Clinical aspects of localized and systemic sclerosis.

Now that renal disease is no longer the leading cause of death in patients with systemic sclerosis, attention has shifted to cardiopulmonary involvement. Several reports addressed the issue of whether the pulmonary vasculature in patients with systemic sclerosis is vasoactive or fixed, and one report addressed the use of high-resolution computed tomographic lung scan to diagnose active alveolitis. The issue of whether the clinical syndrome of thrombotic thrombocytopenic purpura in systemic sclerosis is part of, or is distinct from, scleroderma renal crisis has again been raised. Worsening of cutaneous and visceral systemic sclerosis following radiotherapy was noted in several reports.


Eosinophilia-myalgia syndrome, toxic-oil syndrome, and diffuse fasciitis with eosinophilia.

The eosinophilia-myalgia syndrome, which is associated with the ingestion of L-tryptophan that contained products, occurred as an epidemic in the United States in 1989. Eosinophilia-myalgia syndrome is similar in many ways to the toxic-oil syndrome, which occurred in Spain in 1981, and to diffuse fasciitis with eosinophilia, which has been noted since 1974 to occur sporadically. Recent studies have clarified the epidemiology, histopathology, and clinical features of eosinophilia-myalgia syndrome. These studies are reviewed, and comparisons to the related syndromes, toxic-oil syndrome and diffuse fasciitis with eosinophilia, are made.


Genetic and environmental factors in systemic sclerosis.

The occurrence of autoantibodies in patients with systemic sclerosis has suggested a role for immune dysregulation in this disease. Recent genetic studies have concentrated on the major histocompatibility complex-encoded antigens and found an association of particular HLA-DQ alleles with anticentromere antibodies. Although the role of major histocompatibility complex antigens and autoantibodies in the pathogenesis of systemic sclerosis remains unclear, determination of major histocompatibility complex alleles may have clinical value in identifying patients who are at increased risk for development of pulmonary fibrosis or rapidly advancing skin disease. A variety of environmental factors have been associated with systemic sclerosis-like skin diseases, including silica, vinyl chloride, paraffin, adulterated L-tryptophan, and "toxic" rapeseed oil. It has been suggested that silicone used during breast augmentation may be a risk factor for development of systemic sclerosis, but ascertainment bias in case reporting makes interpretation of these studies difficult. The heterogeneity of clinical features, major histocompatibility complex status, and autoantibody profiles in systemic sclerosis suggest that this disorder may actually be a group of distinct disorders, each of which has its own characteristic genetic and environmental predisposing risk factors.


Immunologic aspects of scleroderma.

Recent investigations of immunologic events in systemic sclerosis focus on the identification of which immune system cells are participating in the disease process, what antigens are stimulating the T and B cells, which cytokines are involved, and which cell adhesion molecules promote cell-cell and cell-extracellular matrix interactions. Increased numbers of gamma/delta and activated CD4+ T cells are present in involved skin of line-200 chickens, an animal model of systemic sclerosis. CD4+ T cells from patients with systemic sclerosis are stimulated by human type I collagen, and immunoglobulins from some patients with systemic sclerosis bind retroviral proteins, the terminal galactosyl (alpha 1-3)-galactose disaccharide of laminin, or a 138 amino acid region of the PM-Scl antigen. The development of an anticentromere antibody response in patients with systemic sclerosis appears to require the presence of a polar amino acid at position 26 in the antigen-binding cleft of the HLA-DQB1 molecule. Interleukin-2, interleukin-4, interleukin-6, and transforming growth factor-beta have been implicated as cytokines that may be involved in the pathogenesis of systemic sclerosis. Increased expression of intercellular adhesion molecule 1 (ICAM-1) on systemic sclerosis fibroblasts is responsible for increased binding of T cells to those fibroblasts through ICAM-1/lymphocyte function-associated antigen 1 interactions. beta 1 and beta 2 integrins, ICAM-1, and endothelial leukocyte adhesion molecule 1 all may be involved in the homing of lymphocytes to involved skin in patients with systemic sclerosis.


Treatment of systemic sclerosis.

A new awareness of the challenges and pitfalls of clinical research in patients with systemic sclerosis has recently arisen. Several editorials discussed concern about the design of therapeutic trials and the need to use established scientific standards to find better markers of disease activity and better ways to measure improvement or deterioration of organ involvement, including the heart, lung, and gastrointestinal tract. This year, an uncontrolled experience in the use of D-penicillamine in the treatment of patients with rapidly progressive skin involvement was reported. In addition, a multicenter study of photopheresis demonstrated benefit compared with D-penicillamine. Several new prokinetic drugs demonstrated promise for the treatment of gastrointestinal disease in patients with systemic sclerosis. Although studies continue to demonstrate the benefit of intravenous prostaglandins in the treatment of Raynaud's phenomenon and digital ulcers in scleroderma, an initial report of oral prostaglandins was disappointing. Clinical researchers are now working together to design multicenter studies and to define new uniform standards of disease activity so that the appropriate treatment for systemic sclerosis can be determined.


Connective tissue metabolism including cytokines in scleroderma.

Scleroderma fibrotic lesions demonstrate vascular disease, mononuclear cell infiltrates, and increased collagen. Fibroblasts in these lesions are activated to synthesize increased extracellular matrix substances, a phenotype that continues when these cells are removed and grown in tissue culture. Levels of messenger RNA for connective-tissue substances, measured directly in biopsies of scleroderma skin, show increased message for type I collagen, but not type III collagen or fibronectin. Increased procollagen type I in scleroderma skin occurs in the papillary dermis, perivascular areas, and deep interstitium, even in skin areas that are not yet fibrotic. Scleroderma fibroblasts express more intercellular adhesion molecule 1 on their surfaces than do normal cells, and this molecule is increased in endothelial cells, mononuclear cells, and fibroblasts. In vitro scleroderma fibroblasts adhere more frequently to extracellular matrix substances and retract collagen lattices to a greater extent. Peripheral blood lymphocytes from scleroderma patients produce excessive amounts of interleukin-2 when incubated with type I collagen, and circulating basophils release more histamine than do normal cells. There is evidence for activated eosinophils both in the dermis and pulmonary lesions in scleroderma, which may play a role in fibrosis. Transforming growth factor-beta is overexpressed by alveolar macrophages from patients with fibrotic pulmonary disease. Scleroderma fibroblasts, when exposed to transforming growth factor-beta, overexpress the alpha-type receptor for platelet-derived growth factor. Scleroderma sera more frequently contain measurable quantities of interleukin-4, interleukin-6, and interleukin-2. Interleukin-4 causes adult dermal fibroblasts to proliferate and to make interleukin-6. Interleukin-6 has been shown to stimulate fibroblast synthesis of collagen and glycosaminoglycans.(ABSTRACT TRUNCATED AT 250 WORDS)


The effect of pH on the thermal resistance of Clostridium sporogenes (PA 3679) in asparagus purée acidified with citric acid and glucono-delta-lactone.

The influence of type of acid, pH and temperature on heat resistance of Clostridium sporogenes (PA 3679) spores were investigated in white asparagus pureé acidified with citric acid and glucono-delta-lactone (GDL). The pH values studied were: 4.5, 4.8, 5.1 and 5.4 at temperatures of 110, 115, 118 and 121 degrees C. The addition of citric acid and GDL to reduce pH significantly diminished heat resistance of the spores. The two acids investigated differed in their effect on heat resistance at the various pH-levels. The most pronounced effect was observed at the lower heat treatment temperatures investigated. The z values ranged from 10.24 to 13.09 degrees C in the asparagus purée with acids added and with significant differences between the two acids and the various pH levels.


