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Dystrophic amyloidosis: a local complication of tissue damage with heterogeneous distribution

Looi LM

Histopathology, 1991 Aug;19(2):169-72.
PMID: 1757071

Seventeen consecutive patients with dystrophic amyloidosis are reported here (eight Chinese, three Indian, three Iban, two Malay and one Caucasian). Ten were females and seven males, with ages ranging from 12 to 80 years (mean of 48 years). Five instances of dystrophic amyloidosis occurred in areas of tissue damage in the cardiovascular system, including fibrotic cardiac valves and an atheromatous plaque. Three occurred in osteoarthritic joint tissue. Of note were three occurrences in endometriotic cyst walls, four in the fibrotic walls of epidermal cysts, one in a hernial sac and one at the edge of a skin ulcer. All deposits were congophilic and exhibited green-birefringence and permanganate-resistance. Immunohistochemistry did not reveal reactivity for AA protein or immunoglobulin lambda or kappa light-chains. AP protein was detected in 35% of cases. Our results show that, besides the usual sites of osteoarthritic joints and damaged heart valves, dystrophic amyloidosis can complicate other areas of chronic tissue damage and fibrosis such as walls of cysts and ulcers. While the pathogenesis and biochemical nature remain unresolved, immunohistochemistry indicates that neither AA nor AL proteins are present in the deposits, and suggests that a different amyloid protein is involved.
The pattern of amyloidosis in a Malaysian patient population

Looi LM

Histopathology, 1991 Feb;18(2):133-41.
PMID: 1901294

Congo red screening of 27,052 routine biopsy specimens from 22,827 patients over a 5 1/2-year period in the Department of Pathology, University of Malaya detected 186 cases of amyloidosis. The categories of amyloidosis encountered and their prevalences in relation to each other were: systemic AL (5.9%); systemic AA (3.2%); isolated atrial (14%); primary localized cutaneous (7.5%); other primary localized deposits (3.2%); localized intratumour (58%); and dystrophic (8.6%). A third of patients with systemic AL amyloidosis had coexistent immunocyte abnormality. The commonest underlying pathology for systemic AA amyloidosis was leprosy. Notable among the types of localized amyloidosis revealed by this study were isolated atrial amyloidosis, which appeared to complicate chronic rheumatic heart disease, and intratumour amyloidosis complicating nasopharyngeal carcinoma. Other tumours in which amyloid deposits were observed included basal cell carcinoma, islet cell tumour and medullary carcinoma of the thyroid. Dystrophic amyloidosis was observed in fibrotic tissues, such as damaged cardiac valves and osteoarthritic joints. Heredofamilial amyloidosis, senile systemic amyloidosis and degenerative cerebral amyloidosis were notably absent from this study.
Histomorphological variations in systemic AA amyloidosis: clues of AA protein polymorphism

Looi LM

Histopathology, 1989 Feb;14(2):111-20.
PMID: 2707747

The histological location of amyloid within various organs in 25 cases of systemic AA amyloidosis was studied with a view to determine whether different morphological patterns exist in this category of amyloidosis. Although morphological variations due to progressive severity of disease were observed, there were appreciable variations in the patterns of amyloid deposition in the kidney and spleen that could not be simply explained on those grounds. Eleven (61%) of 18 kidneys examined showed severe glomerular involvement with mild degrees of vascular deposition while the remaining seven showed predominantly vascular involvement. The glomerular pattern appeared to be more ominous, being significantly associated with severe proteinuria or chronic renal failure. In nine (69%) of 13 spleens examined, amyloid was confined to the walls of small and medium-sized arteries while in the remaining four, vascular involvement was less severe and amyloid was deposited mainly along the reticulin of the white pulp. Possible explanations for these different patterns included resorption and redistribution of amyloid within the body during the course of the disease, and variation in tissue deposition as a manifestation of polymorphism of amyloid proteins. The latter appeared more feasible in view of the recent demonstration of SAA polymorphism and AA heterogeneity in man.
Hepatitis B virus surface antigen in glomerular immune complex deposits of patients with systemic lupus erythematosus

