BUN as an Independent Predictor of Post-Hospital-Discharge Mortality among Older Veterans.

BACKGROUND/OBJECTIVES: An elevated blood urea nitrogen (BUN) in known to be an important prognostic indicator in patients with end-stage heart or kidney disease or certain other life-threatening illnesses. However, it is less certain as to whether an elevated BUN is an independent predictor of long-term mortality risk in less seriously ill patients. To address this issue, we examined the relationship between BUN and long-term mortality after adjusting for potential confounders and other indicators of health status/disease severity, in a select population of older medically stable Veterans. DESIGN: Long-term prospective cohort study. SETTING: Outpatient follow-up of patients discharged from a recuperative care and rehabilitation unit (RCRU) of a Department of Veterans Affairs Community Living Center. PARTICIPANTS: 383 older Veterans (mean age = 78.6±7.6 years, 98% male, and 87% white) discharged alive and in stable medical condition. MEASUREMENTS: At discharge, each subject completed a comprehensive assessment and was then monitored as an outpatient for up to 9.3 years. Associations between blood urea nitrogen at RCRU discharge and mortality were identified utilizing Cox proportional hazards (PH) regression analyses adjusting for conditions known to confound this relationship. RESULTS: Within the follow-up period, 255 subjects (67%) died. In the unadjusted Cox PH model, a BUN ≥ 30 mg/dL was associated with a nearly 2-fold increased risk of mortality (hazard ratio 1.90, 95%CI 1.41 - 2.56). The association between BUN and long-term mortality remained highly significant after adjusting for potential confounders (hazard ratio 1.78, 95%CI 1.29 - 2.44). CONCLUSION: Our findings support BUN levels as an independent predictor of long-term mortality in older, medically stable Veterans. An elevated BUN may be reflective of global health status rather than solely an indicator of the severity of acute illness or unstable chronic disease.

Loss of estrogen upregulates osteoblastogenesis in the murine bone marrow. Evidence for autonomy from factors released during bone resorption.

Loss of sex steroids causes an increase in both the resorption and formation of bone, with the former exceeding the latter. Based on evidence that the increased bone resorption after estrogen loss is due to an increase in osteoclastogenesis, we hypothesized that estrogen loss also stimulates osteoblastogenesis. We report that the number of mesenchymal osteoblast progenitors in the murine bone marrow was increased two- to threefold between 2 and 8 wk after ovariectomy and returned to control levels by 16 wk. Circulating osteocalcin, as well as osteoclastogenesis and the rate of bone loss, followed a very similar temporal pattern. Inhibition of bone resorption by administration of the bisphosphonate alendronate led to a decrease of the absolute number of osteoblast progenitors; however, it did not influence the stimulating effect of ovariectomy on osteoblastogenesis or osteoclastogenesis. These observations indicate that the increased bone formation that follows loss of estrogen can be explained, at least in part, by an increase in osteoblastogenesis. Moreover, they strongly suggest that unlike normal bone remodeling, whereby osteoblast development is stimulated by factors released from the bone matrix during osteoclastic resorption, estrogen deficiency unleashes signals that can stimulate the differentiation of osteoblast progenitors in a fashion that is autonomous from the need created by bone resorption, and therefore, inappropriate.

Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin.

Glucocorticoid-induced osteoporosis may be due, in part, to increased apoptosis of osteocytes and osteoblasts, and bisphosphonates (BPs) are effective in the management of this condition. We have tested the hypothesis that BPs suppress apoptosis in these cell types. Etidronate, alendronate, pamidronate, olpadronate, or amino-olpadronate (IG9402, a bisphosphonate that lacks antiresorptive activity) at 10(-9) to 10(-6) M prevented apoptosis of murine osteocytic MLO-Y4 cells, whether it was induced by etoposide, TNF-alpha, or the synthetic glucocorticoid dexamethasone. BPs also inhibited apoptosis of primary murine osteoblastic cells isolated from calvaria. Similar antiapoptotic effects on MLO-Y4 and osteoblastic cells were seen with nanomolar concentrations of the peptide hormone calcitonin. The antiapoptotic effect of BPs and calcitonin was associated with a rapid increase in the phosphorylated fraction of extracellular signal regulated kinases (ERKs) and was blocked by specific inhibitors of ERK activation. Consistent with these in vitro results, alendronate abolished the increased prevalence of apoptosis in vertebral cancellous bone osteocytes and osteoblasts that follows prednisolone administration to mice. These results suggest that the therapeutic efficacy of BPs or calcitonin in diseases such as glucocorticoid-induced osteoporosis may be due, in part, to their ability to prevent osteocyte and osteoblast apoptosis.

