redundant measures. Serum lipase is a better test than serum amylase either to exclude or to support a diagnosis of acute pancreatitis.

Spontaneous mutations recovered as mosaics in the mouse specific-locus test.

The specific-locus test (SLT) detects new mutants among mice heterozygous for seven recessive visible markers. Spontaneous mutations can be manifested not only as singleton whole-body mutants in controls (for which we report new data), but as mosaics-either visible (manifesting mottled coat color) in the scored generation (G2) or masked, among the wild-type parental generation (G1). Masked G1 mosaics reveal themselves by producing clusters of whole-body mutants in G2. We provide evidence that most, if not all, mosaics detected in the SLT (both radiation and control progenies) result from a single-strand spontaneous mutation subsequent to the last premeiotic mitosis and before the first postmeiotic one of a parental genome-the "perigametic interval." Such events in the genomes of the G1 and Gzero results, respectively, in visible and masked 50:50 mosaics. Per cell cycle, the spontaneous mutation rate in the perigametic interval is much higher than that in pregamete mitotic divisions. A clearly different locus spectrum further supports the hypothesis of different origin, and casts further doubt on the validity of the doubling-dose risk-estimation method. Because mosaics cannot have arisen in mitotic germ cells, and are not induced by radiation exposure in the perigametic interval, they should not be included in calculations of radiation-induced germ-line mutation rates. For per-generation calculations, inclusion of mosaics yields a spontaneous frequency 1.7 times that calculated from singletons alone for mutations contributed by males; including both sexes, the multiple is 2.2.

Cost of acid peptic disorders in a managed-care organization.

The purpose of this study was to determine the cost of managing ambulatory patients with symptoms of acid peptic disorders in a managed-care organization under actual clinical conditions. Study data were collected in a large independent practice association model health maintenance organization in Gainesville, Florida, from prescription records maintained in a computerized database and from patient medical records. Patients had to be started on a histamine2-receptor antagonist (H2RA) or the proton pump inhibitor omeprazole between 1992 and 1994. A total of 113 patients qualified for inclusion in the study; 57 received H2RAs, 27 received omeprazole, and 29 received combination therapy. The costs of procedures, physician visits, and drug therapy were considered in the economic evaluation. Costs were evaluated using two methods: the capitation total cost (CTC) and the fee-for-service total cost (FSTC). The mean CTC and FSTC for managing a patient with acid peptic symptoms for 6 months were $382 +/- 356 (range, $14 to $1820) and $456 +/- 368 (range, $52 to $1925), respectively. Drug costs represented 52% of the total FSTC and 62% of the total CTC. Drug costs were followed by the costs for encounters with primary care physicians, endoscopy, referral to specialists, and upper gastrointestinal (UGI) tract procedures. Documented outcomes were available for 85 patients. Compared with patients receiving H2RAs (n = 41), patients receiving omeprazole (n = 18) had significantly lower FSTCs ($317 +/- 219 compared with $423 +/- 307, respectively); diagnostic testing costs (for endoscopy, $0 compared with $44 +/- 119, respectively; for UGI procedures, $22 +/- 42 compared with $55 +/- 54, respectively); physician encounter costs ($66 +/- 40 compared with $86 +/- 38, respectively); and referral to specialist costs ($0 compared with $18 +/- 60, respectively). Patients receiving omeprazole also had more positive clinical outcomes than patients receiving H2RAs (78% compared with 49%, respectively), resulting in a more favorable cost of producing a successful outcome compared with patients receiving an H2RA. The cost of success was $407 for patients treated with omeprazole compared with $869 for patients treated with H2RAs. The findings of this analysis conducted under actual clinical conditions support findings of randomized clinical trials showing the cost-effectiveness of proton pump inhibitors.

Prediction of long-term ventilatory support in trauma patients.

