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PubMed2000

Endocervical intraepithelial glandular atypia (dysplasia): a histopathologic, human papillomavirus, and MIB-1 analysis of 25 cases.

The purpose of this study was to determine the likelihood that intraepithelial endocervical glandular atypias that are less severe than adenocarcinoma in situ (AIS) are precursors to AIS and, if so, whether they can be recognized by morphological or other means. We first assessed the frequency of atypias found in association with either AIS or invasive adenocarcinoma (ACA) and then tested these cases and additional randomly encountered cases for the presence of human papillomavirus (HPV) and for their proliferative (Ki-67) index. Lesions not fulfilling the classic criteria for AIS were subdivided into high-grade (HGGA) and low-grade glandular atypias (LGGA). Atypias and controls were microdissected and tested for HPV by the polymerase chain reaction. Serial sections were labeled for Ki-67 by immunohistochemistry with the MIB-1 antibody. Eight cases (6.8%) containing glandular atypia were found in a search of 117 consecutive cone biopsy or hysterectomy specimens that also had either AIS, ACA, or both. An additional 17 cases were either randomly encountered or were received in consultation. In 3 cases, both HGGA and LGGA were present, yielding a total of 28 lesions for study. Of the 9 HGGA cases that were associated with either AIS, ACA, or CIN II/III, 6 were positive for HPV; MIB-1 reactivity in all 6 was present in greater than 25% of the nuclei. Of the 3 HPV-negative HGGA cases in this group, the 2 that were tested showed low MIB-1 reactivity. All 3 cases of HGGA that were not associated with a diagnostic lesion were HPV-negative and had low MIB-1 reactivity. Of the 6 LGGAs associated with either AIS, ACA, or CIN II/III, 1 was positive for HPV; MIB-1 was nonreactive in this case and was low in all of the HPV-negative cases in this group that were tested. Of 10 LGGAs not associated with a diagnostic lesion, or with a low-grade squamous lesion as the only other abnormality, 2 were positive for HPV. Of these 2, one had an MIB-1 reactivity of greater than 25% and also had intestinal differentiation. MIB-1 reactivity was elevated in 2 of the 8 HPV-negative LGGAs from this group. All 10 ciliated atypias (3 HGGA, 7 LGGA) were HPV-negative and had low MIB-1 reactivity. One HPV-positive AIS control case was focally ciliated. Six of 7 foci with apoptotic bodies (5 HGGA, 2 LGGA) were HPV-positive. The infrequent occurrence of glandular atypias with AIS and ACA and the low rate of HPV DNA positivity when they are found in isolation are evidence that most AIS lesions do not evolve through morphologically identifiable antecedents and that most isolated atypias are not AIS precursors. HGGAs associated with AIS or CIN II/III maybe either precursors to or subtle variants of AIS. However, LGGAs similarly encountered are unlikely to be either. Elevated MIB-1 reactivity may be helpful diagnostically in selected cases, but it is not reliable as an independent criterion. The presence of cilia in isolated glandular atypias favors a nonneoplastic process, whereas intestinal differentiation and apoptotic bodies each suggest neoplasia.

Adolescent↗

PubMed1998

The status and distance of cone biopsy margins as a predictor of excision adequacy for endocervical adenocarcinoma in situ.

Cervical cone biopsy has become an important surgical procedure for endocervical adenocarcinoma in situ (AIS), especially for patients who desire to retain their fertility. Establishing the usefulness of the endocervical margin status in cone biopsy specimens as a predictor of residual AIS is paramount. We examined the status of the endocervical margin in the cone biopsy specimen, the distance between the most proximal AIS and the endocervical margin in the cone biopsy specimen, and the endocervical curettage (ECC) specimen performed at the time of cone biopsy and residual AIS in the hysterectomy specimens of 61 patients with specimens accessioned from 1968 through 1997; 43 (30%) of patients with a negative endocervical margin had residual AIS in the hysterectomy specimen. Conversely, 10 of 18 (56%) patients with a positive endocervical margin in the cone biopsy specimen had no AIS in the hysterectomy specimen. All 6 patients with AIS in the ECC specimen had residual AIS. No patient with an endocervical margin in the cone biopsy specimen greater than 10 mm had residual AIS. Patients with distances less than 10 mm had equal percentages of residual AIS. In general, more patients with a negative endocervical margin in the cone biopsy specimen had no residual AIS in the hysterectomy specimen than those with a positive endocervical margin in the cone biopsy specimen. However, the status of this margin is not useful for predicting the presence of residual AIS. Pathologists should report the distance between the endocervical cone biopsy margin and the closest AIS.

Adenocarcinoma↗

PubMed2003

Audibility-index predictions of normal-hearing and hearing-impaired listeners' performance on the connected speech test.

