First trimester maternal serum biochemical markers of aneuploidy in pregnancies with abnormally invasive placentation.

OBJECTIVE: To examine whether differences exist in routine first trimester maternal serum screening analyte measurements between normal pregnancies, placenta praevia and abnormally invasive placentation (AIP). DESIGN: Multidisciplinary audit. SETTING: Associated university teaching hospital with 9000 annual deliveries. POPULATION: Five hundred and sixteen pregnancies in total, including 344 normal controls, 17 with AIP and 155 placenta praevia cases. METHODS: Comparison of maternal serum free ßhCG and PAPP-A MoMs distribution in pregnancies with abnormally invasive placentation, placenta praevia and normal controls, after correcting for known confounding factors between October 2005 and September 2013. Data from a previously published first trimester AIP and biochemistry study were combined with our study data and compared in the above way to complete the analysis. MAIN OUTCOME MEASURES: Differences in first trimester maternal serum PAPP-A and free ßhCG in AIP, placenta praevia, and normal pregnancies. RESULTS: Median free ßhCG MoM in the control group was 1.04, and 1.08 (P = 0.859) in the placenta praevia group compared with 0.81 in the AIP group (P = 0.06). Median PAPP-A MoM was 1.01 in the control group and 1.05 (P = 0.83) in praevia, compared with 1.22 in AIP cases (0.16). The combined AIP dataset gave an overall PAPP-A median MoM of 1.40, and free ßhCG of 0.85. Both markers showed a significantly different distribution from controls (PAPP-A P = 0.002 and free ßhCG P = 0.031). CONCLUSIONS: There may be differences between first trimester maternal serum biochemical markers between normal pregnancies and those complicated by abnormally invasive placentation. If upheld, this may provide useful information for the early identification of abnormally invasive placentation. More studies are required.

Squamous cell carcinoma growth in mice and in culture is regulated by c-Jun and its control of matrix metalloproteinase-2 and -9 expression.

Squamous cell carcinoma (SCC) is an invasive malignancy of epidermal keratinocytes. Surgical excision is currently the main treatment; however, this can cause scarring and disfigurement. There is accordingly, an acute need for alternative strategies to treat SCC. The transcription factor c-Jun is expressed in human SCC and another common form of invasive skin cancer, basal cell carcinoma together with the mitogenic marker-proliferating cell nuclear antigen. Here, we have employed DNAzymes (catalytic DNA molecules) targeting c-Jun (Dz13) to inhibit c-Jun expression in SCC cells. Dz13 inhibits SCC proliferation and suppresses solid SCC tumor growth and tumor angiogenesis in severe combined immunodeficient mice. We further demonstrate that Dz13 inhibits c-Jun, together with matrix metalloproteinase (MMP)-2 and MMP-9 expression in the tumors, consistent with DNAzyme inhibition of MMP-2 and MMP-9 gelatinolytic activity by zymography. Dz13 also suppressed the expression of vascular endothelial growth factor and fibroblast growth factor-2 in the tumors. These findings demonstrate that c-Jun regulates SCC growth and suggest that DNAzymes targeting this transcription factor may potentially be useful as inhibitors of cutaneous carcinoma.

Histologic assessment of equivocal cytologic smears.

OBJECTIVE: To determine if the conversion of equivocal cytologic smears into histologic sections would provide additional diagnostic information in those cases in which it was difficult to obtain additional cytologic samples. STUDY DESIGN: Over a year, eight equivocal cytologic smears were converted to histologic sections by removing the coverslips, rehydrating the smears, scraping off the smears into centrifuge tubes, making cell blocks, and sectioning and staining the blocks. RESULTS: The histologic sections enabled cell patterns to be studied and special staining (including immunoperoxidase studies) to be performed. In the eight cases studied, the additional information provided by histology led to a definitive diagnosis in six (75%). CONCLUSION: When cytologic findings are equivocal and it is difficult to obtain additional cytologic samples, conversion of the smears into histologic sections may provide additional information for diagnosis.

The changing face of pathology in Australia: implications for public and private services.