Mechanical ventilatory support requiring tracheal intubation may be necessary for variable lengths of time in injured patients. Criteria useful in predicting the need for prolonged tracheal intubation has not been clearly established in the trauma population. Early identification of patients requiring prolonged tracheal intubation and mechanical ventilatory support could lead to earlier tracheostomy and subsequent reductions in complications associated with prolonged endotracheal intubation. This study evaluated the ability of clinical measures of injury severity, mental status, oxygenation, and ventilation to predict the need for prolonged mechanical ventilatory support (> or = 14 days) early in the postinjury course of the adult trauma patient requiring endotracheal intubation and mechanical ventilatory support within the first 24 hours of injury. All adult trauma patients admitted to our Level I trauma center over a 4-year period between January 1990-December 1993 were evaluated. A total of 212 patients met study criteria that included intubation within the first 24 hours of injury, ventilatory support requirement > or = 72 hours, and a survival time of at least 14 days postinjury. Data pertaining to measures of injury severity (RTS, AIS, ISS), mental status (GCS), oxygenation [(A-a)O2], and ventilation (VE,EDC) were recorded for postinjury Day 1 and Day 5. There were 157 males and 55 females (age range of 16-91 years, mean 39.5 years). Mechanism of injury was blunt in 198 and penetrating in 14 patients. One hundred patients required prolonged mechanical ventilatory support. Data were analyzed by stepwise logistic regression analysis. Age and GCS values on Day 1 predicted the need for long term mechanical ventilatory support in a select group of patients, age 20 and GCS of 3 (P < 0.05). At Day 5, age, GCS, and (A-a)O2 gradient were predictive of the need for prolonged mechanical ventilatory support (P < 0.05). On Day 5, GCS of 3 predicted the need for long-term mechanic al ventilatory support regardless of age or (A-a)O2 gradient. GCS < or = 5 and (A-a)O2 > or = 150 predicted prolonged mechanical ventilatory support in young patients (age 20). At ages of 40 to 60, GCS < or = 7 and (A-a)O2 > or = 150 indicated the need for long term mechanical ventilatory support. In older patients (age > or = 80), GCS < or = 7 and (A-a)O2 gradient > or = 100 were predictive of long-term mechanical ventilatory support. Appropriate use of these clinical indicators may assist in early identification of patients requiring prolonged mechanical ventilatory support, and subsequent conversion from endotracheal intubation to tracheostomy with anticipated reduction in complications.

Postoperative pulmonary complications and morbidity after abdominal aneurysmectomy: a comparison of postoperative epidural versus parenteral opioid analgesia.

Patients undergoing aortic aneurysm repair have a high prevalence of coexisting cardiac and pulmonary disease, and the postoperative recovery is especially delayed by pulmonary complications. A review of all elective abdominal aneurysm repairs over a 29-month period was undertaken to evaluate the effectiveness of postoperative epidural analgesia in decreasing morbidity and mortality, and specifically pulmonary complications. Patients were placed into two groups; Group 1 (34 patients) used an epidural catheter for postoperative pain control, and Group II (31 patients) used standard parenteral opioid analgesia. The two groups were similar in preoperative combined factors including known risk factors for atherosclerotic cardiovascular disease, preexisting cardiac or pulmonary disease, and preexisting renal insufficiency. A statistically significant decrease (P = < 0.05) was found in both cardiac (P = 0.0002) and pulmonary (P = 0.019) complications in comparison, favoring Group I patients. A significant decrease was also seen in the time to liquid intake (P = 0.044), time out of bed to a chair (P = 0.002), length of stay in the Intensive Care Unit (P = 0.024), and overall hospital charges (P = 0.046) in favor of Group I patients. Although no significant difference (P = > 0.05) was seen in decreasing time to ambulation (P = 0.054), average time required on the ventilator (P = 0.053), or hospital days (P = 0.181), all of these did show a trend in favor of epidural catheter utilization. There were no complications or infections related to the use of the epidural catheter during this study period. In conclusion, the use of an epidural catheter for postoperative pain control has been shown to decrease time of intubation, time in the ICU, number of cardiac and pulmonary complications, which should lead to an overall decrease in hospital charges after elective repair of abdominal aortic aneurysms.

