Why standards?

My experiences of growing up in a general practitioner's home and practice led me to want to be a general practitioner myself.

The early 1950s were critical years for general practice. Three developments — the foundation and work of the College, the introduction of vocational training, and the development of postgraduate medical centres — have led to its revival.

The next main change may well be the interest in, and development of, clinical standards. In my opinion this ought to be done by general practitioners themselves rather than by society via the Ombudsman.

     

Acute low back pain: patients' perceptions of pain four weeks after initial diagnosis and treatment in general practice

In a nationwide study of the treatment of acute low back pain with and without radiation in general practice in the Netherlands the subjective well-being of patients was evaluated by means of a short questionnaire sent to patients four weeks after the initial contact with their general practitioner.

After this period pain had disappeared in 28% of the patients, was diminished in 47%, was unchanged in 2% and was aggravated in 4%. There was no difference in the pain score of patients with and without follow-up encounters with their general practitioner. In all instances patients with low back pain without radiation fared significantly better than those with radiation. Radiation of pain was not constant — during the four-week follow-up period it developed in 19% of the patients originally without radiation and it disappeared in 44% of the patients originally suffering radiation.

     

Casualty and surgical services in Perthshire general practitioner hospitals 1954-84

The results are reported of a study of casualty and surgical services in five general practitioner hospitals in Perthshire — Aberfeldy, Auchterarder, Blairgowrie, Crieff and Pitlochry. Details of the total workload, the nature of the conditions treated and the referral rate to major hospitals are given. Figures for the Royal Infirmary, Perth, the main referral hospital for the county, are also given for comparison. The surgical service at one of the rural hospitals is described.

Experience has demonstrated the usefulness of these hospitals in providing casualty and surgical services to both the local population and to visitors, and their superiority in providing these services over health centres because staff and beds are available 24 hours a day.

Rural general practitioner hospitals merit a continuing share of resources and bed allocation as they spare major hospitals surgical and medical work. The general practitioners serving the hospitals studied here undertook almost 40% of the total accident and emergency workload in the Perth and Kinross area of Scotland.

     

Family practitioner committee records — a neglected resource. 3. Three inner city areas compared

Data from the family practitioner committees of three inner city areas — Kensington, Chelsea and Westminster; Lambeth, Lewisham and Southwark; and Manchester — were compared. The information about general practitioners over one year included number of principals, distribution by partnership size and numbers working from health centre premises. Data about practices covered the five years 1979—83, with figures for mean list size, registrations and removals, temporary residents and claims for various items of service. Comparisons between the three areas showed great differences for which no convincing explanation could be found. The possibility that people living in these areas have different primary care health services suggests that comparisons should be made nationally; this requires family practitioner committees to be fully computerized and to collect their data in the same way.     

L chain peptide maps of rabbit IgG of different allotypes

Light (L) chains of IgG from rabbits homozygous and heterozygous for allotypic specificities (As4, 5 and 6) at the b locus were examined by the technique of peptide mapping.

They have between twenty-six and thirty dark peptides, 40 per cent of them being common to all three allotypic specificities. About 60 per cent peptides are shared by any two specificities (As4—5, As4—6 and As5—6). Amongst the peptides unique for each specificity there was always one most prominent peptide present by which the specificity could be identified by peptide maps.

The L chains from IgG of heterozygous rabbits have in general all the peptides characteristic of both specificities of the homozygous animal, although As4 peptides are always most prominent. Thus multiple peptide differences between L chains of three allotypic specificities were found.

     

The threshold conditions for initiation of action potentials by excitable cells

1. The relation between the strength and duration of a just threshold stimulus (strength—duration curve) is analysed for an excitable membrane polarized uniformly and for an excitable cable polarized at one point.

2. The effect on the strength—duration curve of non-linearity in the membrane current—voltage curve has been analysed. The strength—duration curve can be derived if the membrane current—voltage relation is independent of time. The effects of changes in the current—voltage curve with time due to the existence of a finite membrane activation time and membrane accommodation are analysed.

