Death following rapidly progressive demyelinating disorder in a young female-a case report.

Multiple sclerosis (MS) is a debilitating, demyelinating disease of the central nervous system, with manifestations ranging from numbness and blindness to paralysis. Typical MS is a slowly progressive demyelinating disease, causing significant morbidity spanning over many years. In contrast, "Marburg's disease" is a rare variant of MS which demonstrates a malignant monophasic disease progression leading to death within weeks to months. We present a rapidly fatal demyelinating disease with the clinicopathological findings on par with the handful of reported cases of "Marburg's disease" in the literature. A previously healthy 30-year-old mother of two children was extensively investigated for focal neurological signs succumbing to death 5 weeks after the onset. Antemortem investigations for tuberculosis, autoimmune diseases, and viral studies were negative. Magnetic resonance imaging of the brain showed hyperintense lesions with contrast enhancement compatible with MS. Histopathologic examination confirmed numerous inflammatory and demyelination foci scattered throughout the brain and brain stem predominantly involving the white matter. There were extensive perivascular inflammatory cell cuffs containing lymphocytes admixed with histiocytes. Also, a few foci of vasculitis with fibrinoid necrosis, mediated by lymphocytes and neutrophils were noted associated with parenchymal haemorrhages. Considered a rare variant of MS, the case of Marburg's disease presented here shows an infrequent association with active vasculitis and haemorrhage, described only a few times in the literature. This wide spectrum of rapidly fatal demyelinating diseases consisting of rare variants with overlapping clinicopathological features makes diagnosis challenging. Therefore, it is important to correlate clinical-radiological and histopathological findings to arrive at an accurate final diagnosis.

Laparoscopic Resection of Pancreatic Tail Solid Pseudopapillary Tumour in a Young Male.

Background. Solid Pseudopapillary Tumours of the pancreas are a rare entity and more commonly seen in women than in men. These tumours have typically reached large sizes when clinically detected. Case Description. A 21-year-old male was found to have a left hypochondrial mass on physical examination following a trivial soft tissue injury. Contrast-enhanced computed topography (CT) of the abdomen showed a 10.3 × 7.6 × 10.3 cm size arising from the body and the tail of the pancreas. He underwent laparoscopic resection of distal pancreatic tumour en bloc with spleen. Large tumour was noted originating from the body and tail of the pancreas with dilated veins surrounding the tumour. Histology revealed a clear cell variant of solid pseudopapillary neoplasm with steatotic pattern. Resection margin was free of tumour. Discussion. Several studies have shown significant short term advantages using laparoscopic approach compared to open surgery, in terms of lower blood loss, resumption of oral intake, and hospital stay. This case and few other case reports published in world literature have shown that laparoscopic approach is safe and oncologically adequate.

Pathological characteristics of fifty patients with renal amyloidosis in Sri Lanka

Renal involvement is the most important cause of morbidity and mortality in systemic amyloidosis. This retrospective analysis was conducted to analyse the clinico-pathological characteristics of renal amyloidosis in a group of Sri Lankan patients undergoing renal biopsy. Renal amyloidosis was observed in 50/ 9712 (0.5%) renal biopsies. The underlying cause for amyloidosis was not known in most. Of the known causes multiple myeloma was the commonest. Nephrotic range proteinuria was the most common clinical outcome and most had grade I to III chronic kidney disease at the time of diagnosis. Glomerulosclerosis was associated with the deterioration of renal function.

Star fruit toxicity: a cause of both acute kidney injury and chronic kidney disease: a report of two cases.