Bacteriocin (monocin) interactions among Listeria monocytogenes strains.

Monocin interactions of 97 strains of Listeria monocytogenes were assessed using an improved production method and standardisation of the monocins against the type strain of L. ivanovii. Monocins were resistant to trypsin, sensitive to heating at 56 degrees C for 30 min and stable at 4 degrees C. Only serovar 4 strains acted as indicators. A typing system using 8 producer and 11 indicator strains showed poor discrimination.


Salmonella and Vibrio cholerae in brackishwater cultured tropical prawns.

The occurrence of Salmonella and Vibrio cholerae in brackishwater ponds was monitored over a 2-year period in one of the major prawn exporting countries in Southeast Asia. The principal production areas were identified and regular samples taken for Salmonella and V. cholerae analysis. Results demonstrated that brackishwater ponds and cultured prawns were inherently contaminated with both bacterial pathogens. Salmonella spp. were present in 16.0% of prawns and 22.1% of mud/water samples from ponds; and V. cholerae present in 1.5% of prawns and 3.1% of mud/water samples. Culturing by intensive methods tended to favour contamination by these pathogens, which is most likely due to the accumulation of waste and increase in the volume of sediments in ponds. Typical environmental factors such as water temperature, pH, and salinity were all favourable for growth of microorganisms. The incidence of the pathogens increased during the wet season and was marginally higher when ponds were located close to urban areas. S. weltevreden was identified as the principal serotype found in ponds, and to a lesser extent S. anatum (11%) S. wandsworth (8%) and S. potsdam (8%). The V. cholerae belonged to the non-O1 serogroup.


Accelerated natural lactic fermentation of cereal-based formulas at reduced water activity.

Energy required to dehydrate fermented cereal-based food formulas plays a significant part in the production cost. Therefore the effect of reduced moisture content on the fermentation was investigated. Generally, lactic fermentation at reduced moisture content resulted in increased final pH. Significant acidification still occurred at 0.33 kg water/kg dry matter corresponding to either aW = 0.925 in a sorghum-maize-soya (SMS) mixture, or aW = 0.950 in a sorghum-maize-milk powder (SMM) mixture. Acidification adequate for microbiological safety (pH < or = 4.5) was achieved at 0.54 kg water/kg dm in SMS (aW = 0.950) and 0.43 kg/kg dm in SMM (aW = 0.965). In stable accelerated natural lactic fermentations obtained by inoculum recycling ('back-slopping') at 30 degrees C, dominant lactic acid bacteria included Lactobacillus plantarum, L. brevis, L. acidophilus and Lactococcus lactis. Dominating yeasts were Saccharomyces cerevisiae and Candida krusei. L. plantarum isolated from high-moisture (1.5 kg/kg dry matter) SMS fermentations had higher specific growth rates than L. plantarum isolated from reduced moisture (0.54 kg/kg dm) SMS fermentations, when tested under similar aW conditions. This effect was not caused by previous culturing conditions; probably different strains of L. plantarum having different aW-optima dominate at high or reduced moisture conditions.


Minimal water activity levels for growth and survival of Listeria monocytogenes and Listeria innocua.

Following initial range-finding experiments, total count determinations were used to determine minimal water activity (aW) levels for the growth and survival of Listeria monocytogenes (L.m.) and L. innocua (L.i.). Media containing three different humectants; NaCl, sucrose or glycerol were used to determine minimal aW levels for growth in the above media which were 0.92, 0.92 and 0.90 respectively. The growth minima for L.i. were similar, or slightly higher than for L.m. in these media. Survival rates were generally lower in NaCl-adjusted media than in systems adjusted with sucrose or glycerol. Survival of L.m. and L.i. in these experiments was similar.


Antibacterial activity of essential oil components.

Antibacterial activity of fifteen essential oil components towards food borne Staphylococcus sp., Micrococcus sp., Bacillus sp. and Enterobacter sp. was studied by an agar plate technique. Cinnamic aldehyde was the most active compound followed by citral, geraniol, eugenol and menthol. At 500 micrograms/ml, cinnamic aldehyde completely inhibited the bacterial growth for more than 30 days at 30 degrees C that was comparable to 200 micrograms/ml of butylated hydroxy anisole (BHA). At lower temperatures, 25 and 20 degrees C, antibacterial activity of the five essential oil components increased. Addition of sodium chloride at 4% level (w/v) in the medium had no effect on the inhibitory activity of cinnamic aldehyde. In mixtures of cinnamic aldehyde and eugenol or BHA an additive effect was observed.


Preliminary examinations on the enterotoxigenicity of isolates of Klebsiella pneumoniae from seafoods.

One hundred and eighty-five seafood samples, consisting of 96 freshwater fish, 37 marine fish, 13 freshwater prawn, 13 marine prawn and 26 molluscs were screened for presence of Klebsiella. Out of these, 12 isolates of Klebsiella were identified, Four K. pneumoniae var. ozaenae were isolated from marine fish samples and eight K. pneumoniae var. pneumoniae, six from freshwater fish and two from freshwater prawns. All 12 isolates were tested for enterotoxigenicity by the vasopermeability factor test in rabbits, the mouse foot pad test, the latex agglutination test and the coagglutination test. One isolate of K. pneumoniae var pneumoniae, isolated from fresh water prawn was found enterotoxigenic.


Rectal administration of perforated nifedipine capsules in acute severe hypertension in children.

Nine hypertensive children (mean age: 5.0 years (SD: 4.5), range: 10 months to 15 years) were administered nifedipine (capsule) rectally (0.2 to 0.5 mg/kg) when their blood pressures were over 170 mmHg systolic and/or over 110 mmhg diastolic, independent of their ages. The causes of hypertension were acute glomerulonephritis (n = 2), chronic glomerulonephritis (n = 2), renovascular hypertension (n = 4), and polycystic kidney (n = 1). Both systolic and diastolic blood pressures fell in all children after rectal administration of nifedipine, although the response of blood pressure was weak in one child with renovascular hypertension. Blood pressures were lowest at 30 to 60 minutes, and remained under 140 mmHg systolic and 80 mmHg diastolic at least for three hours. Side-effects were headache in one child, palpitations in two children, and facial flushing in three. All of these symptoms were mild, and no special treatment was required. These findings suggest that rectal administration of nifedipine may be effective and the most reliable way to treat young children with severe or urgent hypertension.


Hypothalamo-pituitary-adrenal axis suppression in asthmatic adults taking high dose beclomethasone dipropionate.

Inhaled corticosteroids control symptoms of chronic asthma in most patients. Use of drugs such as beclomethasone dipropionate (BDP) and budesonide is being encouraged as the importance of airways inflammation in asthma is increasingly appreciated. Beclomethasone dipropionate is used in doses of up to 2000 micrograms daily (equivalent to eight puffs of Beclorforte inhaler) and the Data Sheet warns that systemic absorption sufficient to cause suppression of the hypothalamo-pituitary-adrenal (HPA) axis may occur in some patients taking 2000 micrograms. HPA suppression to an extent which is clinically relevant has not been reported in asthmatic adults taking lower doses of BDP. We report six cases of HPA hypofunction occurring in patients on long-term treatment with BDP, in a dose of 1500 micrograms daily. Patients taking BDP in a dose of 1500 micrograms daily might be at risk of adrenal crisis and should carry steroid cards unless HPA function has been assessed and found normal.