3. The strength—duration curve for the Hodgkin—Huxley membrane equations (Hodgkin & Huxley, 1952) is compared to that of Hill's (1936) two-time constant model.

4. The relation between membrane current—voltage curves and those for a point-polarized cable are derived for the steady-state condition. The cable properties tend to linearize the current—voltage curve and to sharpen the voltage threshold.

5. The strength—duration curve for a point-polarized cable whose membrane obeys the Hodgkin—Huxley equations is computed numerically. There is an additional large effect on the cable strength—duration curve arising from the redistribution of charge during passage of a constant current; and the resulting strength—duration curve lies within the range of curves predicted by Hill's model.

6. The conditions required for a constant charge threshold (Hodgkin & Rushton, 1946) are shown to be satisfied for short, intense stimuli applied to a cable at one point.

7. The results are discussed with reference to the experimental studies available.

     

Immune and non-immune responses to monovalent low molecular weight penicilloyl—polylysines and penicilloyl—bacitracin in rabbits and guinea-pigs

Rabbits and guinea-pigs have been immunized with low molecular weight penicilloyl—polylysines (BPO₁—PLL_{1 2}, BPO₆—PLL_{1 2}) with varying degrees of substitution and with monovalent penicilloyl—bacitracin (BPO₁—BAC). The immune response to the penicilloyl (BPO) determinant has been followed by skin tests, passive haemagglutination, passive cutaneous anaphylaxis (PCA), immunodiffusion and immunoelectrophoresis.

Maximally substituted BPO₆—PLL_{1 2} was found to be non-immunogenic. Apparently monovalent BPO₁—PLL_{1 2}, which inhibits precipitation of anti-BPO antibodies in vitro, was found to induce delayed-type hypersensitivity and antibodies for BPO in most of our random bred and in all strain 2 guinea-pigs. The delayed hypersensitivity in some of the sensitized guinea-pigs was hapten (BPO)-specific. BPO₁—PLL_{1 2} was very poorly immunogenic in rabbits.

Monovalent BPO₁—BAC induced BPO-specific delayed hypersensitivity and anti-BPO antibodies in some random bred guinea-pigs but not in strain 2 animals. BPO₁—BAC induced good levels of haemagglutinating anti-BPO antibodies in most random bred rabbits.

Truly monovalent compounds, such as BPO₁—BAC or BPO—ε-aminocaproate, do not elicit antibody-dependent reactions such as anaphylactic or Arthus reactions, but inhibit them.

On the other hand, apparently monovalent BPO₁—PLL_{1 2} was found to elicit BPO-specific PCA and Arthus reactions in immunized rabbits and guinea-pigs. When administered in higher doses, similar reactions were produced in non-immunized guinea-pigs. The possibility is discussed that some of the reactions observed with basic polypeptide antigens are due to the formation of mixed `specific antibody—polypeptide—non-specific protein' complexes formed in vivo by electrostatic interaction.

     

Immune complexes in rheumatoid synovitis: a mixed staining immunofluorescence study

Complexes of IgG—rheumatoid factor (RF) and IgG—β_1C were demonstrated in the synovial membrane obtained from patients with rheumatoid arthritis (RA) by a mixed immunofluorescence method that shows simultaneously the two components of the complex.

IgG—RF was found only in the synovia of cases with circulating RF, while IgG—β_1C deposits could be detected in both seropositive and seronegative cases.

These findings are discussed in connection with the pathogenesis of rheumatoid synovitis in the light of the immune complex pathogenetic mechanism.