OBJECTIVE: In a previous study (Sherbecoe & Studebaker, 2002), we derived a frequency-importance function and a transfer function for the audio compact disc version of the Connected Speech Test (CST). The current investigation evaluated the validity of these audibility-index (AI) functions based on how well they predicted data from four published studies that presented the CST to normal-hearing and hearing-impaired subjects. DESIGN: AI values were calculated for the test conditions received by 78 normal-hearing and 72 hearing-impaired subjects from the selected studies. The observed CST scores and AI values for these conditions/subjects were then plotted and the dispersion of the data compared to the expected range based on critical differences. The AI values for the conditions/subjects were also converted into expected CST scores and subtracted from their corresponding observed scores to determine the distribution of the resulting difference scores and the relationship between the difference scores and subject age. RESULTS: Good predictions were obtained for normal-hearing subjects who had been tested under audio-only conditions but not those who had received audiovisual tests. The expected scores for the latter subjects were too low when the AI accounted only for audibility and too high when it included the correction for visual cues from ANSI S3.5-1997. All of the hearing-impaired subjects had been tested under audio-only conditions. In their case, the mean difference between the observed and the expected scores was comparable with the audio-only mean for the normal-hearing subjects when the AI included corrections for speech level distortion and hearing loss desensitization. However, the hearing-impaired subject data had greater variability. The predictions for these subjects also decreased in accuracy when subject age increased beyond 70 yr despite the application of an AI correction for age. CONCLUSIONS: The results of this study suggest that the AI functions derived for the CST satisfactorily predict the scores of normal-hearing subjects when they listen in speech babble under audio-only conditions but not when they receive visual cues. To obtain accurate predictions for the audiovisual form of the CST, it will be necessary to develop new ANSI-style AI correction equations for visual cues or new AI functions based on audiovisual test scores. If the current AI functions are used to predict the scores of hearing-impaired listeners tested under audio-only conditions, the AI should include corrections for the effects of speech level and hearing loss. A correction for subject age also could be applied, if it seems appropriate to do so. In either case, however, the predictions are still likely to be less accurate than the predictions for normal-hearing subjects. This may be because speech recognition deficits in people with hearing loss are not due solely to diminished audibility. Hearing-impaired subjects, particularly if they are elderly, also may be more susceptible to masking effects or other factors not accounted for by the AI.

Adolescent↗

PubMed2006

Regional differences in anatomical landmarks for placing anterior instrumentation of the thoracic spine in both normal patients and patients with adolescent idiopathic scoliosis.

STUDY DESIGN: A retrospective analysis of patients who had magnetic resonance imaging (MRI) of the thoracic spine, comparing those with a normal straight spine and those with a right thoracic adolescent idiopathic scoliosis (AIS). OBJECTIVE: To analyze the position of the rib head with respect to the spinal canal and vertebral body in normal patients and those with right thoracic AIS using MRI. SUMMARY OF BACKGROUND DATA: When placing anterior vertebral body screws in thoracic AIS, the most cephalad screws are most at risk for loosening because of smaller vertebral body size and the position of the rib heads, which may obscure more of the vertebral bodies. To our knowledge, there are no studies defining the relationship of the rib head to the vertebral anatomy in thoracic AIS. METHODS: Transverse MRIs of the vertebral bodies from the 4th thoracic (T4) vertebra to the 12th thoracic (T12) vertebra in normal patients (n = 21) and patients with AIS (n = 21) group were analyzed regarding the following parameters: (1) percent vertebra obscured by rib head (i.e., the percent of the sagittal plane vertebral body length obscured by the overlapping rib head); (2) posterior safe angle, defined as the most posterior angle a screw can be placed, which avoids the spinal canal; and (3) anterior safe angle, defined as the most anteriorly directed screw trajectory that safely obtained good screw purchase. RESULTS: In both the normal and AIS groups, the percent vertebra obscured by rib head significantly decreased from T4 (30% in normal group and 34.7% in AIS group) to T12 (-0.4% in normal group and 3.5% in AIS group) (P < 0.05). The rib head was positioned more anterior to the vertebral body in the cephalad-thoracic spine when compared to a more posterior position in the caudal thoracic spine. In each group, the posterior safe angle significantly decreased from T4 (23 degrees in normal group and 20.8 degrees in AIS group) to T12 (-0.9 degrees in normal group and 2.1 degrees in AIS group) (P < 0.05), while the anterior safe angle significantly increased from T4 (27.5 degrees in normal group and 26.6 degrees in AIS group) to T12 (38.3 degrees in normal group and 38.5 degrees in AIS group) (P < 0.05). CONCLUSIONS: It is important to understand the relationship of the rib head to the vertebral body to provide-excellent screw purchase within the vertebral body without risking penetration into the spinal canal. In both normal and AIS groups, the relationship of the rib head to the vertebral body and spinal canal changes so that the rib head is positioned more anteriorly in the cephalad-thoracic spine and more posteriorly in the caudal thoracic spine. When placing anterior thoracic screws, at the cephalad- thoracic spine (T4, T5, T6, and T7), removal of rib heads is recommended to allow for good screw purchase. However, at the caudal thoracic spine (T10-T12), staying anterior to the rib head is important to avoid penetration into the spinal canal.