Looi LM, Prathap K

Histopathology, 1982 Mar;6(2):141-7.
PMID: 7042512

In view of a high prevalence of hepatitis B virus infection in the Malaysian population, indirect immunofluorescence examination for hepatitis B surface antigen (HBsAg) was routinely performed on renal biopsy specimen at the University Hospital, Kuala Lumpur, over a 3-year period. Examination of renal tissue from 259 patients, including 47 with systemic lupus erythematosus (SLE), revealed 43 cases with HBsAg in glomerular immune complexes. A significantly high proportion (30/43) of these were SLE patients. The deposits were granular in nature, situated in both the capillary walls and mesangium and associated with immunoglobulin deposition. Morphological patterns of lupus nephritis involved were focal proliferative (one case), diffuse proliferative (23 cases) and membranous (six cases). None of these patients showed clinical evidence of liver disease. The significance of these findings remains uncertain, but the possibility exists that the hepatitis B virus may have a role in the pathogenesis of SLE in the tropics where both SLE and HBs antigenaemia are common.
Histomorphological patterns of renal amyloidosis: a correlation between histology and chemical type of amyloidosis

Looi LM, Cheah PL

Hum Pathol, 1997 Jul;28(7):847-9.
PMID: 9224755

A retrospective study was conducted to investigate whether there was a correlation between the histological pattern of renal amyloidosis, the chemical type of amyloid protein involved and the clinical presentation. Eighteen consecutive cases of systemic amyloidosis that had renal biopsies processed and examined histopathologically at the Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur were reviewed. The age range of patients was 25 to 64 yrs (mean, 46 yrs). The male:female ratio was 2.6:1. Three patients were Malay, 9 Chinese, 3 Indian, 1 Indonesian, 1 Iban, and 1 Bisaya. According to the predominant site of amyloid deposition, 14 cases showed a glomerular pattern and 4 a vascular pattern. 8 cases were designated as 2 anti-human amyloid-A (AA) amyloidosis on the basis of permanganate-sensitivity and immunoreactivity of deposits with anti-human AA protein antibody. Ten cases contained deposits that were permanganate-resistant and nonimmunoreactive for AA protein and were designated as AL in type. The histomorphologic pattern of renal amyloidosis did not provide a reliable means of differentiating AA from AL amyloidosis. The glomerular pattern tended to present with renal manifestations such as nephrotic syndrome and chronic renal failure, whereas the vascular pattern tended to present with nonrenal manifestations such as diarrhoea. These findings may have a bearing on the pathophysiology of amyloidosis and provide clues to appropriate management.
Isolated atrial amyloidosis: a clinicopathologic study indicating increased prevalence in chronic heart disease

Looi LM

Hum Pathol, 1993 Jun;24(6):602-7.
PMID: 8505038

Congo red screening of 211 consecutive cardiac biopsy specimens obtained during cardiac surgery from 167 patients revealed 26 (16%) instances of isolated atrial amyloidosis (IAA). The ages of IAA-positive patients ranged from 25 to 52 years (mean age, 39 years). Twenty-three (88%) IAA-positive biopsy specimens were from patients with chronic rheumatic heart disease (CRHD) while three (12%) were from patients with an atrial septal defect (ASD). The prevalence of IAA in the CRHD patients was 23%, appreciably higher than that in the ASD patients (15%) and in other patients with atrial biopsies. The prevalence of IAA in both CRHD and ASD patients was significantly higher (P < .001) than in controls. Controls consisted of 247 healthy adults who were autopsied after traumatic deaths, with an age range of 18 to 89 years (mean age, 38 years). Only seven (3%) control subjects were IAA positive; all were over 40 years of age. Isolated atrial amyloidosis deposits were permanganate resistant and immunohistochemically positive for human amyloid P (AP) protein and negative for human amyloid-associated (AA) protein and immunoglobulin light chains. They were observed as fine congophilic and birefringent deposits in intramyocardial vessel walls, along the myocardial sarcolemma, and in the subendocardium. There was associated myocyte hypertrophy but no atrophy. Electron microscopy demonstrated typical nonbranching amyloid fibrils. It is postulated that stretching of the atria in chronic heart disease results in a raised prevalence of IAA. Recent reports that IAA contains atrial natriuretic peptide, a polypeptide hormone product of atrial myocytes, supports this view.
Morphologic differences in the pattern of liver infiltration between systemic AL and AA amyloidosis