Home sweet HEN--a guide to home enteral nutrition.

Initial experience of home enteral nutrition (HEN) was gained from malnourished patients with Crohn's disease. The rationale for HEN was to improve the patients' lifestyle by reducing the need for repeated admissions for nutritional support: this method is extremely useful in correcting nutritional problems. Over the past ten years the use of HEN has expanded to cover other clinical areas including correction of growth retardation secondary to gastrointestinal disease, cystic fibrosis, inborn errors of metabolism, congenital heart disease, and chronic renal failure, in addition to many types of neoplasia and chronic neurological diseases. At the present time, approximately 150 patients receive HEN within the catchment area of the Greater Glasgow Health Board (population 940,000). Despite the increasing availability of HEN many clinicians and dietitians are still reluctant to consider HEN as a 'routine adjunct' to clinical management, claiming that it is too dangerous or complicated. The aims of this article are to explain our method of running a HEN service, offer advice on practical problems and discuss further developments and potential difficulties.


The role of echocardiography in the diagnosis and management of infective endocarditis.

The echocardiographic appearance in suspected endocarditis must always be interpreted in the context of the clinical findings. Thus although echocardiography may contribute to the early diagnosis of infective endocarditis, it should rarely be used as a screening test. It is highly sensitive for the detection of complications such as abscesses or valvular regurgitation and can estimate their severity. Although transthoracic imaging will allow a complete study in many cases, the transoesophageal approach is superior for the detection of abscesses and the assessment of prosthetic mitral valves. Patients with large vegetations, particularly on the mitral valve, are at increased risk of embolism but there is no convincing evidence to support prophylactic surgery in these cases.


Exercise in post infarct rehabilitation.

In 1957, Hellerstein and Ford defined rehabilitation as 'the process by which a patient is returned realistically to his greatest physical, mental, social, vocational and economic usefulness and, if employable, is provided an opportunity for gainful employment in a competitive industrial world'. They stressed the importance of starting the rehabilitation process 'at the moment the patient is first stricken with his disease', of mobilising the patient as soon as is practical and of paying close attention to the emotional as well as physical consequences of the attack. They believed that 80% of the aftercare of cardiac patients could be managed by the 'private physician' and only a minority required the attention of a specialist team. The time scale used in 1957 (three to four weeks in hospital) was rather different to the one we use today, but otherwise most of what he suggested then has scarcely been improved upon since. In 1968 Hellerstein went on to describe the physical training programme he had devised to improve the fitness of 'habitually lazy, hypokinetic, sloppy, endomesomorphic over-weight males' who were the usual victims of myocardial infarction. He wished to 'add life to years and perhaps add years to life'. The conclusions from his original study were that 'an active intervention programme of conditioning including exercise, weight reduction, diet therapy, and cessation of smoking is feasible, reasonably acceptable and appears to be of benefit in the treatment of coronary heart disease'.


Can selection of medical staff be improved?

Selection procedures for medical staff have been reviewed. Much can be learnt from industrial practices, including the adoption of 'person specifications', improved references, structured interviews and training for interviewers. Possible supplementation with personality assessments is discussed. The clinical (and financial) importance of appointing the best candidate increased with the seniority of the post.


Aortic dissection.

Aortic dissection, once thought to be rare, is the most common catastrophe of the aorta, being twice as common as ruptured abdominal aortic aneurysm. In one Inner London borough, aortic dissection accounted for 4.2% of sudden deaths in men over a three-year period. Early diagnosis and prompt treatment are crucial to achieving a successful outcome, because the events that influence survival occur early in the course of the disease. Surgical repair of aortic dissection is an uncommon operation in the United Kingdom. The Cardiac Surgical Register for 1988 (the most recent year available for analysis) reveals that 208 operations were performed to replace the ascending aorta, 12 operations to replace the aortic arch and 15 operations on the descending aorta during that year.


Assessment of reversibility in patients with chronic airflow obstruction.

Reversibility of airflow obstruction was considered for many years to be a hallmark of asthma. It is now clear that many patients with chronic airflow obstruction, often labelled as chronic obstructive airways disease or chronic bronchitis and emphysema, show some bronchodilation following various drugs. At present there is no clinical or physiological factor which reliably predicts the bronchodilator response of such patients to a given medication, and individual testing of these drugs is necessary. However, the literature on bronchodilator responses in chronic airflow obstruction is confused. There are differences in the selection of patients, the tests used and the interpretation of the results. The aim of this review is to highlight the main problems found when measuring reversibility in such patients, the different factors that influence the reversibility testing and the biases which may confound the interpretation of the results.


Primary hyperparathyroidism and renal cell carcinoma in an elderly patient: a rare association.

A case of an elderly female patient, presented with a rare association of primary hyperparathyroidism and renal cell carcinoma, is reported. As a common finding in the elderly, the patient had mild hypercalcaemia for many years but she developed several complications from untreated hyperparathyroidism. The mechanisms of malignant hypercalcaemia are discussed and the importance of properly investigating and managing symptomatic primary hyperparathyroidism in the elderly is emphasised.


Quinine-induced cutaneous vasculitis.

We report a 60-year-old woman who developed severe cutaneous vasculitis three weeks after commencing quinine sulphate (300 mg at night) for nocturnal cramps. The patient died despite immunosuppressive treatment with prednisolone and cyclophosphamide. We review three previous cases and conclude that cutaneous vasculitis is a rare but life-threatening complication of treatment with this widely-prescribed drug. Quinine sulphate is prescribed frequently for nocturnal cramps, although its efficacy is unsupported by stringently controlled clinical trials. Adverse reactions to the drug are unusual. We describe a 60-year-old woman with fatal cutaneous vasculitis related to quinine treatment.


Hallucinations as a presenting feature in malignant hypertension.

A 68-year-old man with malignant hypertension of renovascular origin presented with visual impairment and complex visual hallucinations. Four weeks after the hypertension had been controlled by drugs, the hallucinations ceased and electroencephalographic evidence of encephalopathy resolved.


Perforation of an abdominal viscus associated with a pneumothorax.

Pneumothorax is a very unusual presenting complication of a perforated abdominal viscus. We present two such cases. The importance of close scrutiny of chest radiographs taken for abdominal disease is stressed.


A presentation of anaplastic carcinoma of the thyroid with symptomatic intra-abdominal metastases.

Anaplastic thyroid carcinoma usually presents with symptoms related to local invasion and compression of structures in the neck. We report a patient with intra-abdominal metastases presenting with symptoms suggestive of local gastrointestinal disease. Abdominal CT scan and initial laparotomy findings were suggestive of an abdominal aortic aneurysm.


Alveolar rhabdomyosarcoma: a case presentation.

We present a case report of an unusual tumour, presenting as a mass on the forearm. We have used this case to review the current literature and histological classification of rhabdomyosarcoma.


Idiopathic retroperitoneal haematoma.

A case of asymptomatic idiopathic retroperitoneal haematoma presenting as an abdominal tumour, is described. A review of English literature has not revealed any description of this condition.


Apparent elevation of serum CK-MB not due to acute myocardial infarction.

An increased serum level of the MB isoenzyme of creatine kinase (CK-MB) is a useful marker for acute myocardial infarction. Although described extensively in clinical chemistry literature, there is little information in standard medical references about false positives for this test. We report two cases where high levels of measured CK-MB activity were in fact due to another form of CK, associated with internal malignancy.