BACKGROUND: Star fruit (Averrhoa carambola) is commonly consumed as a herbal remedy for various ailments in tropical countries. However, the dangers associated with consumption of star fruit are not commonly known. Although star fruit induced oxalate nephrotoxicity in those with existing renal impairment is well documented, reports on its effect on those with normal renal function are infrequent. We report two unique clinical presentation patterns of star fruit nephrotoxicity following consumption of the fruit as a remedy for diabetes mellitus-the first, in a patient with normal renal function and the second case which we believe is the first reported case of chronic kidney disease (CKD) due to prolonged and excessive consumption of star fruits. CASE PRESENTATION: The first patient is a 56-year-old female diabetic patient who had normal renal function prior to developing acute kidney injury (AKI) after consuming large amount of star fruit juice at once. The second patient, a 60-year-old male, also diabetic presented with acute on chronic renal failure following ingestion of a significant number of star fruits in a short duration with a background history of regular star fruit consumption over the past 2-3 years. Both had histologically confirmed oxalate induced renal injury. The former had histological features of acute tubulo-interstitial disease whilst the latter had acute-on-chronic interstitial disease; neither had histological evidence of diabetic nephropathy. Both recovered over 2 weeks without the need for haemodialysis. CONCLUSION: These cases illustrate the importance of obtaining the patient's detailed history with respect to ingestion of herbs, traditional medication and health foods such as star fruits especially in AKI or CKD of unknown cause.

Endemic chronic kidney disease of unknown etiology in Sri Lanka: Correlation of pathology with clinical stages.

Chronic kidney disease of unknown etiology (CKDU) is endemic among the rural farming communities in several localities in and around the North Central region of Sri Lanka. This is an interstitial type renal disease and typically has an insidious onset and slow progression. This study was conducted to identify the pathological features in the different clinical stages of CKDU. This is a retrospective study of 251 renal biopsies identified to have a primary interstitial disease from regions endemic for CKDU. Pathological features were assessed and graded in relation to the clinical stage. The mean age of those affected by endemic CKDU was 37.3 ± 12.5 years and the male to female ratio was 3.3:1. The predominant feature of stage I disease was mild and moderate interstitial fibrosis; most did not have interstitial inflammation. The typical stage II disease had moderate interstitial fibrosis with or without mild interstitial inflammation. Stage III disease had moderate and severe interstitial fibrosis, moderate interstitial inflammation, tubular atrophy and some glomerulosclerosis. Stage IV disease typically had severe interstitial fibrosis and inflammation, tubular atrophy and glomerulosclerosis. The mean age of patients with stage I disease (27 ± 10.8 years) was significantly lower than those of the other stages. About 79.2%, 55%, 49.1% and 50% in stage I, II, III and IV disease respectively were asymptomatic at the time of biopsy.

Prevalence of Helicobacter pylori in benign gastric ulcers in a cohort of Sri Lankan patients.

Helicobacter pylori prevalence is decreasing globally and prevalence of non H. pylori gastric ulcers is increasing. The following study was conducted to assess the prevalence of H. pylori in benign gastric ulcers in a sample of Sri Lankan patients. This was a cross-sectional study of 59 dyspeptic patients with benign gastric ulcers. Multiple endoscopic gastric biopsies were obtained and histology, immunohistochemistry and polymerase chain reaction were performed for H. pylori detection. An immunochromatography assay was performed to detect blood anti H. pylori antibodies. Four (6.8%) were positive for H. pylori. Therefore, it is likely that most benign gastric ulcers are of non-H. pylori aetiology.

Acute septicemia caused by Streptococcus gallolyticus subsp. pasteurianus in turkey poults.

Streptococcus gallolyticus, previously known as Streptococcus bovis biotypes I and II/2, is a well-known cause of sepsis and meningitis in humans and birds. The present case report describes an outbreak of fatal septicemia associated with S. gallolyticus subsp. pasteurianus (S. bovis biotype II/2) in 11 turkey flocks in Pennsylvania between 2010 and 2013. Affected poults were 2-3 wk of age. Major clinical observation was sudden increase in mortality among turkey poults without any premonitory clinical signs. Postmortem examination findings revealed acute septicemia with lesions such as fibrinous pericarditis, meningitis, splenic multifocal fibrinoid necrosis, hepatitis, osteochondritis, myositis, and airsacculitis. Gram-positive cocci were isolated from several organs by routine bacterial culture. Biotyping identified bacteria as streptococci, whereas 16S ribosomal RNA gene sequencing identified them as S. gallolyticus subsp. pasteurianus. Antibiotic susceptibility profiles revealed that all the strains isolated were sensitive to penicillin and erythromycin with different sensitivity profiles for other antibacterial agents tested. The present study reports the first confirmed case of acute septicemia in turkey poults caused by S. gallolyticus subsp. pasteurianus.