Looi LM, Sumithran E

Hum Pathol, 1988 Jun;19(6):732-5.
PMID: 2454214

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.
Fulltext Autopsy findings in 35 cases of leprosy in Malaysia

Jayalakshmi P, Looi LM, Lim KJ, Rajogopalan K

Int. J. Lepr. Other Mycobact. Dis., 1987 Sep;55(3):510-4.
PMID: 3655465

The findings of autopsies performed on 35 leprosy subjects in the University Hospital, Kuala Lumpur, between January 1981 and December 1985 are presented. This is the first report based on autopsy findings from Malaysia. The patients were elderly subjects with a mean age of 74 years. Sixty-six percent had lepromatous leprosy. None had active skin lesions. The most common cause of death was pyogenic infection, particularly bronchopneumonia. Tuberculosis was noted in 25% of the cases. The other important causes of death included cardiac and renal failure. Renal lesions were evident in 71% of the cases, and the most common pathology was interstitial nephritis. Generalized amyloidosis complicated six (17%) patients.
Cyclophosphamide-induced transitional cell carcinoma of bladder in lupus nephritis

Chow SK, Looi LM, Loh CS, Yeap SS

Intern Med J, 2002 Mar;32(3):114-6.
PMID: 11885838 DOI: 10.1046/j.1445-5994.2002.d01-29.x
Histiocytosis X and vulvar ulceration

Wong KK, Lin HP, Looi LM

Int J Gynaecol Obstet, 1992 Oct;39(2):131-4.
PMID: 1358712

Vulvar ulceration is a rare manifestation of histiocytosis X. A 13-year-old girl had a nonhealing vulvar ulcer for 1 year. She had been in remission from histiocytosis X and the ulcer was not recognised as a sign of disease recurrence until tissue biopsy was obtained for histopathological and immunohistochemical studies. This article stresses the importance of establishing an accurate diagnosis when chronic vulvar ulcers are encountered and reviews the literature on this uncommon presentation of histiocytosis X.
Fulltext Metastatic Adenocarcinoma Presenting as Extensive Cavoatrial Tumor Thrombus

Johari B, Abdul Aziz YF, Krishnasamy S, Looi LM, Hashim SA, Raja Mokhtar RA

Iran J Radiol, 2015 Apr;12(2):e11197.
PMID: 26060549 DOI: 10.5812/iranjradiol.11197

The presence of tumor thrombus in the right atrium is frequently the result of direct intraluminal extension of infra-diaphragmatic malignancy into the inferior vena cava (IVC) or supradiaphragmatic carcinoma into the superior vena cava (SVC). Right atrial tumor thrombus with extension into both SVC and IVC has not been reported in the literature. We present a patient who presented with symptoms of right atrial and SVC obstruction. Imaging revealed presence of a thrombus in the right atrium, extending to the SVC and IVC, with the additional findings of a left adrenal mass and multiple liver lesions. The histopathological examination of the right atrial mass revealed metastatic adenocarcinoma cells. The patient was given a presumptive diagnosis of metastatic adenocarcinoma, most likely adrenal in origin, with multiple hepatic lesions suspicious for metastasis. The clinical outcome of the patient was not favorable; the patient succumbed before the adrenal mass could be confirmed to be the primary tumor. This case highlights that in patients manifesting with extensive cavoatrial thrombus as, the existence of primary carcinoma should be considered especially in the adrenal cortex or in the lung.
Telomerase activation and human papillomavirus infection in invasive uterine cervical carcinoma in a set of Malaysian patients

