History of the National Health Service

The name National Health Service (NHS) is used to refer to the free public health services of England, Scotland and Wales, individually or collectively. Northern Ireland is known as 'Health and Social Care' to promote its dual integration of health and social services.
For details of the history of each National Health Service, particularly since 1999, see:
The NHS was one of the first universal health care systems established anywhere in the world. A leaflet was sent to every household in June 1948 which explained that
The NHS in Scotland was established as a separate entity with its own legislation, the National Health Service (Scotland) Act 1947, from the foundation of the NHS in 1948. Northern Ireland likewise had its own legislation in 1948. Wales, however, was managed from England and treated much like an English region for the first 20 years of the NHS. In 1969, responsibility for the NHS in Wales was passed to the Secretary of State for Wales from the Secretary of State for Health, who was thereafter just responsible for the NHS in England.
Background.
Dr Benjamin Moore, a Liverpool physician, in 1910 in "The Dawn of the Health Age" was probably the first to use the words 'National Health Service'. He established the State Medical Service Association which held its first meeting in 1912 and continued to exist until it was replaced by the Socialist Medical Association in 1930.
Before the National Health Service was created in 1948, patients were generally required to pay for their health care. Free treatment was sometimes available from charitable voluntary hospitals. Some local authorities operated hospitals for local ratepayers (under a system originating with the Poor Laws). The London County Council (LCC) on 1 April 1930 took over from the abolished Metropolitan Asylums Board responsibility for 140 hospitals, medical schools and other medical institutions. The Local Government Act 1929 allowed local authorities to run services over and above those authorised by the Poor Laws and in effect to provide medical treatment for everyone. By the outbreak of the Second World War, the LCC was running the largest public health service in Britain.
Dr A. J. Cronin's controversial novel "The Citadel", published in 1937, had fomented extensive criticism about the severe inadequacies of health care. The author's innovative ideas were not only essential to the conception of the NHS, but his best-selling novels are also said to have greatly contributed to the Labour Party's victory in 1945.
Systems of health insurance usually consisted of private schemes such as friendly societies or welfare societies. Under the National Insurance Act 1911, introduced by David Lloyd George, a small amount was deducted from weekly wages, to which were added contributions from the employer and the government. In return for the record of contributions, the workman was entitled to medical care (as well as retirement and unemployment benefits) though not necessarily to the drugs prescribed. To obtain medical care, he registered with a doctor. Each doctor in General Practice who participated in the scheme thus had a 'panel' of those who have made an insurance under the system, and was paid a capitation grant out of the fund calculated upon the number. Lloyd George's name survives in the "Lloyd George envelopes" in which most primary care records in England are stored, although today most working records in primary care are at least partially computerised. This imperfect scheme only covered workers who paid their National Insurance Contributions and was known as 'Lloyd George's Ambulance Wagon'. Most women and children were not covered.
Foundation.
Bertrand Dawson was commissioned in 1919 by Christopher Addison, the first British Minister of Health to produce a report on "schemes requisite for the systematised provision of such forms of medical and allied services as should, in the opinion of the Council, be available for the inhabitants of a given area". An "Interim Report on the Future Provision of Medical and Allied Services" was produced in 1920, though no further report ever appeared. The report laid down plans for a network of primary and secondary health centres, and was very influential in subsequent debates about the National Health Service. However, the fall of the Lloyd George government prevented any implementation of those ideas at that time.
The Labour Party in 1932 accepted a resolution moved by Somerville Hastings calling for the establishment of a State Medical Service and in 1934 the Labour Party Conference at Southport unanimously accepted an official document on a National Health Service.
Prior to the Second World War there was already consensus that health insurance should be extended to the dependants of the wage-earner, and that the voluntary and local authority hospitals should be integrated. A British Medical Association (BMA) pamphlet, "A General Medical Service for the Nation" was issued along these lines in 1938. However, no action was taken due to the international crisis. During the war, a new centralised state-run Emergency Hospital Service employed doctors and nurses to care for those injured by enemy action and arrange for their treatment in whichever hospital was available. The existence of the service made voluntary hospitals dependent on the Government and there was a recognition that many would be in financial trouble once peace arrived. The need to do something to guarantee the voluntary hospitals meant that hospital care drove the impetus for reform.
In February 1941 the Deputy Permanent Secretary at the Ministry of Health recorded privately areas of agreement on post-war health policy which included "a complete health service to be available to every member of the community" and on 9 October 1941, the Minister of Health Ernest Brown announced that the government proposed to ensure that there was a comprehensive hospital service available to everyone in need of it and that local authorities would be responsible for providing it. The Medical Planning Commission set up by the professional bodies went one stage further in May 1942 recommending (in an interim report) a National Health Service with general practitioners working through health centres and hospitals run by regional administrations. When in 1942 Arthur Greenwood, the Labour Party Deputy Leader and cabinet minister with responsibility for post-war reconstruction, successfully pressed the cabinet to commission a report into social insurance from economist and social reformer William Beveridge, Beveridge attached an assumption to the Beveridge Report that this same idea would be implemented; his report stressed the importance of it.
Developing the idea into firm policy proved difficult. Although the BMA had been part of the Medical Planning Commission, at their conference in September 1943 the association changed policy to oppose local authority control of hospitals and to favour extension of health insurance instead of GPs working for state health centres. When Conservative MP and Health Minister Henry Willink prepared a white paper endorsing a National Health Service, it was attacked by Brendan Bracken and Lord Beaverbrook and resignations were threatened on both sides. However, the Cabinet endorsed the White Paper which was published in 1944. This White Paper includes the founding principles of the NHS: it was to be funded out of general taxation and not through national insurance, and services would be provided by the same doctors and the same hospitals, but:
Willink then set about trying to assuage the doctors, a job taken over by Aneurin Bevan in Clement Attlee's Labour Party government after the war ended. Bevan decided that the 1944 white paper's proposal for local authority control of voluntary hospitals was not workable, as he felt that local authorities were too small to manage hospitals. He decided that "the only thing to do was to create an entirely new hospital service, to take over the voluntary hospitals, and to take over the local government hospitals and to organise them as a single hospital service". This structure of the NHS in England and Wales was established by the National Health Service Act 1946 which received royal assent on 6 November 1946. The Act implemented a system where each person resident would be signed up to a specific general practitioner (GP) as the point of entry into the system, building on the foundations laid in 1912 by the introduction of National Insurance and the list system for general practice. Patients would have access to all medical, dental and nursing care they needed without having to pay for it at the time.
Many doctors were initially opposed to Bevan's plan, primarily on the grounds that it reduced their level of independence. The British Medical Association voted in May 1948 not to join the new service, but Bevan worked hard to bring them on board by the time the new arrangements launched on 5 July 1948 knowing that without doctors, there would be no health service. Being a shrewd political operator, Bevan managed to push through the radical health care reform measure by dividing and cajoling the opposition, as well as by offering lucrative payment structures for consultants. On this subject he stated, "I stuffed their mouths with gold".
Establishment.
In 1979 across the whole UK there were about 2,750 NHS hospitals with about 480,000 beds, accounting for about 70% of total NHS expenditure. About one-third of beds in England were then provided in new or converted accommodation built since 1948 with a higher proportion in Northern Ireland, but lower in Scotland and Wales. Beds for mental illness, geriatric patients and mental handicap were much more likely to be in older buildings than acute or maternity services.
The development of the workforce in the NHS.
The National Health Service was a major employer from its foundation. After nationalising Britain's voluntary and municipal hospitals, the new NHS took responsibility for 360,000 staff in England and Wales and a further 45,000 in Scotland. These included 9,000 full-time doctors (with thousands more consultants working in multiple part-time roles), 149,000 nurses and midwives (23,000 of whom were part-time), 128,000 ancillary staff (catering, laundry, cleaning and maintenance), 25,000 administrative and clerical staff, and 19,000 professional and technical staff, of whom the 2,800 physiotherapists, 1,600 laboratory technicians and 2,000 radiographers were the largest groups. This workforce would continue to grow throughout the 20th and 21st Centuries, overtaking the National Coal Board to become Britain's largest employer in 1961. By the end of the 1970s, the NHS had passed 1,000,000 staff and in 2015 was the world's fifth largest work organisation with 1.7m. Nurses are the largest single group of professionally qualified staff in the NHS, with 306,000 employed in English hospitals and community health services as at December 2020.
The workforce.
The NHS has long had one of Britain's most varied workforces, with employees from a diverse range of backgrounds in terms of class, occupation, gender, race and nationality. In the early NHS doctors were overwhelmingly men from middle and upper class backgrounds, and were often privately educated. Nurses in general hospitals were usually women and generally from a mixture of middle and working class origins. Men constituted a significant minority of nurses but were largely concentrated in mental hospitals, where their role historically had been more associated with manual labour, particularly the physical control of the patients. Professional organisations like the Royal College of Nursing tended to promote the idea that nurses were middle-class professionals, whilst trade unions encouraged nurses to see themselves as workers. Like nursing, ancillary tasks were also heavily gendered with portering and maintenance largely done by men, and laundry and cleaning largely women.
Increasing demand for health services led to a steady expansion in total staff numbers throughout the second half of the 20th Century and into the 21st century. However, NHS wage rates were usually comparatively low and hours often long and anti-social. Consequently, under conditions of full employment in the 1950s and 1960s the NHS experienced regular recruitment crises in virtually all categories of staff, particularly doctors and nurses in some peripheral provincial areas. One solution adopted by health authorities was to encourage married nurses to return to the workforce part-time. In Britain, historically many nurses expected to leave work after getting married and into the 1960s senior nursing posts were disproportionately likely to be held by unmarried women. Nurse training also had a very high drop out rate, in part related to students leaving to get married (in addition to rejection by some of the strict discipline imposed on them). Part-time work brought many of these women back into the workforce and the NHS was a key site in the growth of this kind of work in post-war Britain, employing 65,000 part-time ancillary staff (mostly domestics) and 79,000 part-time nurses and midwives by 1967.
Alongside this rise in part-time work, hospitals increasingly looked overseas for staff, recruiting particularly heavily in Britain's colonies from the 1950s. By 1955, the Ministry of Health had official recruitment campaigns in 16 British colonies and former colonies. By 1965, there were more than 3,000 Jamaican nurses working in British hospitals and in 1977, 12% of student nurses and midwives came from overseas, 66% of them from the Caribbean, with substantial numbers also coming from the Philippines and South Asia. Large numbers of ancillary staff also migrated to fill NHS vacancies. Doctors were also recruited from across Britain's colonies and former colonies, particularly from India, Pakistan, Bangladesh and Sri Lanka. Doctors born and qualified overseas constituted 31% of all doctors in 1971. Nurses and doctors recruited by the NHS were often marginalised in job allocation. Early nurse migrants were often forced to re-validate their qualifications on arrival in Britain and instructed to take the less academic State Enrolled Nurse (SEN) training, rather than the more prestigious State Registered Nurse (SRN) qualification. SENs had worse pay and fewer promotion prospects. Similarly, employment discrimination often meant South Asian doctors were forced into less desirable posts in run-down provincial hospitals.
The NHS was also a site of expansion in new categories of scientific and technical workers. In 1967, the service employed 31,000 professional and technical staff connected with diagnosis and treatment, including audiologists, biochemists, dietitians, more than 9000 laboratory technicians, occupational therapists, physicists, physiotherapists, psychologists and radiographers. This category of staff had more than doubled in size ten years later, rising to 64,700 people or 6.5% of the total workforce. Although at the start of the period many of these roles had relatively informal career paths, with individuals sometimes recruited as assistants before training as technicians, from the 1970s onwards it became increasingly common for roles to have more formal training schemes and associated degree courses. Professional associations like the College of Occupational Therapists and the Association for Clinical Biochemistry and Laboratory Medicine became better organised and took a greater role both in regulating their professions and in collective bargaining with the Ministry of Health.
The 1980s saw further changes in the NHS' workforce. The Thatcher Government encouraged (and eventually forced) health authorities to put most ancillary services out for competitive tender, effectively outsourcing the jobs of those workers. This led to a substantial reduction in numbers, with one-third of ancillary posts disappearing between 1980 and 1987. Those that remained were largely employed by private agencies and no longer subject to national agreements or trade union collective bargaining. For nurses, the introduction of Project 2000 meant that their profession now centred around degree courses run by universities rather than nurse training courses run by teaching hospitals. This effectively removed student nurses from hospital workforces and helped raise the status of the profession. Much of the physical labour done by student nurses was now passed to a new category of health worker, the healthcare assistant, a role that mirrors that of "auxiliary nurses" in the early NHS. The status of general practitioners as outside contractors was largely confirmed by the market-based reforms introduced by the Thatcher, Major and Blair governments. The working lives of hospital doctors changed from the 1970s onwards, as career paths and work patterns became increasingly formalised. Set rules on hours were introduced in the 1970s and refined in the 1980s and 1990s to dramatically reduce the number of hours junior doctors were expected to contribute.
Industrial relations.
1948–72.
Between 1948 and 1972 the NHS largely remained free of strikes, but nevertheless did experience some other industrial disputes. The foundation of the service was opposed by many doctors, particularly general practitioners, who feared that a state medical service would reduce their independence. Doctors expressed this opposition through their largest professional organisation, the British Medical Association, which held a number of ballots canvassing its members' (largely negative) opinions on arrangements for the new service. After a threat to boycott the new service, the BMA secured some concessions from Aneurin Bevan, the Minister of Health responsible for implementing the NHS Act. The BMA's intransigence did not stop the new health service coming into being, but did secure the right to be paid on a "capitation" basis (per patient) rather than on a set salary. More importantly for doctors the government's concessions established the conventional wisdom in the Ministry of Health that changes to the NHS were impossible without the consent of the medical profession, effectively giving doctors a "medical veto". Winning consent from physicians remained a problem for health ministers, who faced regular complaints, particularly relating to pay. In 1962 the government gave up control over doctors' pay to the independent Review Body on Doctors' and Dentists' Remuneration.