Long-term survival of a patient with malignant lymphoma of bone.

Malignant lymphoma of bone is an uncommon tumour. A number of studies have outlined the clinicopathological findings and overall favourable prognosis in adults. We report on a woman whose tumour was originally diagnosed as a secondary carcinoma of the upper femur. Twenty-three years later following proximal femoral replacement, the original histology was reviewed using immunohistochemical techniques and revised to B-cell malignant lymphoma of bone.


Quality of sleep in the medical department.

The quality of sleep in 134 patients admitted to two medical departments and an intensive coronary care unit was studied by comparing pre- and post-admission sleeping scores. Four aspects of sleep have been evaluated: duration of sleep; number of awakenings; personal assessment of quality of sleep; and the need for using sleeping pills. Results were expressed in scores ranging from 1 (worst) to 4 (best). A significant reduction in the mean quality of sleep for the entire group was found for all scores employed (P < 0.01-P < 0.001). Of the 134 patients, 51% had a reduction in post-admission total sleep score (23 +/- 3%, mean +/- SE); 31% had no change or mixed trends in the various scores, with a change in total sleep score not exceeding 3 +/- 3%; and 18% had an improved total sleep score (16 +/- 2%). Of the individual scores, a deterioration was found in the following order of frequency: number of awakenings (37%); personal assessment of quality of sleep (32%); duration of sleep (31%); and the need for using sleeping pills (26%). Of the reasons specified for impaired quality of sleep, the most important were noise made by other patients or by the medical staff (47%), and the patient's own disease (30%). Significant differences in the quality of sleep between the two medical departments located in different hospitals have been encountered (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)


Are non-steroidal anti-inflammatory drugs always necessary? A general practice survey.

The number of patients receiving long-term 'repeat prescriptions' for non-steroidal anti-inflammatory drugs (NSAIDs) was examined in a General Practice; a group of them with osteoarthritis or musculoskeletal pain attempted to withdraw their NSAID treatment and substitute alternative analgesics. Thirty-eight randomly selected patients, with conditions other than rheumatoid arthritis, were interviewed and alternative analgesics prescribed to replace their NSAID therapy. After one month, 22 had very satisfactory pain relief without their NSAID but 16 had resumed therapy, with four of them on a reduced dosage; three others wished to try an alternative analgesic again. Five initially with gastro-intestinal symptoms were asymptomatic within a month of discontinuing their NSAID. After four months, 24 of the 38 had discontinued NSAIDs, including one who had an upper gastrointestinal haemorrhage during the study; two others were taking a reduced dosage.


Dyspepsia in the community: a follow-up study.

We have repeated a population-based survey of the pattern and prevalence of dyspeptic symptoms in 2460 subjects two years after the original survey, in order to document the changes in dyspeptic symptoms and consultation behaviour. A validated postal questionnaire was sent to 2460 subjects randomly selected in ten-year age bands from the lists of eight general practitioners working in the south of England. A total of 1417 individuals (58%) responded to both questionnaires. The overall six month prevalence of dyspepsia was unchanged (38%), but while 74% of dyspeptic patients were still getting symptoms, 13% became symptom-free each year. Over half of those who had reported dyspepsia before, but not at the time of, the first survey had experienced recurrence of their symptoms. In the two-year study period 113 individuals experienced dyspepsia for the first time, giving an annual incidence of 11.5%. One in four patients consulted their general practitioner, and 75% of those who had not consulted in the first survey still had not done so two years later. Resolution of symptoms appeared independent of consulting behaviour. Peptic ulcers were identified in 14 patients, mostly those with new dyspepsia, during the study period.


Humeral fractures in 'arm wrestlers'.

We report three cases of fractures of the shaft of the humerus occurring during arm wrestling contests, which have now become a common pub--and even professional--sport. We then review all the literature on the subject. This is an unusual injury occurring in arm wrestling, but does occur and it should be remembered that radiological assessment is vital if this injury is not to be missed and the injury mismanaged.


Glomerular abnormalities in children undergoing orthotopic liver transplantation.

A prospective study of renal function was undertaken on an unselected group of 8 children with chronic progressive liver disease on whom a renal biopsy was performed subsequently at the time of orthotopic liver transplantation. Two patients had abnormal urinalyses and 2 elevated urinary albumin/creatinine ratios. The remainder had no clinical evidence of renal dysfunction. All had normal serum creatinine concentrations. Glomerular abnormalities were present in all renal biopsies and were of two types: hepatic glomerulosclerosis (n = 5) and minor glomerular abnormalities (n = 3). IgM immunofluorescence was present in all biopsies and IgA in 6. Elevated serum immunoglobulin levels were observed in all patients, with IgM elevation in 6, IgA in 4 and IgG in 6. C3 and/or C4 were reduced in 5 patients and increased circulating immune complexes containing IgM were noted in 4. The clinical significance of these cirrhosis-associated glomerular abnormalities can only be established by long-term follow-up studies after orthotopic liver transplantation.


Prognosis of patients with unilateral renal agenesis.

The clinical course was reviewed in 157 patients with unilateral renal agenesis and a normal contralateral kidney for the purpose of establishing a prognosis. There were 85 males (54%) and 72 females (46%). The mean age at diagnosis of unilateral renal agenesis was 37 years. The mean years at risk was 56. Proteinuria (> 150 mg/24 h) was found in 19% of the 37 patients tested (P < 0.001), hypertension developed in 47% of the 47 patients tested (P = 0.010), and renal function (adjusted for age and sex) was decreased in 13% of the 32 patients tested (P = 0.001). An increased filtration fraction was found in 7 (54%) of 13 patients evaluated. At the completion of this study, 114 patients (73%) were alive, and the survival rate was similar to that of age-, sex-matched United States life tables. Forty-three patients (27%) died; 6 deaths (4%) were caused by renal failure. Our review indicates that patients with unilateral renal agenesis and a normal solitary kidney are at increased risk of proteinuria, hypertension, and renal insufficiency. Therefore, it is essential to have prolonged and careful follow-up and to employ strategies that maximize renal preservation.


Association of Kawasaki disease and interstitial nephritis.

Renal insufficiency is a rare manifestation of Kawasaki disease. We report a 2.5-year-old boy with Kawasaki disease who developed acute renal failure during the acute phase of his illness. A percutaneous renal biopsy revealed acute interstitial nephritis. No etiological agent could be identified and renal recovery occurred with supportive care alone.


What makes red cells dysmorphic in glomerular haematuria?

Although red cell morphology has been used to localise the site of haematuria in the urinary tract, the cause of red cell deformity is still speculative. We have conducted experiments in vitro using venous red cells which indicate that hypochromia depends mainly upon sodium concentration and occurs when this falls below 75 mmol/l. We simulated the passage of red cells through the renal tubule by sequentially treating them with fluids of composition similar to those in different tubular segments, and produced anisocytosis and hypochromia but not the typical "bizarre deformity"--the hallmark of glomerular haematuria. We conclude that dual injury is required to produce the "typical" dysmorphic red cells in glomerular haematuria. First, mechanical damage caused by passage of red blood cells through the glomerular basement membrane followed by a second, osmotic, injury sustained by red cells during passage through the hypotonic tubular segment.


Renal hypoplasia and postnatally acquired cortical loss in children with vesicoureteral reflux.

