Nanostrain sensitivity in a wire torsion experiment.

The feasibility of a thin-wire torsion stress-strain experiment with nanostrain sensitivity is demonstrated. A gauge length of 50 m was made possible by using The Monument, London, thereby restoring it to its original purpose as a scientific instrument. A wire of 150 µm diameter was studied using the load-unload method, and data were recorded in the elastic regime and through the elastic-plastic transition. Analysis of this preliminary experiment suggested some necessary improvements to the equipment and methods. Progress towards definitive experiments is described together with difficulties still to be overcome.

A conical slit for three-dimensional XRD mapping.

Traditionally, depth resolution in diffraction experiments is obtained by inserting pinholes in both the incoming and diffracted beam. For materials science investigations of local strain and texture properties this leads to very slow data-acquisition rates, especially when characterization is performed on the level of the individual grains. To circumvent this problem a conical slit has been manufactured by wire-electrodischarge machining. The conical slit has six 25 microm-thick conically shaped openings matching six of the Debye-Scherrer cones from a face-centred-cubic powder. By combining the slit with a microfocused incoming beam of hard X-rays, an embedded gauge volume is defined. Using a two-dimensional detector, fast and complete information can be obtained regarding the texture and strain properties of the material within this particular gauge volume. The average machining and assemblage errors of the conical slit are found both to be of the order of 5 microm. An algorithm for alignment of the slit is established, and the potential of the technique is illustrated with an example of grain mapping in a 4.5 mm-thick Cu sample.

Horner's syndrome: a rare presentation of cervical sympathetic chain schwannoma.

We describe a cervical sympathetic chain schwannoma in a 77-year-old woman who presented with a neck mass and Horner's syndrome. Such schwannomas are rare and this is the first documented case of a Horner's syndrome at presentation. The mass was excised via a cervical approach and her post-operative course was uneventful. The prognosis is excellent, with recurrence being rare. A brief discussion of the pathology, presentation, diagnosis, and treatment of this condition is made in this paper. The relevance of the uncertainty in diagnosis is discussed with the message that a pre-operative Horner's syndrome may guide the surgeon in the care of the patient but we suggest that in all cases proper counselling of the possible neurological consequences of this surgery be conducted.

L-Arginine, nitric oxide, and intestinal secretion: studies in rat jejunum in vivo.

BACKGROUND: L-Arginine has been shown to induce fluid secretion in human jejunum. Nitric oxide, a derivative of L-arginine is thought to have an important role as an intestinal secretagogue. AIM: To determine the effect of L-arginine and the nitric oxide synthase inhibitor, nitro L-arginine methyl ester (L-NAME), on fluid and electrolyte movement in rat jejunum. METHODS: A 25 cm segment of rat jejunum was perfused in situ with iso-osmotic solutions containing either (1) saline, (2) D-arginine 20, (3) L-arginine 20, (4) L-NAME 0.1, 1, or 20 mmol/l, or (5) a combination of L-arginine 20 and L-NAME 0.1, 1, or 20 mmol/l. In further groups the effect of a subcutaneous injection of L-NAME 100 mg/kg was examined in rats pretreated with either D-or L-arginine 500 mg/kg. RESULTS: L-Arginine, unlike D-arginine, induced fluid secretion despite being better absorbed (mean -7.3 v 17.0 microliters/min/g; p < 0.01). L-NAME at 0.1 mmol/l had no effect on basal fluid movement but reversed L-arginine induced secretion (7.8; p < 0.05). L-NAME at 1 and 20 mmol/l induced fluid secretion (-15.4 and -28.4, respectively), which was enhanced by the addition of L-arginine (-30.0 and -41.0, respectively; both p < 0.05). A subcutaneous injection of L-NAME resulted in marked fluid secretion (-39.9) and histological evidence of intestinal ischaemia. These changes were attenuated or reversed by pretreatment with subcutaneous L- but not D-arginine. CONCLUSIONS: L-arginine induces intestinal fluid secretion through production of nitric oxide. There is a delicate balance between the effect of nitric oxide as a secretagogue and its effect on maintaining blood flow and thus preventing intestinal ischaemia.