The first dispute involving nurses took place when student nurses opened their first NHS pay packets in July 1948. Despite having received a modest pay rise, an increase in National Insurance contributions meant their take-home pay had gone down. Outraged students at St. Mary's Hospital, Plaistow, organised a protest rally and a march, threatening to resign "en masse" if their demands for better pay, shorter hours and general improvements in conditions weren't met. The march made headlines but won few concessions from the Ministry of Health. Complaints from student nurses about poor conditions, long hours and low pay were common for much of the post-war period. Up to the 1970s, student nurses were responsible for as much as 75% of the physical labour on hospital wards and were often subject to intense disciplinary regimes both on the wards and in their private lives, with many student nurses living in strictly-supervised hospital nurses' accommodation.
The conflicts of 1947-48 were not very representative of the prevailing industrial relations culture in the NHS. Despite recurrent complaints about low pay and long hours, NHS staff were not prone to outbreaks of collective protest in the 1950s and 1960s. With the exception of an overtime ban and work-to-rule by administrative staff in 1957, organised by NALGO, and a go-slow by laundry workers in Carshalton in 1950, the NHS had little formal workplace conflict. Groups of miners, printers, dockers and car workers did stage a one-hour strike in solidarity with nurses' claims for pay increase in 1962, but the nurses' professional organisation the Royal College of Nursing (RCN) repudiated their actions and generally preferred to trade on respectability rather than militancy. At that time the RCN was reluctant to refer to itself as a trade union and nurses looking for more conventional workplace representation looked to the Confederation of Health Service Employees (COHSE) and the National Union of Public Employees (NUPE). The latter was generally strongest amongst ancillary staff and former amongst psychiatric nurses. Recognising the sensitive nature of hospital work both remained cautious regarding industrial action in the NHS until the 1970s, fearing that advocating action that might affect patients would drive away potential members. A combination of cautious organisations, staff who often saw their work as a vocation, and the domineering influence of doctors over the rest of the workforce, led to an "old colonial" system of industrial relations, structured largely by personal patronage and paternalism.
1972–1979.
This largely broke down in the 1970s with unions like NUPE, COHSE and ASTMS recruiting large numbers of all categories of staff, and professional organisations like the RCN and BMA becoming more aggressive in collective bargaining. In December 1972, ancillary staff, the worst paid and most marginalised section of the workforce, organised mass demonstrations across the country with around 150,000 workers and supporters protesting poverty level wages. Action continued in March 1973 with ancillaries organising the NHS' first national strike. In the years to come other groups took action over similar issues, with nurses mounting a sustained campaign over pay in 1974 and radiographers following suit in 1975 under the slogan "no raise, no rays". Doctors also took strike action in 1975, with junior doctors walking out over long hours and inadequate pay for extra time and consultants taking action in defence of their right to place their private patients in NHS beds.
Although strikes in the NHS remained rare, changes in everyday industrial relations were more profound. The NHS saw a significant expansion in the number of workplace representatives in this period, sometimes forcing managers to consider the views of sections of the workforce, like the ancillary staff, who they had long ignored. This sometimes caused conflict between different groups. The "pay beds" dispute pitched nurses and ancillaries, who opposed private practice, against consultants, the direct beneficiaries of private practice. Other aspects of the upsurge in workplace activism were less controversial and all categories of staff were active in lobbying central government for better funding. The second half of the 1970s also saw a series of campaigns aimed at saving local hospitals, some of which involved "work-ins" where staff took over hospitals and continued to provide services after health authorities had shut them down. In November 1976, health workers took over Elizabeth Garrett Anderson Women's Hospital saving it from closure. The occupation of Hounslow Hospital in 1977 was less successful with the local authority forcibly removing the patients after two months.
By the end of the 1970s, industrial relations in the NHS were widely considered to be in crisis, with poor management and inadequate personnel procedures causing endemic conflict in a substantial minority of hospitals. The participation of large numbers of health workers in the events of 1978-79 Winter of Discontent was one reflection of this. Ambulance drivers and ancillary staff were both involved in strikes over pay in January 1979, reducing 1,100 hospitals to emergency services only and causing widespread disruption to ambulance services.
1980–2010.
As in other sectors, industrial relations under the Thatcher Government continued to be a conflict. Successive health ministers looked to hold down pay in the public sector and to outsource ancillary staff where possible. Following the 1983 Griffiths Report, the NHS also tried to import a business model more similar to the private sector with professional managers taking over cost control, reducing the power of the medical profession. There were disputes over all of these policies. In 1982 there was another conflict over pay restraint involving ancillaries and nurses. Campaigning by NUPE, COHSE and RCN won an interim pay rise for nurses who were also granted their own independent pay review body, as the doctors had been 20 years earlier. The status and pay for registered nurses subsequently tended to improve, particularly when nurse education was shifted to university degree courses under Project 2000 in 1986.
Ancillary staff, in contrast, were increasingly marginalised during the 1980s. The Conservative Government put pressure on health authorities to outsource their catering, cleaning, laundry and maintenance services to private companies. Trade unions fought these policies, in some cases successfully, but many hospital services finally ended up in private hands, sometimes with companies who refused to recognise trade unions. Outsourcing dissipated some of the influence unions had built up during the 1970s and towards the end of decade increasingly occupied many shop stewards in detailed negotiations over grading and contract details rather than recruitment and organising.
Doctors' relationship with the government deteriorated during the 1980s. The advance of managerialism under Griffiths irritated many doctors, previously accustomed to a dominant role in NHS governance. By 1989 doctors were extremely hostile to government reforms and were active in lobbying against the implementation of the 1989 government white paper, "Working for Patients", which introduced an internal market to the NHS. Their defence of public ownership and opposition to market-based reforms marked a substantial shift from doctors' original opposition to the NHS, reflecting how far doctors' mindsets had changed in relation to state medicine.
Relations between the NHS and the government were generally much improved under the Blair Government. Substantial investment in staff and new facilities were appreciated by many nurses and doctors, although there were concerns about the introduction of private sector suppliers, the use of public–private partnerships to fund much investment and the development of an intensive culture of achievement targets. There was also no attempt to reverse the outsourcing of ancillary services, something health service unions linked to recurrent crises over hospital cleanliness.
Cultural history of the NHS.
Film and television.
Film and television have played important roles in forming cultural understandings of the National Health Service. Hospitals and GP practices, in particular, have been repeatedly dramatised as locations that lend themselves to displaying wider life stories - love, birth, ageing, dying, friendships and feuds. The NHS has also been an important topic within public health, often forming a central part in public information films about health and wellbeing.
Public information films.
From the launch of the National Health Service in 1948, film was used as an important cultural tool for spreading governmental health messages. During the Second World War, film grew in popularity as a way for the British government to keep citizens informed, impart advice and help raise morale on the Home Front. This commitment to producing public information films continued after the end of the War in 1945 with the newly formed Central Office of Information taking responsibility for the production of these films. This ensured that the launch of the NHS was accompanied by a number of public information films shown nationwide during Spring and Summer 1948. Three main films were produced - "Charley: You're Very Good Health" (Halas & Batchelor, 1948), "Here's Health" (Douglas Alexander, 1948) and "Doctor's Dilemma" (Unknown, 1948). These films introduced the NHS in three distinct ways with "Charley: You're Very Good Health" focused on explaining how the NHS would work upon its launch in a light-hearted manner with Charley standing in as the 'everyman' within the film's narrative. The film used a series of 'suppose' scenarios to outline how the new NHS system would work in practice in comparison to the pre-NHS health care system. "Here's Health" instead employed the narrative techniques of melodrama to dramatise one family's response to a household accident and the sudden need for medical attention during the Christmas of 1947. It uses flash-forwards to show how these type of care and the cost of it will be altered by the introduction of the NHS. The third main film used to advertise the launch of the NHS was a much briefer, information short, centred on the use of voice-over and a combination of still and moving images to encourage members of the public to register with an NHS GP before the National Health Service Act came into force on 5 July 1948.
Popular films and television.
Within a few years of the NHS, popular fictional films were beginning to focus on the NHS as a location for dramatic narratives. Films such as "White Corridors" (Pat Jackson, 1951) and "Mandy" (Alexander MacKendrick, 1952), shown within the early years of the NHS, showed day-to-day life in an NHS hospital as well as dealing with specific single-issue topics such as deafness within postwar British society. The Doctor series, starring firstly Dirk Bogarde and later Leslie Philips, took a comedic look at the antics of a young doctor in an NHS hospital and the "Carry On" comedies "Carry On Nurse" (Gerald Thomas, 1959), "Carry On Doctor" (Gerald Thomas, 1967) and "Carry On Matron" (Gerald Thomas, 1972) also used comic situations within the NHS hospital to poke fun at both the NHS as an institution and the capers of doctors, nurses and patients alike. From the late 1950s, the NHS also became an important subject within the wider history of British soap operas. "Emergency – Ward 10" was first broadcast in 1957 on ITV and ran until 1967 and followed the life and loves of the staff and patients of the fictionalised Oxbridge General. ITV later followed this up with "General Hospital" which borrowed much from Emergency Ward 10 in terms of its themes and focus.
The idea of a medical hospital as a suitable and popular setting for a soap opera continued to take root in the 1980s. "Casualty," set in an A&E department, was first broadcast in 1986 and has since become the longest running medical drama in the world. At a time when controversy over the NHS was high on the public agenda, Paul Unwin and Jeremy Brock began their proposal for "Casualty" by declaring that ‘In 1948 a dream was born: a National Health Service. In 1985 the dream is in tatters.’ This politicised agenda remained in evidence during the first three series of "Casualty", with the programme showing how those who fictionally worked for the NHS were also dissatisfied with the new direction of the service. During the 1990s television began more overtly showing medical practitioners who were critical or cynical of the NHS. In particular, "Cardiac Arrest", broadcast on BBC 1, utilised this type of cynicism within its narrative plots.
Television has also forged a place for the NHS within reality television programming. In particular "24 Hours in A&E" and "One Born Every Minute" have adopted medical documentary formats to show the inner workings of particular NHS hospital departments. Fly-on-the-wall footage is interwoven with interviews with patients, staff and relatives as they give their perspectives on the medical cases shown in each episode.
Comedy.
Comedy films, books, and cartoons have been produced about the NHS. These have shaped as well as reflected how people think about this institution.
Cartoons.
There have been lots of cartoons about the NHS throughout the institution's history. Even before the NHS was launched, there were cartoons documenting the political debates about its form. In the 1940s, the British Medical Association was opposed to the idea of doctors becoming state employees on fixed salaries. Cartoonists made their opinions about this conflict known. David Low published a cartoon in the "Evening Standard" on 14 December 1944 showing Charles Hill, the BMA Secretary, being examined by a doctor. The doctor states, 'Don't be alarmed. Whatever's the trouble, you're not going to die from enlargement of the social conscience.'
When the NHS was launched, many cartoons showed how people responded to the NHS being free at the point of access. One cartoon, published in 1951 by Antonia Yeoman, portrayed women in a doctor's waiting room, one of whom stated that she had seen eighteen doctors and seven psychiatrists. Eventually, she had been diagnosed with a 'deep-seated guilt about getting things free from the National Health Service.' Analysing cartoons about health featured in Punch magazine from 1948, the psychiatrist Bernard Zeitlyn argues that they 'centred on the bonanza of free spectacles, beards and trips abroad' that the NHS would bring. Cartoonists also portrayed public excitement about the availability of free wigs on the NHS. In one such example, from January 1949, cartoonist Joseph Lee showed an irate man chasing a child, asking, 'Who's been practising Home Perms on my free National Health Service wig?'
Cartoons were also used to criticise NHS policy. From 1948, Zeitlyn also found cartoons portraying concern about the 'bureaucratic consequences' of the NHS. The number of critical cartoons about NHS policy increased from the 1960s, as the NHS faced cuts, and the satire movement emerged in Britain. In December 1960, cartoonist Victor Weisz drew an image for the "Evening Standard" showing Minister for Health Enoch Powell as a surgeon covered in blood, accusing him of making too many cuts. Other cartoonists suggested that too much was being spent on the NHS. For example, in the "Daily Mail" in 1968, John Musgrave-Wood drew a man to portray the NHS, who was wearing a dunce's cap and being fed 'Defence Cuts'. Many cartoons have been very interested in portraying NHS staff, both their lives and industrial conflict. The cartoonist Carl Giles, who often drew for the "Daily Express", was very interested in drawing nurses in particular. Historian Jack Saunders has argued that Giles' presentation shifted from presenting nurses from 'caring and sexualised' to 'bolshie and assertive'. Giles sent a cartoon of nurses stealing peas from patients directly to the East Suffolk Nurses League. On the cartoon, Giles wrote 'with deepest sympathy', referring to the cutting of food allowances.
Everyday humour.
Patients and staff have made jokes about the NHS to one another, on a daily basis, throughout time. However, it is very hard to locate and to understand these. Sometimes 'everyday' jokes about the NHS are mentioned in passing in newspaper coverage. For example, one letter published by the "Daily Mail" in October 1988 described the experiences of an NHS secretary who 'seethed with anger' when hearing a consultant joke about spending his days on a golf course. The People's History of the NHS project at the University of Warwick has collected more such memories on its website, and invites contributions for more.
Researchers and clinicians hope that humour and laughter may be able to be used to improve human health. The term 'gelotology', to denote the study of laughter, was created in 1964 by Edith Trager and W. F. Fry. One experiment from 2011, led by researchers at the University of Oxford, suggested that watching comedy videos may raise people's pain thresholds, when watched in a group. This effect did not hold when videos were watched alone, or if research participants watched videos such as scenes of nature. In 2003, the artist Nicola Green and film-maker Lara Agnew created a 'laughter booth' at the Royal Brompton Hospital. In this booth, patients and staff could watch videos of people laughing. The idea of laughter as healing has also influenced language, through the phrase 'laughter is the best medicine'.


