Biomedical subjects
Publications and source records attributed to G Lau.
A 37-year-old woman that presented with cervical lymphadenopathy and leukocytosis was found to have precursor T-lymphoblastic leukemia (T-ALL). Cytogenetic study of the leukemic cells showed a 46,XX, t(1;22)(p34;q13) karyotype. The t(1;22)(p34;q13) is a novel chromosomal abnormality in human malignancies and is probably a variant form of the t(1;14)(p34;q11) found in precursor T-ALL.
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INTRODUCTION: In Singapore, published maternal mortality rates (MMR) over the last decade (1990 to 1999) have been so low (0.0 to 1.0 per 1000 live births and still births) as to imply that maternal deaths are rare to the point of being non-existent in some years. This inference is counterintuitive, and earlier studies on maternal mortality, amniotic fluid embolism (AFE) and pulmonary thromboembolism (PTE) have also suggested otherwise. Accordingly, local trends in maternal mortality warrant further examination. MATERIALS AND METHODS: A descriptive and comparative study, comprising a clinico-pathological review of maternal deaths, for which autopsies were conducted by the Centre for Forensic Medicine, during a 10-year period from 1990 to 1999. The annual necropsy-based, MMR (estimated MMR), as well as the prevalence of maternal deaths during this time, were estimated with the aid of the relevant, published demographic data on live births and still births. These were compared with the corresponding rates calculated (calculated MMR) from raw demographic data on maternal deaths classified as such in the published data. RESULTS: Coronial autopsies were conducted on a total of 51 cases of maternal death, of which 33, 17 and 1 were direct, indirect and fortuitous deaths, respectively. The annual, estimated MMR ranged from 0.4 to 1.8 per 10,000 live births and still births. The estimated MMR was twice as high as the calculated MMR and a statistically significant upward linear trend was demonstrated for the former (P = 0.046). AFE (16/51) and PTE (10/51) were the two most common causes of maternal death; their corresponding cause-specific, 10-year prevalence being 0.33 and 0.21 per 10,000 live births and still births, respectively. There was apparent clustering of the cases of PTE during the earlier part of the last decade (1990 to 1995), corresponding to a statistically significant, upward trend in its overall necropsy incidence during that time (P = 0.019). Cardiovascular and pulmonary disorders constituted the bulk of indirect deaths (13/17), while antenatal suicides accounted for 3 of these deaths (0.06 per 10,000 live births and still births). CONCLUSIONS: This was an upward trend in MMR, as reflected in coronial casework, over the last decade. It would appear that the local, estimated (direct and indirect) maternal mortality prevalence compares favourably with the MMR reported in developed countries. The apparent rate of AFE was no less than 4 times higher than that reported in the United Kingdom, while the maternal mortality rate from PTE was at least as high. Allowing for the possibility that such deaths were under-reported, the actual annual MMR and 10-year prevalence could be appreciably higher than the estimates presented here. There may well be a case for the establishment of a comprehensive database of maternal deaths, that is updated continually and contemporaneously, in Singapore.
A 34-year-old lady developed a constellation of dermatitis, fever, lymphadenopathy and hepatitis, beginning on the 17th day of a course of oral sulphasalazine for sero-negative rheumatoid arthritis. Cervical and inguinal lymph node biopsies showed the features of severe necrotising lymphadenitis, associated with erythrophagocytosis and prominent eosinophilic infiltrates, without viral inclusion bodies, suggestive of an adverse drug reaction.A week later, fulminant drug-induced hepatitis, associated with the presence of anti-nuclear autoantibodies (but not with other markers of autoimmunity), and accompanied by multi-organ failure and sepsis, supervened. She subsequently died some 5 weeks after the commencement of her drug therapy.Post-mortem examination showed evidence of massive hepatocellular necrosis, acute hypersensitivity myocarditis, focal acute tubulo-interstitial nephritis and extensive bone marrow necrosis, with no evidence of malignancy. It is thought that the clinico-pathological features and chronology of this case bore the hallmarks of the so-called "3-week sulphasalazine syndrome", a rare, but often fatal, immunoallergic reaction to sulphasalazine.