The morphology of juxtaglomerular cell hyperplasia and hypertrophy in normotensive rats and monkeys given an angiotensin II receptor antagonist.

L-694,492 (DUP 532), an angiotensin II (AII) receptor antagonist, was given orally at 125 mg/kg/day to rats and monkeys for up to 6 mo to assess the effects of the compound on juxtaglomerular (JG) cells. In rats, mild JG cell hypertrophy/hyperplasia occurred and was associated with a 12-fold increase in the bromodeoxyuridine-labeling index of JG cells and a 10-fold increase in renal renin content. Ultrastructurally, intermediate cells with characteristics of both smooth muscle cells and granulated renin-producing cells as well as hypertrophied renin-synthesizing cells were seen in the afferent arterioles. In monkeys, marked hypertrophy and hyperplasia were seen with an 80% increase in JG cell numbers, mitotic activity, and a greatly increased renin content compared to controls. Three mo after drug withdrawal, an increased number of cells remained, which showed features of smooth muscle cells with essentially no renin. These results show that AII receptor antagonism stimulates increased renal renin production by hypertrophy of existing granulated cells, metaplasia of smooth muscle cells to renin-synthesizing cells, and cell proliferation. When treatment was discontinued, the renin-producing cells redeveloped the features of smooth muscle, but, as we have shown with enalapril (angiotensin-converting enzyme inhibitor), the increase in their number persists for at least 3 mo.

The morphology of juxtaglomerular cell hyperplasia and hypertrophy in normotensive rats and monkeys given an angiotensin II receptor antagonist.

L-694,492 (DUP 532), an angiotensin II (AII) receptor antagonist, was given orally at 125 mg/kh/day to rats and monkeys for up to 6 mo to assess the effects of the compound on juxtaglomerular (JG) cells. In rats, mild JG cell hypertrophy/hyperplasia occurred and was associated with a 12-fold increase in the bromodeoxyuridine-labeling index of JG cells and a 10-fold increase in renal renin content. Ultrastructurally, intermediate cells with characteristics of both smooth muscle cells and granulated renin-producing cells as well as hypertrophied renin-synthesizing cells were seen in the afferent arterioles. In monkeys, marked hypertrophy and hyperplasia were seen with an 80% increase in JG cell numbers, mitotic activity, and a greatly increased renin content compared to controls. Three mo after drug withdrawal, an increased number of cells remained, which showed features of smooth muscle cells with essentially no renin. These results show that AII receptor antagonism stimulates increased renal renin production by hypertrophy of existing granulated cells, metaplasia of smooth muscle cells to renin-synthesizing cells, and cell proliferation. When treatment was discontinued, the renin-producing cells redeveloped the features of smooth muscle cells, but, as we have shown with enalapril (augioteusin-converting enzyme inhibitor), the increase in their number persists for at least 3 mo.

Juxtaglomerular cell hypertrophy and hyperplasia induced in rhesus monkeys by angiotensin II receptor antagonists.