Evaluating the value, accuracy, and operational feasibility of DUE criteria.

The purpose of this investigation was to evaluate the value, accuracy, and operational feasibility of indicators/criteria in a drug use evaluation (DUE) examining IV histamine2-receptor antagonists (H2-RA). Pharmacists in 40 hospitals collected DUE data concurrent with hospital stays on a total of 1,200 patients. After completing the DUE, pharmacist data collectors were asked to evaluate each DUE criterion. Most reported that criteria relating to indications for use, therapeutic drug monitoring, and adverse drug reactions/drug interactions should be included in a DUE, but some criteria were not easy to collect or were inaccurate. The data suggest the need to carefully select DUE criteria that can be used for continuous improvements that meet JCAHO accreditation requirements.

Efficacy of screening MR angiography and Doppler ultrasonography in the evaluation of carotid artery stenosis.

Significant progress has been made in the development of noninvasive screening techniques for evaluation of the carotid bifurcation prior to contrast angiography. The role and significance of Magnetic Resonance Angiography (MRA) as an efficient cost effective screening examination for carotid artery stenosis remains to be determined. To that end, 120 carotid vessels, in 60 consecutive patients with carotid artery disease, were studied using MRA, Duplex ultrasonography (U/S), and conventional Digital Subtraction Arteriography (DSA). In a prospective blinded manner, using a standard scoring schematic, each carotid artery was evaluated with regard to degree of stenosis, zone of stenosis, and quality of the screening examination. The efficacy of MRA and U/S for detection of extracranial carotid stenoses was correlated with conventional DSA, which was used as a "standard of reference" for each patient. Screening studies were considered positive if the vessel stenosis was determined to be greater than 40 per cent. As a screening examination, U/S yielded a sensitivity of 88 per cent and a specificity of 81 per cent with 11 false positive and 7 false negative studies. MRA yielded a sensitivity of 84 per cent and a specificity of 81 per cent with 11 false positive and 9 false negative studies. Range of cost of each imaging modality was surveyed from our region as well as ease of access to each modality. MRA and U/S achieved equivalent accuracy as screening examinations and correlated well in sensitivity and specificity when quality of the examination and experience of the examination center was taken into consideration.(ABSTRACT TRUNCATED AT 250 WORDS)

Cost-effectiveness of preoperative localization studies in primary hyperparathyroid disease.

OBJECTIVE: To evaluate the effect of preoperative localization studies on the surgical management of patients with primary hyperparathyroid disease (PHPT). SUMMARY BACKGROUND DATA: Reported cure rates of initial surgical exploration for PHPT are close to 95%. Preoperative localization studies are frequently obtained to improve surgical success and decrease operative time. METHODS: Initial cervical exploration was performed in 113 patients with PHPT from 1981 to 1993. Twenty-four patients (21%) had surgery without preoperative localization studies. The remaining 89 patients (79%) had 132 noninvasive preoperative localization studies. Success of the localization studies in tumor localization, pathologic findings, postoperative serum calcium levels, and operative times were compared. Patient costs of the studies were calculated. RESULTS: Disease was identified during operation in 23 of 24 patients (96%) having cervical exploration without preoperative localization studies, and they had normal calcium levels after surgery. Eighty-seven of 89 patients (98%) having preoperative localization studies were surgically cured. The highest sensitivity rate (60%) and highest positive predictive value (79%) of the localization studies were found with thallium-technetium scintiscanning. Average cost of the localization studies was $901 per patient. Combination studies were obtained in 32 patients at an average cost of $1,314 per patient without improving sensitivity. Mean operating time did not differ for localized and nonlocalized patients. CONCLUSIONS: Preoperative localization studies did not improve parathyroid localization or cure rate and did not substantially shorten operating time in initial cervical exploration for PHPT. The economic burden of routine preoperative localization studies in these patients is not justified.