     

The influence of epitope density on the immunological properties of hapten—protein conjugates: II. The in vivo and in vitro metabolism of heavily and lightly conjugated protein

In earlier experiments we showed that lightly hapten-coupled bovine serum albumin (e.g. DNP₅—BSA) elicited mainly IgG anti-DNP antibodies and concomitant immunological memory in mice, whereas DNP₅₀—BSA induced a primary IgM response, little IgG antibody and poor memory. Although the latter are characteristic of T cell-independent antibody responses, antibody formation to DNP₅₀—BSA was found to be highly thymus-dependent.

In the present study the metabolism of DNP₅—BSA and DNP₅₀—BSA was investigated. In vivo DNP₅₀—BSA was rapidly cleared from the bloodstream, but persisted at much higher levels in the liver and spleen than DNP₅—BSA. DNP₅₀—BSA was taken up more efficiently by macrophage cultures than DNP₅—BSA, but released comparatively slowly. Analysis of culture supernatants showed that macrophages degrade both antigens to the same degree. We conclude that heavy dinitrophenylation decreases the susceptibility of DNP—BSA to degradation by lysosomal proteases, but the relationship between the metabolic behaviour of various DNP—BSA conjugates and their immunogenic properties is at present unclear.

     

The applicability of anaphylactic tests in studies of antigen mixtures: II. The discriminatory capacity of the tests

Some assumptions underlying the attribution of a high discriminatory capacity to anaphylactic tests have been investigated in model systems, using two tests of the anaphylactic response—the Dale—Schultze reaction and the measurement of histamine released from chopped lung.

It has been demonstrated that there may be no response to challenge with a second antigen after desensitization to the first even though the tissues can be shown to be sensitized to the second antigen, i.e. there is a possibility of the occurrence of `false' negative results. The potentiality of response to the second antigen appears to depend partly on the proportion it formed of the sensitizing mixture and partly on the absolute dose used in sensitization.

It has been confirmed that desensitization is a graded phenomenon related to dose of antigen and it is shown that it is reversible with time. These factors are likely to complicate the performance and/or interpretation of experiments with tissue extracts and constitute a source of potential false positive results. These factors are of less importance with the histamine-release test than with the Dale—Schultz test. For the Dale—Schultz reaction the ileum proved to be a more satisfactory test tissue than the uterus.

In general, there was no significant difference in discriminatory capacity between the histamine-release test and the Dale—Schultz test, but there were more sources of error in the performance of the Dale—Schultz test, while the histamine-release test though more laborious to do gave results which were more amenable to statistical analysis. It is concluded that with careful experimental design the tests could possibly be of use in some investigations of antigen mixtures provided that the sources of false positive results were recognized and due precautions taken.

     

Array based CGH and FISH fail to confirm duplication of 8p22-p23.1 in association with Kabuki syndrome

Background: Kabuki (Niikawa–Kuroki) syndrome comprises a characteristic facial appearance, cleft palate, congenital heart disease, and developmental delay. Various cytogenetically visible chromosomal rearrangements have been reported in single cases, but the molecular genetic basis of the condition has not been established. A recent report described a duplication of 8p22–p23.1 in 13/13 patients.

Objective: To determine the frequency of an 8p duplication in a cohort of patients with Kabuki syndrome.

Methods: An 8p duplication was sought using two independent methods—array based comparative genomic hybridisation (aCGH) and fluorescence in situ hybridisation (FISH)—in 15 patients with a definitive clinical diagnosis of Kabuki syndrome.

Results: No evidence for a duplication of 8p was obtained by FISH or aCGH in any of the 15 patients.

Conclusions: 8p22–p23.1 duplication may not be a common mechanism for Kabuki syndrome. Another genetic abnormality may be responsible for the aetiology in many patients.

     

Measuring learning by trainees in general practice

Twenty simulated consultations with patients having a respiratory illness were carried out by 20 trainees at the start and finish of a training year in general practice, using the same method as used in a previous study of principals in general practice.

During the course of the year, the trainees as a group closely approached the behaviour—in the defined terms of the study—of principals as a group. The trend was more marked for doctors on a three-year training programme than for those on a one-year programme.