Retrospective analysis of renal histology in asymptomatic patients with probable chronic kidney disease of unknown aetiology in Sri Lanka.

OBJECTIVES: To study the early pathological changes in renal lesions of asymptomatic patients with kidney diseases, with no definite aetiology living in regions endemic for chronic kidney disease of unknown etiology (CKDUe). Design Retrospective study. SETTING: Regions endemic for CKDUe in and around the North Central Province of Sri Lanka. STUDY POPULATION: Two hundred and eleven asymptomatic patients living in endemic regions detected with renal disease by screening for proteinuria using the dipstick method. Those with long standing hypertension, diabetes mellitus, histological diagnosis of primary glomerular diseases, immunocomplex mediated diseases or renal lesions secondary to systemic diseases were excluded. MEASUREMENTS: Renal lesions were divided into seven histological categories depending on the pathological changes: Category 0: no detectable changes. Category 1: Interstitial fibrosis ± mild interstitial inflammation ± tubular atrophy; no glomerulosclerosis. Category 2: Interstitial fibrosis ± mild interstitial inflammation ± tubular atrophy; glomerulosclerosis. Category 3: Moderate or severe interstitial fibrosis, interstitial inflammation and tubular atrophy ± glomerulosclerosis; Category 4: Interstitial inflammation ± tubular atrophy ± glomerulosclerosis; no interstitial fibrosis. Category 5: The prominent change is interstitial inflammation with tubulitis. Category 6: Severely scarred kidney. Histological categories were compared with calculated glomerular filtration rates and age of the patients. RESULTS: Number of cases in histological categories 0 to 6 were: 7 (3.3%), 71 (33.6%), 53 (25.1%), 63 (29.9%), 0, 2 (0.9%) and 15 (7.1%) respectively. The mean glomerular filtration rate was >90 ml/min in patients in category 0 and 1 and declined progressively in categories 2 and 3. Apart from category 0, all had interstitial fibrosis and in category 1, 62 (87.3%) had interstitial fibrosis without inflammation. Severity of interstitial inflammation increased from category 1 to 3. CONCLUSIONS: The early disease among asymptomatic patients is characterized by interstitial fibrosis without significant interstitial inflammation and glomerular sclerosis with preserved glomerular function. Although the role of interstitial inflammation in the initiation of the disease is not clear, it appears to have a role in the progression of the disease.

Mechanism of contraction of rat isolated tail arteries by hyposmotic solutions.

Contraction induced by hyposmotic swelling was examined in rat tail arteries mounted on a myograph containing a modified Krebs physiological saline solution (PSS) containing 50 mM mannitol (300 mosm/l). Hyposmotic swelling was induced by removing mannitol. In arteries having basal tone or arteries precontracted with K(+) or the thromboxane mimetic U-46619, removal of mannitol caused a concentration dependent contraction of rat tail arteries. Concurrent measurement of tension and intracellular calcium [Ca(2+)](i )in arteries loaded with fura-2 showed that both tension and [Ca(2+)](i) increased on exposure to a hyposmotic solution. Removal of endothelium or inhibition of nitric oxide and cyclooxygenase together did not affect contractile responses. Removal of extracellular Ca(2+) abolished the contractile response to hyposmotic solution and NiCl(2), a nonspecific inhibitor of Ca(2+) influx pathways, blocked the rise in [Ca(2+)](i) and tension in response to a hyposmotic solution. Verapamil and nisoldipine, inhibitors of Ca(v)1.2 (L-type) calcium channels significantly reduced the contractile response to a hyposmotic solution. Addition of NiCl(2) to nisoldipine caused an additional inhibition of the response to a hyposmotic solution. Inhibition of calcium release from the sarcoplasmic reticulum by ryanodine or cyclopiazonic acid (CPA) did not cause any change in the tension response to a hyposmotic solution. CPA did not significantly inhibit the response to a hyposmotic solution in the presence of N(G)-methyl-L-arginine, oxyhaemoglobin and indomethacin. We conclude that contraction induced by a hyposmotic solution is largely due to Ca(v)1.2 calcium channels although other Ca(2+) influx pathways also contribute.