Dramatic changes in pathology services in Australia over the past few decades have radically altered the way the discipline is practised. Although these developments are not unique to Australia, the recent pace of change in this country has been particularly rapid. It is time to reflect on the course of events, examine the issues and (possibly) predict the future.

Problems in the histological assessment of hydatidiform moles: a study on consensus diagnosis and ploidy status by fluorescent in situ hybridisation.

Hydropic villi in products of conception continue to pose a diagnostic problem for the anatomical pathologist. It is important to distinguish between complete hydatidiform mole (CM), partial hydatidiform mole (PM) and hydropic degeneration (HD), as hydatidiform moles (especially CM) have a tendency to develop persistent trophoblastic disease. Several studies have demonstrated interobserver variability in the diagnosis of the three conditions, but there have been no studies testing the accuracy of the consensus diagnosis of pathologists experienced in the field. In this study four anatomical pathologists with experience in diagnosing hydatidiform moles selected five cases of HD, seven cases of PM and ten cases of CM on the basis of consensus diagnosis using established criteria. Ploidy studies were done on these 22 cases using fluorescent in situ hybridisation. The 15 cases of HD and CM were diploid, confirming the histological diagnosis. However only five of the seven cases of PM were triploid, the other two being diploid. Review of these two diploid cases showed a mixture of small and large villi with moderate to marked trophoblastic proliferation. On the basis of the significant trophoblastic proliferation and the DNA information, the two cases were reclassified as early complete moles. This study demonstrates that even pathologists experienced in the field have difficulty separating PM from CM. The findings suggest that, in the absence of DNA information, a lesion with hydropic villi showing moderate to marked trophoblastic proliferation should be classified as a complete mole, even if there is a mixture of small and large villi. Ploidy studies are an important adjunct to histological diagnosis, especially when there is an overlap of features.

Combined cytological and histological diagnosis of hepatocellular carcinoma in ultrasonically guided fine needle biopsy specimens.

This study evaluates the usefulness of a combined cytological and histological approach to the diagnosis of hepatocellular carcinoma (HCC) when applied to fine needle biopsy specimens obtained under ultrasonic guidance. The material, aspirated from 51 focal liver lesions, was handled in such a way that there was sufficient material for both cytological and histological (cell block) assessment. Of the 29 cases of HCC studied, a confident cytological diagnosis was made in 23 (79%). In the remaining six cases, the cytological features were considered to be suspicious but not diagnostic of HCC. Examination of cell blocks in the six cases enabled a confident diagnosis of HCC to be made in all cases. This was due to the supplementary visual information provided by the histological features, particularly the pattern of arrangement of the tumour cells.

Concomitant mucinous tumors of appendix and ovary. Result of a neoplastic field change?

BACKGROUND: Mucinous tumors of the appendix and ovary are known to occur together in association with pseudomyxoma peritonei. It has been postulated that this association may be attributable to the development of independent tumors or to metastasis from one site to another. METHODS AND RESULTS: This article reports two patients with concomitant mucinous ovarian and appendiceal tumors in the absence of pseudomyxoma peritonei. CONCLUSIONS: The evidence suggests that these tumors are independent primary neoplasms that develop as a result of neoplastic field change that affects colonic-type epithelium.

Pharmacologic nephrectomy with chronic angiotensin converting enzyme inhibitor treatment in renovascular hypertension in the rat.