A pharmacoeconomic analysis of IV H2-receptor antagonist use in 40 hospitals.

The objectives of this study were to determine (1) the expenditures of hospitals for IV histamine2-receptor antagonists (H2-RA), and (2) the cost savings that might be realized if only a single IV H2-RA was purchased for use. Forty hospitals provided data about purchase prices for each IV H2-RA dosage form purchased (cimetidine, ranitidine, and famotidine), the number of each dosage form used during the 12-month study period, purchase price and extent of usage for supplies, labor costs for preparing and administering IV H2-RAs, and IV H2-RA dosage schedules. The study showed that most hospitals were spending more money for IV H2-RAs than necessary given the pricing structures of the three products available to them at the time of this study. Also, that significant cost savings could be realized if a single H2-RA was used exclusively.

Risk for adverse events among patients receiving intravenous histamine2-receptor antagonists.

OBJECTIVE: To identify risk factors for adverse drug reactions (ADRs) in patients receiving intravenous histamine2-receptor antagonists (H2-RAs). DESIGN: The study hypothesis was evaluated by performing a logistic regression procedure with a backward elimination of the explanatory variables associated with ADRs. MAIN OUTCOME MEASURES: ADRs temporally associated with the use of intravenous H2-RAs served as the dependent variable. Background information about the patients and drug use evaluation criteria in three general areas were entered into the regression analysis. SETTING: Hospitals were selected from the southeastern US, based on their willingness to participate and their characteristics. Participating hospitals exhibited a variety of sizes and ownership arrangements. PATIENTS: 1200 adult patients who were receiving intravenous H2-RAs. RESULTS: Seven percent of patients experienced a presumed ADR (PADR) to intravenous H2-RAs. The only risk factor for ranitidine was for patients who did not have their dosage corrected for renal function ("overdose"); these patients were twice as likely to experience a PADR compared with patients who received the correct dosage as determined by their renal function. Two risk factors for cimetidine were identified: (1) patients taking cimetidine with another medication known to cause a drug interaction; and (2) patient age. No risk factors were identified for famotidine. CONCLUSIONS: The two risk factors for ADRs identified in this study are preventable. Healthcare providers should strive to prevent ADRs by adjusting patients' dosages based on their renal function and by monitoring patients receiving cimetidine with another medication known to interact with cimetidine.

Use of i.v. cimetidine, ranitidine, and famotidine in 40 hospitals.

The drug experiences of 1200 patients receiving i.v. histamine H2-receptor antagonists were studied. Forty hospitals in five southeastern states participated in a drug-use evaluation (DUE). In addition to supplying background information, a pharmacist at each hospital used a standardized form to perform a concurrent review of 30 consecutive adult patients who had been started on i.v. cimetidine, ranitidine, or famotidine. In addition to the patient's age and the prescriber's medical specialty, specific DUE criteria included the reason given in the medical record for use; dosage regimen and adjustments made on the basis of the patient's renal function; other GI drugs taken concurrently; pharmacist intervention; simultaneous use of oral medications; occurrence of adverse events; H2-antagonist use with specified drug products known to affect serum drug concentrations of one or both medications; and use of gastric pH monitoring. Therapy with i.v. H2 antagonists was usually started by internal medicine specialists or surgeons, and most of the evaluated patients received such therapy for prevention of stress-related mucosal damage. According to estimated creatinine clearance, 34% of patients were in need of dosage adjustments, but such adjustments were made in only 49% of these. Forty percent of patients began therapy while taking at least one medication orally, and almost one fourth of patients were receiving an additional drug for the treatment of an acid-peptic or related indication. The occurrence of adverse events was similar for the three H2 antagonists studied. The findings identify several problematic areas in the way H2 antagonists are used in clinical practice.