Cheah PL, Looi LM, Ng MH, Sivanesaratnam V

J Clin Pathol, 2002 Jan;55(1):22-6.
PMID: 11825919

AIM: Telomerase activity was studied in invasive uterine cervical carcinoma to assess whether it was activated during cervical malignant transformation and to look for a possible association with human papillomavirus (HPV) infection in a set of Malaysian patients.
METHODS: Histologically confirmed invasive cervical carcinoma and benign cervices were assayed for telomerase activity using a commercial telomerase polymerase chain reaction (PCR) enzyme linked immunosorbent assay kit. The same cases were subjected to PCR detection of HPV using type specific (HPV types 6b, 11, 16, and 18) followed by L1 open reading frame (ORF) consensus primers.
RESULTS: HPV was detected in 18 (13 HPV-16, one HPV-6b, four only L1 ORF) of 20 invasive cervical carcinoma and one (only L1 ORF) of 19 benign cervices. Raised telomerase activity (A(450 nm) > 0.215) was detected in 11 cervical carcinomas, with A(450 nm) ranging between 0.238 and 21.790 (mean, 3.952) in positive squamous carcinomas, whereas A(450 nm) was only 0.222 in the one positive adenosquamous carcinoma. Five of 11 cervical carcinomas in stage I, three of six in stage II, both in stage III, and the only case in stage IV showed telomerase activation. Increased telomerase activity was noted in five of the 12 lymph node negative, five of the seven lymph node status unknown cases, and the one case with presumed lymph node metastasis. Ten of 18 HPV positive and one of two HPV negative cervical carcinomas showed telomerase upregulation.
CONCLUSIONS: Telomerase is activated in invasive cervical carcinoma. Although larger studies are needed, there seems to be no clear association between telomerase upregulation and HPV status, although there is a suggestion of increased telomerase activity in squamous carcinomas and late stage disease.
Squamous cell carcinoma antigen as an adjunct tumour marker in primary carcinoma of the lung

Cheah PL, Liam CK, Yap SF, Looi LM

J Clin Pathol, 1994 Jun;47(6):535-7.
PMID: 8063936

AIMS: To determine (1) the detection rate of primary carcinoma of the lung by serological assay of CEA (carcinoembryonic antigen); and (2) whether addition of seroassay of squamous cell carcinoma related antigen before treatment improves detection sensitivity.
METHODS: A prospective study spanning 27 months was conducted at the University Hospital, Kuala Lumpur. Serum CEA (Abbott IMx) and serum squamous cell carcinoma antigen (Abbott IMx) from patients clinically suspected of having primary carcinoma of the lung, were assayed using the microparticle enzyme immunoassay method.
RESULTS: Thirty seven cases of histologically confirmed primary lung carcinoma were studied. Of these, 17 were squamous cell carcinomas, 10 adenocarcinomas, nine small cell carcinomas, and one large cell carcinoma. The patients' ages ranged from 34-82 years. The male:female ratio was 3.6:1. Squamous cell carcinoma antigen was raised above the cutoff value of 1.5 ng/ml in 94.1% of squamous cell carcinomas, 20.0% of adenocarcinomas, and 11.1% of small cell carcinomas. By comparison, CEA was raised above the cutoff value of 3.0 ng/ml in 70.6% of squamous cell carcinomas, 77.8% of small cell carcinomas, and 100% of adenocarcinomas. CEA and squamous cell carcinoma antigen were not raised in the patient with large cell carcinoma and in 14 healthy volunteers. None of 15 patients with a variety of benign lung diseases showed a rise of CEA, while two patients--a 25 year old Indian woman with pneumonia and a 64 year old Malay man with bronchial asthma--had raised squamous cell carcinoma antigen values above the cutoff. Serum CEA and squamous cell carcinoma antigen values did not seem to correlate with stage or degree of differentiation of the tumours.
CONCLUSIONS: The findings suggest that CEA is a good general marker for carcinoma, particularly adenocarcinoma. In contrast, squamous cell carcinoma antigen is more specific for squamous carcinoma.
Esophageal squamous cell carcinomas in a Malaysian cohort show a lack of association with human papillomavirus

Cheah PL, Koh CC, Khang TF, Goh KL, Lau PC, Chin KF, et al.