A 93-year-old lady with dementia, neurological dysphagia and aspiration pneumonia, died from massive retroperitoneal haemorrhage which developed as a rare and, it is believed, hitherto unreported, complication of percutaneous endoscopic gastrostomy (PEG), which was performed for feeding purposes. It is postulated that the initial, unsuccessful attempt at needle puncture of the stomach, under endoscopic guidance, had resulted in iatrogenic perforation and laceration of the splenic and superior mesenteric veins close to their confluence with the portal vein. It would also appear that dense fibrous adhesions between the pyloro-antral region of the stomach and the posterior hepatic surface had altered the immediate anatomical relations of the stomach in such a manner as to have predisposed to these events.
Cellular transformation by the BCR/ABL oncogene depends on the ABL-encoded tyrosine kinase activity. To block BCR/ABL function, we created a unique tyrosine phosphatase by fusing the catalytic domain of SHP1 (SHP1c) to the ABL binding domain (ABD) of RIN1, an established binding partner and substrate for c-ABL and BCR/ABL. This fusion construct (ABD/SHP1c) binds to BCR/ABL in cells and functions as an active phosphatase. ABD/SHP1c effectively suppressed BCR/ABL function as judged by reductions in transformation of fibroblast cells, growth factor independence of hematopoietic cell lines, and proliferation of primary bone marrow cells. In addition, the leukemogenic properties of BCR/ABL in a murine model system were blocked by coexpression of ABD/SHP1c. Both the "escort" function provided by ABD and the inhibitor function provided by the phosphatase of SHP1c were necessary for effective BCR/ABL interference. Expression of ABD/SHP1c also reversed the transformed phenotype of K562, a human leukemia-derived cell line. These results have direct implications for leukemia therapeutics and suggest an approach to block aberrant signal transduction in other pathologies through the use of appropriately designed escort/inhibitors.
INTRODUCTION: In previous triennial reviews of Coroner's perioperative autopsies conducted during the periods 1989 to 1991 and 1992 to 1994, it was observed that the necropsy incidence of such deaths rose from 2% to 2.6% (P < 0.05). Concurrently, the rate of iatrogenic deaths had nearly doubled from 15.2% to 28.8% (P < 0.02). These findings spurred a review of the subsequent triennium (1995 to 1997), in order to monitor the apparent rise in these trends and to study the frequency and occurrence of iatrogenic deaths in relation to the number of invasive procedures performed, as well as during emergency and elective procedures. MATERIALS AND METHODS: A retrospective (descriptive and comparative) study, comprising a clinico-pathological review of a series of 270 perioperative deaths (defined as deaths occurring during or after invasive therapeutic or diagnostic procedures, up to a week after discharge, and excluding cases of major trauma from suicides, homicides, as well as road and industrial accidents) reported to the Coroner, for which autopsies were conducted at the Department of Forensic Medicine from 1995 to 1997. RESULTS: The necropsy incidence of 4.4% (270/6074) represented a significant rise over the previous triennia (P < 0.01). As in previous years, there was a predominance of males (M:F = 1.65:1) and middle-aged to elderly patients (range 0 to 92 years, mean 55.8 years, median 63 years), most of whom had died after a variable, but usually brief, postoperative interval [0 to 97, 4.2, 1 day(s)] and a more variable period of hospitalisation (< 1 to 289, 12.6, 7 days). A total of 408 invasive procedures were performed, amounting to an average of 1.5 per patient; 101 patients (37.4%) underwent multiple (> 1) interventions, which were initially classified as elective procedures in 27 cases. There were 66 (24.4%) iatrogenic deaths, of which 2 (0.7%) were due to anaesthetic mishaps; 18/64 iatrogenic deaths, unrelated to anaesthesia, occurred after the first postoperative day. The proportions of such deaths amongst patients subjected to multiple interventions, or initial elective procedures, were more than twice as high as amongst those undergoing single procedures, and those initially classified as emergencies (35.6% versus 16.6% and 33.3% versus 13.2%, respectively; P < 0.01). Only 51/66 (77.3%) iatrogenic deaths received Coroner's verdicts of misadventure; no verdict of criminal negligence was recorded during the period in question. CONCLUSIONS: There appears to have been a steady increase in the number of perioperative deaths reported to the Coroner over the previous triennia (1989 to 1997) for which autopsies were conducted. While this observation may not denote an increase in perioperative morality rates per se, it may be indicative of an increasingly "aggressive" or defensive approach to the clinical management of seriously ill patients, particularly over the past decade. Although the rate of iatrogenic deaths appears to have stabilised, it is too early to say whether this apparent trend will persist in the future. It is perhaps not surprising that the risk of iatrogenic injury appears to increase with the number of interventions performed; however, it is not clear why initial, supposedly elective, interventions should be associated with an apparently greater risk of iatrogenic injury than those classified as emergency procedures. The substantial divergence between the autopsy finding of an iatrogenic death and the corresponding Coroner's verdict of misadventure may be comforting to clinicians, but certainly warrants further examination.
