The presence of disseminated tumour cells in the bone marrow is inversely related to circulating free DNA in plasma in breast cancer dormancy.

BACKGROUND: The aim of this study was to gain insight into breast cancer dormancy by examining different measures of minimal residual disease (MRD) over time in relation to known prognostic factors. METHODS: Sixty-four primary breast cancer patients on follow-up (a median of 8.3 years post surgery) who were disease free had sequential bone marrow aspirates and blood samples taken for the measurement of disseminated tumour cells (DTCs), circulating tumour cells (CTCs) by CellSearch and qPCR measurement of overlapping (96-bp and 291-bp) amplicons in circulating free DNA (cfDNA). RESULTS: The presence of CTCs was correlated with the presence of DTCs measured by immunocytochemistry (P=0.01) but both were infrequently detected. Increasing cfDNA concentration correlated with ER, HER2 and triple-negative tumours and high tumour grade, and the 291-bp amplicon was inversely correlated with DTCs measured by CK19 qRT-PCR (P=0.047). CONCLUSION: Our results show that breast cancer patients have evidence of MRD for many years after diagnosis despite there being no overt evidence of disease. The inverse relationship between bone marrow CK19 mRNA and the 291-bp amplicon in cfDNA suggests that an inverse relationship between a measure of cell viability in the bone marrow (DTCs) and cell death in the plasma occurs during the dormancy phase of breast cancer.

Comparison of bone marrow, disseminated tumour cells and blood-circulating tumour cells in breast cancer patients after primary treatment.

The purpose of this study was to determine whether primary breast cancer patients showed evidence of circulating tumour cells (CTCs) during follow-up as an alternative to monitoring disseminated bone marrow tumour cells (DTCs) by immunocytochemistry and reverse transcriptase (RT)-PCR for the detection of micrometastases. We planned to compare CTC and DTC frequency in low-risk and high-risk patients. We identified two cohorts of primary breast cancer patients who were at low (group II, T(1)N(0), n=18) or high (group III, >3 nodes positive (with one exception, a patient with two positive nodes) n=33) risk of relapse who were being followed up after primary treatment. We tested each cohort for CTCs using the CellSearch system on 1-7 occasions and for DTCs by immunocytochemistry and RT-PCR on 1-2 occasions over a period of 2 years. We also examined patients with confirmed metastatic disease (group IV, n=12) and 21 control healthy volunteers for CTCs (group I). All group I samples were negative for CTCs. In contrast, 7 out of 18 (39%) group II primary patients and 23 out of 33 (70%) group III patients were positive for CTCs (P=0.042). If we count only samples with >1 cell as positive: 2 out of 18 (11%) group II patients were positive compared with 10 out of 33 (30%) in group III (P=0.174). In the case of DTCs, 1 out of 13 (8%) group II patients were positive compared with 19 out of 27 (70%) in group III (P<0.001). Only 10 out of 33 (30%) patients in group III showed no evidence of CTCs in all tests over the period of testing, compared with 11 out of 18 (61%) in group II (P=0.033). A significant proportion of poor prognosis primary breast cancer patients (group III) have evidence of CTCs on follow-up. Many also have evidence of DTCs, which are more often found in patients who were lymph node positive. As repeat sampling of peripheral blood is more acceptable to patients, the measurement of CTCs warrants further investigation because it enables blood samples to be taken more frequently, thus possibly enabling clinicians to have prior warning of impending overt metastatic disease.

Cancer patterns in Karachi division (1998-1999).