We reviewed histologically 86 nephrectomy specimens from patients with vesicoureteral reflux (with or without ureterovesical obstruction) to investigate the relationship between coexisting hypoplasia and postnatally acquired cortical damage. Hypoplasia was assessed independently of the acquired cortical loss using medullary ray glomerular counting. Severe hypoplasia (glomerular number < 25% of normal) was detected in 47 of 86 patients. These patients underwent nephrectomy at a significantly younger age than those with minimal or no hypoplasia (P < 0.01). There was no significant relationship between the severity of hypoplasia and the presence or absence of obstruction. Severe acquired cortical loss was found in 68 of 86 patients. There was no significant association between the severity of cortical loss and the presence or absence of obstruction, age at nephrectomy or degree of coexisting hypoplasia. The findings suggest a strong association of hypoplasia and vesicoureteral reflux. Therefore, early postnatal presentation with minimal renal function need not necessarily reflect a failure of management but rather a pre-existing limitation of renal capacity. Furthermore, in a significant proportion of fetuses with ultrasonographic evidence of urinary tract abnormality, renal pathology may be present prior to the time at which in utero surgical intervention may be considered.


Effects of enalapril on adriamycin-induced nephrosis.

Adriamycin induces proteinuria and glomerular changes in rats similar to those found in human focal segmental glomerulosclerosis (FSGS). Progression of this lesion may be slowed by use of angiotensin converting enzyme inhibition. To evaluate this we injected two groups of Sprague-Dawley rats with Adriamycin (2 intravenous doses of 2 mg/kg given at an interval of 3 weeks). One group of rats received enalapril (50 mg/l) in their drinking water. Control rats were injected with saline. After 28 weeks, the mean whole kidney glomerular filtration rate was significantly less and proteinuria and sclerotic index were significantly greater in rats receiving adriamycin compared with controls (P < 0.05). Administration of enalapril did not decrease proteinuria (545 +/- 398 mg/day vs 494 +/- 325 mg/day, P >0.05) or improve the glomerular filtration rate (0.31 +/- 0.18 ml/min per g kidney weight vs 0.41 +/- 0.21 ml/min per g, P = 0.27). However, treatment with enalapril significantly reduced the mean glomerular sclerotic index compared with untreated rats (1.62 +/- 0.88 vs 0.82 +/- 0.49, P = 0.05). Enalapril may be beneficial in preserving glomerular structure in this experimental model of FSGS.


Accelerated growth in short children with chronic renal failure treated with both strict dietary therapy and recombinant growth hormone.

In a 12-month study, nine boys, aged 4.8-15.6 years, with bone ages 4.6-13 years, with moderate to severe chronic renal failure and resultant growth failure were treated with daily recombinant human growth hormone (rhGH), in conjunction with a strict low-protein/low-phosphate diet supplemented with keto and amino forms of the essential amino acids, histidine and additional energy. Improved growth had previously been observed with this dietary management over that obtained with conventional treatment for chronic renal failure. Each child had been on this diet for at least 2 years before rhGH was commenced. Mean height velocity increased from 4.6 +/- 1.3 to 9.0 +/- 1.3 cm/year (P < 0.001) in the pre-pubertal group, and in the pubertal group from 5.4 +/- 1.4 to 10.4 +/- 1.8 cm/year (P < 0.01). The mean height velocity standard deviation scores (SDSs) increased from -1.2 +/- 0.6 to +2.3 +/- 0.9 (P < 0.001) in the pre-pubertal group and from -0.4 +/- 0.6 to +1.9 +/- 1.1 (P < 0.01) in the pubertal group. Mean height SDS for chronological age increased from -2.2 +/- 0.7 to -1.5 +/- 0.5 (P < 0.01) in the pre-pubertal group and from -1.9 +/- 0.7 to -1.3 +/- 0.9 in the pubertal group (P < 0.02). There was no significant deterioration in renal function or renal bone disease, and bone age did not advance more than chronological age over the 12-month period.


Psychosocial adaptation of children and adolescents with chronic renal failure.

In a multicentre study comprising five paediatric nephrology centres in Western Germany, psychosocial and educational parameters were assessed (during 1987) in 479 children and adolescents with chronic renal failure (CRF) in order to gain insight into their psychosocial adaptation to the disease. At the time of assessment, 31% of patients were on conservative treatment, 14% on haemodialysis, 9% on continuous ambulatory peritoneal dialysis and 46% had a functioning transplant. The mean age at assessment was 13.6 years. Additional disabilities were noted in 29% of patients. School attendance of the 233 children of school age was in general satisfactory; 22% of patients attended schools for disabled or handicapped children. Vocational training was frequently inadequate, especially for dialysed patients, and only 14 of 53 adolescents over 16 years had graduated. Of 49 adult patients, only 21 were in some form of employment. A lack of age-appropriate independence was observed in a large proportion (86%) of patients over 17 years, who continued to live with their parents or other persons taking care of them, whilst only 14% were living alone or with a partner. We conclude that, despite improved survival, psychosocial adaptation continues to be impaired in paediatric patients with CRF, especially in adolescents and those on dialysis.


Altered in vitro lymphocyte response in childhood nephrotic syndrome.

The immune system, and disturbed T lymphocyte function in particular, has previously been implicated in the pathogenesis of childhood idiopathic nephrotic syndrome. As this disorder is commonly responsive to steroid therapy, we set out to determine whether in vitro suppression of lymphocyte blastogenic response to the mitogen phytohaemagglutinin (PHA) could predict the clinical situation. Comparing nine nephrotic children with nine healthy controls we were able to show the inhibitory prednisolone dose that suppressed lymphocyte blastogenesis by 50% (ID50) at a known concentration of PHA was significantly greater (P < 0.005) for nephrotic individuals. However, the in vitro assay did not reliably predict the clinical response to prednisolone. This study further implicates altered lymphocyte function in the mechanisms underlying idiopathic nephrotic syndrome.


Lupus nephritis in a pediatric renal transplant recipient.

A case of aggressive lupus nephritis in a pediatric renal transplant patient is described. She initially presented with end-stage glomerulonephritis for which an underlying etiology could not be determined. Ten months after cadaveric renal transplantation, systemic lupus erythematosus was diagnosed, when she developed diffuse proliferative glomerulonephritis in association with antinuclear antibody, anti-double-stranded DNA antibody and extrarenal manifestations of lupus. It is plausible that she developed recurrent rather than de novo lupus nephritis following transplantation. Reactivation of lupus nephritis in a renal transplant is unusual in adults, and is previously unreported in children.


Practical peritoneal dialysis--the Tenckhoff catheter in acute renal failure.

The problem of acquiring secure peritoneal access encompasses most of the history of peritoneal dialysis. We review the catheters available for children and describe a simple method of insertion of Tenckhoff catheters for acute dialysis. Two series of Tenckhoff catheters inserted in this way are presented and compared with results obtained with trocar- and guidewire-inserted catheters. Tenckhoff catheters inserted as described allow significantly longer periods of dialysis (P < 0.02) with significantly fewer problem episodes (P < 0.001). We conclude that the use of the Tenckhoff catheter for acute dialysis, when inserted in the way described, confers significant advantages over other catheters and permits secure peritoneal access.


Nephrogenic diabetes insipidus: clinical symptoms, pathogenesis, genetics and treatment.