Tyrosine kinases act directly on the alpha1 subunit to modulate Ca(v)2.2 calcium channels.

Voltage-operated calcium channels are modulated by tyrosine kinases in different cell types. In this study, I(Ba) was measured by the whole cell voltage-clamp technique in single COS-7 cells overexpressing the Ca(v)2.2 calcium channels encoding N-type currents. Bath application of genistein, a nonselective PTK inhibitor (50-300 microM), concentration-dependently inhibited calcium channel currents, whereas the inactive structural analogue, daidzein, was without effect over the same concentration range. Similarly, PP1, a src family-selective tyrosine kinase inhibitor, inhibited I(Ba) in a concentration-dependent manner (500 nM-5 microM) over a range of test potentials. Expression of the Ca(v)2.2alpha1 (alpha(1B)) subunit alone gave rise to functional channels, and genistein (100 microM) also inhibited currents elicited by the alpha(1B) subunit alone. These results indicate that tyrosine kinase inhibitors are likely to inhibit Ca(v)2.2 calcium channels via an action on the pore-forming alpha(1) subunit and suggest that an endogenous member of the Src family may play a physiological role in modulating these channels.

Effects of protein tyrosine kinase inhibitors on voltage-operated calcium channel currents in vascular smooth muscle cells and pp60(c-src) kinase activity.

1. Tyrosine kinases have been proposed as regulators of voltage-operated calcium channels. The effects of a range of structurally different inhibitors of protein tyrosine kinases (PTK) were examined on voltage-operated calcium channel currents (I(Ba)) and pp60(c-src) kinase (c-src) activity in vitro. 2. I(Ba) was measured in single myocytes isolated from rabbit ear artery by conventional whole cell voltage-clamp techniques. The activity of purified human c-src was measured in vitro using a non-radioactive assay. 3. Bath application of tyrphostin-23 and genistein (non-selective PTK inhibitors), bistyrphostin (a receptor-PTK-selective inhibitor) and PP1 (a src family-selective inhibitor) inhibited I(Ba) in a concentration-dependent manner over a range of test membrane potentials. Intracellular application of peptide-A, a peptide inhibitor of c-src also inhibited currents. Inhibitor potency series against I(Ba) was PP1 > genistein > tyrphostin 23 > bistyrphostin. 4. Tyrphostin-23, genistein, PP1, and peptide-A shifted the steady-state inactivation curves in a hyperpolarized direction without altering their slope. The inhibitors had no significant effects on I(Ba) activation calculated from current-voltage relationships. 5. The agents inhibited c-src activity in a concentration-dependent manner. The order of potency was PP1 > genistein > peptide-A > tyrphostin-23 > bistyrphostin. The IC(50) for inhibition of c-src activity was similar to the IC(50) for inhibition of I(Ba) in all cases. 6. Western blot analysis with a specific antibody to c-src showed the presence of this cytoplasmic tyrosine kinase in rabbit ear artery cells. 7. A range of structurally dissimilar inhibitors of PTKs inhibit I(Ba) and c-src activity with similar potency. These data provide further evidence implicating endogenous c-src in the modulation of L-type calcium channels in vascular smooth muscle cells.

Effect of hypercholesterolaemia on voltage-operated calcium channel currents in rabbit arterial smooth muscle cells.

Cholesterol is a major component of cell membranes and influences membrane fluidity. Watanabe heritable hyperpercholesterolaemic rabbits (WHHL) possess defective receptors for low density lipoprotein leading to increased plasma cholesterol, accumulation of cholesterol in the arterial wall and atherosclerosis. In this study calcium channel currents (IBa) were compared using conventional whole cell voltage clamp techniques in ear artery cells isolated from control New Zealand White rabbits (NZ) with those from WHHL. IBa were larger in cells isolated from NZ than from WHHL, however cell capacitance was also greater in NZ cells. Consequently, there was no significant difference in current density between NZ and WHHL cells either in the absence of drug or in the presence of the calcium channel agonist (+)202 791. Current voltage-relationships, kinetics of fast inactivation and steady-state inactivation of IBa also did not differ significantly between WHHL and NZ. These findings suggest that hypercholesterolaemia in WHHL has no direct effect on calcium channel current density or voltage-modulation in arterial smooth muscle cells.