Adolescent↗

PubMed1997

Androgen insensitivity syndrome: a survey of diagnostic procedures and management in the UK.

OBJECTIVE: A two year survey of androgen insensitivity syndrome (AIS) to assess current diagnostic and management strategies. METHODS: Cases were ascertained by inclusion on the British Paediatric Surveillance Unit monthly report card for 24 months. RESULTS: Fifty one of 139 notifications were confirmed as AIS; 29 cases were complete AIS and 22 cases partial AIS. Seventy six per cent of complete AIS presented with an inguinal hernia, and half the complete AIS patients had an established family history of the disorder. Presentation in the partial AIS group was through ambiguous or undermasculinised genitalia; 59% of partial AIS were raised as male. CONCLUSIONS: The importance of karyotyping girls with inguinal hernias is confirmed, and further attention should be given to genetic counselling for families of complete AIS patients. A large number of cases were misreported as partial AIS, emphasising the importance of undertaking a comprehensive diagnostic evaluation in intersex states. A large percentage of children with partial AIS were raised as boys despite severe genital undermasculinisation, indicating the current lack of validated measures that predict genital response to androgen treatment. The management of AIS is discussed and diagnostic guidelines provided to improve the diagnostic yield in AIS.

Adolescent↗

PubMed2000

The importance of seminal plasma on the fertility of subsequent artificial inseminations in swine.

Yorkshire x Landrace sows and gilts were used in a 3x2 factorial arrangement of treatments to determine the effect of uterine inflammation induced by either killed spermatozoa (KS) or bacterial lipopolysaccharide (LPS) on the fertility of a subsequent, optimally timed AI. Estrus was detected with a mature boar twice daily. Twelve hours after the first detection of estrus, females received intrauterine infusions of an inflammatory stimulus consisting of a 100-mL dose of extender containing 3x10(9) KS (n = 40), 20 microg of LPS (n = 40; positive control) or extender alone (n = 40; negative control). An insemination was performed 12 to 18 h later with 3x10(9) motile spermatozoa (i.e., fertile AI) suspended in either 100 mL of seminal plasma (SP; n = 60) or extender replenished with of estrogens (5 microg of estradiol-17beta, 4.5 microg of estrone sulfate, and 2 microg of estrone; n= 60). Transcutaneous ultrasound was performed at the time of fertile AI and again 24 h later to detect the presence or absence of preovulatory follicles. A fertile AI performed within 24 h before ovulation was considered optimal. Conception (CR) and farrowing rates (FR) were greater in females that received a fertile AI diluted with SP compared with extender (P<.01), and there was a significant (P<.05) treatment x fertile AI dilution medium interaction for both CR and FR. Females that received a fertile AI 12 h after infusion of extender had similar CR and FR regardless of fertile AI dilution medium. After inducing an inflammatory response with either KS or LPS, CR and FR were higher in females that received a fertile AI diluted with SP compared with fertile AI dilution with extender (P<.05). The effects of treatment and AI dilution media and their interactions were not significant for litter size in females that farrowed. These results show that the fertility of a subsequent AI can be impaired when semen is deposited into an inflamed environment created by an earlier AI, and this impairment was offset by inclusion of SP in the subsequent insemination.

Animals↗

PubMed2003

Effect of boar exposure at time of insemination on factors influencing fertility in gilts.

The effect of boar exposure during artificial insemination (AI) on semen backflow, fertilization, and embryo quality was evaluated. Gilts (approximately 170 d) were induced into estrus with PG600, and ovulation was synchronized using hCG 72 h later. Estrus detection was initiated after PG600 and continued at 12-h intervals. At estrus, gilts were allotted to receive boar exposure (BE, n = 20) or no boar exposure (NBE, n = 20) during AI. Gilts receiving NBE were identified to be in estrus prior to AI and the boar was then removed for 1 h, whereas gilts in the BE group received 15 min of exposure during AI. Insemination occurred in crates at 12 and 24 h after onset of estrus with 3 x 10(9) sperm/80 mL. Backflow was collected continuously with samples taken at time 0, (during AI), and at 0.25, 0.5, 0.75, 1, 2, 4, and 8 h after first and second AI. The effect of treatment was evaluated for time of insemination (min), backflow (mL), and sperm in backflow samples. Oviducts were flushed 2 d after first AI to evaluate the effect oftreatment on fertilization rate, accessory sperm numbers on embryos (scored 1 to 5), and embryo quality. There was no effect of first or second AI; therefore, data were pooled. Average duration of AI was 3.7 +/- 0.2 min and was not influenced by BE (P < 0.10). However, during the initial stage of AI, BE reduced the volume of semen (18.6 vs 32.4 +/- 3 mL) and the number of sperm lost (0.8 vs 1.3 +/- 0.15 x 10(9) sperm) compared to NBE (P < 0.05). There was a treatment x time effect (P < 0.05) for volume of backflow. By 45 min, the BE gilts lost more volume (9.0 vs 3.6 mL) compared to the NBE group, but sperm loss did not differ. Between 1 and 8 h after AI, neither volume nor sperm loss was influenced by treatment. By 8 h, total leakage (65 vs 63 mL) and total sperm loss (1.6 x 10(9) vs 1.8 x 10(9) sperm) were not influenced by BE (P > 0.10). However, more accessory sperm (P < 0.01) were found on embryos for the NBE (> or = 11 sperm/embryo) compared to BE embryos (< or = 10 sperm/embryo). Despite this observation, percentages of fertilized embryos (99.5 +/- 0.5 %) and number of embryos (11.5 +/- 0.1) were not different (P > 0.10). In conclusion, AI in the presence of a mature boar did not affect total semen leakage, sperm loss, fertilized embryos, or embryo quality. The importance of boar exposure during insemination was evident from less leakage during insemination, but had no effect on fertility; this suggests that the elimination of boar exposure during AI may not be deleterious to reproductive performance.