Quantitative variation of the common acute lymphoblastic leukemia antigen (gp100) on leukemic marrow blasts.

Marrow blasts from children with B cell precursor acute lymphoblastic leukemia (ALL) were studied for differences in quantitative expression of the common ALL antigen (CALLA). Of 42 untreated patients, 35 had detectable amounts of CALLA by flow cytometric (FCM) analysis of J-5 monoclonal antibody binding. Using an FCM technique that provides correlated measurements of a given cell surface antigen, cell size, and DNA content, we detected increased CALLA expression as lymphoblasts moved from G0/G1 phase through S phase of the cell cycle. The density of the antigen (per unit of blast surface area) remained relatively constant over the same interval, indicating that the change was not due to S phase-specific enhancement of CALLA expression. Eight cases had hyperdiploid cellular DNA content and in seven of these, only cells with clonal abnormalities of DNA content expressed the CALLA marker. Mean amounts of CALLA for each patient ranged widely within the study group, from very high to marginally detectable. This variation had no discernible relation to cell size, stem-line DNA content, percentage of cells in S phase, or the presence or absence of cytoplasmic immunoglobulin. Results of a univariate proportional hazards analysis showed that both quantitative level of CALLA for S phase cells (P = 0.048) and white blood cell count (P = 0.012) had made significant contributions to treatment outcome. Patients with relative amounts of CALLA less than the median value for the entire CALLA+ group had a higher rate of failure, which was virtually identical to that for the seven HLA-DR+ patients whose blasts lacked detectable CALLA. The observed interpatient variation in quantitative expression of CALLA is consistent with recognized steps in B cell precursor differentiation and may be useful in distinguishing patients with a less favorable prognosis.

Hyperdiploidy and chromosomal rearrangements define the anaplastic variant of Wilms' tumor.

Flow cytometric measurement of the DNA content of Wilms' tumor cells revealed a striking correspondence with the histologic subtype and treatment outcome. In the 48 cases studied, a hyperdiploid DNA content ranging from 1.7 to 3.2 times the result for normal diploid cells distinguished all but one of the ten anaplastic tumors. Lower values, from 1.0 to 1.4 times the diploid DNA content, characterized the nonanaplastic specimens. By Kaplan-Meier analysis, the probability of achieving 3 years of relapse-free survival was significantly lower in the group with higher DNA content (0.42 v 0.87, P less than .01). Analysis of banded chromosomes for a subset of 22 patients contributed important information beyond the flow cytometric study. Cases of anaplasia associated with poorer responses to therapy showed numerous complex translocations, whereas all others lacked such changes. By combining flow cytometric techniques and conventional methods of chromosome analysis, it should be possible to identify those patients with Wilms' tumor who are most likely to fail therapy. The biologic implication of these findings is that the development of clinical drug resistance in Wilms' tumor is a result of the genetic instability of the malignant clone.

Cytogenetics of pre-B-cell acute lymphoblastic leukemia with emphasis on prognostic implications of the t(1;19).

In earlier studies of the cytogenetic characteristics of leukemic lymphoblasts from children with pre-B-cell acute lymphoblastic leukemia (ALL), we concluded that certain chromosomal abnormalities explain, in part, the increased presence of high-risk features at diagnosis and the less favorable response to therapy among patients with this immunologic subclass of ALL. With extended follow-up and a larger patient population, we have further evaluated the biologic and clinical aspects of pre-B leukemia. Of 686 cases of ALL with adequate immunophenotyping, 150 were classified as pre-B cell. Seventy-seven (69%) of the 112 pre-B cases with fully banded karyotypes had a translocation. The t(1;19) accounted for 28 (25%) of these pre-B cases and 31 (6.5%) of all 480 consecutively banded ALL cases. Three (2.6%) of the pre-B cases had a novel dicentric (7;9)(p1?3;p11) translocation. A t(9;22)(q34;q11) and a t(4;11)(q21;q23) were observed in seven (6%) and three (2.6%) of the cases, respectively. Within the pre-B subgroup, comparison of t(1;19) cases (n = 28) with those having other translocations (n = 49) or no identifiable translocations (n = 35) indicated that higher leukocyte counts (P = .002), absence of DNA indexes greater than 1.16 (P = .02), higher serum lactate dehydrogenase levels (P less than .0001), and a higher frequency of nonwhite race (P = .006) were significantly related to the t(1;19). Both the t(1;19) and other chromosomal translocations were associated with an adverse prognosis in the subset of patients treated from 1979 to 1984 (Total Therapy study X). In a more recent and more intensive chemotherapy program (Total Therapy study XI), neither the t(1;19) nor other chromosomal translocations has conferred an inferior outcome, suggesting that effective treatment can offset the negative impact of chromosomal rearrangements in cases of childhood pre-B ALL.

