Suppression of serum adrenal cortex hormones by chronic low-dose polychiorobiphenyl or polybromobiphenyl treatments

Studies evaluate serum adrenal cortical hormones during chronic intoxication with low levels of polychlorinated biphenyls (PCB) and polybrominated biphenyl (PBB). Serum levels of corticosterone (B) (the principal glucocorticoid in rats), dehydroepiandrosterone (DHEA) (an androgen), and dehydroepiandrosterone sulfate (DHS) were assessed at regular intervals over 5–7 months treatment in female Sprague-Dawley rats. Aroclors^® 1254, 1242, 1016 or hexabromobiphenyl (Fire master BP-6^®) were supplemented in the food at following concentrations: 0, 1, 5, 10 or 50 ppm wt/wt in the food.Corticosterone in the serum decreased at all levels during PCB or PBB treatment. Decreases were cumulative and dose-dependent. Serum B in the 50 ppm Aroclor 1254 treated group were depressed by 5-fold below controls and pre-treatment levels. Groups treated with 1, 5, and 10 ppm had serum B levels reduced by one-half. Hexabromobi phenyl decreased serum B levels to one-half of control and pre-treatment levels, but overall the decreases were not as dramatic as Aroclor 1254 treatment.Serum dehydroepiandrosterone levels were decreased by approximately one-half compared to controls and pretreatment levels by day 140 of PCB or PBB treatment. Corticosterone levels began to decrease only after the first month of PCB or PBB treatment. Control DHS levels increased steadily during the 5–7 month study period, but PCB and PBB treated did not increase similarly. In conclusion, PCB and PBB intoxication exerted profound reductions in circulating adrenal cortex hormones, as well as reductions in adrenal weights, suggesting toxicity to the adrenal. Rather than responding to the stress of PCB or PBB by increasing the release of glucocorticoids, the opposite seems to have occurred. Data suggests that damage to the adrenal cortex may have occurred in such a manner as to decrease the serum levels of Corticosterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate.     

Impact of laparoscopic cystectomy of endometriotic and non-endometriotic cysts on ovarian volume,antral follicle count (AFC) and ovarian doppler velocimetry

Objective: To evaluate the effect on ovarian reserve and blood flow of unilateral laparoscopic stripping of endometriotic versus non-endometriotic cysts.

Design: Prospective observational study.

Setting: Tertiary university gynecology unit.

Patients: During the study period, 71 subjects underwent the first laparoscopic surgery for removal of a monolateral benign ovarian cyst.

Interventions: Trans-vaginal ultrasound scans of the pelvis about six months after surgery.

Main outcome measures: Ovarian volume, Antral Follicle Count (AFC) and Resistance Index (RI) of ovarian artery of the operated and the contralateral ovary.

Results: Among 71 cysts, 39.4% were endometriotic and 60.6% non-endometriotic benign cysts. All the procedures were performed by the same experienced surgeons with a standardized technique. No major complications were reported during surgery. The mean (±SD) age and BMI of women were 31.0?±?6.8 years and 24.2?±?3.3?kg/m², respectively. Mean diameter of the removed cysts was smaller for endometriotic than non-endometriotic cysts (4.35?±?1.77?cm versus 6.33?±?3.71?cm, p?=?0.046). In comparison to non-operated, volume of the operated ovary was significantly lower and with a reduced AFC, with no difference between endometriotic and non-endometriotic cysts (?2.41?±?2.35 versus ?2.00?±?2.23?cm³, p?=?0.496) (?3.45?±?3.07 versus ?2.43?±?1.95, p?=?0.11). Ovarian artery RI was higher in the operated ovary with no difference between endometriotic and non-endometriotic cysts (0.19?±?0.14 versus 0.14?±?0.10, p?=?0.455). The difference in ovarian volume (r?=?0.178), AFC (r?=?0.094) and RI (r?=?0.079) between operated and non-operated ovary was not dependent on the diameter of the removed cyst.

Conclusion: Ovarian surgery is associated with a decline of ovarian reserve, independently on the histological type and the diameter of the removed cyst.     

Serum microRNAs as novel biomarkers for primary sclerosing cholangitis and cholangiocarcinoma

The diagnosis of primary sclerosing cholangitis (PSC) is difficult due to the lack of sensitive and specific biomarkers, as is the early diagnosis of cholangiocarcinoma (CC), a complication of PSC. The aim of this study was to identify specific serum miRNAs as diagnostic biomarkers for PSC and CC. The levels of 667 miRNAs were evaluated in 90 human serum samples (30 PSC, 30 CC and 30 control subjects) to identify disease‐associated candidate miRNAs (discovery phase). The deregulated miRNAs were validated in an independent cohort of 140 samples [40 PSC, 40 CC, 20 primary biliary cirrhosis (PBC) and 40 controls]. Receiver operating characteristic (ROC) curves were established and only miRNAs with an area under the curve (AUC) > 0·70 were considered useful as biomarkers. In the discovery phase we identified the following: 21 miRNAs expressed differentially in PSC, 33 in CC and 26 in both in comparison to control subjects as well as 24 miRNAs expressed differentially between PSC and CC. After the validation phase, miR‐200c was found to be expressed differentially in PSC versus controls, whereas miR‐483‐5p and miR‐194 showed deregulated expression in CC compared with controls. We also demonstrate a difference in the expression of miR‐222 and miR‐483‐5p in CC versus PSC. Combination of these specific miRNAs further improved the specificity and accuracy of diagnosis. This study provides a basis for the use of miRNAs as biomarkers for the diagnosis of PSC and CC.     