BACKGROUND: Juxtaglomerular (JG) cell hypertrophy and hyperplasia were investigated in rhesus monkeys given angiotensin II (AII) AT1 receptor antagonists L-158,338 and DUP 753 (MK-0954, losartan). EXPERIMENTAL DESIGN: In 2 initial studies, L-158,338 was given orally at 10, 30, and 90 mg/kg/day for 3 or 14 weeks. To investigate the observed JG hypertrophy and hyperplasia, in a third 5-week experiment L-158,338 was given alone at 90 mg/kg/day, or with physiologic saline supplementation at 25 ml/kg/day, or coadministered with the angiotensin converting enzyme inhibitor enalapril at 10 mg/kg/day. Physiologic saline was given to attempt to suppress renin release through volume expansion and/or sodium retention. Enalapril was given to lower plasma AII levels and observe whether JG cell hypertrophy and hyperplasia were increased or decreased. For comparison, DUP 753 was given at 90 and 300 mg/kg/day. Plasma renin activity and AII concentration were measured in this study. RESULTS: Dose- and time-dependent increases in JG cell hypertrophy and hyperplasia were seen in the 2 initial experiment. In the third experiment, plasma renin activity and AII concentration were increased 3-fold and 6-fold over pretest values by L-158,338 at 90 mg/kg/day for 5 weeks. Saline supplementation had no effect on these parameters but diminished the group mean severity grade for JG hypertrophy and hyperplasia from 1.5 to 1.0. Enalapril coadministration had no effect on plasma renin activity, whereas it blunted the plasma AII increase caused by L-158,338 and increased the group mean grade to 2.5. DUP 753 at 300 mg/kg/day produced similar increases in plasma renin activity and AII concentration but only resulted in grade 1 JG cell hypertrophy and hyperplasia. CONCLUSIONS: L-158,338-induced JG cell hypertrophy and hyperplasia is an exaggerated pharmacologic response that can be modulated by saline supplementation and angiotensin converting enzyme inhibition. These results suggest that decreased renal perfusion or altered sodium homeostasis and plasma AII concentration are important variables that contribute to AT1 receptor blockade to induce JG cell hypertrophy and hyperplasia.

Acid secretion from a Meckel's diverticulum: the unsuspected mimic of Crohn's disease?

The commonest causes of ulceration in the terminal ileum are Crohn's disease, infection, and neoplasia. Meckel's diverticulum is said to be found more commonly in patients with Crohn's disease than in the general population. We describe a patient who developed extensive terminal ileal ulceration caused by acid secretion from gastric mucosa within a Meckel's diverticulum, a condition that has not been recognized before. Our patient demonstrated a number of clinical features that would be consistent with Crohn's disease, and we wonder whether the rare condition of "Meckel's ileitis" is occasionally misdiagnosed as Crohn's disease in other patients.

Association between Meckel's diverticulum and Crohn's disease: a retrospective review.

The operation notes and pathology records of 294 consecutive patients who had right hemicolectomy for Crohn's disease were reviewed. A Meckel's diverticulum was found in 17 (5.8%) of these patients, 2-3 times the expected rate in the general population. At least 50% of diverticula in the normal population contain heterotopic mucosa, but none was found in those diverticula that were examined from this group. The increased prevalence of Meckel's diverticulum in patients with Crohn's disease confirms previous anecdotal reports, but the cause for the increased frequency remains unexplained. The significance of this finding is discussed.

Renal papillary cytoplasmic granularity and potassium depletion induced by carbonic anhydrase inhibitors in rats.

Renal papillary cytoplasmic granularity (RPCG) induced by carbonic anhydrase inhibitors (CAIs) in rats is characterized by the accumulation of dense secondary lysosomes in epithelial, endothelial, and interstitial cells and may be related to drug-induced potassium depletion. Female Sprague-Dawley rats were given the CAI, acetazolamide, by gavage. Half were supplemented with 1% potassium chloride in the drinking water. Two treated groups were allowed to recover for 1 or 2 mo. Potassium supplementation inhibited RPCG by 80% but produced little amelioration of the mild 13% decrease in serum potassium induced by 200 mg/kg/day acetazolamide for 28 days. Acetazolamide-induced RPCG is reversible because 1- and 2-mo recovery periods decreased the incidence by 75% and 80%, respectively. The results support the hypothesis that RPCG is related to potassium depletion secondary to carbonic anhydrase inhibition. Because supplementation of potassium chloride had little effect on serum potassium, these data suggest that depletion of renal medullary potassium content is important in the pathogenesis of RPCG as previously suggested by others. Other types of diuretics that produce hypokalemia as a side effect may not deplete medullary potassium since RPCG has not been reported in humans or animals given these drugs.

