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.

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.

Comparison of the effects of isoprenaline, orciprenaline, salbutamol and isoetharine on the cardiovascular system of anaesthetized dogs.

1. The intravenous injection of isoprenaline, orciprenaline, salbutamol and isoetharine increased heart rate in anaesthetized dogs. Log dose-response curves obtained with a series of doses of salbutamol and isoetharine were flatter than those for isoprenaline and orciprenaline. The order of activity of the drugs in increasing heart rate was isoprenaline, orciprenaline, and salbutamol=isoetharine.2. The injection into the external iliac artery of isoprenaline, orciprenaline, salbutamol and isoetharine produced dose dependent increases in femoral blood flow. Log dose-response curves for all drugs were parallel. The order of activity of the drugs was isoprenaline, salbutamol=isoetharine and orciprenaline.3. Salbutamol and isoetharine were less active than orciprenaline in increasing heart rate but more active in increasing femoral blood flow.4. These observations indicate that salbutamol and isoetharine have a greater effect on beta(2) than on beta(1)-adrenoceptors in the cardiovascular system.

Effects of lignocaine and propranolol on experimental cardiac arrhythmias.

1. The effects of intravenous injection of lignocaine and propranolol were studied in dogs.2. Ventricular ectopic beats produced by intravenous injection of adrenaline in anaesthetized dogs respired with halothane were abolished in four out of six dogs by lignocaine. Propranolol was effective in all three dogs tested.3. Intravenous infusion of lignocaine at (0.2 and 1.0 mg/kg)/min to total doses of 3.0 +/- 1.0 and 2.2 +/- 0.5 mg/kg, respectively, abolished the ventricular tachycardia produced in anaesthetized dogs by ouabain. A similar effect was produced by infusion of propranolol at (0.2 mg/kg)/min to a total dose of 1.9 +/- 0.4 mg/kg. Intravenous injection of single doses of lignocaine (4.0-8.0 mg/kg) also abolished the arrhythmia.4. The frequency of the ventricular ectopic beats occurring in conscious dogs 20-44 h after ligation of the anterior descending branch of the left coronary artery was reduced, with an increase in the number of sinus beats, after intravenous injection of lignocaine (8.0 mg/kg). Larger doses produced excitement. Propranolol (4.0 mg/kg) had a greater effect than the same dose of lignocaine but after 8.0 mg/kg, three of the four dogs died.5. Propranolol was more effective than lignocaine in abolishing the three different types of arrhythmia.6. Dose-response curves showed that lignocaine was more active in abolishing the ouabain induced arrhythmia than the halothane-adrenaline arrhythmia and was least active on the arrhythmia caused by ligation of the coronary artery.

The effect of Kö 1173, a new anticonvulsant agent on experimental cardiac arrhythmias.

1. The effects of the intravenous injection of Kö 1173, a new anticonvulsant drug, phenytoin and procainamide were studied on three types of cardiac arrhythmia in dogs.2. Ventricular ectopic beats produced by intravenous injection of adrenaline in anaesthetized dogs respired with halothane were abolished by Kö 1173, 0.6 +/- 0.1 mg/kg, phenytoin, 1.1 +/- 0.3 mg/kg and procainamide, 4.1 +/- 1.8 mg/kg.3. Ventricular tachycardia was produced in anaesthetized dogs by the intravenous injection of ouabain and the three drugs infused intravenously at 0.2 (mg/kg)/min until sinus rhythm returned. Kö 1173 was effective in 8 out of 9 dogs after a mean dose of 1.3 +/- 0.3 mg/kg; phenytoin in all 3 dogs after 2.7 +/- 0.6 mg/kg and procainamide in the 3 dogs tested after 16.6 +/- 1.3 mg/kg.4. The intravenous injection of Kö 1173, 8.0 mg/kg, greatly reduced the number of ventricular ectopic beats occurring in conscious dogs 18-44 h after ligation of the anterior descending branch of the left coronary artery, with a resultant increase in the number of sinus beats. Phenytoin, 8.0 mg/kg, had a similar effect but procainamide was much less effective.5. These results indicate that Kö 1173 is effective in abolishing experimental cardiac arrhythmias and suggest that its effects should be studied in 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.

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.

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.

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.

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.

Hemodynamic effects of arteriovenous fistula and bovine graft fistula used for hemodialysis.

This study shows that arteriovenous fistulas created for vascular access to hemodialysis result in an increase in cardiac output and pulse rate, and a decrease in the total peripheral resistance. These changes are severe with bovine graft fistula; physicians should be aware of this potentially dangerous hemodynamic change in these patients.

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.

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.

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.

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.