This review summarizes various aspects of the inherited kidney disorder nephrogenic diabetes insipidus (NDI). The clinical manifestations of the disease are presented. The important role of the genetic localization of the NDI gene to the X-chromosome long arm, in region Xq28, for carrier detection and early (prenatal) diagnosis of the disorder is emphasized. Following an overview of the cellular physiology involved in the antidiuretic action of vasopressin, possible mechanisms in the pathogenesis of NDI are discussed. We hypothesize that NDI is most probably due to the absence or abnormality of the renal V2 receptor. This assumption is strengthened by recent findings in receptor studies, which indicate a general V2 receptor defect in NDI, and in experiments with somatic cell hybrid cell lines, which are consistent with a co-localization of the genes for NDI and for the V2 receptor in the Xq28 region. Finally, the efficacy of the combination amiloride-hydrochlorothiazide, compared with the indomethacin-hydrochlorothiazide regimen, in the treatment of NDI is presented and the advantages of the former combination are discussed.


Renal effects of growth hormone. II. Electrolyte homeostasis and body composition.

Growth hormone (GH), either directly or through insulin-like growth factor-1 (IGF-1), has a wide spectrum of physiological and renal effects. This review concentrates on the effects of GH (derived from either pituitary or recombinant technology) and IGF-1 in three main areas: (1) sodium and water homeostasis; (2) calcium and phosphate balance, bone density and interactions with mineral regulating hormones; (3) fat and lean body mass. Observations of physiological changes in states of GH deficiency and excess in humans and animal models are presented. The lack of long-term toxicological data indicates that GH treatment for short stature in non-GH deficient children, with or without renal disease, should proceed with caution.


The renal cytochrome P-450 arachidonic acid system.

In addition to cyclooxygenase and lipoxygenase, arachidonic acid (AA) is metabolized by the cytochrome P-450 monooxygenase system. The kidney is one of the major extrahepatic tissues that display cytochrome P-450 enzyme activities, in particular the cortex, specifically the proximal tubule demonstrate the highest concentration. AA is metabolized by the renal cytochrome P-450 epoxygenase and omega/omega 1 hydroxylases to epoxyeicosatrienoic acids and omega/omega-1 alcohols (20- and 19-mono-hydroxyeicosatetraenoic acids), respectively. These metabolites possess a broad spectrum of biological and renal effects which include: vasodilation, vasoconstriction, inhibition and stimulation of Na(+)-K(+)-ATPase, inhibition of ion transport mechanisms, natriuresis, inhibition of renin release and stimulation of cell growth. These metabolites are endogenous constituents of the kidney and are present in urine with increasing concentration under pathological conditions such as pregnancy-induced hypertension. The cytochrome P-450-dependent metabolism of AA is specifically localized to the proximal tubule and exhibits developmental changes, i.e., renal production of metabolites is very low in the fetus, newborn and up to 3 weeks of age, after which a remarkable increase in enzyme activities is observed. These characteristics call attention to the importance of this enzyme system in producing cellular mediators for regulating renal function in normal and diseased states.


Interstitial photodynamic therapy in a rat liver metastasis model.

Photodynamic therapy (PDT) of hepatic tumours has been restricted owing to the preferential retention of photosensitizers in liver tissue. We therefore investigated interstitial tumour illumination as a means of selective PDT. A piece of colon carcinoma CC531 was implanted in the liver of Wag/Rij rats. Photofrin was administered (5 mg kg-1 i.v.) 2 days before laser illumination. Tumours with a mean (+/- s.e.) diameter of 5.7 +/- 0.1 mm (n = 106, 20 days after implantation) were illuminated with 625 nm light, at 200 mW cm-1 from a 0.5 cm cylindrical diffuser and either 100, 200, 400, 800 or 1600 J cm-1. Control groups received either laser illumination only, Photofrin only or diffuser insertion only. Short-term effects were studied on the second day after illumination by light microscopy and computer-assisted integration of the circumference of damaged areas. Long-term effects were studied on day 36. To determine the biochemistry of liver damage and function, serum ASAT and ALAT levels were measured on day 1 and 2, and antipyrine clearance on day 1. Tumour and surrounding liver necrosis increased with light dose delivered (P < 0.001). Best long-term results were obtained at 800 J cm-1 with complete tumour remission in 4 out of 6 animals. No deterioration in liver function was found. The results of this study show the ability of interstitial PDT to cause major destruction of tumour tissue in the liver combined with minimal liver damage.


Epidermal growth factor receptor in ovarian tumours: correlation of immunohistochemistry with ligand binding assay.

Epidermal growth factor receptor (EGFR) was studied in ovarian tumours with immunohistochemical (IH) and ligand-binding assay (LBA). Two different monoclonal antibodies (MoAbs: 2E9, EGFR1) with respect to detecting EGFR with different ligand-binding affinities (low, high and low) were used. When comparing the IH data of MoAbs, 2E9 and EGFR1 a significant correlation was found (2P < 0.0001). Both antibodies stained 77% of the adenocarcinoma samples. The incidence of positivity as well as the mean percentage of stained cells was increased in metastases when compared with primary lesions. In 12.5% overexpression of EGFR (score 3) was noticed in some of the tumour cells. This was not due to amplification of the EGFR gene in any of the 25 ovarian tumours studied (including 6 which showed high expression of EGFR in IH). EGFR was detected in 66% of the adenocarcinomas analysed with LBA. A statistically significant correlation was found between the maximum binding capacities of EGFR obtained from Scatchard plots and the percentage of positive tumour cells determined by MoAb EGFR1 (2P < 0.0001). A weaker correlation was found between the reactivity of MoAb 2E9 and LBA (2P < 0.1). Clinical studies are necessary to determine the possible prognostic impact of EGFR determined with either method, or whether a combination of both will give a better discrimination between high- and low-risk patients.


Differential expression of cAMP-kinase subunits is correlated with growth in rat mammary carcinomas and uterus.

The expression of the regulatory (RI and RII) and catalytic (C) subunits of cAMP-dependent protein kinase was found to depend on the growth-state in oestrogen-dependent DMBA-induced mammary adenocarcinomas as well as in uteri of the rat. Castration-induced atrophy of the oestrogen-dependent tissues was accompanied by a decrease of the concentration of regulatory subunits (RI and RII) relative to both the catalytic subunit (C) and total protein, decreasing the R/protein and R/C ratios. A hyperplastic burst caused by high-dose oestrogen-replacement treatment was associated with an increased level of RI and little change in RII and C levels. Only minor differences were noted for the expression of mRNA for the alpha and beta subtypes of RI, RII and C between rat uteri from castrated and oestrogen-treated animals, or between mammary tumours from normal and castrated animals. Expression of RI beta-mRNA was detected only in the uterus. Our findings provide an experimental correlate for the reported value of the parameter R/protein in human mammary cancer biopsies to predict prognosis and outcome of therapy. Due to the sensitivity of the R/protein ratio towards changes in extracellular protein content, we recommend the biologically more meaningful R/C ratio in further clinical evaluations of mammary tumour biopsies.


Vascular function and tissue injury in murine skin following hyperthermia and photodynamic therapy, alone and in combination.