Angiotensin converting enzyme (ACE) inhibitor treatment in renovascular hypertension is associated with acute compromise of renal function in patients with bilateral renal artery stenosis or with arterial stenosis to a single functioning kidney. Recent evidence has suggested that renal function is also compromised in the stenosed kidney of patients with unilateral renal artery stenosis. The long-term consequence of this reduction in renal function is not known. We have studied the effect of chronic ACE inhibition with enalapril on renal structure and function in rats with the two-kidney one-clip model of renovascular hypertension. Four weeks after placement of a clip on the left renal artery, hypertensive rats were randomized to treatment with enalapril, minoxidil, or to a no treatment group. Twelve months later split kidney function was determined by chromium 51-labeled ethylenediamine-tetraacetic acid clearance in surviving rats. Clearance of the clipped kidney was 0.0 ml/min (enalapril group), 0.26 +/- 0.23 ml/min (minoxidil group), and 0.74 +/- 0.13 ml/min (untreated group). The clipped kidney from the enalapril treated rats weighed much less than the minoxidil group or the untreated group (0.46 +/- 0.1 gm, 1.2 +/- 0.07 gm, and 1.14 +/- 0.10 gm, respectively). Enalapril treatment was stopped for 2 weeks in five rats. The clipped kidney remained small and nonfunctional. Histologic examination revealed marked interstitial fibrosis and tubular atrophy of the clipped kidneys from the enalapril treated group in contrast to minor changes in the minoxidil treated and untreated groups. After 12 months of treatment, survival in the enalapril group was 84%, 48% in the minoxidil group, and 15% in the untreated group.(ABSTRACT TRUNCATED AT 250 WORDS)

An assessment of the value of frozen sections in gynecological surgery.

In 203 consecutive gynecological operations where frozen sections were performed, 35.6% were from conditions of the ovary, 22.7% from the cervix, 18.2% from the endometrium, and 11.4% from the vulva. There were 0.5% false-positive, 1.0% false-negative and 2.0% deferred diagnosis. Incorrect interpretation was the cause of the single false-positive diagnosis, while the false-negative diagnoses were due to errors in block selection. The deferred diagnoses mainly occurred in gynecological conditions where diagnosis was difficult, required extensive sampling or a formal mitotic count. As in other surgical fields, gynecological frozen sections were used principally to guide the extent of surgery. The most valuable frozen sections were in those instances where the operation was affected most. These were on lymph nodes in cases of carcinoma of the vulva and cervix, myometrial lesions in young women where myomectomy was being considered, and ovarian tumours to distinguish primary from secondary tumours. Occasionally, frozen sections were also found useful to establish margins of vulval and cervical tumours, in hysterectomy specimens of endometrial carcinomas to determine prognostic factors, and in suspected recurrences and metastases of tumours to determine the adequacy of the biopsy material. Frozen sections in obviously benign conditions, e.g., ovarian cysts without papillary or solid areas, were found to be unnecessary. Frozen sections are contraindicated when only a small amount of crucial material is available, as the paraffin diagnosis may be compromised. Pathologists should have a clear idea of the role of frozen sections in gynecological surgery and work closely with the surgeon in the management of gynecological oncology patients.

Cardiac 3,4-dihydroxyphenylethylene glycol (DHPG) and catecholamine levels during perindopril therapy of chronic left ventricular failure in rats.

1. Left ventricular myocardial infarction was induced in female Wistar rats by ligation of the left anterior descending coronary artery. 2. One month following operation, rats with infarcts developed marked cardiomegaly compared to sham operated rats, indicating the presence of chronic left ventricular failure. 3. The ratio of the noradrenaline metabolite 3,4-dihydroxyphenylethylene glycol (DHPG) to noradrenaline (NA) was elevated in the right ventricle of rats with heart failure one month following infarction, suggesting a chronic increase in cardiac sympathetic activity. 4. Perindopril therapy for one month commenced 4 weeks after infarction returned cardiac weights to normal and significantly reduced right ventricular DHPG/NA ratios. 5. The results suggest that ACE inhibition with perindopril reduces elevated levels of cardiac sympathetic activity in rats with chronic left ventricular failure and leads to regression of cardiomegaly.

Chronic angiotensin converting enzyme inhibition in the two-kidney, one clip hypertensive rat.