Lifespan and autopsy findings in the first-generation offspring of X-irradiated male mice.

Male mice of the C3Hf strain were exposed to 600 R of acute X-rays and, along with unirradiated control males, mated with 101-strain females. The offspring of the treated males were all conceived more than 7 weeks after irradiation, thereby ensuring that they were derived from germ cells exposed as stem-cell spermatogonia. After weaning, the offspring were caged individually and allowed to live their normal lifespan. Tumors and other major pathological disorders were recorded at a careful post-mortem examination. The lesions encountered were typical of those characteristically seen in aging (101 x C3Hf)F1 mice. The results showed no significant differences in lifespan between experimentals and controls. This held true when allowance was made for littermate correlations and for other factors that might contribute to differences among litters. Likewise, there were no significant differences between experimentals and controls in the frequency, severity, or age distribution of neoplasms and other diseases.

Laparoscopic hernia repair: a preliminary report.

Advances in laparoscopic technique have provided the opportunity to perform preperitoneal herniorrhaphy and potentially avoid the morbidity associated with open techniques. From January 1991 to May 1992, two primary surgeons repaired 63 inguinal hernias (42 indirect, 20 direct, 1 femoral) on 48 patients using a standardized laparoscopic technique. The hernia defect was visualized laparoscopically, and the peritoneum anterior to the defect was incised. The hernia sac was dissected from the inguinal canal. The hernia defect was then loosely packed with rolled 1 x 6-inch polypropylene mesh (average number of rolls used was 3.4). A sheet of polypropylene mesh (average 5 x 8 cm) was then placed over the mesh rolls and the hernia defect and anchored with an endostapler. The peritoneum was closed over the mesh sheet with standard laparoscopic clips. There were 44 males and 4 females in the study group. The mean age was 55 years (range, 17-89 years). The mean follow-up was 5.8 months (range, 1-12 months). Thirty-three patients underwent unilateral hernia repair, and 15 patients underwent bilateral hernia repair. Clinically unsuspected contralateral hernias were identified at the time of laparoscopy in seven patients. The mean duration of surgery was 118 minutes (range, 80-165 minutes) for bilateral hernia repair, and 70 minutes (range, 45-100 minutes) for unilateral hernia repair. All patients with laparoscopic hernia repairs were treated on a same-day or less-than-24-hour in-hospital stay. Complications were designated as minor, moderate, or severe. There were 14 minor complications, which included subcutaneous hematomas at the trocar site, scrotal ecchymosis, groin swelling emphysema, and testicular asymmetry.(ABSTRACT TRUNCATED AT 250 WORDS)

Laparoscopic inguinal herniorrhaphy in a swine model. Third place winner of the Conrad Jobst Award in the Gold Medal paper competition.

A simplified method of laparoscopic inguinal herniorrhaphy using prosthetic materials was evaluated in a swine hernia model. The goals of this study were to determine 1) effectiveness of repair in a rapidly growing animal, 2) effectiveness and extent of adhesion formation of different prosthetic materials, 3) the effect of repair on testicular growth, and 4) histologic effects on the hernia site and surrounding structures. In a prospective randomized study, 30 juvenile male swine (average, 23 kg) with 35 congenital indirect inguinal hernias underwent laparoscopic herniorrhaphy using one of three prosthetic materials: Group 1 (polytetrafluoroethylene/Gore-Tex), N = 10; Group 2 (polypropylene mesh/Marlex), N = 10; Group 3 (polypropylene mesh/Prolene), N = 10. A standardized laparoscopic herniorrhaphy technique consisting of stapling prosthetic material over the hernia defect without peritoneal dissection was employed. During the 3-month postoperative period, animals were sequentially examined for normal growth and development, normal testicular development, and signs of hernia recurrence. Clinically apparent complications related to herniorrhaphy occurred in five animals (17%) during the observation period (one with repair failure, one with testicular torsion, two with repair failure and bowel obstruction, and one with intestinal obstruction secondary to adhesions). All three animals with bowel obstruction died. At 90 days after surgery all remaining animals (N = 27) were euthanized (Group 1 = 9, Group 2 = 8, Group 3 = 10). Average weight was 84 kg. Necropsy findings included no additional hernia recurrences, and one mesh erosion into the urinary bladder.(ABSTRACT TRUNCATED AT 250 WORDS)

Frequency and nature of specific-locus mutations induced in female mice by radiations and chemicals: a review.