Blood-stage Plasmodium infection induces CD8+ T lymphocytes to parasite-expressed antigens, largely regulated by CD8alpha+ dendritic cells

Although CD8(+) T cells do not contribute to protection against the blood stage of Plasmodium infection, there is mounting evidence that they are principal mediators of murine experimental cerebral malaria (ECM). At present, there is no direct evidence that the CD8(+) T cells mediating ECM are parasite-specific or, for that matter, whether parasite-specific CD8(+) T cells are generated in response to blood-stage infection. To resolve this and to define the cellular requirements for such priming, we generated transgenic P. berghei parasites expressing model T cell epitopes. This approach was necessary as MHC class I-restricted antigens to blood-stage infection have not been defined. Here, we show that blood-stage infection leads to parasite-specific CD8(+) and CD4(+) T cell responses. Furthermore, we show that P. berghei-expressed antigens are cross-presented by the CD8alpha(+) subset of dendritic cells (DC), and that this induces pathogen-specific cytotoxic T lymphocytes (CTL) capable of lysing cells presenting antigens expressed by blood-stage parasites. Finally, using three different experimental approaches, we provide evidence that CTL specific for parasite-expressed antigens contribute to ECM.     

The isozyme-specific effects of cyclooxygenase-deficiency on bone in mice

Prostaglandin E(2) (PGE(2)) plays a critical role in skeletal physiology and bone loss. PGE(2) production is regulated in vivo by at least two cyclooxygenase (COX) isozymes, COX-1 and COX-2. The purpose of this study was to investigate the in vivo effects of the selective deletion of COX-1 or COX-2 on bone mineral density (BMD), bone microarchitecture and bone strength in wild type (WT), COX-1(-/-) and COX-2(-/-) mice. Using a LUNAR PIXImus, BMD was measured in 18 (WT), 18 COX-1(-/-) and 16 COX-2(-/-) mice. COX-1(-/-) mice exhibited significantly higher BMD (0.0506 g/cm(2) +/- 0.0014 g/cm(2)) than either WT (0.0493 g/cm(2) +/- 0.0019, P < or = 0.05) or COX-2(-/-) (0.0473 g/cm(2) +/- 0.0034, P < or = 0.01) mice. COX-2(-/-) mice had significantly lower BMD than WT (P < or = 0.01) or COX-1(-/-) (P < or = 0.01). Flexure stress of the femurs, determined by breaking the bones with three-point bending, correlated with bone density. Although plasma levels of both Ca(2+) and PTH were comparable in wild type and COX-1(-/-) mice, both were elevated in COX-2(-/-) mice consistent with primary hyperparathyroidism. These studies suggest that COX enzymes are important regulators of BMD and bone strength in mice. The beneficial effect of absence of the COX-1 enzyme on skeletal parameters may be secondary to decreases in PGE(2). On the other hand, primary hyperparathyroidism and lower bone magnesium content may account for the lower BMD and impairments in bone strength of COX-2(-/-) mice. Further elucidation of the effects of the COX pathway on bone remodeling may provide important information on potential therapeutic targets for preventing and/or treating osteoporosis.     

Combined radiotherapy and chemotherapy with cyclophosphamide,adriamycin, methotrexate,procarbazine (camp) in 64 consecutive patients with epidermoid bronchogenic carcinoma,limited disease: A prospective study

Sixty-four consecutive patients with inoperable epidermoid bronchogenic carcinoma (limited disease) were treated with radiotherapy to the primary and nodal areas and combination chemotherapy with cyclophosphamide, adriamycin, methotrexate and procarbazine. The overall response rate (CR + PR) to combined treatment was 62%. The median survival time was 12.7 months. The toxicity was acceptable and no treatment-related death occurred.     

Is peripheral arterial pressure a satisfactory substitute for ascending aortic pressure when measuring aortic valve gradients?

Substitution of peripheral arterial pressure for ascending aortic pressure is a common but poorly validated practice in the assessment of aortic valve gradients by catheterization. The accuracy of this practice was assessed by comparing the left ventricular-ascending aortic mean gradient in 26 cases of aortic stenosis with the left ventricular-femoral artery gradient, both with and without compensation for temporal delay in femoral artery pressure. Aligned left ventricular-femoral artery gradients (matching upstrokes to compensate for peripheral time delay) underestimated the left ventricular-ascending aortic gradient by 10 mm Hg (range 0 to -17). Unaltered simultaneous left ventricular-femoral artery gradients overestimated the left ventricular-ascending aortic gradient by an average of 9 mm Hg (range +1 to +18). For both peripheral techniques, the error was relatively constant throughout the range of aortic valve gradients. The most accurate estimate of both aortic valve gradient and area was obtained by averaging the gradients and areas derived from aligned and unaltered left ventricular-peripheral arterial simultaneous tracings. Although only occasionally critical for clinical decision-making, these errors may be overwhelming in certain types of research applications, such as comparisons of valve prosthesis gradients and serial evaluations of aortic stenosis. An additional source of error is a coexistent peripheral arterial gradient that was present in 21% of otherwise technically suitable patients in the screened study group.