Treatment with an angiotensin converting enzyme (ACE) inhibitor in renovascular hypertension produces acute effects on renal function; however, the long-term consequences of this are not known. We have studied the effect of chronic enalapril treatment on renal structure and function in the two-kidney, one clip model of renovascular hypertension in the rat. Four weeks after the left renal artery was clipped, the hypertensive rats were randomly allocated to treatment with enalapril, minoxidil or to no treatment. The drug dose was titrated for maximal hypotensive effect. After 4 months of treatment blood pressures were 129 +/- 3 mmHg (enalapril), 193 +/- 5 mmHg (minoxidil) and 220 +/- 4.8 mmHg (no treatment). Twelve months later survival was 84% (enalapril group), 48% (minoxidil group) and 15% (untreated group). Split kidney function (51Cr-EDTA clearance, ml/min) of the clipped kidneys was 0.0 (enalapril group), 0.26 +/- 0.23 (minoxidil group) and 0.74 +/- 0.13 (untreated group). The clipped kidney from enalapril-treated rats weighed 0.46 +/- 0.1 g, much less than in the minoxidil-treated group (1.2 +/- 0.07) or the untreated group (1.14 +/- 0.10). Enalapril treatment was withdrawn for 2 weeks in five rats, but the clipped kidney remained small and non-functional. Histological examination revealed marked interstitial fibrosis and tubular atrophy in clipped kidneys from both enalapril groups, in contrast to minor changes in the minoxidil-treated and the untreated groups. We conclude that chronic enalapril treatment of two-kidney, one clip hypertension in the rat improved survival and preserved total renal function, but was associated with irreversible fibrotic atrophy of the clipped kidney.

Cardiac hypertrophy and salt status in chronic myocardial infarction in the rat: effects of enalapril versus salt restriction.

The effects of salt restriction and the ACE inhibitor enalapril were compared in a model of chronic myocardial infarction in the rat. Total exchangeable sodium was measured by an isotopic dilution technique to quantitate the effects of the low salt diet and ACE inhibitor on body sodium and extracellular fluid. Rats with infarction developed a marked increase in cardiac weight (4.29 +/- 0.18 mg/g body weight) compared with control rats (3.64 +/- 0.08 mg/g, p less than 0.01). There was hypertrophy of both left and right ventricles. Salt restricted rats with infarction developed identical cardiomegaly (4.30 +/- 0.11 mg/g), although total exchangeable body sodium fell by 10% (p less than 0.001). In contrast, rats with infarction receiving enalapril developed significantly less cardiomegaly (3.97 +/- 0.10 mg/g) while body sodium remained unchanged. Rats with infarction had a significant increase in lung weight which was not changed by salt restriction but which was abolished by enalapril. These results suggest that salt restriction does not prevent the progression of cardiomegaly in chronic left heart failure. In contrast our results confirm the ability of ACE inhibitors to prevent progressive cardiomegaly and left heart failure without affecting long-term changes in sodium balance.

Neurohumoral responses to chronic myocardial infarction in rats.

In chronic cardiac failure, various neurohumoral mechanisms are activated to sustain blood volume, blood pressure, and organ perfusion. Using the coronary artery ligation model of heart failure in the rat, we have measured changes in vasoactive hormone secretion and related these changes to salt and water status during a 1-month period. When compared with controls, rats with infarction had a marked rise in plasma atrial natriuretic peptide (294 +/- 59 vs. 79 +/- 10 pg/ml, p less than 0.001) although there was no increase in total exchangeable body sodium. Plasma renin activity and plasma aldosterone concentrations were the same for both rats with infarction and controls. Similarly, there were no significant differences in plasma arginine vasopressin, plasma osmolality, or plasma sodium concentration in rats with infarction. Ventricular norepinephrine levels were reduced in animals with infarction (p less than 0.01). Plasma atrial natriuretic peptide levels were raised in this model of chronic left ventricular failure. However, there was no salt retention and little stimulation of the renin-angiotensin-aldosterone system or vasopressin. The results suggest that high circulating atrial natriuretic peptide levels may prevent or limit salt and water retention, either directly or indirectly, by inhibiting the renin-angiotensin-aldosterone system.

Atrial natriuretic peptide and total exchangeable body sodium: relationships in rats with chronic myocardial infarction.