OBJECTIVE: A minimal cancer incidence data for Karachi, the largest city of Pakistan, is being presented here, for the years 1998-1999. The city has a population of 9,802,134; males 5,261,712 (52.6%) and females 4,540,422 (47.4%); census 1998. METHODOLOGY: A predominantly mixed (passive and active) registration system has evolved in Karachi, the data sources being the hospitals within the Karachi Division. The reported/retrieved cancer data sets at the Karachi Cancer Registry are checked, coded, computerised in an analytical format and analysed. RESULTS: The incident cancer cases registered in Karachi, during the 2-year period, 1st January 1998 to 31st December 1999 were analysed. The age-standardised incidence rate (ASR) of cancer, all sites was 132.4/100,000 for the males. Cancer of the lung 10.8%; ASR 17.3 was the most frequently recorded malignancy, followed by oral cavity 10.5%; ASR 13.2 and larynx 5.0%; ASR 7.4. The age-standardised incidence rate (ASR) of cancer, all sites was 133.0/100,000 in the females. Cancer of the breast, 32.0%; ASR 40.7 was the most frequently recorded malignancy, followed by oral cavity 8.1%; ASR 11.7 and gall bladder 3.6%; ASR 5.5. CONCLUSION: The present data has been calculated with an estimated 15-20% probable under ascertainment. Tobacco-associated cancers in Karachi were responsible for 38.3% of the tumours diagnosed amongst the males. Two principal cancers, breast and oral cavity were responsible for 40.1% of the cancers in females. A rare finding was the high incidence of gall bladder cancer in the females. At present it is difficult to determine whether this indicates a genuine high risk or a selection bias. A continuous process of cancer registration to study the trends in the incidence and an adequate cancer control program are possible and essential for Pakistan and can be based on the pattern being practiced in Karachi.

HIV associated thrombotic microangiopathy.

Thrombotic microangiopathy (TMA) is a known complication of HIV infection. Endothelial cell injury appears to be the primary event causing platelet activation and deposition in the microvasculature. Direct cytopathic roles of HIV as well as other factors such as malignancy, drugs, and infectious agents have been implicated in the pathogenesis of HIV-TMA. Although the the majority of patients present in a more advanced stage of HIV disease, TMA can be the initial presenting symptom of HIV infection. Clinical features are those of idiopathic TMA, and the diagnosis should be suspected in any patient with new onset thrombocytopenia and microangiopathic haemolytic anaemia. Therapy with plasma exchange or infusion appears to be efficacious. A rapid diagnosis and institution of plasmapheresis is crucial for a favourable outcome. The long term prognosis of HIV-TMA is unfavourable and may depend on the stage of HIV infection. The recent data after the use of highly active retroviral treatment, however, are unavailable and current prognosis is therefore uncertain.

Lipids in biliary lithogenesis.

Serum and biliary lipoproteins, total cholesterol (Tc) and triglycerides (TG) were measured in patients with gallstones and in those without gallstones. Serum and biliary LDLc, TG and Tc were significantly higher (P < 0.001) in cases having gall stones than those without stones while HDLc were low (P < 0.001) in those with stones. No difference was found in very low density lipoproteins (VLDLc) in the two groups. Present data showed that there is a statistically significant correlation of serum and biliary lipoproteins specifically LDLc and HDLc (r = +.67 and r = +.56). This report shows that serum HDLc (67.42%) and LDLc (70.28%) play a more critical role in comparison to total cholesterol (59.43%) and triglyceride (57.15%) levels in the formation of gallstone.

Gender perspectives and quality of care in underdeveloped countries: disease, gender and contextuality.

There is indisputable evidence that health indices for women are far worse than those for men, yet women have limited access to health resources. Numerous reasons have been cited for the poor health of women, and include legal constraints to owning property, the lack of participation in the planning process, preferential treatment for boys, and social values, norms and customs. Most of the research on women while adequately documenting these facts, fails to contextualize them in a social, economic and political setting which is often responsible for the problems in the first place. This serious shortcoming negates the efficacy of the well-intentioned and well-meaning solutions in redressing the gender balance. Unless one examines the structural factors which actually cause disease, both in men and women in underdeveloped countries, solutions will be ineffective. The paper also highlights the important fact that there are many more similarities between men and women of the same social class than is appreciated, similarities which are possibly greater than those between the same gender across different social classes.

Detection of embryologic ventral pancreatic parenchyma with endoscopic ultrasound.