Effect of inhibition of tyrosine phosphatases on voltage-operated calcium channel currents in rabbit isolated ear artery cells.

1. The effect of increasing cellular tyrosine phosphorylation by inhibiting endogenous tyrosine phosphatases was examined on voltage-operated calcium channel currents in vascular smooth muscle cells. 2. In single ear artery smooth muscle cells of the rabbit, studied by the whole cell voltage clamp technique, intracellular application of the tyrosine phosphatase inhibitors, sodium orthovanadate (100 microM) and peroxyvanadate (100 microM orthovanadate + 1 mM H2O2) increased voltage-operated calcium channel currents by 56% and 83%, respectively. 3. Bath application of two other membrane permeant tyrosine phosphatase inhibitors, phenylarsine oxide (100 microM) and dephostatin (50 microM) also increased voltage-operated calcium channel currents by 48% and 52%, respectively. 4. The selective tyrosine kinase inhibitor, tyrphostin-23 (100 microM) reduced calcium channel currents by 41%. Pre-incubation with tyrphostin-23 abolished the effects of peroxyvanadate, phenylarsine oxide and dephostatin on calcium channels. 5. Western blot analysis of rabbit ear artery cell lysates showed increased tyrosine phosphorylation of several endogenous proteins following treatment with peroxyvanadate. 6. These results indicate that a number of structurally dissimilar inhibitors of tyrosine phosphatases increase voltage-operated calcium channel currents in arterial smooth muscle cells presumably due to increased tyrosine phosphorylation.

Role of tyrosine phosphorylation in excitation-contraction coupling in vascular smooth muscle.

Increasingly it is recognized that tyrosine phosphorylation plays an important part in the regulation of function in differentiated contractile vascular smooth muscle. Tyrosine kinases and phosphatases are present in large amounts in vascular smooth muscle and have been reported to influence a number of processes crucial to contraction, including ion channel gating, calcium homeostasis and sensitization of the contractile process to [Ca2+]i. This review summarizes current understanding regarding the role of tyrosine phosphorylation in excitation-contraction coupling in blood vessels.

Activation of endogenous c-Src or a related tyrosine kinase by intracellular (pY)EEI peptide increases voltage-operated calcium channel currents in rabbit ear artery cells.

The effect of activation of endogenous c-Src tyrosine kinase by (pY)EEI peptide was examined on voltage-operated calcium channel (VOC) currents in arterial smooth muscle cells. In single rabbit ear artery cells intracellular application of (pY)EEI peptide increased calcium channel currents. Inactive, non-phosphorylated YEEI peptide had no effect on currents. Peptide-A, a 21 amino acid inhibitor of c-Src inhibited currents and prevented the effect of (pY)EEI peptide on calcium channel currents. These results indicate that activation of intrinsic c-Src increases VOC and support a role for c-Src in the regulation of VOC in vascular smooth muscle cells.

alpha2-Adrenoceptor activation increases calcium channel currents in single vascular smooth muscle cells isolated from human omental resistance arteries.

Single cells were freshly isolated from human omental resistance arteries using an enzymatic dispersion technique. Calcium channel currents (IBa) were recorded using whole cell voltage clamp techniques with Ba2+ as the charge carrier. BHT 933, a selective alpha2-adrenoceptor agonist, increased IBa. The effect of BHT 933 was reversible following washout. The action of BHT 933 was blocked by yohimbine. Pretreatment of tissues with pertussis toxin for 18 h or inclusion of GDP-beta-S in the intracellular patch pipette solution also prevented the BHT 933-induced rise in IBa, but had no effect on IBa in the absence of BHT 933. Activation of alpha2-adrenoceptors in human vascular smooth muscle cells increases IBa by a mechanism involving a pertussis toxin-sensitive G protein.

pp60c-src increases voltage-operated calcium channel currents in vascular smooth muscle cells.