The authors undertook a review of fatal falls from a height, that occurred in 1991-92 in Singapore, with the objective of constructing mathematical models relating the height of fall to the injuries sustained. The 603 cases studied showed a mean age of 41.4 years with a male to female ratio of approximately 2:1. A sub-sample of 416 (69%) of these subjects had fallen from known heights (mean, 26.9 m; range, 3-69.6 m) and were studied in further detail. Bivariate analysis of this group showed that their injury severity score (ISS) was significantly correlated with the height of fall (H) and age (P < 0.01; r = 0.412 and 0.187, respectively). As the ISS is not strictly a continuous variable and varied markedly with H, it was categorised into bands (ISSB) before being subjected to further analysis. Regression modelling to adjust for mutual confounding showed that both height of fall and age were significant independent determinants of the ISSB (P < 0.0001). A model with H as the dependent variable was then constructed to relate the height of fall to ISSB and other statistically significant indicators of the extent and the severity of the injuries sustained. A second model with bands of height (HB) as the dependent variable was similarly constructed to assess the effect of banding both height and ISS. Our findings suggested that the height of fall was significantly associated with age, ISS and the extent of injury (mostly AIS > or = 3), and confirmed the usefulness of these models for investigative purposes. Statistical models could be designed and used to assess any apparent discrepancy between injury severity as determined at autopsy and the suspected/alleged height of fall.
An unusual case of metastatic bronchioloalveolar carcinoma of the lung presented as a pituitary tumour in a young adult Chinese female, who subsequently died after having undergone trans-sphenoidal resection. Metastatic cancers of the pituitary are uncommon even in necropsy series and rarely give rise to clinical symptoms. This case draws attention to the fact that, although uncommon, pituitary metastases have been noted with increasing frequency and their distinction from primary pituitary tumours is often difficult. A metastatic pituitary tumour may be the initial presentation of an unknown primary malignancy, wherein the metastatic deposits may also be limited to the pituitary gland. Clinicians and pathologists alike should consider a metastatic lesion in the differential diagnosis of a non-functioning pituitary tumour.
The authors reviewed 369 consecutive pedestrian fatalities, which occurred from 1990 to 1994. This represented 28.5% (range 23.3 to 37.2; 95% CI 26% to 31%) of all road accident autopsies during that time. The mean and median ages of this population were 51 (95% CI 48.63 to 53.37) and 54 years, respectively. There were 160 (43.3%) who were in the economically productive ages of 20 to 59 years. Of the 369 victims, 224 (60.7%) were males and 145 (39.3%) females, there being a preponderance of males across all age groups. Most of these accidents occurred during the hours of daylight and in conditions of good weather and visibility. It was estimated that pedestrian behaviour contributed, in part, to at least three-quarters of these fatalities. The majority of these pedestrians died from multiple injuries (181; 49.1%) and closed head injury (146; 39.6%). The vast majority of subjects (357; 96.7%) had injury severity scores (ISS) > or = 16. A total of 100 subjects (27.1%) died at the sites of the accidents. Of these, 99 had ISS > or = 16, with 31 having had ISS = 75 (maximum score). Similarly, all 55 deaths that occurred in the A & E departments were associated with ISS > or = 16, with 6 having ISS = 75. This would imply that most of the deaths that had occurred on site and at A & E departments were not unexpected. Interestingly, no pedestrian aged < or = 12 years had an ISS < or = 16, suggesting that they may be more vulnerable to serious or life-threatening injury than adults. There were 46 (12%) victims who had detectable levels of ethanol in their blood samples, of whom, 10 had ISS = 75. However, the difference between the latter proportion and that of the rest of the pedestrian population who had no alcohol detected in their blood samples (31/323), was only marginally significant (95% CI 0.002 to 0.245). There was a high prevalence of pre-existing and intercurrent diseases, such as ischaemic heart disease (58.8%), hypertensive heart disease (30.4%), chronic obstructive airways disease (47.4%), bronchopneumonia (18.2%) and evidence of systemic hypertension (40.7%). It is submitted that the existence of these underlying conditions should be anticipated, or suspected, in the management of injured pedestrians, particularly the elderly, as they may influence the outcome of their critical care.