Correlation of karyotype and immunophenotype in childhood acute lymphoblastic leukemia.

To correlate leukemic cell karyotype with immunophenotype, we studied 364 children with acute lymphoblastic leukemia (ALL). A prognostically favorable cytogenetic feature, hyperdiploidy greater than 50 chromosomes, was found in 33% of cases classified as common ALL antigen positive (CALLA+) early pre-B (common) ALL, in contrast to 18% of pre-B cases (P = .012), 5% of T cell cases (P less than .001), and none of the B cell cases (P less than .001) or cases of CALLA negative (CALLA-) early pre-B ALL (P = .002). The frequency of translocations, an adverse cytogenetic feature, was significantly lower in CALLA+ early pre-B ALL cases (35%) than in B cell (100%; P less than .0001), pre-B (59%; P less than .001), or CALLA- early pre-B (62%; P = .016) cases. Thus, patterns of chromosomal change differ widely among the major immunophenotypic groups of ALL and may account for reported differences in responsiveness to treatment.

MACOP-B treatment in children and adolescents with advanced diffuse large-cell non-Hodgkin's lymphoma.

From 1986 through 1990, 13 previously untreated pediatric patients with advanced diffuse large-cell non-Hodgkin's lymphoma (LC-NHL) were treated with a 12-week MACOP-B regimen at St Jude Children's Research Hospital. Although 12 patients (92%) achieved a complete response, and one had a partial response, the 2-year event-free survival was only 54 +/- 15% (SE). Seven patients remain in continuous complete remission at a median of 40 months after therapy (range 23-57 months). Relapses occurred at sites of initial involvement in five patients at a median of 3.0 months after remission (range 1.2-8.5 months). Salvage therapy with radiation, and high-dose chemotherapy and bone marrow transplantation produced four durable second remissions. The 2-year overall survival for the entire group is 84 +/- 10% (SE). The 12-week MACOP-B regimen proved feasible in an ambulatory clinic setting with only minimal toxicity. We found that MACOP-B is an effective and tolerable treatment for pediatric patients with LC-NHL but did not provide improved survival over that of a similar group of children treated in previous trials at this institution.

Trisomy 21 as the sole acquired chromosomal abnormality in children with acute lymphoblastic leukemia.

Most studies of cytogenetic abnormalities in leukemia patients have focused on structural chromosomal rearrangements. Less attention has been paid to the role of single numerical abnormalities in the complex mechanisms of leukemia pathogenesis. We therefore studied 11 cases of acute lymphoblastic leukemia (ALL) with trisomy 21 as the sole chromosomal abnormality, representing 1.8% of 601 completely banded cases of ALL seen during a 10-year period. Bone marrow cells from all but one of these cases also had normal karyotypes, representing 8 to 77% of the completely analyzed metaphases. Each of the five cases tested lacked evidence of trisomy 21 mosaicism of constitutional origin in peripheral blood samples. The presenting features of these five girls and six boys were heterogeneous but tended to reflect lower-risk ALL: median age, 3.3 years (range 1-18 years), median leukocyte count, 11.6 x 10(9)/l (range 1.8-82 x 10(9)/l), white race, and a B-cell precursor immunophenotype. Complete remissions were readily induced in all 11 patients. With follow-up ranging from 1+ months to 6.4+ years, the only relapses have been extramedullary (testis and central nervous system) in two patients, both of whom have since achieved second remissions of greater than 76 and greater than 65 months. Trisomy 21 as the sole chromosomal abnormality in childhood ALL appears related to favorable presenting risk features and may represent a good prognosis subset within the group of patients with 47-50 chromosomes.