The murine tail has been used as a model for injury to skin when hyperthermia (HT) and photodynamic therapy (PDT) using haematoporphyrin derivative, are used in combination. Skin injury by either agent alone was quantitated by the probability of tail necrosis as a function of dose of agent. 'Tolerance' doses of each modality were given and changes in skin vascular function were measured by the rate of clearance of 133Xenon. This was promptly inhibited but restored to normal by 7 days. The absolute numbers of hypodermal vessels of different sizes were measured in tail cross-sections and capillary numbers were found to be greatly reduced between 1 and 7 days, and restored to normal by 21-28 days. When a tolerance dose of PDT was followed at 1, 7, 21 and 28 days by test doses of HT, or vice versa, marked enhancements in probability of necrosis were observed when the interval was 1 or 7 days (Enhancement ratio (ER)PDT-HT = 1.5 and ERHT-PDT = 1.8). Prolonging the interval between modalities to 21-28 days spared the tissue (ERHT-PDT/21 DAYS = 1.1; ERPDT-HT/28 DAYS = 1.0). Close temporal apposition of PDT and HT, such as has been advocated to improve tumour control, may also increase injury to normal tissue through vascular effects common to both.


The anti-tumour effects of the prodrugs N-l-leucyl-doxorubicin and vinblastine-isoleucinate in human ovarian cancer xenografts.

N-l-leucyl-doxorubicin and vinblastine-isoleucinate can be considered as relatively non-toxic prodrugs from doxorubicin and vinblastine, respectively. A comparative analysis was carried out of the anti-tumour activity of the four compounds as well as vintriptol in four human ovarian cancer xenografts different in histology, growth rate and chemosensitivity. Injections were given i.v. weekly twice into mice bearing well-established s.c. tumours. At equitoxic doses, the amount of drug administered for N-l-leucyl-doxorubicin and vinblastine-isoleucinate was respectively 3-fold and 2-fold higher than the doses of the parent compound. N-l-leucyl-doxorubicin induced a growth inhibition > 50% in three out of four human ovarian cancer lines. The anti-tumour effects obtained were significantly better (P < 0.01) than in the case of doxorubicin. Vinblastine-isoleucinate studied in two of these lines could induce a growth inhibition of > 50%. This prodrug appeared slightly less effective than vinblastine. Insignificant growth inhibition (< 50%) was obtained by vintriptol.


131I-meta-iodobenzylguanidine therapy in neuroblastoma spheroids of different sizes.

Mathematical models have predicted that targeted radiotherapy of neuroblastoma with metaiodobenzylguanidine (mIBG) is less likely to cure small rather than large micrometastases if 131I is the conjugated radionuclide. This study uses multicellular tumour spheroids as an in vitro model to test the hypothesis that smaller tumours of sub-millimetre dimensions are relatively resistant to 131I-mIBG. Spheroids of the human neuroblastoma cell line SK-N-BE(2c), either 250 microns or 400 microns diameter, were incubated with 131I-mIBG at concentrations of up to 6.0 MBq ml-1. Using both regrowth delay and spheroid 'cure' as endpoints, the greater vulnerability of larger spheroids was confirmed. From this in vitro result we conclude that when used in vivo 131I-mIBG may spare smaller micrometastases. Therefore, either a radionuclide such as 211At which emits a shorter path length radiation should be conjugated to mIBG, or targeted radiotherapy should be combined with a treatment such as total body irradiation, the efficacy of which is not reduced in smaller tumours.


Enhancement of the cytotoxicity of SR 4233 to normal and malignant tissues by hypoxic breathing.

The bioreductive cytotoxic agent SR 4233 (1,2,4-benzotriazine 3-amine 1,4-dioxide) has been shown to markedly potentiate the cell killing of mouse tumours when combined with fractionated radiation therapy. Differential metabolism under oxic compared to hypoxic conditions results in SR 4233 exhibiting selective cytotoxicity to hypoxic cells. This is thought to result from the production of a cytotoxic free radical which is generated predominantly in the absence of oxygen. We have examined a way of enhancing the effectiveness of this antitumour agent in vivo by artificially increasing the hypoxic fraction of tumours by hypoxic breathing. Mice are placed in a chamber containing 10% Oxygen 90% Nitrogen for 1 h after each administration of SR 4233. Our results in the SCCVII tumour model indicate that this manoeuvre results in a 10-fold increase in antitumour effectiveness of SR 4233 when administered in a fractionated regime with radiotherapy (8 x 2.5 Gy and 0.08 mmol kg-1), but not when a single treatment regime (1 x 20 Gy and 0.3 mmol kg-1) is used. Mathematical modelling of this effect is used to illustrate this phenomenon and can be used to predict the dependence of this type of therapy on the modification of tumour oxygenation.


Increasing the effect of photodynamic therapy on the RIF-1 murine sarcoma, using the bioreductive drugs RSU1069 and RB6145.

The effect of combining photodynamic therapy (PDT) and bioreductive drugs has been investigated using the RIF-1 experimental murine tumour. Light was delivered interstially to the tumour at 675 nm using a single optical fibre attached to an argon-ion dye laser. The photosensitizer was disulphonated aluminium phthalocyanine (AlS2Pc) and the bioreductive drugs were the dual function nitroimidazole RSU1069 and its pro-drug RB6145. Varying the time between administration of the photosensitizer and light delivery (TL) from 30 min to 24 h had little influence on the extent of the anti-tumour effect of PDT alone, as measured by the regrowth delay endpoint. When the bioreductive drug was included in the treatment, administered 20 min before light irradiation, regrowth delay was greatly increased. The effectiveness of the combined treatment was optimum for short values of TL (about 1 h). Fluorescence microscopy was used to investigate the distribution of the photosensitizer within the tumours. This showed that the compound was mainly confined to the tumour vasculature over the first few hours post-treatment. The high efficacy of the combined treatment of PDT and bioreductive drugs for short values of TL suggest that photodynamic action, during the period when the photosensitizer AlS2Pc is confined to the vasculature, enhances the severity of tumour hypoxia which is sufficient to induce activation of the bioreductive drugs.


Effects of staurosporine, K 252a and other structurally related protein kinase inhibitors on shape and locomotion of Walker carcinosarcoma cells.

The structure/activity relationship of the protein kinase inhibitors, staurosporine and K 252a and their analogues on motility of Walker carcinosarcoma cells has been studied in vitro. Staurosporine and K 252a, similar to phorbol myristate acetate (PMA) and diacylglycerols, suppress cell polarity and locomotor activity of Walker carcinosarcoma cells. Staurosporine inhibits spontaneous and colchicine-induced front-tail polarity (ID50 of about 6.0 x 10(-8) M) as well as spontaneous and colchicine-stimulated locomotion at 10(-7) M. K 252a suppresses cell polarity (ID50 of about 4.5 x 10(-6) M) and inhibits spontaneous and colchicine-stimulated locomotion at 10(-5) M, but suppression of locomotor activity is not complete in the presence of colchicine. CGP 41251, a staurosporine derivative with a much higher specificity for protein kinase C (PKC) than staurosporine, induces a dose-dependent increase in the proportion of polarised cells, and stimulates cell locomotion. Two K252a analogues, KT 5720 and KT 5822, which act preferentially on cyclic nucleotide-dependent protein kinases, and CGP 42700, an inactive staurosporine analogue, had no effect on cell polarity and locomotion. The findings suggest that protein kinase inhibitors acting preferentially on PKC may be of interest in pharmacological regulation of tumour cell locomotion.


Oestrogen receptor isoforms, their distribution and relation to progesterone receptor levels in breast cancer samples.