J Dig Dis, 2018 May;19(5):272-278.
PMID: 29722130 DOI: 10.1111/1751-2980.12605

OBJECTIVE: With an age-standardized incidence rate of 2 per 100 000, esophageal cancer is not common among Malaysians, but they are nevertheless important due to its poor prognosis. The study is to clarify whether the human papillomavirus (HPV) is associated with esophageal cancer in Malaysians as there has been no report to date on this in Malaysians and other South East Asians.
METHODS: Altogether 67 esophageal squamous cell carcinomas histologically diagnosed between 1 January 2004 and 31 December 2014 at the Department of Pathology, University of Malaya Medical Center, Malaysia were considered for HPV analysis using two commercially available methods, polymerase chain reaction with flow-through hybridization (21 HPV GenoArray Diagnostic Kit) and multiplex real-time polymerase chain reaction (Anyplex II HPV28 Detection). The DNA amplifiability of the formalin-fixed, paraffin-embedded tumor was checked by amplification of a 268 bp segment of the human β-globin gene (GH20/PC04) prior to HPV detection.
RESULTS: HPV detection was finally carried out in 51 patients. HPV16 was detected in the moderately differentiated, stage IV lower esophageal tumor of a 32-year-old Malaysian-born Chinese woman by both methods. Except for a predilection for Indians, the clinical characteristics of esophageal squamous cell carcinomas in this Malaysian cohort were generally similar to those of other populations.
CONCLUSION: It appears that HPV is rare and an unlikely oncovirus in esophageal squamous cell carcinomas of Malaysians.
Outcome of biliary atresia in Malaysia: a single-centre study

Lee WS, Chai PF, Lim KS, Lim LH, Looi LM, Ramanujam TM

J Paediatr Child Health, 2009 May;45(5):279-85.
PMID: 19493120 DOI: 10.1111/j.1440-1754.2009.01490.x

This study aimed to determine the outcome of the operation of children with biliary atresia (BA) at a tertiary paediatric referral centre in Malaysia.
alpha1-Antitrypsin deficiency is not an important cause of childhood liver diseases in a multi-ethnic Southeast Asian population

Lee WS, Yap SF, Looi LM

J Paediatr Child Health, 2007 Sep;43(9):636-9.
PMID: 17688648

We conducted a prospective study to determine the role of alpha1-antitrypsin (alpha1AT) deficiency in the pathogenesis of neonatal cholestasis and other childhood liver diseases in a multi-ethnic Southeast Asian population.
Clostridium difficile-related necrotizing pseudomembranous enteritis in association with Henoch-Schonlein purpura

Boey CC, Ramanujam TM, Looi LM

J Pediatr Gastroenterol Nutr, 1997 Apr;24(4):426-9.
PMID: 9144126
Effect of soy protein on the small bowel mucosa of young infants recovering from acute gastroenteritis

Iyngkaran N, Yadav M, Looi LM, Boey CG, Lam KL, Balabaskaran S, et al.