BACKGROUND: The prevalence of detecting the embryologic ventral pancreas (ventral anlage) with endoscopic ultrasound (EUS) is unknown. PURPOSE: To determine the frequency of, and factors associated with, EUS findings consistent with the ventral anlage. METHODS: One hundred patients undergoing upper gastrointestinal EUS for any indication were prospectively evaluated for the presence of a focal, hypoechoic area in the pancreatic head using a radial scanning echoendoscope. Multiple clinical and EUS variables were tested against the ability to detect the ventral anlage. RESULTS: The overall detection rate of the ventral anlage was 59%. The ventral anlage was detected in 75% of patients undergoing EUS for nonpancreatic indications, compared to 40% of patients undergoing EUS to evaluate suspected pancreatic disease (p< 0.001). EUS detected the ventral anlage in 72% of patients with a normal EUS-appearing pancreatic head, compared to 29% of patients who had abnormal pancreatic head parenchyma (mass or chronic pancreatitis) on EUS (p < 0.001). Multivariate analysis revealed the only variable associated with detecting the ventral anlage was abnormal pancreatic head parenchyma on EUS. CONCLUSION: The ventral anlage is frequently detected during pancreatic EUS, with a significantly lower rate of detection in patients with EUS findings of a pancreatic head mass or diffuse chronic pancreatitis.

Short-term IgM and IgG antibody responses to hepatitis E virus infection.

53 adult patients with acute hepatitis caused by hepatitis E virus were identified by the presence of IgM antibody to hepatitis E virus, and followed for 12 months to evaluate the kinetics of anti-HEV antibodies. All but 1 female Kuwaiti patient were expatriate workers from the Indian subcontinent, temporarily working in Kuwait. Follow-up samples obtained at 1, 3, 6 and 12 months were evaluated for IgM and IgG antibodies to hepatitis E virus. IgM-class antibodies to hepatitis E virus were detectable in 12/27 (44%) patients at 1 months, in 0/26 at 3 months, in 0/8 at 6 months and 0/6 at 12 months. IgG antibodies to hepatitis E virus were detectable in 46/47 (98%) at onset, 26/27 (96%) at 1 month, in 26/29 (90%) at 3 months, 16/16 (100%) at 6 months and 8/8 (100%) at 12 months of follow-up. This study suggests that IgM antibodies to hepatitis E virus decline rapidly after an acute infection but IgG antibodies to hepatitis E virus persists for at least 1 year in many patients.

Planning in the health sector: for whom, by whom?

To state that there are vested interests in health planning is to state the obvious. One can identify numerous actors ranging from international agencies, government officials, pharmaceutical companies, health personnel and community and citizen's groups which would like to stake a claim on the direction and nature of planning and implementing health policy. We argue that the role of specific actors can only be seen in the broader social, economic and ideological framework which, consequently, determines the working of the model of health care. Probably the most important factor influencing health planning is the influence of international donors, governments and agencies. The present ideological tilt towards the market, privatization, less government and more liberalization, has had important repercussions on health planning and delivery. Furthermore, the debt crisis, and the stabilization and structural adjustment programmes being followed by a very large number of underdeveloped countries, are transforming health systems. Essentially, vested interests in health planning within countries, need to be seen in the light of recent ideological and economic changes, and international relations of aid, power and domination.

Control of poliomyelitis in Kuwait.

The use of oral poliovirus vaccine (OPV) in the early 1960s marked the beginning of the State's effort in controlling poliomyelitis in Kuwait. During the next two decades, despite the vaccine's availability and use, the disease continued to cause disability and death. However, with the massive and sustained use of the trivalent OPV since 1963G and the introduction of neonatal supplementary immunization with monovalent type 1 (MOPV) in 1976G along with strengthening of the surveillance activities against poliomyelitis, the incidence of the paralytic disease began declining and by the mid-eighties it disappeared altogether. With no cases of paralytic poliomylelitis reported in Kuwait since 1986G, the disease is largely controlled. The epidemiology of poliomyelitis in Kuwait has been examined here in retrospect. The paper profiles about 3 1/2 decades (1958G to 1992G) of efforts that led to this impressive virtual elimination of poliomyelitis. In order to maintain this status and eventually achieve the goal of eradication without the rare occurrence of vaccine-associated paralysis, it is, in our opinion, necessary to adopt an approach of combined vaccination with the inactivated polio vaccine (IPV), preferably in the neonatal age, followed by OPV. Simultaneously, monitoring the presence and circulation of wild poliovirus in the environment and continuous surveillance should be carried out for timely intervention.