Dodecafluoropentane Emulsion Extends Window for tPA Therapy in a Rabbit Stroke Model.

Dodecafluoropentane emulsion (DDFPe) nanodroplets are exceptional oxygen transporters and can protect ischemic brain in stroke models 24 h without reperfusion. Current stroke therapy usually fails to reach patients because of delays following stroke onset. We tested using DDFPe to extend the time window for tissue plasminogen activator (tPA). Longer treatment windows will allow more patients more complete stroke recovery. We test DDFPe to safely extend the time window for tPA thrombolysis to 9 h after stroke. With IACUC approval, randomized New Zealand white rabbits (3.4-4.7 kg, n = 30) received angiography and 4-mm blood clot in the internal carotid artery for flow-directed middle cerebral artery occlusion. Seven failed and were discarded. Groups were IV tPA (n = 11), DDFPe + tPA (n = 7), and no therapy controls (n = 5). DDFPe (0.3 ml/kg, 2 % emulsion) IV dosing began at 1 h and continued at 90 min intervals for 6 doses in one test group; the other received saline injections. Both got standard IV tPA (0.9 mg/kg) therapy starting 9 h post stroke. At 24 h, neurological assessment scores (NAS, 0-18) were determined. Following brain removal percent stroke volume (%SV) was measured. Outcomes were compared with Kruskal-Wallis analysis. For NAS, DDFPe + tPA was improved overall, p = 0.0015, and vs. tPA alone, p = 0.0052. For %SV, DDFPe + tPA was improved overall, p = 0.0003 and vs. tPA alone, p = 0.0018. NAS controls and tPA alone were not different but %SV was, p = 0.0078. With delayed reperfusion, DDFPe + tPA was more effective than tPA alone in preserving functioning brain after stroke. DDFPe significantly extends the time window for tPA therapy.

Quantification of vitamin D receptor mRNA by competitive polymerase chain reaction in PBMC: lack of correspondence with common allelic variants.

It has been recently claimed that polymorphism for the vitamin D receptor (VDR) influences several aspects of calcium and bone metabolism. To evaluate the physiologic plausibility of these claims, we compared the abundance of the VDR mRNA in peripheral blood mononuclear cells (PBMCs) between different VDR genotypes using a quantitative reverse transcribed polymerase chain reaction-based method. The method is based on the coamplification of VDR cDNA and an internal standard consisting of known concentrations of a human VDR CDNA mutated at a BglII restriction site; the interassay coefficient of variation is 11%. To validate the method, we made use of earlier receptor binding studies indicating that normal human monocytes and activated, but not resting, lymphocytes expressed the VDR. The concentration of the VDR mRNA was 10(-8) to 10(-7) g/g of total RNA in cell-sorted monocytes and in in vitro activated lymphocytes, but only 10(-12) g/g of total mRNA in resting lymphocytes, establishing that the VDR mRNA determined by our method in PBMCs is due to constitutive expression in monocytes. Following an initial genotype screening of 85 normal volunteers by polymerase chain reaction or restriction fragment length polymorphism analysis, 14 individuals with the Bb genotype, 12 with the bb genotype, and 12 with the BB genotype were selected. The concentration of the VDR mRNA, corrected for the number of monocytes, was similar among the three genotype groups, as were the other variables examined: serum calcitriol, serum osteocalcin, and vertebral and hip bone density. We conclude that VDR polymorphism does not affect the abundance of the VDR mRNA.

Comparison of two clonogenic assays for determining cell growth patterns in childhood acute myeloid leukemia: relationships to clinical findings and prognosis.

Bone marrow cells from 99 patients with acute myeloid leukemia were cloned in either agar stimulated by leukocyte feeder layers (AG/F) or methylcellulose supplemented with medium conditioned by phytohemagglutinin stimulation of leukocytes (MC/P). Although cell growth in the two systems was correlated (r = 0.74, p less than 0.0001), there was increased formation and size of clusters and colonies in AG/F, suggesting that the clonogenic cells from children with AML are more readily assayed in AG/F. The number and size of clones in either system did not show a relationship to the morphologic subtype of leukemia. Depending on the scoring system used, increased growth in MC/P was related to abnormal karyotype. Also dependent on scoring system, the ability of leukemic cells to form small clusters in AG/F was associated with resistance to induction therapy: cells of patients with resistant disease were more likely to produce small clusters (p = 0.02). Our results suggest that clonogenic cells from children with AML grow more readily in AG/F than in MC/P, but that neither culture system supports the growth of cells from all patients. Depending on scoring criteria, in-vitro growth patterns in AG/F correlate with response to induction therapy.