The authors reviewed a total of 481 deaths, which occurred in an accident and emergency (A&E) department of a major general hospital, over a 3-year-period, from 1 January, 1992 to 31 December, 1994. Of these, 428 (89.0%) were referred to the coroner, with full medico-legal autopsies being conducted in 236 (55.1%) of the latter. There was a marked preponderance of male subjects (male:female ratio = 1.86) and, not unexpectedly, the likelihood of an autopsy being performed decreased with the patient's age. Nevertheless, all patients who died from trauma (or unnatural causes) underwent autopsies, irrespective of age. In all, autopsies were conducted for 70 traumatic and 166 natural deaths, with the mean age (95% CI) of the former group being some 19 years less than that of the latter (33.2 (28.4-38.1) vs. 52.0 (48.6-55.4), (P < 0.001). A comparison of the provisional causes of death (as recorded by the attending physicians in their clinical notes) with the autopsy findings yielded a higher diagnostic accuracy for traumatic deaths than for natural fatalities (correct diagnoses: 44/70 vs. 36/166; discordant diagnoses: 2/70 vs. 24/166, P < 0.01). This difference was accentuated after the patients who were dead upon arrival were excluded (44/55 vs. 36/96; 2/55 vs. 24/96, P < 0.005). As the injury severity score (ISS) is closely correlated with mortality, the autopsy findings were also used to calculate these values for 59 of a total of 70 patients who died from trauma or from unnatural causes. This showed that 24 had scores of 75 (incompatible with life), while 33 had ISS values above 16 (poor prognosis). The remaining 11 cases were not amenable to evaluation by means of the ISS. It was estimated that in approximately a third (18/55) of the misdiagnosed and undiagnosed natural fatalities, a correct diagnosis might have substantially altered acute management. This, in turn, could have improved patient survival, at least at the A&E level. By comparison, the perceived clinical impact of wrong diagnoses (two) and failure to diagnose (four) on traumatic deaths would have been almost negligible, as these patients generally had ISS values ranging from 30-75, with only one notable exception where the score was 10. Generally, given the circumstances under which physicians are required to work in A&E departments, the time spent with each patient is necessarily short. Furthermore, as there is usually limited access, if at all, to patients' medical records, very little relevant clinical or thanatological information is available, when death occurs. Therefore, in this instance, the medico-legal autopsy assumes the role of being an important investigative tool for the emergency physician. It may also contribute, substantially, towards medical audit and the enhancement of physicians' clinical acumen.
A total of 206 cases of sudden infant deaths examined at the Institute of Science and Forensic Medicine, Singapore, over a 5 year period (1989-93) were identified to assess the pattern of sudden death in this age group, which was subdivided into the neonatal and post-neonatal periods. A total of 34% (70) of infant deaths occurred in neonatal life and the remaining 66% (136) in the post-neonatal period; 90% of the neonatal deaths were natural, of which over half were due to congenital heart disease and complications of prematurity. Unnatural deaths in this period were uncommon, there being only seven such deaths. In the post-neonatal period, unnatural deaths constituted 25% of the total with trauma and aspiration heading the list. Natural deaths in the post-neonatal period are predominantly due to infections (34%) and a group of sudden natural deaths with minimal findings (31%). The latter group may arguably represent cases of Sudden Infant Death Syndrome (SIDS). The yearly incidence of this group in our study varied between 0.08 to 0.2 per 1000 live births, which is considerably lower than the incidence quoted for Western populations. The criteria for the classification and the impact of sudden infant deaths in Asian countries are discussed.
A patient with acute lymphoblastic leukaemia was mistakenly given vincristine intraventricularly, as part of an intensified course of chemotherapy. Despite a CNS washout and supportive treatment, the patient developed progressive ascending paralysis, gradually lapsed into coma and died some 10 days later. Autopsy and post-mortem histological examination showed evidence of brain death caused by florid encephalomyelitis, apparently induced by the intraventricular administration of vincristine.