Biochemical alterations in the levels of DNA, RNA and protein in discrete areas of rat brain following Nuvacron toxicity.

The levels of DNA, RNA and Protein were estimated in cerebral hemisphere, cerebellum and brain stem of male albino rats with Nuvacron (0, 0, dimethyl-0-1 methyl 3-methylamino-3-oxe-1-propenyl phosphate) 4 mg/kg body weight intraperitoneally (i.p.) daily for 10 days. The daily i.p. dose of Nuvacron depleted the level of DNA and protein in all brain regions. Increased level of RNA was observed in cerebral hemisphere, cerebellum and brain stem.

Poverty and disease: need for structural change.

In underdeveloped countries, more than 70% of the population suffers from infectious and communicable diseases. These diseases are transmitted with the help of poor water, sanitation, housing, etc. Further, education and nutrition also affect the vulnerability of the individual. All these factors responsible for disease, are themselves dependent on income--the lower the income, the lower education and nutritional status, and the poorer quality the water, and housing. An increase in the absolute income for some, and a redistribution of income for all, are necessary to cure the ills of society. It is possible to increase the real income of individuals by giving them hand-outs or dealing with the problems of their 'basic needs'. However, these approaches do not take into account the underlying factors responsible for disease, and are severely limited in scope. The elite in a country, who, to a great extent, determine the role of the State and of the government, are only willing to give a certain amount of charity, and nothing more. They will, clearly never give to the poor, so much that their own (relative and absolute) position is threatened. The only way possible is through a government which works for the majority of the people, rather than for a small elite.

The release of luteinizing hormone from pituitaries perifused with thymic extracts.

Medium obtained by the perifusion of fragments of adult male CSE rat thymuses stimulates the release of luteinizing hormone (LH) from the anterior pituitary gland in vitro. The release of the stimulatory factor/s from the thymus appears to be stimulated by the depolarizing concentration of K+ and to be Ca++-dependent. Perifusates from heart, liver and spleen did not elicit the response suggesting that the effect is specific to the thymus gland. Neither LH nor its releasing hormone, LHRH, were detectable in the thymus perifusates by RIA. Levels of facteur thymique serique (FTS), as measured by bioassay are highest in K+ stimulated fractions that exhibit the greatest LH releasing activity. In separate experiments in vitro FTS, but not two other thymic peptides, thymopoietin and thymosin alpha 1, caused a dose-related release of LH from pituitary tissue. That ability of thymic perifusates to cause the release of LH was age-related because tissue from neonatal and ageing males failed to release compounds with any significant effect on the pituitary release of LH. However, when the thymus was enlarged in ageing rats as a result of orchidectomy 1 month before sacrifice LH release was similar to that observed in young male adults.

Significance of blood lactate levels in critically ill patients with liver disease.