Correlation of pathologic features with clinical outcome in pediatric adrenocortical neoplasia. A study of a Brazilian population. Brazilian Group for Treatment of Childhood Adrenocortical Tumors.

Although the relationship between pathologic features and clinical outcome is well established in adult adrenocortical neoplasms, the prognostic value of these features in pediatric adrenocortical neoplasms (PACN) is unclear. In a series of PACNs from 54 Brazilian children, the authors retrospectively investigated the prognostic value of histologic classification, ploidy, proliferative index, and size (as tumor weight or greater diameter). Histologic classification was most predictive of clinical behavior: there were no failures in 11 adenomas, 5 failures in 27 low-grade carcinomas, and 9 failures in 16 high-grade carcinomas (P = .0003). Tumor weight was predictive of failure in tumors weighing > or = 100 versus < 100 g (P = .04), and a trend was found toward failure among tumors measuring > or = 5 cm, as opposed to those < 5 cm (P = .07). Proliferative index was marginally related to failure (P = .05 at < 11% vs. > or = 11% and .07 at < 10% vs. > or = 10%), and ploidy was not significantly predictive of outcome (P = .25). Histologic type and tumor weight were the most reliable predictors of outcome in PACN.

Intralesional injection of mumps or Candida skin test antigens: a novel immunotherapy for warts.

BACKGROUND: Warts are common and induce physical and emotional discomfort. Numerous therapies exist, yet none is optimal. Despite theoretical advantages, immunotherapeutic modalities are often neglected as first-line wart therapies. OBJECTIVE: To compare treatment with intralesional skin test antigen injection of 1 wart vs cryotherapy of all warts. DESIGN: Pilot study. SETTING: University dermatology outpatient clinic. PATIENTS: A total of 115 consecutive patients with at least 1 nongenital wart. INTERVENTIONS: Patients with warts were tested for immunity to mumps and Candida using commercial antigens. Nonresponders received cryotherapy and immune individuals received cryotherapy or intralesional injection of 1 antiserum. RESULTS: Thirty-four (30%) of the 115 patients did not respond to the test injections and 81 (70%) had detectable immunity. Of the immune group, 26 (32%) received cryotherapy, 45 (56%) received intralesional mumps antiserum, and 10 (12%) received intralesional Candida antiserum. Of the anergic patients, 28 (82%) were treated with cryotherapy; 6 (18%) refused cryotherapy. Of the 39 patients who were treated with immunotherapy and completed the protocol, 29 (74%) had complete clearing of the treated wart. Fourteen (78%) of 18 patients with complete resolution of their immunotherapy-treated wart also had resolution of untreated, distant warts. CONCLUSIONS: Intralesional injection of mumps or Candida antigens into warts of immune individuals represents effective treatment. Observation of clearing of anatomically distinct and distant warts suggests acquisition of human papillomavirus-directed immunity in some patients. We conclude that this novel approach to immunotherapy may serve as first-line treatment in immune individuals with multiple or large warts and as second-line treatment in immune patients for whom cryotherapy fails.

Pain assessment and treatment in children with cognitive impairment: a survey of nurses' and physicians' beliefs.

OBJECTIVE: To gather information about healthcare providers' beliefs regarding pain and its treatment in children with cognitive impairment. DESIGN: A survey consisting of two acute pain vignettes (a child undergoing surgery and a child undergoing an outpatient medical procedure) was completed by 440 nurses and 146 physicians at Arkansas Children's Hospital. Respondents completed one of four different surveys that systematically varied the child's level of cognitive impairment (none, mild, moderate, severe) in both vignettes. Questions addressed expected pain, pain assessment methods, pharmacologic regimens, and nonpharmacologic interventions. RESULTS: In general, provider discipline and level of cognitive impairment did not significantly influence responses about pain experience and treatment. Potent analgesia, regularly scheduled dosing, and nonpainful administration were selected most frequently. Self-report of pain, patient-controlled analgesia, and behavioral interventions requiring higher cognitive skills were selected less frequently for children with more severe cognitive impairment. CONCLUSIONS: The presence of cognitive impairment appeared to influence provider decisions regarding the appropriateness of specific pain assessment and treatment methods requiring skills on the part of the child. Overall, healthcare provider views regarding analgesia and sedation were similar for all children, regardless of impairment. Whether these beliefs are consistent with clinical practice is yet to be documented.