Intracellular application of pp60c-src, a nonreceptor tyrosine kinase present in large amounts in smooth muscle cells increased voltage-operated calcium channel currents in rabbit ear artery cells. Intracellular peptide-A, an inhibitor of pp60c-src, reduced calcium channel currents and abolished the action of pp60c-src. Selective tyrosine kinase inhibitors, tyrphostin-23 and genistein also abolished the effect of pp60c-src, but inhibition of protein kinase C did not prevent the action of pp60c-src. These results suggest that endogenous pp60c-src modulates voltage-operated calcium channels by a mechanism dependent on tyrosine phosphorylation but not involving activation of protein kinase C.

Effect of platelet-derived growth factor on voltage-operated calcium channels in rabbit isolated ear artery cells.

1. Platelet derived growth factor (PDGF), AB and BB isoforms (100 pM) increased calcium channel currents measured by whole cell voltage clamp technique in single vascular smooth muscle cells isolated from rabbit ear arteries. 2. Tyrphostin-23 (100 microM) a selective inhibitor of protein tyrosine kinases, reduced calcium channel currents. Pre-incubation with tyrphostin-23 prevented PDGF-AB induced increase in calcium channel currents. However, in these same cells 10 nM (+)-202791, a dihydropyridine calcium channel agonist, did increase calcium channel currents. 3. Bistyrphostin (10 microM), a selective inhibitor of epidermal growth factor (EGF)-kinase also reduced calcium channel currents and inhibited PDGF-AB-induced increases in calcium channel currents. 4. Genistein (100 microM) a selective inhibitor of tyrosine kinases, structurally unrelated to the tryphostins, also inhibited calcium channel currents and pre-incubation with genistein prevented the PDGF-AB-induced rise in calcium channel currents. 5. These results indicate that PDGF increases calcium channel currents in vascular smooth muscle. This action of PDGF probably involves a tyrosine kinase.

Comparison of effects of platelet-derived growth factor isoforms on signaling and DNA synthesis of human cultured saphenous vein cells.

We examined the effect of platelet-derived growth factor (PDGF)-AA, PDGF-AB, and PDGF-BB isoforms on DNA synthesis, Ca2+ mobilization, and tyrosine phosphorylation in cultured human saphenous vein cells cultured by an explant technique; confluent cells derived from passage 3 were used for all studies. DNA synthesis was measured by [methyl3H]thymidine uptake, intracellular [Ca2+] ([Ca2+]i) was measured with the Ca(2+)-sensitive indicator fura-2, and tyrosine phosphorylation was measured by Western blotting techniques. All three isoforms of PDGF stimulated [methyl3H]thymidine uptake concentration dependently, with similar potency. PDGF-AB induced significantly greater [methyl3H]-thymidine uptake than PDGF-BB, and PDGF-AA was much less effective than either PDGF-AB or PDGF-BB. The effects of all three isoforms were inhibited by tyrphostin-23, a selective inhibitor of tyrosine kinases PDGF-AB and PDGF-BB increased [Ca2+]i, although the maximum response to PDGF-AB was significantly less than that to PDGF-BB. Both isoforms increased [Ca2+]i by stimulating influx and intracellular release of Ca2+. PDGF-AA had no measurable effect on [Ca2+]i. All three isoforms increased tyrosine phosphorylation of a 170-kDa protein detected by Western blotting. Quantitative densitometry indicated that PDGF-BB induced greater tyrosine phosphorylation than PDGF-AB and both PDGF-BB and PDGF-AB induced markedly more tyrosine phosphorylation than PDGF-AA. PDGF isoforms have differing efficacies in terms of DNA synthesis, Ca2+ mobilization, and tyrosine phosphorylation by human saphenous vein cells.

Isolation of single vascular smooth muscle cells from human omental resistance arteries.

Small arteries less than 500 microns make a significant contribution to peripheral vascular resistance. Single vascular smooth muscle cells were isolated from human omental resistance arteries by enzymatic dispersion. The method yielded relaxed vascular smooth muscle cells approximately 120 microns long and 7 microns wide. The cells were studied using whole cell voltage clamp techniques and a number of passive and active membrane properties were described.