1. The relationship between plasma atrial natriuretic peptide (ANP) and body sodium was determined in rats 1 month after myocardial infarction induced by coronary artery ligation. After operation rats received a normal or a low salt diet, and total exchangeable body sodium was measured sequentially. 2. Rats with infarction receiving a normal salt intake did not retain sodium when compared with sham-operated controls. Rats receiving a low salt diet had a 10% decrease in body sodium (P less than 0.01). The decrease was the same in rats with infarction as in controls. 3. Plasma ANP was similar in control rats irrespective of salt status. Plasma ANP levels were markedly elevated in rats with infarction irrespective of salt status (P less than 0.01). 4. The rise in plasma ANP was correlated with cardiac hypertrophy and infarct size in animals fed both normal and low salt diets. However, there was no relationship between plasma ANP and exchangeable body sodium. 5. These results suggest that in this model of heart failure plasma ANP is raised by increased left atrial stretch in proportion to the severity of left ventricular dysfunction. In contrast, plasma ANP concentrations do not appear to be elevated as a consequence of increased right atrial pressure caused by sodium retention and expanded extracellular volume.

Morphologic differences in the pattern of liver infiltration between systemic AL and AA amyloidosis.

Biopsy and necropsy tissue from 31 unselected patients with systemic amyloidosis, in which there was histologic evidence of liver involvement, were reviewed with reference to the location and pattern of amyloid deposition in the liver. Amyloidosis was classified into AA and AL types on the basis of immunohistochemistry and permanganate reaction of the amyloid deposits. Nineteen were categorized as AA (secondary) and 12 as AL (primary) amyloidosis. Deposition of AA amyloid was limited to the walls of vessels in the portal tract, constituting a "vascular" pattern. In AL amyloidosis, the deposits exhibited a "sinusoidal" pattern in that they were seen along hepatic sinusoids as well as in vessel walls. This difference was statistically significant (P less than .001). The histologic pattern of liver infiltration offers a valuable clue in the classification of systemic amyloidosis and provides information that may be useful in the selection of patients for therapy.

The prognostic significance of grading in borderline mucinous tumors of the ovary.

Fifty-three stage I borderline mucinous tumors of the ovary were placed into four histologic grades according to a simple system of grading based on degree of cell layering, nuclear characteristics, and mitotic count. Three patients died of recurrence and spread of their tumors. All three patients had grade 4 tumors, suggesting that there may be some prognostic value in grading borderline mucinous ovarian tumors.

The enhancement of aminonucleoside nephrosis by the co-administration of protamine.

An experimental model of focal segmental glomerular sclerosis (FSGS) was developed in rats by the combined administration of puromycin-aminonucleoside (AMNS) and protamine sulfate (PS). Male Sprague-Dawley rats, uninephrectomized three weeks before, received daily injections of subcutaneous AMNS (1 mg/100 g body wt) and intravenous PS (2 separated doses of 2.5 mg/100 g body wt) for four days. The series of injections were repeated another three times at 10 day intervals. The animals were sacrificed on days 24, 52, and 80. They developed nephrotic syndrome and finally renal failure. The time-course curve of creatinine clearance dropped and showed significant difference (P less than 0.01) from that of each control group, such as, AMNS alone, PS alone or saline injected. Their glomeruli showed changes of progressive FSGS. The ultrastructural studies in the initial stage revealed significant lack of particles of perfused ruthenium red on the lamina rara externa and marked changes in epithelial cell cytoplasm. Therefore, it is suggested that the administration of PS enhances the toxicity of AMNS on the glomerulus and readily produces progressive FSGS in rats resulting in the end-stage renal disease.

Ovarian ectopic pregnancy--a diagnostic dilemma.

A recent case of ovarian pregnancy, the diagnosis of which is often retrospective, is presented. The discussion is based on current literature concerning the diagnostic difficulties associated with this condition.

Sarcomatous change in granulosa cell tumor.

Granulosa cell tumors have a tendency for indolent growth and late recurrence. The present case of granulosa cell tumor in a 67-year-old woman is the first, to the authors' knowledge, to be reported as showing sarcomatous transformation with a rapid fatal course. Both the granulosa cell and fibrothecomatous elements appear to have undergone sarcomatous change with some evidence to suggest rhabdomyosarcomatous differentiation. The sarcomatous component was present in metastatic deposits.