In 11 cases direct comparison between trainee and trainer was possible. It was difficult to identify changes in behaviour as being due to either group influences or individual trainer influences, but it appeared that atypical trainers do not necessarily produce atypical trainees and typical trainers do not prevent the development of individuality in trainees.

The technique of simulated consultation may assist the difficult task of evaluating training for general practice.

     

An audit of the care of diabetics in a group practice

The diabetics in a general practice of 20,175 patients were identified during one year and 119 were found—a prevalence of 5·9 per thousand.

The age and sex distribution, method of treatment, criteria of diabetic control, complications, and present method of care were analysed from the medical records to examine the process of medical care of a chronic disease in general practice.

     

Antigenicity and tolerance of some synthetic polypeptides related to collagen

Guinea-pigs immunized with poly-L-proline, poly-L-proline—glycine or poly-L-proline—glycine—acetyl-hydroxy-L-proline develop antibodies which appear to be exclusively directed against determinants composed of sequences of proline.

(2) All three antigens also induce delayed hypersensitivity but the determinants involved include both glycine- and acetyl-hydroxyproline when the antigen is poly-proline—glycine—acetyl-hydroxyproline and glycine when the antigen is poly-proline—glycine.

(3) The administration of either polyproline or poly-proline—glycine in incomplete adjuvant produces a state of tolerance as revealed by subsequent injection of the peptides with Freund's complete adjuvant.

(4) Tolerance induced with poly-proline cannot be broken by immunization with poly-proline—glycine with regard to circulating antibody but is broken with regard to delayed hypersensitivity.

     

β Toxin of Clostridium welchii : Cytotoxic Effects Produced by the • on Guinea-Pig Monocytes

The cytopathic effects of Cl. welchii β toxin on guinea-pig monocytes in vitro have been studied using the uptake of eosin-Y^* as evidence of cell death.

The experiments show that these effects are due to antigen—antibody reaction probably on the cell surface, and that these reactions are not dependent on the presence of complement. Monocytes can be actively sensitized in vivo, and passively sensitized in vitro. The serum used to passively sensitize the monocytes need not possess a precipitating antitoxin titre.

Comparable experiments using an ovalbumin antigen—antibody system produced the same cytopathic effects on the monocytes as those which occurred in the β toxin—cellular system.

     

Quantitative aspects of sensitivity and summation in the cat retina

1. Properties of the central response mechanism of on-centre ganglion cells in the cat retina were studied by recording, from optic tract fibres, responses evoked by stimuli modulated with time in a sinusoidal or square-wave fashion.

2. The shape of averaged square-wave responses resulting from the central mechanism alone was identified. This shape was identical from one cell to another. Such an identification permits the early recognition of peripheral antagonism.

3. Threshold sensitivity for a sinusoidal stimulus was determined for fifty cells along one horizontal and vertical axis, passing through the most sensitive portion of the receptive field. These sensitivity profiles were described in terms of a central segment of constant maximum sensitivity (uniform centre) and sloping outer segments of exponentially decreasing sensitivity (exponential annulus). The dimensions of the uniform centre (horizontal axis × vertical axis) varied from 0·1° × 0·1° to 2·5° × 2·2°, the half width of the exponential annulus ranged from 0·1° to 0·63°.

4. Adapting spots of varying diameter were placed concentric with the receptive field and the (unmodulated) luminance, at each diameter, that reduced a small central (sinusoidal) stimulus to threshold, was determined. The resulting area—adaptation curve, (adapting luminance plotted against diameter) showed that within defined limits the state of adaptation is determined by the flux independent of its distribution.

5. Sinusoidal stimuli of varying diameter were placed concentric with the receptive field and the threshold luminance at each diameter was determined. Suprathreshold square-wave stimuli indicated that the central mechanism alone contributed to the response. These area-sensitivity curves did not show any decrease in sensitivity at larger diameters.