Lactic acidosis unrelated to tissue hypoxia has been described in patients with liver disease. This raises questions regarding the utility of the arterial lactate level as an indicator of tissue hypoperfusion in critically ill patients with hepatic dysfunction. The incidence of hyperlactatemia in a group of critically ill patients with liver disease and its association with clinical indicators of circulatory shock as well as hospital mortality were examined. The medical records of all patients admitted to the medical intensive care unit of Detroit Receiving Hospital between July 1, 1984, and June 30, 1985, with parenchymal liver disease and a total bilirubin level of more than 2 mg/dl were reviewed. Patients were excluded if lactate was not assayed. The severity of liver disease was assessed by Child's classification. Shock was defined as a systolic blood pressure of less than 90 mm Hg and at least two of the following: urine output of less than 20 ml/hour, evidence of decreased skin perfusion, or acutely altered mentation. These criteria were met in 35 patients; three patients had two medical intensive care unit admissions separated by more than one week. There were two patients in Child's class A, three in class B, and 30 in class C. Shock was identified in 27 of the 38 medical intensive care unit admissions. In the group with shock, the maximal lactate level ranged from 1.2 to 30 mM (mean, 9.6). The lactate level was significantly lower (p less than 0.0005) in the group without shock, ranging from 0.6 to 2.0 mM (mean, 1.3). The mean bilirubin level was significantly higher in the group without shock (16.7 mg/dl) than in the group with shock (8.5 mg/dl). A maximal arterial lactate concentration of more than 2.2 mM was significantly associated with hospital mortality. Thus, lactic acidosis in critically ill patients with liver disease is associated with clinical evidence of shock and with increased hospital mortality.

Undergraduate medical education in underdeveloped countries: the case of Pakistan.

The type of medical education of a country is closely linked with its system of health care. Any health care system, with its own peculiarities, requires a certain type of doctor who can function effectively in the given environment. The same is the case with underdeveloped capitalist countries, such as Pakistan, where a skewed, elitist, curative model of health care exists. In Pakistan, where the literacy levels in the native tongue are very low, medicine is taught in English, and nearly all prescribed textbooks are written in and for the West. Conditions specific to Pakistan, such as the degree of cheating in exams, the time lost due to closure, and the level of debate concerning the medical system may find their parallels in other UDCs. Since it is the social and economic forces, which, in the final analysis, determine the system of health care and medical education, one cannot expect any significant improvement within the existing class structure. Only in a country where the masses have control over the production and distribution of resources, can the systems of health care and medical education be brought in line with the real needs of the community and of the country.

Why medical students will not practice in rural areas: evidence from a survey.

A survey of medical students was held in order to determine the reasons why they were not willing to set up practice in rural areas after graduation. The reasons they gave were quite typical: lack of facilities, lack of opportunities for themselves and their family, poor income, etc. We also discovered that not many were acquainted with rural health conditions and a very great percentage wanted to go to the West for specialisation. We have tried to set their responses in light of the socio-economic and political system prevalent in a typical capitalist UDC. The conclusion that we have reached is that it is the class system in these societies which has determined the responses of the students, and it is the main factor which causes a dearth of medical manpower in rural areas.

Measles and age of vaccination.

Measles is responsible for high morbidity and mortality in children particularly in developing countries. Infants, found by analytical studies to constitute a high risk group, are usually not covered by current vaccination programmes. In Kuwait in the epidemic years during the period 1976-1982, the incidence of measles in infants under one year was found to be more than five times that in the population over one year of age, ranging between 758 and 992 per 100000 live births. During this period as many as one fifth of the total cases (13.3-21.7%) and about one-third of the total deaths (35%) occurred in infants. The mean fatality rate for infants under one year was 3.3 while for the population one year and above it was 1.4. As the immunity derived from the mother declines markedly a large majority of children over six months of age become susceptible to measles. There is a strong case for lowering the age of vaccination against measles to protect the infants, at least in the developing countries, and to control and eventually eradicate the disease.

Observations on haemodynamic effects of mexiletine.

The haemodynamic effects of intravenous mexiletine have been studied in 16 patients with valvular heart disease without clinical evidence of heart failure. A bolus injection of 150 mg administered to 6 of the 16 patients resulted in a mean plasma concentration above the therapeutic range for at least 5 minutes after the drug was given. A small but significant rise in the mean pulmonary artery pressure occurred. In 10 patients, the effects of intravenous mexiletine were compared with those of intravenous saline in a double blind trial. No significant difference was found in the haemodynamic effects, though both saline and mexiletine produced a small rise in the mean pulmonary artery pressure. Mexiletine when administered to patients without heart failure in doses known to be clinically effective did not have important adverse haemodynamic effects.