An earlier retrospective, clinicopathological review of 132 perioperative Coroner's autopsies (excluding cases of preoperative major trauma), conducted by the Department of Forensic Medicine during the period from January 1989 to December 1991, showed that such cases accounted for an average of 2% of all Coroner's autopsies performed during that time. Of these, 15.2% were iatrogenic deaths which were unrelated to anaesthetic complications. Over the subsequent 3-year period (January 1992 to December 1994), there were 170 similar cases, arising from a total of 6468 Coroner's autopsies, representing a composite necropsy incidence of 2.6% (annual incidence: 2.5% to 2.8%) and an absolute increase of 38 cases over the previous period (P < 0.05). Also, the proportion of non-anaesthetic, iatrogenic deaths almost doubled to 28.8% (P < 0.02). Although these observations do not, considered alone, denote a rise in perioperative mortality during the second period (1992 to 1994), as compared to the first, since both studies were limited to deaths reported to the Coroner, they do seem to emphasize the need for a comprehensive ongoing clinical and medico-legal audit of perioperative deaths locally. At present, the proportion of perioperative deaths which are not reported to the Coroner and, thereby, escape medico-legal review, remains undertermined. In addition, as at the end of June 1995, only 23 of 51 pathologically unnatural deaths received a Coroner's verdict of misadventure, with an additional 11 such cases pending inquiry. This rather wide divergence between medical opinion and legal judgement could be a subject of further research.
A 5-year retrospective study of 140 necropsies conducted on drivers of vehicles (excluding motorcyclists) involved in fatal motoring events, drawn from 1285 traffic deaths, showed a marked preponderance of males (95%) and of Chinese subjects (87.1%), with over half (53.6%) aged between 20 and 39 years. Approximately a third was free of morphological evidence of natural disease, while the remainder showed evidence of various combinations of ischaemic heart disease (64.3%), hypertensive heart disease (38.6%), chronic obstructive airways disease (25.7%), benign hypertensive nephrosclerosis (15%), cerebral atheroma (15%) and other conditions. While the majority succumbed to the effects or complications of severe trauma, 35 subjects (25%) died from natural (that is, non-traumatic) causes, with 17 or almost half of these having occurred as sudden deaths "at the wheel", not associated with any form of collision. The mean age of the former (traumatic deaths) was 35.3 years while that of the latter (natural deaths) was 55.2 years (P < 0.001). Notably, ischaemic heart disease was the predominant natural cause, accounting for 31 of all such cases, none of which resulted in death or injury to any passenger, pedestrian or another motorist. It was also the cause of death in 12 vocational drivers, corresponding to 0.9% of all traffic deaths during this period. Although 34 drivers (24.3%) had detectable blood ethanol levels at autopsy, of which 28 (20%) exceeded the current legal limit of 80 mg/100 ml, all of the cases where death was attributed to natural causes were free of ethanol. However, 15 subjects (10.7%) who had died from trauma but had significant underlying pathology, comprising 13 cases of ischaemic heart disease, had blood ethanol concentrations well above the legal limit. It is possible that, in at least some of the latter, alcohol consumption might have acutely aggravated the underlying pathology and combined to contribute to the occurrence of these fatal accidents.
An elderly patient with borderline tuberculoid Hansen's disease (leprosy) developed the diaminodiphenylsulphone syndrome after approximately 8 weeks of multi-drug therapy comprising dapsone and rifampicin. Postmortem histological examination, following autopsy, demonstrated features consistent with drug-induced hepatitis, tubulo-interstitial nephritis and myocarditis. Although these could have been engendered by dapsone toxicity, it was thought that a concommitant adverse reaction to rifampicin, which is known to be hepatotoxic, nephrotoxic and possibly capable of predisposing to the dapsone syndrome, could not be excluded.
Three patients with end-stage renal failure died from acute haemorrhage which, in the first two cases, was related to the use of internal jugular catheters for haemodialysis. In the third instance, severe haemorrhage was caused by the apparent self-insertion of a 16-gauge butterfly needle, connected to a siliconised cannula (also designed for haemodialysis) into the superficial median cubital vein of the left forearm. The hazards associated with the use of internal jugular catheters and the medicolegal implications of these cases are briefly discussed.
A medico-legal autopsy conducted on a young Chinese man, a victim of sudden unexpected death, with a vague and unconfirmed history of congenital cardiovascular disease, revealed the presence of a congenital right coronary artery (arteriosystemic) fistula communicating with the markedly hypertrophied left ventricle, which showed microscopic evidence of myocardial ischaemia. The pathology of this rare condition is described and briefly reviewed.