Animals↗

PubMed2006

Risk of cancer treatment-associated bone loss and fractures among women with breast cancer receiving aromatase inhibitors.

BACKGROUND: Aromatase inhibitors (AIs) are a novel hormonal therapy for patients with breast cancer. However, AIs can cause bone loss by blocking estrogen production. This study aims to assess the association between AIs and treatment-related bone loss in a large managed-care population of women with breast cancer. PATIENTS AND METHODS: With use of medical and pharmacy claims, data from > 5 million beneficiaries between January 1, 1998, and January 31, 2005, we identified 12,368 patients with > or = 2 breast cancer claims in a 6-month period who also had no bone metastases and no previous osteoporosis or fracture claims. Patients who had received antiestrogen (eg, tamoxifen) therapy were also excluded. One thousand three hundred fifty-four patients receiving an AI (anastrozole, exemestane, or letrozole) were compared with 11,014 controls who did not receive an AI with respect to their risk of bone loss. The observation start date for the AI and control groups was defined as the service date of the first AI claim and breast cancer claim, respectively. The endpoints include (1) bone loss, consisting of osteoporosis or osteopenia, and (2) clinical fractures. RESULTS: The univariate analysis found that the prevalence of bone loss was 8.7% in the AI group versus 7.1% in the control group, resulting in a significant relative risk of 1.3 (95% confidence interval [CI], 1.1-1.6; P = 0.01). The prevalence of bone fracture was also significantly increased in the AI group compared with the controls (13.5% vs. 10.3%) with a relative risk of 1.4 (95% CI, 1.2-1.6, P = 0.001). Multivariate Cox proportional hazards regressions showed that after adjusting for age and comorbidities, the risk of bone loss remained significantly higher in the AI group than in the non-AI group, with a 27% (95% CI, 4%-55%; P = 0.02) and 21% (95% CI, 3%-43%; P = 0.02) increase in the risk of bone loss and fractures, respectively. CONCLUSION: This retrospective longitudinal analysis of a large cohort of patients with breast cancer corroborates previous findings from smaller clinical trials and demonstrates that AI therapies carry an increased risk of bone loss. Monitoring and treatment management strategies to reduce bone loss risk are warranted in women receiving an AI for breast cancer.

Aged↗

PubMed2003

Inadequate calcium intake is a significant determinant on generalised osteopenia in Hong Kong Chinese adolescents with idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is a serious 3-dimentional deformity of the spine affecting mostly girls. The prevalence rate is 3%-4% in Hong Kong. Generalised osteopenia are found in AIS patients. This study attempted to study whether low bone mineral density (BMD) is related to calcium intake in AIS. 582 AIS patients & 206 healthy controls aged 11-16 years were enrolled. Areal BMD (aBMD) and volumetric BMD (vBMD) were evaluated by DXA (Norland-XR-36) and pQCT (Densiscan-1000) respectively. Calcium and other nutrients intakes were assessed by a food-frequency method. The results showed that absolute calcium intake of the subjects were low (< 500 mg/d). Mean calcium intake of AIS girls was significantly higher than that of controls[(441 +/- 344) mg/d vs. (390 +/- 281) mg/d, P = 0.015]. BMD of AIS was significantly lower than that of controls at most skeletal sites from age 11-16 years (P < or = 0.05). The percentage difference in BMD increased with age between the AIS and control group. Furthermore, calcium intake was significantly correlated with BMD at most skeletal sites from age 15-16 years. However, this association was not found in the controls. Calcium intake was an independent determinant to predict variation of BMD after controlling for confounding variables in multivariate analysis. It is suggested that absolute calcium intake of AIS was low. BMD at various skeletal sites of the AIS was consistently lower than those of controls across different adolescent years, and that the correlation between calcium intake and BMD occurs only in AIS but not in healthy control girls implying the importance of calcium in bone mineral gain among the AIS, and it also reflected an abnormal mechanism of calcium homeostasis and bone turnover in AIS. Further calcium interventional study is warranted to confirm the effect of calcium on BMD acquisition in AIS.