Marie Louis Victor Galippe

Marie Louis Victor Galippe (29 May 1848 – February 1922, Auteuil) was a French microbiologist and an eminent physician. He conducted experiments on microbiology in human life and also published notes on a variety of subjects including dental hygiene.
Born to a pharmacist in Grandvilliers, he studied at the Ecole Supérieure de Pharmacie and became a pharmacist before going on to study medicine. He demonstrated by experimenting on himself that copper sulphate was not as toxic as thought. He later made studies on bacteriology and specialized in dental health.
Among his other studies, Galippe examined bacteria present in various parts of cultivated food plants and found them to be nearly always present. He tried growing vegetables with sewage and then cut the plant parts above ground and tested them for bacteria by culturing them. Galippe discovered that the bacteria in the sewage entered all the plant tissues except for the garlic. Galippe also examined micro-organisms that were preserved in fossil bearing amber.
Galippe recovered bacteria from gallstones and hypothesized that they were produced by bacteria. This theory of bacterial causation of gallstones however has little support though viable bacteria have been found within stones even in later studies.


Group-specific antigen

Group-specific antigen, or gag, is the polyprotein that contains the core structural proteins of an Ortervirus (except "Caulimoviridae"). It was named as such because scientists used to believe it was antigenic. Now it is known that it makes up the inner shell, not the envelope exposed outside. It makes up all the structural units of viral conformation and provides supportive framework for mature virion.
All orthoretroviral "gag" proteins are processed by the protease (PR or "pro") into MA (matrix), CA (capsid), NC (nucleocapsid) parts, and sometimes more.
If Gag fails to cleave into its subunits, virion fails to mature and remains uninfective.
It comprises part of the "gag-onc" fusion protein.
Gag in HIV.
Numbering system.
By convention, the HIV genome is numbered according to HIV-1 group M subtype B reference strain HXB2.
Transcription and mRNA processing.
After a virus enters a target cell, the viral genome is integrated into the host cell chromatin. RNA polymerase II then transcribes the 9181 nucleotide full-length viral RNA. HIV Gag protein is encoded by the HIV "gag" gene, HXB2 nucleotides 790-2292.
MA.
The HIV p17 matrix protein (MA) is a 17 kDa protein, of 132 amino acids, which comprises the N-terminus of the Gag polyprotein. It is responsible for targeting Gag polyprotein to the plasma membrane via interaction with PI(4,5)P2 through its highly basic region (HBR). HIV MA also makes contacts with the HIV trans-membrane glycoprotein gp41 in the assembled virus and, indeed, may have a critical role in recruiting Env glycoproteins to viral budding sites.
Once Gag is translated on ribosomes, Gag polyproteins are myristoylated at their N-terminal glycine residues by N-myristoyltransferase 1. This is a critical modification for plasma membrane targeting. In the membrane-unbound form, the MA myristoyl fatty acid tail is sequestered in a hydrophobic pocket in the core of the MA protein.
Recognition of plasma membrane PI(4,5)P2 by the MA HBR activates the "myristoyl switch", wherein the myristoyl group is extruded from its hydrophobic pocket in MA and embedded in the plasma membrane. In parallel to (or possibly concomitant with) myristoyl switch activation, the arachidonic acid moiety of PI(4,5)P2 is extracted from the plasma membrane and binds in a channel on the surface of MA (which is distinct from that previously occupied by the MA myristoyl group. HIV Gag is then tightly bound to the membrane surface via three interactions: 1) that between the MA HBR and the PI(4,5)P2 inositol phosphate, 2) that between the extruded myristoyl tail of MA and the hydrophobic interior of the plasma membrane, and 3) that between the PI(4,5)P2 arachidonic acid moiety and the hydrophobic channel along the MA surface.
CA.
The p24 capsid protein (CA) is a 24 kDa protein fused to the C-terminus of MA in the unprocessed HIV Gag polyprotein. After viral maturation, CA forms the viral capsid. CA has two generally recognized domains, the C-terminal domain (CTD) and the N-terminal domain (NTD). The CA CTD and NTD have distinct roles during HIV budding and capsid structure.
When a Western blot test is used to detect HIV infection, p24 is one of the three major proteins tested for, along with gp120/gp160 and gp41.
While MA, IN, VPR, and cPPT had been previously implicated as factors in HIV's ability to target non-dividing cells, CA has been shown to be the dominant determinant of retrovirus infectivity in non-dividing cells, which is key in helping to avoid insertional mutagenesis in lentiviral gene therapy.
SP1.
Spacer peptide 1 (SP1, previously 'p2') is a 14-amino acid polypeptide intervening between CA and NC. Cleavage of the CA-SP1 junction is the final step in viral maturation, which allows CA to condense into the viral capsid. SP1 is unstructured in solution but, in the presence of less polar solvents or at high polypeptide concentrations, it adopts an α-helical structure. In scientific research, western blots for CA (24 kDa) can indicate a maturation defect by the high relative presence of a 25 kDa band (uncleaved CA-SP1). SP1 plays a critical role in HIV particle assembly, although the exact nature of its role and the physiological relevance of SP1 structural dynamics are unknown.
NC.
The HIV nucleocapsid protein (NC) is a 7 kDa zinc finger protein in the Gag polyprotein and which, after viral maturation, forms the viral nucleocapsid. NC recruits full-length viral genomic RNA to nascent virions.
SP2.
Spacer peptide 2 (SP2, previously 'p1') is a 16-amino acid polypeptide of unknown function which separates Gag proteins NC and p6.
p6.
HIV p6 is a 6 kDa polypeptide at the C-terminus of the Gag polyprotein. It recruits cellular proteins TSG101 (a component of ESCRT-I) and ALIX to initiate virus particle budding from the plasma membrane. p6 has no known function in the mature virus.
In endogenous retroviruses.
Both Human endogenous retrovirus K and Human Endogenous Retrovirus-W copies carry "gag" genes, usually damaged, that are expressed widely. There is a long history of speculating their involvement in multiple sclerosis and other neurological disorders.
In other viruses.
The "gag" gene of Spumaretrovirinae (e.g. ) and Metaviridae (e.g. ) only have a recognizable nucleocapsid part. It also lacks a myristoylation sequence.
The Spumaretroviral (SV) "gag" is related to orthoretrovieral "gag", as structural work has shown that part of the N-terminal domain shares functional and structural homology with the typical capsid protein. The SV "gag" is not processed like the orthoretrovieral "gag"; only a tiny 3kDa cut at the C-terminal is requried, and other cleavage sites are generally inefficient.
The Metaviral (MV, Ty3/gypsy) "gag", too, is known to have a structurally homologous capsid protein. Each capsid is assembled from 540 proteins. Unlike orthoretroviral CA proteins, it does not require dramatic maturation. The animal Activity-regulated cytoskeleton-associated protein (ARC) gene is repurposed from the metaviral "gag". This gene is responsible for transporting mRNA among neural cells, a key part of neuroplasticity. It has independently arose in Tetrapoda and "Drosophila".
Caulimoviridae members rarely get a "gag" assignment to its capsid-containing ORF, but the CP-PRO-POL layout does show analogy with the canonical "gag"-"pol" setup. Whether the parts stick together into a polyprotein depends on the genus.


Md. Sharfuddin Ahmed

Md. Sharfuddin Ahmed is a Bangladeshi physician and academic. He is serving as Vice-Chancellor of Bangabandhu Sheikh Mujib Medical University (BSMMU). He served as Pro Vice Chancellor (Administration) of BSMMU and Secretary General of Bangladesh Medical Association (BMA).
Early life and education.
Ahmed was born in Gopalgonj in 1956. He passed S.S.C from Kasiani GC High School in 1972 and H.S.C from Government Rajendra College in 1974. He completed MBBS from Sher-e-Bangla Medical College (SBMC) in 1982.
He obtained Diploma in Ophthalmology (DO) from IPGMR (now, BSMMU) in 1985. He achieved MS in Ophthalmology from Bangabandhu Sheikh Mujib Medical University (BSMMU) in 2004.
Career.
Ahmed served as professor and chairman of Community Ophthalmology at Bangabandhu Sheikh Mujib Medical University (BSMMU). He was appointed as Vice-Chancellor of BSMMU in March 2021.
Publications.
He published 40 research articles in national and internationally reputed journals.


Harvard University Health Services

Harvard University Health Services (UHUHS) is an arm of Harvard University serving students, faculty, staff, retirees, and their dependents.
At the beginning of the spring semester 2015, HUHS began restructuring services, closing their Stillman Infirmary to focus on other services. The current central operation is in the Smith Center (formerly Holyoke Center) in Harvard Square.