J Pediatr Gastroenterol Nutr, 1988 Jan-Feb;7(1):68-75.
PMID: 3335989

The effect of soy protein on the small bowel mucosa of 18 infants with acute gastroenteritis was studied. The infants were maintained on a protein hydrolysate formula for 6-8 weeks, following which they were readmitted for soy protein challenge studies. Jejunal biopsy was performed before and 24 h after challenge. On the basis of the clinical and histological reaction to soy protein challenge, three groups were identified. Group 1 consisted of three infants who had clinical and histological reaction. There was associated depletion of mucosal enzymes, lactase, sucrase, malatase, alkaline phosphatase, and blood xylose levels. Group 2 consisted of seven infants who had histological reaction but no clinical symptoms. Two of these seven infants, however, developed clinical reaction when rechallenged with soy protein 2 and 90 days later. Following challenge, mucosal enzymes and blood xylose levels were depressed in five of the seven infants tested. Group 3 consisted of eight infants who did not have either a clinical or a histological reaction. The mucosal enzymes and blood xylose levels were not depressed in four infants tested. The present study shows that the small bowel mucosa of some young infants recovering from acute gastroenteritis remains sensitive to soy protein for a variable period of time. The feeding of soy protein to these infants may result in the persistence of mucosal damage and perpetuation of diarrhea.(ABSTRACT TRUNCATED AT 250 WORDS)
Hearing loss: a global health issue

Looi LM, Ganten D, McGrath PF, Gross M, Griffin GE

Lancet, 2015 Mar 14;385(9972):943-4.
PMID: 25743174 DOI: 10.1016/S0140-6736(15)60208-2
Fulltext Universal health coverage and intersectoral action for health: key messages from Disease Control Priorities, 3rd edition

Jamison DT, Alwan A, Mock CN, Nugent R, Watkins D, Adeyi O, et al.

Lancet, 2018 03 17;391(10125):1108-1120.
PMID: 29179954 DOI: 10.1016/S0140-6736(17)32906-9

The World Bank is publishing nine volumes of Disease Control Priorities, 3rd edition (DCP3) between 2015 and 2018. Volume 9, Improving Health and Reducing Poverty, summarises the main messages from all the volumes and contains cross-cutting analyses. This Review draws on all nine volumes to convey conclusions. The analysis in DCP3 is built around 21 essential packages that were developed in the nine volumes. Each essential package addresses the concerns of a major professional community (eg, child health or surgery) and contains a mix of intersectoral policies and health-sector interventions. 71 intersectoral prevention policies were identified in total, 29 of which are priorities for early introduction. Interventions within the health sector were grouped onto five platforms (population based, community level, health centre, first-level hospital, and referral hospital). DCP3 defines a model concept of essential universal health coverage (EUHC) with 218 interventions that provides a starting point for country-specific analysis of priorities. Assuming steady-state implementation by 2030, EUHC in lower-middle-income countries would reduce premature deaths by an estimated 4·2 million per year. Estimated total costs prove substantial: about 9·1% of (current) gross national income (GNI) in low-income countries and 5·2% of GNI in lower-middle-income countries. Financing provision of continuing intervention against chronic conditions accounts for about half of estimated incremental costs. For lower-middle-income countries, the mortality reduction from implementing the EUHC can only reach about half the mortality reduction in non-communicable diseases called for by the Sustainable Development Goals. Full achievement will require increased investment or sustained intersectoral action, and actions by finance ministries to tax smoking and polluting emissions and to reduce or eliminate (often large) subsidies on fossil fuels appear of central importance. DCP3 is intended to be a model starting point for analyses at the country level, but country-specific cost structures, epidemiological needs, and national priorities will generally lead to definitions of EUHC that differ from country to country and from the model in this Review. DCP3 is particularly relevant as achievement of EUHC relies increasingly on greater domestic finance, with global developmental assistance in health focusing more on global public goods. In addition to assessing effects on mortality, DCP3 looked at outcomes of EUHC not encompassed by the disability-adjusted life-year metric and related cost-effectiveness analyses. The other objectives included financial protection (potentially better provided upstream by keeping people out of the hospital rather than downstream by paying their hospital bills for them), stillbirths averted, palliative care, contraception, and child physical and intellectual growth. The first 1000 days after conception are highly important for child development, but the next 7000 days are likewise important and often neglected.

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