Absorptiometry, Photon↗

PubMed1993

Tonotopic organization, architectonic fields, and connections of auditory cortex in macaque monkeys.

Microelectrode recordings were used to investigate the tonotopic organization of auditory cortex of macaque monkeys and guide the placement of injections of wheat germ agglutinin-horse radish peroxidase (WGA-HRP) and fluorescent dyes. Anatomical and physiological results were later related to histological distinctions in the same brains after sections were processed for cytoarchitecture, myeloarchitecture, acetylcholinesterase (AchE), or cytochrome oxidase (CO). The experiments produced several major findings. (1) Neurons throughout a broad expanse of cortex were highly responsive to pure tones, and best frequencies could be determined for neurons in arrays of recording sites. (2) The microelectrode recordings revealed two systematic representations of tone frequencies, the primary area (AI) and a primary-like rostral field (R) as previously described. The representation of high to low frequency tones in A1 was largely caudorostral along the plane of the sulcus. A reversal of the order of representation of frequencies occurred in R. (3) AI and R together were coextensive with a koniocellular, densely myelinated zone that expressed high levels of AchE and CO. These architectonic features were somewhat less pronounced in R than AI, but a clear border between the two areas was not apparent. (4) Cortex bordering AI and R was less responsive to tones, but when best frequencies for neurons could be determined, they matched those for adjoining parts of AI and R. (5) Architectonically distinct regions were apparent within some of the cortex bordering AI and R. (6) The major ipsilateral cortical connections of AI were with R and cortex immediately lateral and medial to AI. (7) Callosal connections of AI were predominantly with matched locations in the opposite AI, but they also included adjoining fields. (8) Neurons in the ventral (MGV), medial (MGM), and dorsal (MGD) nuclei of the medial geniculate complex projected to AI and cortex lateral to AI. (9) Injections in cortex responsive to high frequency tones labeled more dorsal parts of MGV than injections in cortex responsive to low frequency tones.

Acetylcholinesterase↗

PubMed2005

Association of osteopenia with curve severity in adolescent idiopathic scoliosis: a study of 919 girls.

Generalized osteopenia and spinal deformity occur concomitantly in adolescent idiopathic scoliosis (AIS) during the peripubertal period. No large-scale study has been performed to reveal the link between scoliotic deformity and bone-mineral status in AIS. In a cross-sectional study, the extent of scoliotic-curve severity in relation to bone-mineral status was examined for 619 AIS girls and compared with those of 300 healthy non-AIS counterparts aged 11-16 years. Curve severity was categorized into a moderate (10-39 degrees) and a severe group (> or = 40 degrees) based on Cobb angle. Anthropometric parameters, bone mineral-density (BMD) and bone mineral-content (BMC) of lumbar spine, proximal femur and distal tibia were determined by dual-energy X-ray absorptiometry and peripheral QCT. Differences in anthropometric parameters and bone mass among control and the AIS-moderate and AIS-severe groups were tested by one-way ANOVA. Association between Cobb angle and bone mass was determined by univariate and multivariate analyses. Mean Cobb angle of the moderate and severe groups were 25+/-6.3 degrees and 50.2+/-11.3 degrees, respectively. Arm span and leg length among the moderate and severe AIS subjects were almost all longer than for the controls from age 13 years. Age-adjusted arm span and leg length were significantly correlated with curve severity (p < 0.015). Starting from age 13 years, most axial and peripheral BMD and BMC of the moderate or severe AIS group was significantly lower than for the controls (p < 0.029). Age-adjusted Cobb angle was inversely correlated with BMD and BMC of the distal tibia and lumbar spine among AIS subjects (p < or = 0.042). The proportion of osteopenic AIS girls in the severe group was significantly higher than that in the moderate group (p < or = 0.033). Multivariate analysis indicated that Cobb angle was inversely and independently associated with axial and peripheral BMD and BMC (p < or = 0.042). To conclude, curve severity was an inverse and independent associated factor on bone mineral mass of AIS during peripuberty. The study implied that prevention of osteopenia could be as important as controlling spinal progression in the management of AIS.

Absorptiometry, Photon↗

PubMed2002

Breath-by-breath alveolar oxygen transfer at the onset of step exercise in humans: methodological implications.