Meconium aspiration syndrome

Meconium aspiration syndrome (MAS) also known as neonatal aspiration of meconium is a medical condition affecting newborn infants. It describes the spectrum of disorders and pathophysiology of newborns born in meconium-stained amniotic fluid (MSAF) and have meconium within their lungs. Therefore, MAS has a wide range of severity depending on what conditions and complications develop after parturition. Furthermore, the pathophysiology of MAS is multifactorial and extremely complex which is why it is the leading cause of morbidity and mortality in term infants.
The word "meconium" is derived from the Greek word "mēkōnion" meaning "juice from the opium poppy" as the sedative effects it had on the foetus were observed by Aristotle.
Meconium is a sticky dark-green substance which contains gastrointestinal secretions, amniotic fluid, bile acids, bile, blood, mucus, cholesterol, pancreatic secretions, lanugo, vernix caseosa and cellular debris. Meconium accumulates in the foetal gastrointestinal tract throughout the third trimester of pregnancy and it is the first intestinal discharge released within the first 48 hours after birth. Notably, since meconium and the whole content of the gastrointestinal tract is located ‘extracorporeally,’ its constituents are hidden and normally not recognised by the foetal immune system.
For the meconium within the amniotic fluid to successfully cause MAS, it has to enter the respiratory system during the period when the fluid-filled lungs transition into an air-filled organ capable of gas exchange.
Causes.
The main theories of meconium passage into amniotic fluid are caused by fetal maturity or from foetal stress as a result of hypoxia or infection. Other factors that promote the passage of meconium "in utero" include placental insufficiency, maternal hypertension, pre-eclampsia and maternal drug use of tobacco and cocaine. However, the exact mechanism for meconium passage into the amniotic fluid is not completely understood and it may be a combination of several factors.
Meconium passage as a result of foetal distress.
There may be an important association between foetal distress and hypoxia with MSAF. It is believed that foetal distress develops into foetal hypoxia causing the foetus to defecate meconium resulting in MSAF and then perhaps MAS. Other stressors which causes foetal distress, and therefore meconium passage, includes when umbilical vein oxygen saturation is below 30%.
Foetal hypoxic stress during parturition can stimulate colonic activity, by enhancing intestinal peristalsis and relaxing the anal sphincter, which results in the passage of meconium. Then, because of intrauterine gasping or from the first few breaths after delivery, MAS may develop. Furthermore, aspiration of thick meconium leads to obstruction of airways resulting in a more severe hypoxia.
It is important to note that the association between foetal distress and meconium passage is not a definite cause-effect relationship as over ¾ of infants with MSAF are vigorous at birth and do not have any distress or hypoxia. Additionally, foetal distress occurs frequently without the passage of meconium as well.
Meconium passage as a result of foetal maturity.
Although meconium is present in the gastrointestinal tract early in development, MSAF rarely occurs before 34 weeks gestation.
Peristalsis of the foetal intestines is present as early as 8 weeks gestation and the anal sphincter develops at about 20–22 weeks. The early control mechanisms of the anal sphincter are not well understood, however there is evidence that the foetus does defecate routinely into the amniotic cavity even in the absence of distress. The presence of fetal intestinal enzymes have been found in the amniotic fluid of women who are as early as 14–22 weeks pregnant. Thus, suggesting there is free passage of the intestinal contents into the amniotic fluid.
Motilin is found in higher concentrations in post-term than pre-term foetal gastrointestinal tracts. Similarly, intestinal parasympathetic innervation and myelination also increases in later gestations. Therefore, the increased incidence of MAS in post-term pregnancies may reflect the maturation and development of the peristalsis within the gastrointestinal tract in the newborn.
Pathophysiology.
As MAS describes a spectrum of disorders of newborns born through MSAF, without any congenital respiratory disorders or other underlying pathology, there are numerous hypothesised mechanisms and causes for the onset of this syndrome. Long-term consequences may arise from these disorders, for example, infants that develop MAS have higher rates of developing neurodevelopmental defects due to poor respiration.
Airway obstruction.
In the first 15 minutes of meconium aspiration, there is obstruction of larger airways which causes increased lung resistance, decreased lung compliance, acute hypoxemia, hypercapnia, atelectasis and respiratory acidosis. After 60 minutes of exposure, the meconium travels further down into the smaller airways. Once within the terminal bronchioles and alveoli, the meconium triggers inflammation, pulmonary edema, vasoconstriction, bronchoconstriction, collapse of airways and inactivation of surfactant.
Foetal hypoxia.
The lung areas which do not or only partially participate in ventilation, because of obstruction and/or destruction, will become hypoxic and an inflammatory response may consequently occur. Partial obstruction will lead to air trapping and hyperinflation of certain lung areas and pneumothorax may follow. Chronic hypoxia will lead to an increase in pulmonary vascular smooth muscle tone and persistent pulmonary hypertension causing respiratory and circulatory failure.
Infection.
Microorganisms, most commonly Gram-negative rods, and endotoxins are found in samples of MSAF at a higher rate than in clear amniotic fluid, for example 46.9% of patients with MSAF also had endotoxins present. A microbial invasion of the amniotic cavity (MIAC) is more common in patients with MSAF and this could ultimately lead to an intra-amniotic inflammatory response. MIAC is associated with high concentrations of cytokines (such as IL-6), chemokines (such as IL-8 and monocyte chemoattractant protein-1), complement, phospholipase A2 and matrix-degrading enzymes. Therefore, these aforementioned mediators within the amniotic fluid during MIAC and intra-amniotic infection could, when aspirated "in" "utero", induce lung inflammation within the foetus.
Pulmonary inflammation.
Meconium has a complex chemical composition, so it is difficult to identify a single agent responsible for the several diseases that arise. As meconium is stored inside the intestines, and is partly unexposed to the immune system, when it becomes aspirated the innate immune system recognises as a foreign and dangerous substance. The immune system, which is present at birth, responds within minutes with a low specificity and no memory in order to try to eliminate microbes. Meconium perhaps leads to chemical pneumonitis as it is a potent activator of inflammatory mediators which include cytokines, complement, prostaglandins and reactive oxygen species.
Meconium is a source of pro-inflammatory cytokines, including tumour necrosis factor (TNF) and interleukins (IL-1, IL-6, IL-8), and mediators produced by neutrophils, macrophages and epithelial cells that may injure the lung tissue directly or indirectly. For example, proteolytic enzymes are released from neutrophilic granules and these may damage the lung membrane and surfactant proteins. Additionally, activated leukocytes and cytokines generate reactive nitrogen and oxygen species which have cytotoxic effects. Oxidative stress results in vasoconstriction, bronchoconstriction, platelet aggregation and accelerated cellular apoptosis. Recently, it has been hypothesised that meconium is a potent activator of toll-like receptor (TLRs) and complement, key mediators in inflammation, and may thus contribute to the inflammatory response in MAS.
Meconium contains high amounts of phospholipase A2 (PLA2), a potent proinflammatory enzyme, which may directly (or through the stimulation of arachidonic acid) lead to surfactant dysfunction, lung epithelium destruction, tissue necrosis and an increase in apoptosis. Meconium can also activate the coagulation cascade, production of platelet-activating factor (PAF) and other vasoactive substances that may lead to destruction of capillary endothelium and basement membranes. Injury to the alveolocapillary membrane results in leakage of liquid, plasma proteins, and cells into the interstitium and alveolar spaces.
Surfactant inactivation.
Surfactant is synthesised by type II alveolar cells and is made of a complex of phospholipids, proteins and saccharides. It functions to lower surface tension (to allow for lung expansion during inspiration), stabilise alveoli at the end of expiration (to prevent alveolar collapse) and prevents lung oedema. Surfactant also contributes to lung protection and defence as it is also an anti-inflammatory agent. Surfactant enhances the removal of inhaled particles and senescent cells away from the alveolar structure.
The extent of surfactant inhibition depends on both the concentration of surfactant and meconium. If the surfactant concentration is low, even very highly diluted meconium can inhibit surfactant function whereas, in high surfactant concentrations, the effects of meconium are limited. Meconium may impact surfactant mechanisms by preventing surfactant from spreading over the alveolar surface, decreasing the concentration of surfactant proteins (SP-A and SP-B), and by changing the viscosity and structure of surfactant. Several morphological changes occur after meconium exposure, the most notable being the detachment of airway epithelium from stroma and the shedding of epithelial cells into the airway. These indicate a direct detrimental effect on lung alveolar cells because of the introduction of meconium into the lungs.
Persistent Pulmonary Hypertension.
Persistent pulmonary hypertension (PPHN) is the failure of the foetal circulation to adapt to extra-uterine conditions after birth. PPHN is associated with various respiratory diseases, including MAS (as 15-20% of infants with MAS develop PPHN), but also pneumonia and sepsis. A combination of hypoxia, pulmonary vasoconstriction and ventilation/perfusion mismatch can trigger PPHN, depending on the concentration of meconium within the respiratory tract. PPHN in newborns is the leading cause of death in MAS.
Apoptosis.
Apoptosis is an important mechanism in the clearance of injured cells and in tissue repair, however too much apoptosis may cause harm, such as acute lung injury. Meconium induces apoptosis and DNA cleavage of lung airway epithelial cells, this is detected by the presence of fragmented DNA within the airways and in alveolar epithelial nuclei. Meconium induces an inflammatory reaction within the lungs as there is an increase of autophagocytic cells and levels of caspase 3 after exposure. After 8 hours of meconium exposure, in rabbit foetuses, the total amount of apoptotic cells is 54%. Therefore, the majority of meconium-induced lung damage may be due to the apoptosis of lung epithelium.
Diagnosis.