Port-wine stains. An assessment of 5 years of treatment.

OBJECTIVE: To assess objectively the results of flashlamp-pumped dye laser treatment of port-wine stains (PWS). DESIGN: Pretreatment and posttreatment photographs were compared with the appearance of the lesion at follow-up examination. Clinical response was determined by assigning a percentage of lesional lightening score by 2 physicians and the patient, and by reflectance spectrophotometric measurements. SETTING: University and university-affiliated health center. PATIENTS: One hundred two patients (118 PWS) aged 1 month to 66 years (mean, 20 years; median, 16 years) treated from July 1, 1989, to June 30, 1994. RESULTS: Eighteen (15.3%) of the 118 PWS had more than 90% lesional lightening (complete or almost complete response), 77 (65.3%) had lightening from 50% to 90% (good response), 21 (17.8%) had lightening from 11% to 49% (poor response), and 2 (1.7%) had lightening less than 10% (no response). Clinical response did not vary among age groups, but showed statistically significant differences between anatomical locations. A return of PWS after initial response was observed in patients who were seen more than 1 year following completion of treatment. CONCLUSIONS: Treatment of PWS by flashlamp-pumped dye laser results in a good to complete response in most patients. Anatomical location of the lesion is a valuable prognostic indicator of response to treatment. The initially impressive results of flashlamp-pumped dye laser treatment of PWS may be tempered by the gradual return of the vascular lesion as time elapses after completion of therapy. Our experience indicates that PWS show a tendency to recur at a rate approaching 50% between 3 and 4 years after completion of treatment.

A randomised clinical trial of nicotine patches for treatment of spit tobacco addiction among adolescents.

BACKGROUND: This study tested the efficacy of nicotine patches in combination with behavioural therapy for the treatment of adolescent spit tobacco addiction. Prior interventions had resulted in mean cessation rates below 15% at one year. METHODS: This study, the PATCH Project, used a three group, placebo controlled, randomised clinical trial design. The control group received a standard 3-5 minute counselling followed by a two week follow up phone call. The two intervention groups received a six week behavioural intervention; in addition, one group received active nicotine patches while the other group received placebo patches. Both groups received quarterly stage based telephone counselling. RESULTS: At one year, the usual care group's spit tobacco cessation rate was 11.4% (exact 95% confidence interval (CI) 6.1% to 19.1%), placebo patch 25.0% (95% CI 16.9% to 34.7%), and the active patch 17.3% (95% CI 10.4% to 26.3%). When both patch groups were combined, the cessation rate was 21.2% (95% CI 15.7% to 27.6%). The cessation rates for active and placebo patch were not significantly different (exact two sided p = 0.22), while the combined patch groups had a significantly greater cessation rate than usual care (exact two sided p = 0.04). CONCLUSIONS: The behavioural intervention proved to be about twice as successful as previous interventions, but the nicotine patch offered no improvement in cessation rates. The behavioural intervention is based on publicly available materials and can be easily adapted for widespread use, particularly in high schools.

Effects on pubertal growth and reproduction in rats exposed to lead perinatally or continuously throughout development.