Primary lymphoma of the small intestine. A clinicopathological study of 119 cases.

Small bowel lymphomas account for 20 to 40% of primary gut lymphomas in Western populations and are among the most common malignant tumours of the small bowel. We studied 119 cases of primary small bowel lymphoma presenting over 4 decades. Two thirds of the patients were men with a peak age incidence in the 7th decade. Common presenting features included abdominal pain, weight loss, small bowel obstruction, and acute abdomen. Tumours were classified using the Kiel European Association for Haematopathology Geneva Workshop scheme and phenotyped on paraffin sections; 66% were B cells, and 34% were T cell. In all cases, the antibodies L26 and polyclonal CD3 reliably distinguished between B- and T-cell tumours. Of the B-cell lymphomas, 62% were diffuse high grade, 20% were low-grade lymphomas of mucosa-associated lymphoid tissue, 11% had both low- and high-grade components, and 7% were other low-grade types. Of the T-cell lymphomas, 83% were high grade, and 49% were enteropathy associated. Most T-cell lymphomas were ulcerated plaques or strictures in the proximal small bowel; B-cell lymphomas tended to be annular or polypoid masses in the distal and terminal ileum. Survival data showed that low-grade B-cell lymphomas had the best outcome and T-cell lymphomas the worst. Adverse prognostic features included perforation, high-grade histology, multiple tumours and advanced stage.

High frequency of K-ras mutations in sporadic colorectal adenomas.

The frequency of activating mutations at codons 12 and 13 of the K-ras gene was investigated in 57 sporadic adenomas from 47 patients using the polymerase chain reaction and oligonucleotide hybridisation assay. Sixty eight per cent of the adenomas tested were positive for K-ras mutations. This high frequency, combined with the lack of a correlation between mutations and adenoma size, suggest that K-ras mutations occur earlier in the adenoma-carcinoma sequence than has previously been suggested. The high frequency observed in sporadic adenomas contrasts with the reported low frequency (18%) in adenomas from patients with familial adenomatous polyposis (FAP), suggesting a possible difference in the molecular genesis of FAP and non-FAP adenomas. Finally, it was found that adenomas from patients with a personal history of colorectal cancer were more likely to contain a K-ras mutation than those from patients with no such history. This is a new finding and worthy of further study.

Successful treatment of a primary endodermal sinus tumor of the liver.

A 27-year-old woman had a large hepatic tumor and a markedly increased serum alpha-fetoprotein (AFP) level. A diagnosis of endodermal sinus tumor was made after a needle biopsy was performed on the liver. Clinical and radiologic examinations did not show an alternative primary site. Treatment with cisplatin, etoposide, and bleomycin was started, but, after three cycles, was changed to cisplatin, vincristine, methotrexate, bleomycin, dactinomycin, cyclophosphamide, and etoposide because the serum AFP level was decreasing too slowly. After additional chemotherapy was given, the patient was well but had an increased AFP level and a large residual mass in the liver. A right hemihepatectomy was performed, but no viable tumor was present. The patient is alive and disease-free 5 years later. Thus, AFP levels may be misleading in the presence of large necrotic tumors. The authors stress the need to make a diagnosis of these rare tumors early because aggressive treatment with combination chemotherapy may result in cure.

Urothelial hyperplasia induced by carbonic anhydrase inhibitors (CAIs) in animals and its relationship to urinary Na and pH.

Investigations of MK-0927 and acetazolamide, both carbonic anhydrase inhibitors (CAIs), showed that urothelial hyperplasia develops in rats and mice, but not in rabbits, dogs, or monkeys. Rats given MK-0927 orally had a rapid onset of the change which regresses often completely despite continued treatment. Increased urinary pH and Na excretion, pharmacologic effects of CAIs, tended to be correlated with lesions. Rats given MK-0927 orally and fed either a 5% potassium phosphate meal or a 5% ammonium chloride meal had reduced urinary pH and/or urinary Na excretion and a reduced incidence of urothelial hyperplasia. Rats given MK-0927 orally and fed a low Na diet had very low urinary Na and essentially no urothelial hyperplasia. It was concluded that a clear relation exists between increased urinary Na excretion and pH, and urothelial hyperplasia induced by CAIs. These results in rats confirm the importance of increased Na and pH as stimuli for the development of urothelial hyperplasia.