Respiratory distress in an infant born through the darkly coloured MSAF as well as meconium obstructing the airways is usually sufficient enough to diagnose MAS. Additionally, newborns with MAS can have other types of respiratory distress such as tachypnea and hypercapnia. Sometimes it is hard to diagnose MAS as it can be confused with other diseases that also cause respiratory distress, such as pneumonia. Additionally, X-rays and lung ultrasounds can be quick, easy and cheap imaging techniques to diagnose lung diseases like MAS.
Prevention.
In general, the incidence of MAS has been significantly reduced over the past two decades as the number of post-term deliveries has minimised. Currently, labour is induced in women who have been pregnant for longer than 41 weeks gestation.
Prevention during pregnancy.
Prevention during pregnancy may include amnioinfusion and antibiotics but the effectiveness of these treatments are questionable.
Prevention during parturition.
As previously mentioned, oropharyngeal and nasopharyngeal suctioning is not an ideal preventative treatment for both vigorous and depressed (not breathing) infants.
Treatment.
Most infants born through MSAF do not require any treatments (other than routine postnatal care) as they show no signs of respiratory distress, as only approximately 5% of infants born through MSAF develop MAS. However, infants which do develop MAS need to be admitted to a neonatal unit where they will be closely observed and provided any treatments needed. Observations include monitoring heart rate, respiratory rate, oxygen saturation and blood glucose (to detect worsening respiratory acidosis or the development of hypoglycemia). In general, treatment of MAS is more supportive in nature.
Assisted ventilation techniques.
To clear the airways of meconium, tracheal suctioning can be used however, the efficacy of this method is in question and it can cause harm.
In cases of MAS, there is a need for supplemental oxygen for at least 12 hours in order to maintain oxygen saturation of haemoglobin at 92% or more. The severity of respiratory distress can vary significantly between newborns with MAS, as some require minimal or no supplemental oxygen requirement and, in severe cases, mechanical ventilation may be needed. The desired oxygen saturation is between 90-95% and PaO2 may be as high as 90mmHg. In cases where there is thick meconium deep within the lungs, mechanical ventilation may be required. In extreme cases, extracorporeal membrane oxygenation (ECMO) may be utilised in infants who fail to respond to ventilation therapy. While on ECMO, the body can have time to absorb the meconium and for all the associated disorders to resolve. There has been an excellent response to this treatment, as the survival rate of MAS while on ECMO is more than 94%.
Ventilation of infants with MAS can be challenging and, as MAS can affect each individual differently, ventilation administration may need to be customised. Some newborns with MAS can have homogenous lung changes and others can have inconsistent and patchy changes to their lungs. It is common for sedation and muscle relaxants to be used to optimise ventilation and minimise the risk of pneumothorax associated with dyssynchronous breathing.
Inhaled nitric oxide.
Inhaled nitric oxide (iNO) acts on vascular smooth muscle causing selective pulmonary vasodilation. This is ideal in the treatment of PPHN as it causes vasodilation within ventilated areas of the lung thus, decreasing the ventilation-perfusion mismatch and thereby, improves oxygenation. Treatment utilising iNO decreases the need for ECMO and mortality in newborns with hypoxic respiratory failure and PPHN as a result of MAS. However, approximately 30-50% of infants with PPHN do not respond to iNO therapy.
Antiinflammatories.
As inflammation is such a huge issue in MAS, treatment has consisted of anti-inflammatories.
Glucocorticoids.
Glucocorticoids have a strong anti-inflammatory activity and works to reduce the migration and activation of neutrophils, eosinophils, mononuclear cells, and other cells. They reduce the migration of neutrophils into the lungs ergo, decreasing their adherence to the endothelium. Thus, there is a reduction in the action of mediators released from these cells and therefore, a reduced inflammatory response.
Glucocorticoids also possess a genomic mechanism of action in which, once bound to a glucocorticoid receptor, the activated complex moves into the nucleus and inhibits transcription of mRNA. Ultimately, effecting whether various proteins get produced or not. Inhibiting the transcription of nuclear factor (NF-κB) and protein activator (AP-1) attenuates the expression of pro-inflammatory cytokines (IL-1, IL-6, IL-8 and TNF etc.), enzymes (PLA2, COX-2, iNOs etc.) and other biologically active substances. The anti-inflammatory effect of glucocorticoids is also demonstrated by enhancing the activity of lipocortines which inhibit the activity of PLA2 and therefore, decrease the production of arachidonic acid and mediators of lipoxygenase and cyclooxygenase pathways.
Anti-inflammatories need to be administered as quickly as possible as the effect of these drugs can diminish even just an hour after meconium aspiration. For example, early administration of dexamethasone significantly enhanced gas exchange, reduced ventilatory pressures, decreased the number of neutrophils in the bronchoalveolar area, reduced oedema formation and oxidative lung injury. However, glucocorticoids may increase the risk of infection and this risk increases with the dose and duration of glucocorticoid treatment. Other issues can arise, such as aggravation of diabetes mellitus, osteoporosis, skin atrophy and growth retardation in children.
Inhibitors of phosphodiesterase.
Phosphodiesterases (PDE) degrades cAMP and cGMP and, within the respiratory system of a newborn with MAS, various isoforms of PDE may be involved due to their pro-inflammatory and smooth muscle contractile activity. Therefore, non-selective and selective inhibitors of PDE could potentially be used in MAS therapy. However, the use of PDE inhibitors can cause cardiovascular side effects. Non-selective PDE inhibitors, such as methylxanthines, increase concentrations of cAMP and cGMP in the cells leading to bronchodilation and vasodilation. Additionally, methylxanthines decreases the concentrations of calcium, acetylcholine and monoamines, this controls the release of various mediators of inflammation and bronchoconstriction, including prostaglandins. Selective PDE inhibitors target one subtype of phosphodiesterase and in MAS the activities of PDE-3, PDE-4, PDE-5 and PDE-7 may become enhanced. For example, Milrinone (a selective PDE3 inhibitor) improved oxygenation and survival of neonates with MAS.
Inhibitors of cyclooxygenase.
Arachidonic acid is metabolised, via cyclooxygenase (COX) and lipoxygenase, to various substances including prostaglandins and leukotrienes, which exhibit potent pro-inflammatory and vasoactive effects. By inhibiting COX, and more specifically COX-2, (either through selective or non-selective drugs) inflammation and oedema can be reduced. However, COX inhibitors may induce peptic ulcers and cause hyperkalemia and hypernatremia. Additionally, COX inhibitors have not shown any great response in the treatment of MAS.
Antibiotics.
Meconium is typically sterile however, it can contain various cultures of bacteria so appropriate antibiotics may need to be prescribed.
Surfactant treatment.
Lung lavage with diluted surfactant is a new treatment with potentially beneficial results depending on how early it is administered in newborns with MAS. This treatment shows promise as it has a significant effect on air leaks, pneumothorax, the need for ECMO and death. Early intervention and using it on newborns with mild MAS is more effective. However, there are risks as a large volume of fluid instillation to the lung of a newborn can be dangerous (particularly in cases of severe MAS with pulmonary hypertension) as it can exacerbate hypoxia and lead to mortality.
Previous treatments.
Originally, it was believed that MAS developed as a result of the meconium being a physical blockage of the airways. Thus, to prevent newborns, who were born through MSAF, from developing MAS, suctioning of the oropharyngeal and nasopharyngeal area before delivery of the shoulders followed by tracheal aspiration was utilised for 20 years. This treatment was believed to be effective as it was reported to significantly decrease the incidence of MAS compared to those newborns born through MSAF who were not treated. This claim was later disproved and future studies concluded that oropharyngeal and nasopharyngeal suctioning, before delivery of the shoulders in infants born through MSAF, does not prevent MAS or its complications. In fact, it can cause more issues and damage (e.g. mucosal damage), thus it is not a recommended preventative treatment. Suctioning may not significantly reduce the incidence of MAS as meconium passage and aspiration may occur "in-utero." Thereby making the suctioning redundant and useless as the meconium may already be deep within the lungs at the time of birth.
Historically, amnioinfusion has been used when MSAF was present, which involves a transcervical infusion of fluid during labour. The idea was to dilute the thick meconium to reduce its potential pathophysiology and reduce cases of MAS, since MAS is more prevalent in cases of thick meconium. However, there are associated risks, such as umbilical cord prolapse and prolongation of labour. The UK National Institute of Health and Clinical Excellence (NICE) Guidelines recommend against the use of amnioinfusion in women with MSAF.
Prevalence.
1 in every 7 pregnancies have MSAF and, of these cases, approximately 5% of these infants develop MAS. MSAF is observed 23-52% in pregnancies at 42 weeks therefore, the frequency of MAS increases as the length of gestation increases, such that the prevalence is greatest in post-term pregnancies. Conversely, preterm births are not frequently associated with MSAF (only approximately 5% in total contain MSAF). The rate of MAS declines in populations where labour is induced in women that have pregnancies exceeding 41 weeks. There are many suspected pre-disposing factors that are thought to increase the risk of MAS. For example, the risk of MSAF is higher in African American, African and Pacific Islander mothers, compared to mothers from other ethnic groups.
Future research.
Research is being focused on developing both a successful method for preventing MAS as well as an effective treatment. For example, investigations are being made in the efficiency of anti-inflammatory agents, surfactant replacement therapy and antibiotic therapy. More research needs to be conducted on the pharmacological properties of, for example, glucocorticoids, including dosages, administration, timing or any drug interactions. Additionally, there is still research being conducted on whether intubation and suctioning of meconium in newborns with MAS is beneficial, harmful or is simply a redundant and outdated treatment. In general, there is still no generally accepted therapeutic protocol and effective treatment plan for MAS.