The reproductive, endocrine, and growth effects of developmental lead exposure were assessed using a rat model in which 0.6% lead acetate (w/v) was administered in the drinking water ad libitum during different developmental periods to determine if lead actions were a result of direct effects of continuous exposure to the metal ion or secondary to disrupted neonatal "endocrine imprinting." Sprague Dawley rats were exposed to lead: (1) from gestational d 5 through birth; (2) during pregnancy and lactation; (3) during lactation only; (4) from birth through adulthood; or (5) from gestational d 5 through adulthood. Lead effects were measured on the development of aspects of the reproductive system, adult sex steroid levels, and growth rates in both male and female animals. The relative weights of male secondary sex organs in adult offspring were not significantly affected in any of the lead-treated groups. In contrast, female pups exposed to lead from birth through adulthood or from gestational day 5 through adulthood were observed to have significantly delayed vaginal opening and disrupted estrus cycling. These effects on female reproductive physiology were not observed in animals where lead exposure was confined only to pregnancy or lactation. Significant suppression of adult mean serum testosterone levels was only observed in male pups exposed to lead continuously from gestational age 5 d throughout life. Lead decreased birth weight in all animals exposed in utero and mean body weights were significantly decreased in all lead-treated groups up to weaning. Analysis of growth curves revealed that all lead-treated groups had significantly reduced growth rates during lactation. However, in addition, in male pups exposed to lead during pregnancy and lactation, from birth or from gestational age 5 d, growth rates were also significantly reduced during puberty. Postpubertal growth rates were unaffected in any lead-treated group. Thus, delayed female reproductive development and suppression of adult male serum testosterone concentration required continuous exposure to the heavy metal. Little evidence was observed for an alteration of "endocrine imprinting" by lead on either reproductive or growth parameters. Exposure during early development (pregnancy and lactation) resulted in no permanent effects in this model other than small (10%) decreases in the body weight of pups postpuberty.

Endocrine mechanisms underlying the growth effects of developmental lead exposure in the rat.

A dose-response study was conducted to examine the growth suppression associated with developmental lead exposure in a rat model and to determine the endocrine mechanisms underlying these effects. Ad libitum intake of lead acetate (0.05% to 0.45% w/v) was initiated in time-impregnated female Sprague-Dawley rats (n = 10-15/group) at gestational day 5. At birth, pups were culled to four male and four females per litter. Lead exposure of dams continued until weaning, following which lead exposure of pups was continued until sacrifice at age 2 , 35, 55, and 85 days. Birth weight and prepubertal and pubertal growth rates were significantly suppressed. Growth rates were suppressed to a much greater degree in male as compared to female pups. Decreased growth rates were accompanied by a significant decrease in plasma insulin-like growth factor 1 (IGF1) concentrations and (1) a significant increase in pituitary growth hormone (GH) content during puberty in pups of both sexes, (2) a delay in the developmental profiles of the GH-dependent male-specific liver enzymes cytochrome P-450 CYP2C11 and N-hydroxy-2-acetylaminofluorene sulfotransferase, and (3) continued suppression of these enzymes in lead-exposed adult male pups. In addition, significant decreases in plasma sex steroids, testosterone (male) and 17beta-estradiol (female), were observed during puberty. Postpuberty, at age 85 d, both IGF1 and sex steroid levels were indistinguishable from control pups despite continued lead exposure. Growth rates were also similar in control and lead-exposed pups between age 57 and 85 d. Data suggest that the mechanism underlying lead-induced sex-independent suppression of growth observed in these studies involves disruption of GH secretion during puberty. It is possible that the mechanisms underlying the greater suppression of somatic growth observed at puberty in lead-exposed male offspring may be due to the additional hypoandrogenization produced by the action of lead on the hypothalamic-pituitary-testicular axis.

Neurotic effects of doxycycline sclerotherapy.

A patient experienced phrenic nerve paralysis after doxycycline sclerotherapy for treatment of chylous fistula at our institution. The purpose of this study is to use physiologic testing to determine whether doxycycline is capable of inducing defects in neural function. A nonrandomized, controlled trial was performed with nerve-conduction studies to determine possible deleterious effects of doxycycline sclerotherapy. Thirty-eight CD rats were used and separated into four groups. Doxycycline was applied to the sciatic nerves of rats by either topical application directly on the nerve or by intraneural injection. Nerve-conduction studies were done before surgery and at 1,7, and 21 days after surgery. The results showed a statistically significant decrement in nerve-conduction velocity and strength of transmitted impulse in those nerves injected with doxycycline solution. Complete nerve block was seen frequently. This effect was not seen with topical application of doxycycline or normal saline solution or with intraneural injection of normal saline solution. This study demonstrates that doxycycline can induce a marked decrement in neural function when applied to the subepineural layers of the sciatic nerve in the rat. Therefore doxycycline sclerotherapy should be used with great caution in situations in which it could become exposed to nerves that have sustained surgical trauma.