Rat urinary bladder hyperplasia induced by oral administration of carbonic anhydrase inhibitors.

The carbonic anhydrase inhibitors, acetazolamide and MK-0927, were given by oral route to male Sprague-Dawley rats at 200 mg/kg/day and 25 mg/kg/day, respectively, for up to 4 weeks. Sequential necropsies were performed and urinary bladders were examined by light microscopy (LM), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Similar urinary bladder changes were seen with both compounds. SEM evidenced slight multifocal urothelial changes consisting of cell swelling, dissociation, degeneration, and exfoliation after 3 and 5 days of treatment. After 2 and 4 weeks of treatment, elevated or leafy microridges on the luminal cell surfaces were seen together with foci of swollen cells. After a 2-month-recovery-period, the urothelial surfaces were normal. LM and TEM showed multifocal vacuolation of the urothelium associated with inflammation of the underlying lamina propria after 3 and 5 days of treatment. Cellular hypertrophy and hyperplasia of the transitional epithelium was seen after a 5-day treatment, persisted without increasing severity after 2 and 4 weeks of treatment, and totally regressed after the recovery period. It was concluded that, in the rat urinary bladder, oral administration of acetazolamide and MK-0927 induced early degeneration and inflammation followed by epithelial regeneration, resulting in a reversible hyperplasia of the transitional epithelium.

An intragenic region downstream from the dihydrofolate reductase promoter is required for replication-dependent expression.

The gene encoding dihydrofolate reductase (DHFR) is down-regulated as myoblasts withdraw from the cell cycle and commit to terminal differentiation. To localize cis-acting elements involved in regulating DHFR gene expression, the DHFR promoter and upstream region, together with differing amounts of contiguous intragenic sequence, were fused to the bacterial chloramphenicol acetyltransferase (CAT) gene. The resulting fusion genes were stably transformed into muscle cells, and CAT mRNA levels were measured in proliferative myoblasts and committed myocytes. A gene consisting of the -850/+465 region of DHFR (numbers refer to distance in base pairs from transcription initiation site) fused to CAT was efficiently expressed in proliferating myoblasts and was appropriately down-regulated during commitment. A gene consisting of the -850/+60 region of DHFR fused to CAT was poorly expressed in proliferating myoblasts and was not down-regulated during commitment. When inserted between the Rous sarcoma virus promoter and CAT sequence of RSVpCAT, the +61/+465 region of the DHFR gene augmented CAT mRNA expression in muscle cell transformants but did not confer a regulated pattern of expression. Our data indicate that DHFR sequences between +60 and +465 are required but are not sufficient for replication-dependent expression. The DHFR sequences may be operating at either a transcriptional or posttranscriptional level.

Caecal intussusceptions in horses and the significance of Anoplocephala perfoliata.

A caecocaecal intussusception in a pony and a caecocolic intussusception in a horse, both infected with Anoplocephala perfoliata, are described and the relevance of tapeworms in such intestinal disease of horses is reviewed.

The varied appearances of starch particles in smears and paraffin sections.

Evidence is presented to show that maize starch particles, usually recognized in histological sections by their Maltese cross birefringence under cross-polarized light, lose this characteristic appearance when transected by the microtome blade. Such particles are, therefore, likely to be overlooked. Though maize starch usually enters the abdomen during surgery, the female genital tract is another possible route from sources such as contraceptive devices. Other types of starch particle have different shapes, sizes and surface markings and these may be distinguished from maize starch by light and electron optical methods.