Muriel Ritson

Muriel Ritson (1885–1980) was a career administrator and worked in the civil service. Her most important position was the Scottish representative for the Department of Health on the Beveridge Committee which was responsible for creating the National Health Service of the United Kingdom.
Early life.
Muriel was in born in Gourock to John Fletcher Ritson, a railway agent, and Agnes Jane Catto. She attended Greenock Academy and a German finishing school. She always valued having been educated at a co-educational school, and worked to promote women's equality in the workplace.
She began working as a social worker and rent collector for the Glasgow Workman's Dwellings Company between 1908 and 1911.
Career.
Her work with the GWDC made her familiar with health insurance work. During World War I she served on Public Health Committees and worked social and public health in Glasgow. She joined the Commission of Investigation which visited France in connection with the WAAF.
In 1919 she was appointed the only woman in the Scottish Board of Health, which consisted of only six people. It administered health policy in Scotland between 1919 and 1928. In 1929 she worked for the new Department of Health for Scotland. She sat on the Committee on the Admission of Women to the Diplomatic and Consular Service. Her most prestigious appointment was with the Beveridge Committee representing the Department of Health, which formed the National Health Service. In 1936, she was made a Commander of the Order of the British Empire.
Legacy.
Before her retirement in 1946 she became Scottish Controller of the Ministry of National Insurance. She sat on the Ryan Committee which examined health insurance, and on the Committee on Admission of Women on the Diplomatic and Consular Service. She is remembered for her work in public health, health insurance, and in her promotion of women in public life. Her most important contribution was to the Beveridge Committee, which was instrumental in helping to establish the National Health Service of the United Kingdom.


Zahira Abdin

Zahira Hafez Abdin (Arabic: زهيرة حافظ عابدين), (1917-2002) was an Egyptian paediatrician and specialist in rheumatic heart disease.
Life.
Zahira Abdin was born on 15 June 1917 in Cairo She was a daughter of Hafez Hussein Abdin, a lawyer, who also became a member of parliament. She went to Heliopolis Primary School and the Princess Fawzia Secondary School. In 1936 she secured the top mark in the Thanaweya Amma. She studied medicine at Cairo University. In 1943 she married Abdel Moneim Abdul Fadl, accompanying him to pursue a PhD in England. The pair had three daughters and one son. Mona Abul Fadl was a professor of political science at the Faculty of Economics and Political Science. Hoda Abdul Al-Fadl is a professor of pathology at Al-Qasr Al-Ayni. Omar Abdul-Fadl was an engineer. Adda Abdul Fadl, is Professor of Pediatrics at Benha University.
In 1956 Zahira Abdin became assistant professor at Cairo University, and was made professor in 1966. She pioneered social pediatrics in the Middle East. At that time rheumatic heart disease was a leading cause of childhood mortality in Egypt. Zahira Abdin led the effort against it, establishing the Free Pyramid Rheumatic Heart Center in 1957. in the 1960s she was the first to identify the streptococcal strain causing the disease. In 1975 she set up the Child Health Institute in Dokki, Cairo. In 1986 she set up the Dubai Medical College for Girls (DMCG).
Zahira Abdin co-founded the Association of Egyptian Women Doctors, editing its journal's first issues. She was the first Egyptian doctor, and the first Arab doctor, to become a Fellow of the Royal College of Physicians in London. In 1990 the First Lady of Egypt, Suzanne Mubarak, awarded her the honorary title ‘Mother of Egyptian Doctors’. In 1991 she was the first woman from outside Europe to receive the Elisabeth Norgall prize.