6. The shape of the area—sensitivity curve, and hence the extent of the summating area, was found to be independent of the state of adaptation.

7. For any one cell the shapes of the area—adaptation and area—sensitivity curves were shown to be identical, indicating that adapting flux and stimulus flux are independent of distribution over the same defined limits.

8. The sensitivity of combinations of small disconnected areas of the receptive field was found to be equal to the sum of their individual sensitivities.

     

Incremental responses to light recorded from pigment epithelial cells and horizontal cells of the cat retina

1. Rod-dependent incremental responses were recorded intracellularly in both pigment epithelial cells and horizontal cells of the cat retina. They were elicited by test flashes which were superimposed on background flashes after a delay.

2. In pigment epithelial cells smaller test responses were produced as background intensity was raised. The incremental sensitivity function was linear for about 1·4 log units, with a slope of 0·86, and the approach of saturation occurred at about 2·5 log td scotopic.

3. The amplitude of pigment epithelial test responses could be estimated from the dark-adapted amplitude—log intensity function obtained with single flashes. Test flashes produced the voltage increment predicted by the slope of this function just above the point on the curve equal to the background intensity. The pigment epithelial response to a test flash, therefore, is the response expected if the background were presented alone and made more intense by the amount of the test flash.

4. Rod-dependent incremental sensitivity functions of horizontal cells closely resembled the ones obtained from pigment epithelial cells.

5. It was concluded that the adaptive effects observed in pigment epithelial cells originated in individual rods. These effects arose from the compressive nature of the dark-adapted amplitude—intensity function. In horizontal cell responses these effects may be modified by the failure of the background response to maintain its initial voltage.

     

Characterization of two different agglutinators in the latex fixation test, occurring in normal human sera

Using a sensitive modification of the latex fixation test it is possible to detect a small agglutinating effect in about 60 per cent of normal human sera, after these have been heated for 30 minutes at 56°. This was shown to be caused by an IgM globulin with the properties of a rheumatoid factor. The factor is able to react with human IgG globulin and may represent an antibody to the IgG part of circulating antigen—antibody complexes. The heat treatment probably inactivates an inhibitor of the latex fixation reaction.

In addition all normal human sera give an agglutination reaction with IgG coated latex at incubation temperatures of 37° or lower. It was shown that these reactions are caused by a thermolabile, non-reducible component with a sedimentation constant of about 10. This component is probably identical with the complement component C'_1q. The agglutinating activity was found in the α₂—β₁ region after electrophoresis of untreated serum, but in the slow γ region after treatment of the serum with EDTA. This kind of agglutination may cause false positive reactions in latex tests which are carried out at 37° or less.

     

Antigen—antibody complexes and the weal and erythema skin responses

The smallest amount of purified antibody capable of positive weal and erythema response is of the order of 4 μg N.

Antigen—antibody complexes are capable of producing specific weal and erythema reactions with antigen—antibody ratio of 1:1 or above. In these instances antibodies occupied at one or both sites are responsible for this response. Preformed antigen—antibody complexes are capable of mediating this response.

     

The effect of light chloralose and pentobarbitone anaesthesia on the acid—base state and oxygenation of arterial blood in dogs

1. The effects of light anaesthesia of approximately 8 hr duration using either pentobarbitone or chloralose on the acid—base balance and oxygenation of arterial blood were determined in dogs breathing spontaneously.

2. With pentobarbitone anaesthesia there was a slight initial respiratory acidaemia.

3. With chloralose there was a non-respiratory acidaemia which was probably the result of using an unbuffered solvent.

4. Changes in the acid—base balance and the oxygen concentration of the arterial blood over the course of each experiment were minimal.

5. In one animal a pH of 7·07 was recorded; in others the oxygen tension on occasion was between 50 and 60 mm Hg. The value of monitoring the acid—base state and the oxygenation of blood in experimental preparations is discussed.