The effects of using different algorithms to estimate the time constant of changes in oxygen uptake at the onset of square-wave 120 W cycloergometric exercise were evaluated in seven subjects. The volume of oxygen taken up at the alveoli (VO(2Ai)) was determined breath-by-breath (BB) from the volume of O(2) transferred at the mouth (VO(2mi)) minus the corresponding volume changes in O(2) stores in the alveoli: VO(2Ai)= VO(2mi)-[V(Ai-1)(FO(2Ai)- FO(2Ai-1))+ FO(2Ai) x Delta V(Ai)], where V(Ai-1) is the alveolar volume at the end of the previous breath, FO(2Ai) and FO(2Ai-1) are estimated from the fractions of end-tidal O(2) in the current and previous breaths, respectively, and Delta V(Ai) is the change in volume during breath i. These quantities can be measured BB, with the exception of V(Ai-1) which must be assumed. The respiratory cycle has been defined as the time elapsing between identical fractions of expiratory gas in two successive breaths. Using this approach, since FO(2Ai)= FO(2Ai-1), any assumption regarding V(Ai-1) becomes unnecessary. In the present study, VO(2Ai) was calculated firstly, by using this approach, and secondly by setting different V(Ai-1) values (from 0 to FRC+0.5 l, where FRC is the functional residual capacity). Values for alveolar O(2) flow (VO(2Ai)), as calculated from the quotient of VO(2Ai) divided by breath duration, were then fitted bi-exponentially. The time constant of the phase II kinetics of VO(2Ai) (tau(2)) was linearly related to V(Ai-1), increasing from 36.6 s (V(Ai-1)=0) to 46.8 s (V(Ai-1)=FRC+0.5 l) while tau(2) estimated using the first approach amounted to 34.3 s. We concluded that, firstly, the first approach allowed us to calculate O(2A) during transitions in step exercise; and secondly, when using methods wherein V(Ai-1) must be assumed, tau(2) depended on V(Ai-1).

Adult↗

PubMed2003

The role of aromatase inhibitors in early breast cancer.

The role of hormonal therapy for the treatment of patients with early stage breast cancer has been evaluated in many studies. The results of these studies establish tamoxifen as the gold standard of hormonal therapy for the adjuvant treatment of hormone receptor-positive invasive breast cancer in pre- and postmenopausal women. Studies show tamoxifen reduces the risk of invasive breast cancer in women at increased risk for the disease, including women with ductal carcinoma in situ. Tamoxifen has adverse effects such as hot flashes, increased risk of uterine cancer in postmenopausal women, and rare occurrence of thromboembolic disease. Despite the multiple therapeutic roles of tamoxifen, alternatives are needed. Aromatase inhibitors (AI) are drugs with antiestrogenic activity. AIs function by inhibiting the peripheral conversion of adrenally synthesized androstenedione to estradiol through inhibition of the aromatase enzyme. AIs do not suppress estradiol synthesis by the ovary adequately. Therefore, AIs are effective in reducing circulating estradiol levels in postmenopausal women, but not premenopausal women. Selective nonsteroidal AIs, including anastrozole (Arimidex; AstraZeneca, Wilmington, DE) and letrozole (Femara; Novartis, East Hanover, NJ), and the steroidal AI exemestane (Aromasin; Pharmacia, Peapack, NJ) have been associated with increased specificity and improved therapeutic index compared to nonselective AIs such as aminoglutethamide. Nonsteroidal and steroidal AIs have demonstrated to be superior to megestrol acetate in second-line therapy of postmenopausal women with metastatic breast cancer, and selective nonsteroidal AIs have shown to be superior to tamoxifen in first-line therapy of postmenopausal women with metastatic breast cancer. The ATAC (Arimidex, tamoxifen, alone, or in combination) trial is the only published randomized trial comparing the efficacy of an AI to tamoxifen for the adjuvant treatment of women with early breast cancer. This large study showed that at a median follow-up time of 33 months, anastrozole alone results in significant improvement in disease-free survival rates, reduction in contralateral breast cancers, and increased tolerability, compared to tamoxifen in postmenopausal women. Although the long-term effects of AIs are not known, the early positive results of the ATAC trial led to the approval of anastrozole by the US Food and Drug Administration for use as adjuvant hormonal therapy for postmenopausal women with hormone receptor-positive invasive breast cancer. Thus, there is an alternative to tamoxifen for postmenopausal women with relative/absolute contraindications to tamoxifen use or patients who choose not to take tamoxifen because of its side-effect profile. New AIs may challenge the position of tamoxifen as the gold standard for the treatment of early stage breast cancer in postmenopausal women.

Adult↗

PubMed1982

Effect of hypoxia on the conversion of angiotensin I to II in the isolated perfused rat lung.