Panthera F9

The Panthera F9 is a UAE-designed 5-door armored personnel carrier designed for border protection, policing and low-intensity military operations. The vehicle is designed to have a fully modular weapons system, with a base model sold without any armarment. The F9 comes equipped with a remote controlled, roof-mounted search light, run-flat tyres, a rear-view camera, air conditioning, as well as side and rear facing gun ports.
Variants.
The company that designed and produced the F9, Minerva Special Purpose Vehicles (MSPV), partnered with French defense firm Nexter Systems to offer the M9 Panthera with a Nexter Systems ARX20 remote-controlled 20mm cannon, with an effective range of up to 1,200m. It may also employ a 7.62×51mm NATO belt-fed machine gun with up to 300 rounds, a GALIX Lacroix smoke discharger, as well as electronic fire detection and waste disposal systems.
Any F9 may optionally be fitted with a C4ISR surveillance system, electronic counter-measures, a non-lethal "STORM" or other custom configurations. It can also be fitted with a 360 degree ring mount, which can accept standard small arms.
The Panthera M9 is also offered in an armored ambulance configuration, holding up to 4 stretchers.
Several more vehicles of the Panthera family exist, with sizes ranging from 6 tonne to 23 tonne variants.
Production.
The base model F9 is produced by MSPV in the United Arab Emirates. The Panthera F9 is also produced at a military production plant located in Ankara, Turkey.
History.
The Panthera F9 is officially used by the armed forces of the UAE, Turkey and Egypt. Furthermore, Turkish-made Panthera F9s have been supplied as military aid to various armed groups in the Syrian Opposition during the ongoing Syrian Civil War, while UAE-made models were shown to be in possession of Field Marshal Khalifa Haftar's Tobruk-based Libyan National Army, during the course of the current Second Libyan Civil War.