The inducibility of heritable mutations in female mammals has been measured in the mouse specific-locus test (SLT). For radiation-induced mutations, a large body of data has been accumulated that includes information about biological and physical factors that influence mutation yields. However, relatively few SLT studies in females have been conducted with chemicals to date. A single estimate of the spontaneous mutation rate in oocytes, 6/536,207, has been derived as the most appropriate one to subtract from experimental rates. This rate is highly significantly below the spontaneous mutation rate in males. Mutations recovered from females mutagenized at any time after about the 12th day post-conception are induced in non-dividing cells. In adult females, most oocytes are arrested in small follicles; maturation from this stage to ovulation takes several weeks. High-dose-rate radiations are more mutagenic in mature and maturing oocytes than in spermatogonia of the male; on the other hand, no clearly induced mutations have been recovered from irradiated arrested oocytes. Efficient repair processes have been invoked to explain the latter finding as well as the upward-curving dose-effect relation for acute irradiation, and the fact that dose protraction drastically reduces mutation yield from mature and maturing oocytes. The dose-protraction effect is much greater than that found in spermatogonia. Radiation-induced mutation rates in embryonic, fetal, and newborn females are overall lower than those in the mature and maturing oocytes of adults. A dose-protraction effect has also been demonstrated at an early developmental stage when the nuclear morphology of mouse oocytes most resembles that of the human. Of only 5 chemicals so far explored for their effect in oocytes, 2 (ethylnitrosourea, ENU, and triethylenemelamine, TEM), and possibly a third (procarbazine hydrochloride, PRC), are mutagenic--with at least one of these (ENU) mutagenic in arrested as well as maturing oocytes. However, the mutation rate is, in each case, lower than for treated male germ cells. By contrast, ENU-induced mutation yield for the maternal genome of the zygote is an order of magnitude higher than that for the zygote's paternal genome or for spermatogonia. A high proportion of mutants derived from chemical treatment of oocytes (including the oocyte genome in zygotes) are mosaics, probably owing to lesions affecting only 1 strand of the DNA. A characteristic of specific-locus mutations induced in oocytes is that they include a considerably higher percentage of large (multi-locus) lesions (LLs) than do mutations induced in spermatogonia.(ABSTRACT TRUNCATED AT 250 WORDS)

Limb salvage versus traumatic amputation. A decision based on a seven-part predictive index.

In severe traumatic injuries to the lower extremity, it is often a difficult decision to attempt heroic efforts aimed at limb salvage or to amputate primarily. To answer this question, the authors performed a 5-year review of 70 limbs in 67 patients. Patients were identified as presenting with major lower extremity trauma and an associated arterial injury. Nineteen (27%) of the 70 limbs were amputated. Limb salvage was not related to the presence or absence of shock and order of repair (orthopedic or vascular). No statistical difference was noted between the time of injury to operative repair in either the amputated or limb salvage group. Limb salvage was related to warm ischemia time and the quantitative degree of arterial, nerve, bone, muscle, skin, and venous injury. A limb salvage index (LSI) was formulated based on the degree of injury to these systems. All 51 patients with an LSI score of less than 6 had successful limb salvage (p less than 0.001). All 19 patients with an LSI score of 6 or greater had amputations (p less than 0.001). Although statistics cannot replace clinical judgment, this index can be a valuable objective tool in the evaluation of the patient with a severely traumatized extremity.