Acute hypoxia in the intact animal and in cultured endothelial cells has been shown to be associated with a decrease in conversion of angiotensin I (AI) to angiotensin II (AII). Alterations in capillary surface and in contact time resulting from hemodynamic changes have been shown to influence the rate of pulmonary AI conversion. The dependency of AI conversion on hemodynamics complicates the interpretation of experiments showing changes in AI conversion in intact animals. We studied the effect of acute hypoxia on AI conversion in the isolated rat lung perfused at constant flow without recirculation of perfusate. Three levels of oxygenation were produced by ventilating lungs and equilibrating perfusate with a range of hypoxic gas mixtures. AI (1 microgram) was injected into the pulmonary artery, and the effluent was collected for measurement of AI and AII. Instead of the expected hypoxic inhibition, percent conversion of AI to AII increased slightly but significantly from 69.3 +/- 3.1 (mean +/- S.E.M.) at normal oxygenation to 74.4 +/- 3.0 at moderate hypoxia (P less than 0.005, paired t) and to 73.5 +/- 3.9 at severe hypoxia (P less than 0.01, paired t). Decreasing mean transit time of substrate through the lung (by increasing perfusate flow rate from 5 to 20 ml/min) resulted in a significant decrease in conversion of AI from 88.7 +/- 2.9 to 73.4 +/- 2.1% (P less than 0.001, paired t). These data confirm the effect of contact time on the rate of AI conversion in the lungs. The isolated rat lung preparation does not exhibit the phenomenon of hypoxia-induced inhibition of AI conversion. The authors speculate that hypoxia-induced inhibition of AI conversion in vivo may be secondary to the effects of hypoxia on hemodynamics.

Angiotensin I↗

PubMed2005

Distinct metal dependence for catalytic and structural functions in the L-arabinose isomerases from the mesophilic Bacillus halodurans and the thermophilic Geobacillus stearothermophilus.

L-Arabinose isomerase (AI) catalyzes the isomerization of L-arabinose to L-ribulose. It can also convert d-galactose to d-tagatose at elevated temperatures in the presence of divalent metal ions. The araA genes, encoding AI, from the mesophilic bacterium Bacillus halodurans and the thermophilic Geobacillus stearothermophilus were cloned and overexpressed in Escherichia coli, and the recombinant enzymes were purified to homogeneity. The purified enzymes are homotetramers with a molecular mass of 232 kDa and close amino acid sequence identity (67%). However, they exhibit quite different temperature dependence and metal requirements. B. halodurans AI has maximal activity at 50 degrees C under the assay conditions used and is not dependent on divalent metal ions. Its apparent K(m) values are 36 mM for L-arabinose and 167 mM for d-galactose, and the catalytic efficiencies (k(cat)/K(m)) of the enzyme were 51.4 mM(-1)min(-1) (L-arabinose) and 0.4 mM(-1)min(-1) (d-galactose). Unlike B. halodurans AI, G. stearothermophilus AI has maximal activity at 65-70 degrees C, and is strongly activated by Mn(2+). It also has a much higher catalytic efficiency of 4.3 mM(-1)min(-1) for d-galactose and 32.5 mM(-1)min(-1)for L-arabinose, with apparent K(m) values of 117 and 63 mM, respectively. Irreversible thermal denaturation experiments using circular dichroism (CD) spectroscopy showed that the apparent melting temperature of B. halodurans AI (T(m)=65-67 degrees C) was unaffected by the presence of metal ions, whereas EDTA-treated G. stearothermophilus AI had a lower T(m) (72 degrees C) than the holoenzyme (78 degrees C). CD studies of both enzymes demonstrated that metal-mediated significant conformational changes were found in holo G. stearothermophilus AI, and there is an active tertiary structure for G. stearothermophilus AI at elevated temperatures for its catalytic activity. This is in marked contrast to the mesophilic B. halodurans AI where cofactor coordination is not necessary for proper protein folding. The metal dependence of G. stearothermophilus AI seems to be correlated with their catalytic and structural functions. We therefore propose that the metal ion requirement of the thermophilic G. stearothermophilus AI reflects the need to adopt the correct substrate-binding conformation and the structural stability at elevated temperatures.

Aldose-Ketose Isomerases↗

PubMed2005

Effect of PG600 and adjusted mating times on reproductive performance in weaned sows.

The administration of PG600 to sows at weaning induces >90% of sows to return to estrus within a week, but farrowing rate and litter size are often not improved. This study evaluated the effects of adjusted artificial insemination (AI) times based on weaning to estrus interval (WEI) and estrus to ovulation interval (EOI) following PG600. All sows were given PG600 at weaning and allotted to adjusted (ADJ, n=47) or non-adjusted (NA, n=46) mating times after the onset of estrus. Adjusted mating involved: (1) 2-3 days WEI, AI at 36 h and 48 h; (2) 4 days WEI, AI at 24h and 36 h; (3) 5 days WEI, AI at 12h and 24h; and (4) 6-7 days WEI, AI at 0 h and 12h. Mating for NA occurred at 0 h and 24h after onset of estrus. There was no effect of treatment on return to estrus (92.9% versus 92.5%) or ovulation (92.7% versus 92.5% for ADJ and NA, respectively). The proportion of first AI occurring within 24h prior to ovulation was increased (83.8% versus 50.0%) and closer to ovulation for ADJ compared to NA treatment (19.4h versus 27.3h, P<0.05). Treatment did not influence (P>0.10) the proportion of second AI occurring within 24h of ovulation (72.8% versus 56.6%) but did influence (P<0.05) the interval from second AI to ovulation for ADJ compared to NA (10.6h versus 3.3h). The ADJ treatment increased (P<0.05) the proportion of sows that received an AI within 24h before ovulation (98.8% versus 87.0%). However, treatment did not influence pregnancy (87.4%) or farrowing (79.5%) rates but the NA treatment tended to increase (P<0.10) total number of pigs born (11.8 versus 8.9). In conclusion, while AI times for ADJ appeared to occur within optimal periods, farrowing rates were not improved and litter size decreased, suggesting that two AI at 12h intervals and closer to the time of ovulation may be detrimental. Overall, these data suggest that for sows injected with PG600 at weaning and receiving two AI, breeding at 0 h and 24h after onset of estrus is recommended.