Immune tolerance

Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that have the capacity to elicit an immune response in a given organism. It is induced by prior exposure to that specific antigen and contrasts with conventional immune-mediated elimination of foreign antigens (see Immune response). Tolerance is classified into central tolerance or peripheral tolerance depending on where the state is originally induced—in the thymus and bone marrow (central) or in other tissues and lymph nodes (peripheral). The mechanisms by which these forms of tolerance are established are distinct, but the resulting effect is similar.
Immune tolerance is important for normal physiology. Central tolerance is the main way the immune system learns to discriminate self from non-self. Peripheral tolerance is key to preventing over-reactivity of the immune system to various environmental entities (allergens, gut microbes, etc.). Deficits in central or peripheral tolerance also cause autoimmune disease, resulting in syndromes such as systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, autoimmune polyendocrine syndrome type 1 (APS-1), and immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX), and potentially contribute to asthma, allergy, and inflammatory bowel disease. And immune tolerance in pregnancy is what allows a mother animal to gestate a genetically distinct offspring with an alloimmune response muted enough to prevent miscarriage.
Tolerance, however, also has its negative tradeoffs. It allows for some pathogenic microbes to successfully infect a host and avoid elimination. In addition, inducing peripheral tolerance in the local microenvironment is a common survival strategy for a number of tumors that prevents their elimination by the host immune system.
Historical background.
The phenomenon of immune tolerance was first described by Ray D. Owen in 1945, who noted that dizygotic twin cattle sharing a common placenta also shared a stable mixture of each other's red blood cells (though not necessarily 50/50), and retained that mixture throughout life. Although Owen did not use the term immune tolerance, his study showed the body could be tolerant of these foreign tissues. This observation was experimentally validated by Leslie Brent, Rupert E. Billingham and Peter Medawar in 1953, who showed by injecting foreign cells into fetal or neonatal mice, they could become accepting of future grafts from the same foreign donor. However, they were not thinking of the immunological consequences of their work at the time: as Medawar explains:
However, these discoveries, and the host of allograft experiments and observations of twin chimerism they inspired, were seminal for the theories of immune tolerance formulated by Sir Frank McFarlane Burnet and Frank Fenner, who were the first to propose the deletion of self-reactive lymphocytes to establish tolerance, now termed clonal deletion. Burnet and Medawar were ultimately credited for "the discovery of acquired immune tolerance" and shared the Nobel Prize in Physiology or Medicine in 1960.
Definitions and usage.
In their Nobel Lecture, Medawar and Burnet define immune tolerance as "a state of indifference or non-reactivity towards a substance that would normally be expected to excite an immunological response." Other more recent definitions have remained more or less the same. The 8th edition of Janeway's Immunobiology defines tolerance as "immunologically unresponsive…to another's tissues.".
Immune tolerance encompasses the range of physiological mechanisms by which the body reduces or eliminates an immune response to particular agents. It is used to describe the phenomenon underlying discrimination of self from non-self, suppressing allergic responses, allowing chronic infection instead of rejection and elimination, and preventing attack of fetuses by the maternal immune system.
Typically, a change in the host, not the antigen, is implied. Though some pathogens can evolve to become less virulent in host-pathogen coevolution, tolerance does not refer to the change in the pathogen but can be used to describe the changes in host physiology. Immune tolerance also does not usually refer to artificially induced immunosuppression by corticosteroids, lymphotoxic chemotherapy agents, sublethal irradiation, etc. Nor does it refer to other types of non-reactivity such as immunological paralysis. In the latter two cases, the host's physiology is handicapped but not fundamentally changed.
Immune tolerance is formally differentiated into central or peripheral; however, alternative terms such as "natural" or "acquired" tolerance have at times been used to refer to establishment of tolerance by physiological means or by artificial, experimental, or pharmacological means. These two methods of categorization are sometimes confused, but are not equivalent—central or peripheral tolerance may be present naturally or induced experimentally. This difference is important to keep in mind.
Central tolerance.
Central tolerance refers to the tolerance established by deleting autoreactive lymphocyte clones before they develop into fully immunocompetent cells. It occurs during lymphocyte development in the thymus and bone marrow for T and B lymphocytes, respectively. In these tissues, maturing lymphocytes are exposed to self-antigens presented by medullary thymic epithelial cells and thymic dendritic cells, or bone marrow cells. Self-antigens are present due to endogenous expression, importation of antigen from peripheral sites via circulating blood, and in the case of thymic stromal cells, expression of proteins of other non-thymic tissues by the action of the transcription factor AIRE.
Those lymphocytes that have receptors that bind strongly to self-antigens are removed by induction of apoptosis of the autoreactive cells, or by induction of anergy, a state of non-activity. Weakly autoreactive B cells may also remain in a state of immunological ignorance where they simply do not respond to stimulation of their B cell receptor. Some weakly self-recognizing T cells are alternatively differentiated into natural regulatory T cells (nTreg cells), which act as sentinels in the periphery to calm down potential instances of T cell autoreactivity (see peripheral tolerance below).
The deletion threshold is much more stringent for T cells than for B cells since T cells alone can cause direct tissue damage. Furthermore, it is more advantageous for the organism to let its B cells recognize a wider variety of antigen so it can produce antibodies against a greater diversity of pathogens. Since the B cells can only be fully activated after confirmation by more self-restricted T cells that recognize the same antigen, autoreactivity is held in check.
This process of negative selection ensures that T and B cells that could initiate a potent immune response to the host's own tissues are eliminated while preserving the ability to recognize foreign antigens. It is the step in lymphocyte education that is key for preventing autoimmunity (entire process detailed here). Lymphocyte development and education is most active in fetal development but continues throughout life as immature lymphocytes are generated, slowing as the thymus degenerates and the bone marrow shrinks in adult life.
Peripheral tolerance.
Peripheral tolerance develops after T and B cells mature and enter the peripheral tissues and lymph nodes. It is established by a number of partly overlapping mechanisms that mostly involve control at the level of T cells, especially CD4+ helper T cells, which orchestrate immune responses and give B cells the confirmatory signals they need in order to produce antibodies.
Inappropriate reactivity toward normal self-antigen that was not eliminated in the thymus can occur, since the T cells that leave the thymus are relatively but not completely safe. Some will have receptors (TCRs) that can respond to self-antigens that:
Those self-reactive T cells that escape intrathymic negative selection in the thymus can inflict cell injury unless they are deleted or effectively muzzled in the peripheral tissue chiefly by nTreg cells (see central tolerance above).
Appropriate reactivity toward certain antigens can also be quieted by induction of tolerance after repeated exposure, or exposure in a certain context. In these cases, there is a differentiation of naïve CD4+ helper T cells into induced Treg cells (iTreg cells) in the peripheral tissue or nearby lymphoid tissue (lymph nodes, mucosal-associated lymphoid tissue, etc.). This differentiation is mediated by IL-2 produced upon T cell activation, and TGF-β from any of a variety of sources, including tolerizing dendritic cells (DCs), other antigen presenting cells, or in certain conditions surrounding tissue.
Treg cells are not the only cells that mediate peripheral tolerance. Other regulatory immune cells include T cell subsets similar to but phenotypically distinct from Treg cells, including TR1 cells that make IL-10 but do not express Foxp3, TGF-β-secreting TH3 cells, as well as other less well-characterized cells that help establish a local tolerogenic environment. B cells also express CD22, a non-specific inhibitor receptor that dampens B cell receptor activation. A subset of B regulatory cells that makes IL-10 and TGF-β also exists. Some DCs can make Indoleamine 2,3-dioxygenase (IDO) that depletes the amino acid tryptophan needed by T cells to proliferate and thus reduce responsiveness. DCs also have the capacity to directly induce anergy in T cells that recognize antigen expressed at high levels and thus presented at steady-state by DCs. In addition, FasL expression by immune privileged tissues can result in activation-induced cell death of T cells.
nTreg vs. iTreg cells.
The involvement of T cells, later classified as Treg cells, in immune tolerance was recognized in 1995 when animal models showed that CD4+ CD25+ T cells were necessary and sufficient for the prevention of autoimmunity in mice and rats. Initial observations showed removal of the thymus of a newborn mouse resulted in autoimmunity, which could be rescued by transplantation of CD4+ T cells. A more specific depletion and reconstitution experiment established the phenotype of these cells as CD4+ and CD25+. Later in 2003, experiments showed that Treg cells were characterized by the expression of the Foxp3 transcription factor, which is responsible for the suppressive phenotype of these cells.
It was assumed that, since the presence of the Treg cells originally characterized was dependent on the neonatal thymus, these cells were thymically derived. By the mid-2000s, however, evidence was accruing of conversion of naïve CD4+ T cells to Treg cells outside of the thymus. These were later defined as induced or iTreg cells to contrast them with thymus-derived nTreg cells.
Both types of Treg cells quieten autoreactive T cell signaling and proliferation by cell-contact-dependent and -independent mechanisms including:
nTreg cells and iTreg cells, however, have a few important distinguishing characteristics that suggest they have different physiological roles:
Tolerance in physiology and medicine.
Allograft tolerance.
Immune recognition of non-self-antigens typically complicates transplantation and engrafting of foreign tissue from an organism of the same species (allografts), resulting in graft reaction. However, there are two general cases in which an allograft may be accepted. One is when cells or tissue are grafted to an immune-privileged site that is sequestered from immune surveillance (like in the eye or testes) or has strong molecular signals in place to prevent dangerous inflammation (like in the brain). The second is when a state of tolerance has been induced, either by previous exposure to the antigen of the donor in a manner that causes immune tolerance rather than sensitization in the recipient, or after chronic rejection. Long-term exposure to a foreign antigen from fetal development or birth may result in establishment of central tolerance, as was observed in Medawar's mouse-allograft experiments. In usual transplant cases, however, such early prior exposure is not possible. Nonetheless, a few patients can still develop allograft tolerance upon cessation of all exogenous immunosuppressive therapy, a condition referred to as operational tolerance. CD4+ Foxp3+ Treg cells, as well as CD8+ CD28- regulatory T cells that dampen cytotoxic responses to grafted organs, are thought to play a role. In addition, genes involved in NK cell and γδT cell function associated with tolerance have been implicated for liver transplant patients. The unique gene signatures of these patients implies their physiology may be predisposed toward immune tolerance.
Fetal development.
The fetus has a different genetic makeup than the mother, as it also translates its father's genes, and is thus perceived as foreign by the maternal immune system. Women who have borne multiple children by the same father typically have antibodies against the father's red blood cell and major histocompatibility complex (MHC) proteins. However, the fetus usually is not rejected by the mother, making it essentially a physiologically tolerated allograft. It is thought that the placental tissues which interface with maternal tissues not only try to escape immunological recognition by downregulating identifying MHC proteins but also actively induce a marked peripheral tolerance. Placental trophoblast cells express a unique Human Leukocyte Antigen (HLA-G) that inhibits attack by maternal NK cells. These cells also express IDO, which represses maternal T cell responses by amino acid starvation. Maternal T cells specific for paternal antigens are also suppressed by tolerogenic DCs and activated iTregs or cross-reacting nTregs. Some maternal Treg cells also release soluble fibrinogen-like proteins 2 (sFGL2), which suppresses the function of DCs and macrophages involved in inflammation and antigen presentation to reactive T cells These mechanisms altogether establish an immune-privileged state in the placenta that protects the fetus. A break in this peripheral tolerance results in miscarriage and fetal loss. (for more information, see Immune tolerance in pregnancy).
The microbiome.
The skin and digestive tract of humans and many other organisms is colonized with an ecosystem of microorganisms that is referred to as the microbiome. Though in mammals a number of defenses exist to keep the microbiota at a safe distance, including a constant sampling and presentation of microbial antigens by local DCs, most organisms do not react against commensal microorganisms and tolerate their presence. Reactions are mounted, however, to pathogenic microbes and microbes that breach physiological barriers. Peripheral mucosal immune tolerance, in particular, mediated by iTreg cells and tolerogenic antigen-presenting cells, is thought to be responsible for this phenomenon. In particular, specialized gut CD103+ DCs that produce both TGF-β and retinoic acid efficiently promotes the differentiation of iTreg cells in the gut lymphoid tissue. Foxp3- TR1 cells that make IL-10 are also enriched in the intestinal lining. Break in this tolerance is thought to underlie the pathogenesis of inflammatory bowel diseases like Crohn's disease and ulcerative colitis.
Oral tolerance and hypersensitivity.
Oral tolerance refers to a specific type of peripheral tolerance induced by antigens given by mouth and exposed to the gut mucosa and its associated lymphoid tissues. The hypo-responsiveness induced by oral exposure is systemic and can reduce hypersensitivity reactions in certain cases. Records from 1829 indicate that American Indians would reduce contact hypersensitivity from poison ivy by consuming leaves of related Rhus species; however, contemporary attempts to use oral tolerance to ameliorate autoimmune diseases like rheumatoid arthritis and other hypersensitivity reactions have been mixed. The systemic effects of oral tolerance may be explained by the extensive recirculation of immune cells primed in one mucosal tissue in another mucosal tissue, allowing extension of mucosal immunity. The same probably occurs for cells mediating mucosal immune tolerance.
Oral tolerance may depend on the same mechanisms of peripheral tolerance that limit inflammation to bacterial antigens in the microbiome since both involve the gut-associated lymphoid tissue. It may also have evolved to prevent hypersensitivity reactions to food proteins. It is of immense immunological importance, since it is a continuous natural immunologic event driven by exogenous antigen.
Allergy and hypersensitivity reactions in general are traditionally thought of as misguided or excessive reactions by the immune system, possibly due to broken or underdeveloped mechanisms of peripheral tolerance. Usually, Treg cells, TR1, and Th3 cells at mucosal surfaces suppress type 2 CD4 helper cells, mast cells, and eosinophils, which mediate allergic response. Deficits in Treg cells or their localization to mucosa have been implicated in asthma and atopic dermatitis. Attempts have been made to reduce hypersensitivity reactions by oral tolerance and other means of repeated exposure. Repeated administration of the allergen in slowly increasing doses, subcutaneously or sublingually appears to be effective for allergic rhinitis. Repeated administration of antibiotics, which can form haptens to cause allergic reactions, can also reduce antibiotic allergies in children.
The tumor microenvironment.
Immune tolerance is an important means by which growing tumors, which have mutated proteins and altered antigen expression, prevent elimination by the host immune system. It is well recognized that tumors are a complex and dynamic population of cells composed of transformed cells as well as stromal cells, blood vessels, tissue macrophages, and other immune infiltrates. These cells and their interactions all contribute to the changing tumor microenvironment, which the tumor largely manipulates to be immunotolerant so as to avoid elimination. There is an accumulation of metabolic enzymes that suppress T cell proliferation and activation, including IDO and arginase, and high expression of tolerance-inducing ligands like FasL, PD-1, CTLA-4, and B7. Pharmacologic monoclonal antibodies targeted against some of these ligands has been effective in treating cancer. Tumor-derived vesicles known as exosomes have also been implicated promoting differentiation of iTreg cells and myeloid derived suppressor cells (MDSCs), which also induce peripheral tolerance. In addition to promoting immune tolerance, other aspects of the microenvironment aid in immune evasion and induction of tumor-promoting inflammation.
Evolution.
Though the exact evolutionary rationale behind the development of immunological tolerance is not completely known, it is thought to allow organisms to adapt to antigenic stimuli that will consistently be present instead of expending considerable resources fighting it off repeatedly. Tolerance in general can be thought of as an alternative defense strategy that focuses on minimizing impact of an invader on host fitness, instead of on destroying and eliminating the invader. Such efforts may have a prohibitive cost on host fitness. In plants, where the concept was originally used, tolerance is defined as a reaction norm of host fitness over a range of parasite burdens, and can be measured from the slope of the line fitting these data. Immune tolerance may constitute one aspect of this defense strategy, though other types of tissue tolerance have been described.
The advantages of immune tolerance, in particular, may be seen in experiments with mice infected with malaria, in which more tolerant mice have higher fitness at greater pathogen burdens. In addition, development of immune tolerance would have allowed organisms to reap the benefits of having a robust commensal microbiome, such as increased nutrient absorption and decreased colonization by pathogenic bacteria.
Though it seems that the existence of tolerance is mostly adaptive, allowing an adjustment of the immune response to a level appropriate for the given stressor, it comes with important evolutionary disadvantages. Some infectious microbes take advantage of existing mechanisms of tolerance to avoid detection and/or elimination by the host immune system. Induction of regulatory T cells, for instance, has been noted in infections with "Helicobacter pylori", "Listeria monocytogenes", "Brugia malayi", and other worms and parasites. Another important disadvantage of the existence of tolerance may be susceptibility to cancer progression. Treg cells inhibit anti-tumor NK cells. The injection of Treg cells specific for a tumor antigen also can reverse experimentally-mediated tumor rejection based on that same antigen. The prior existence of immune tolerance mechanisms due to selection for its fitness benefits facilitates its utilization in tumor growth.
Tradeoffs between immune tolerance and resistance.
Immune tolerance contrasts with resistance. Upon exposure to a foreign antigen, either the antigen is eliminated by the standard immune response (resistance), or the immune system adapts to the pathogen, promoting immune tolerance instead.
Resistance typically protects the host at the expense of the parasite, while tolerance reduces harm to the host without having any direct negative effects on the parasite. Each strategy has its unique costs and benefits for host fitness:
Evolution works to optimize host fitness, so whether elimination or tolerance occurs depends on which would benefit the organism most in a given scenario. If the antigen is from a rare, dangerous invader, the costs of tolerating its presence are high and it is more beneficial to the host to eliminate it. Conversely, if experience (of the organism or its ancestors) has shown that the antigen is innocuous, then it would be more beneficial to tolerate the presence of the antigen rather than pay the costs of inflammation.
Despite having mechanisms for both immune resistance and tolerance, any one organism may be overall more skewed toward a tolerant or resistant phenotype depending on individual variation in both traits due to genetic and environmental factors. In mice infected with malaria, different genetic strains of mice fall neatly along a spectrum of being more tolerant but less resistant or more resistant but less tolerant. Patients with autoimmune diseases also often have a unique gene signature and certain environmental risk factors that predispose them to disease. This may have implications for current efforts to identify why certain individuals may be disposed to or protected against autoimmunity, allergy, inflammatory bowel disease, and other such diseases.