Animals↗

PubMed2005

Differences between Belclare and Suffolk ewes in fertilization rate, embryo quality and accessory sperm number after cervical or laparoscopic artificial insemination.

Ewe breed has been shown to have a major effect on pregnancy rates following cervical AI using frozen-thawed semen. The main objective of this study was to examine the differences between purebred Belclare and Suffolk ewes (multiparous) in fertilization rate, number of accessory sperm and stage of embryo development on day 6 after cervical or laparoscopic AI with frozen-thawed semen. In experiment 1, Belclare and Suffolk ewes were synchronized for 12 days and were either cervically inseminated (year 1: n=28 and 31; year 2: n=16 and 15, respectively) or laparoscopically inseminated (year 2: n=13 and 14). In experiment 2, superovulated Belclare (n=4) and Suffolk (n=13) ewes were laparoscopically inseminated. All ewes were slaughtered 6 days after AI; oocytes/embryos were recovered, morphologically graded and stained to assess the number of cells and accessory spermatozoa. Data from both experiments were combined for statistical analysis. The proportion of ewes with fertilized oocytes was significantly higher following laparoscopic AI compared with cervical AI (54% versus 19%). More Belclare than Suffolk ewes yielded fertilized oocyte(s) after cervical AI (34% versus 10%, P<0.02) but there was no difference after laparoscopic AI (62% versus 60%). From the ewes that yielded at least one fertilized oocyte the proportion of Belclare ewes with embryos at the morula/blastocyst stage was significantly greater than for Suffolk ewes (94% versus 59%, P<0.02). A higher proportion of Belclare than Suffolk ewes had evidence of sperm reaching the site of fertilization following cervical AI (39% versus 15%, P<0.02) but there was no difference after laparoscopic AI (62% versus 64%, P>0.8). Amongst the ewes with evidence of sperm at the site of fertilization, laparoscopic AI resulted in a higher number of sperm per oocyte/embryo or per ewe than cervical AI (P<0.01). These results suggested that the difference in pregnancy rate between Suffolk and Belclare ewes following cervical AI was due to: (i) sperm traversing the cervix and uterus in a higher proportion of Belclare than Suffolk ewes, leading to a higher incidence of fertilization and (ii) the lower developmental competence of fertilized oocytes from Suffolk ewes.

Animals↗

PubMed1988

Cortical v trabecular bone aluminum in dialyzed patients.

Differences among measurement of cortical and trabecular bone aluminum (AI) have been observed. Furthermore, its relationship to bone histology has been variable. In order to clarify these points, we have evaluated measurements of bone AI in relation to the source of AI and bone lesion in 25 hemodialysis patients. All patients were dialyzed in the same unit since commencement of dialysis and treated by the same physician. Age of the patients ranged from 29 to 66 years; mean duration of dialysis was 6.6 +/- 3.5 years. Dialysate water has been treated by reverse osmosis since 1980. Bone biopsy was performed in all patients after double tetracycline labeling. AI was measured biochemically in cortical bone (bCAI) and histochemically in trabecular (TAI) and cortical bone (CAI). Mean serum AI (36 +/- 21 micrograms/L) and bCAI (59 +/- 44 micrograms/g) were increased. There were significant correlations between: cortical AI and (1) serum AI (r = 0.71, p less than 0.001); (2) duration of dialysis with softened water (AI content, 55 +/- 21 micrograms/L, r = 0.65, P less than 0.001) but not with total duration of dialysis; and (3) AI ingested since commencement of dialysis (r = 0.57, P less than 0.01). Trabecular AI was not correlated with any of these parameters. None of cortical AI measurements were correlated with bone formation rates (BFR), osteoblastic surfaces (ObS), and resorption surfaces (RS) determined on trabecular bone. However, trabecular AI was inversely correlated with BFR (P less than 0.01) and ObS (P less than 0.05). Serum parathyroid hormone (PTH) was positively correlated with BFR (P less than 0.001) and RS (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