Oestrogen receptors (ER) in breast cancer tumours are highly heterogeneous. In this study, the variability in the profile of ER isoforms and its relation to progesterone receptor (PgR) levels in breast tumours has been studied. Using high resolution isoelectric focusing (IEF) 4 ER isoforms can be detected with pI values of 6.1 (corresponding to the 8S ER), and 6.3, 6.6 and 6.8 (all of which have a sedimentation pI values of 6.1 (corresponding to the 8S ER), and 6.3, 6.6 and 6.8 (all of which have a sedimentation coefficient of approximately 4S in sucrose density gradients). Data were obtained on the soluble receptors from supernatants of 66 ER-positive primary breast tumour homogenates using high resolution IEF. In 43 of these samples PgR levels were also measured. The isoform at pI 6.6 was present in 97.0% of tumours, the isoform at pI 6.1 in 83.3%, the pI 6.3 isoform 39.4% of tumours and the pI 6.8 isoform in only 33.3% of tumours. Only 12.1% of tumours studied contained the full complement of ER isoforms (pI 6.1, 6.3, 6.6 & 6.8). The ER isoforms at pI 6.1 & 6.8 were only found in PgR-positive (> 10 fmol PgR/mg protein) tumours. Some tumours contained only a single ER isoform at pI 6.6 or 6.1, but those at pI 6.3 and 6.8 were never found singly. Tumours containing 3 or 4 ER isoforms had significantly higher levels of PgR (> 90 fmol/mg protein) than those with only 1 or 2 (P < 0.001). The presence of ER isoforms at pI 6.3 and pI 6.8 also significantly correlated with high levels of PgR (P < 0.001). This variability in the ER isoform profile of breast tumours and their correlation with PgR levels may have a bearing on prognosis and tumour response to endocrine therapy.


A model of multiple myeloma: culture of 5T33 murine myeloma cells and evaluation of tumorigenicity in the C57BL/KaLwRij mouse.

The 5T33 multiple myeloma is one of a series of transplantable murine myelomas arising spontaneously in C57BL/KaLwRij mice. This study describes the establishment and characterisation of the 5T33 murine myeloma in vitro as a cultured cell line in terms of its morphology, growth rate, expression of paraprotein (IgG2b) and tumorigenicity in syngeneic animals. The 5T33 cell line has been in continuous culture for over 10 months and has achieved more than passage 34. In culture, 5T33 myeloma grows as single cells or in small clusters of loosely adherent cells on an adherent stromal cell layer. Maximum doubling time is approximately 25 h, and over 90% of the cells express cytoplasmic IgG2b paraprotein. The cultured 5T33 myeloma cells are highly tumorigenic in C57BL/KaLwRij mice with as few as 500 cells inducing paralysis and death as early as day 36 post-tumour inoculation. Kinetics of tumour development and detection of IgG2b paraprotein are dose dependent. Two weeks following intravenous inoculation of 5 x 10(5) cultured 5T33 myeloma cells, tumour cells were readily identified in the bone marrow. By 3 weeks post-tumour inoculation, 5T33 myeloma cells were found in various tissues throughout the animal. Studies are now underway to determine the sensitivity of this cell line to various therapeutic modalities.


Detection of RET oncogene activation in human papillary thyroid carcinomas by in situ hybridisation.

We have recently reported the activation of a new oncogene in human papillary thyroid carcinomas. This oncogene, named PTC, is a novel rearranged version of the ret proto-oncogene. In fact PTC is the product of the fusion of the tyrosine kinase domain of the ret proto-oncogene with the 5'-terminal region of another gene that we have named H4. The ret proto-oncogene shows a pattern of expression restricted to neuroendocrine tissue. Its fusion with H4 allows the expression of the activated form in thyroid papillary carcinomas. Therefore the detection of ret transcripts is a tool to investigate ret activation in thyroid neoplasms. Here we show the detection by in situ hybridisation, of activated ret transcripts in human thyroid papillary neoplasms that were positive for PTC activation by Southern blot analysis. We did not find any ret transcripts in papillary carcinomas negative for PTC activation, nor in normal thyroid and in non-papillary thyroid neoplasias.


Pixel-to-pixel correlation between images of absolute ATP concentrations and blood flow in tumours.

Iodo(14C-)antipyrine autoradiography and imaging bioluminescence have been combined to obtain pixel-to-pixel correlations between absolute values for local blood flow and ATP concentrations at a microscopical level within designated areas in hamster melanomas. Positive pixel-to-pixel correlations were obtained in 4 of 6 tumours. Both flow and ATP values were less in mostly necrotic than in mostly viable tumour regions. The data provide evidence for the energetic state of cancer cells being strongly influenced by the efficiency of tumour microcirculation in several but not in all malignancies investigated.


Reduced drug accumulation as a major mechanism of acquired resistance to cisplatin in a human ovarian carcinoma cell line: circumvention studies using novel platinum (II) and (IV) ammine/amine complexes.

Acquired resistance to cisplatin (cis-diamminedichloroplatinum (II)) has been generated in vitro in the 41M human ovarian carcinoma cell line, established from a previously untreated patient. Three cisplatin-resistant variants were selected at approximately 2, 4 and 6-fold resistance (in terms of 50% inhibitory concentrations), in order to study the underlying mechanisms of acquired cisplatin resistance. Compared to the parent line, platinum accumulation following exposure to equimolar concentrations of cisplatin was on average (across the entire concentration range) 2.9, 3.6 and 4.8-fold lower in the 41McisR2, 41McisR4 and 41McisR6 cell lines, respectively. Thus the difference in uptake corresponded closely with their resistance factor in the three resistant variants. Moreover, a significant reduction in platinum accumulation was observed as early as 5 min after exposure to cisplatin in the 41M vs 41McisR6 cell lines. Platinum accumulation was similar in all cell lines following exposure to equitoxic concentrations (2 h IC50) of cisplatin. Enhanced efflux of drug was not observed between the 41M and 41McisR6 cells. In addition, there was no difference in intracellular glutathione (GSH) levels. Our previous studies have shown no indication of metallothionein involvement and the decrease in cisplatin uptake in the 41McisR6 cells was reflected by a similar reduction in DNA interstrand cross-links (ISC) formation. These results suggest that the mechanism of acquired resistance to cisplatin in the 41McisR6 cell line may be predominantly due to reduced drug uptake. The 41McisR6 cells were not found to be cross-resistant to ouabain, a postulated specific inhibitor of sodium-potassium adenosine triphosphatase (Na+, K(+)-ATPase), suggesting that decreased cisplatin accumulation in these cells is probably not regulated by alterations in their Na+, K(+)-ATPase levels, and Na+ potential across the plasma membrane. Cellular accumulation of a novel class of platinum (IV) ammine/cyclohexylamine dicarboxylates, which exhibit enhanced cytotoxicity over cisplatin and completely circumvent resistance to cisplatin in the 41McisR line, was also examined. The data suggests that increased accumulation of these compounds, as a result of their enhanced lipophilicity, could account for the dramatic increase in their potency over cisplatin.


Intra-hepatic-arterial infusion of misonidazole--an experimental study of regional radiosensitisation by intraarterial embolisation.

The purpose of this study was to generate a selective radiosensitising effect by the intra-hepatic-arterial infusion of misonidazole (MISO). MISO (10 mg) was infused after transcatheter hepatic-arterial embolisation into the livers of rabbits bearing VX2 liver cancer. This procedure was followed by 15 Gy electron irradiation. Evaluation of tumour volume and histological examination was carried out on the 7th day after treatment. The greatest tumour response was obtained in the group which received MISO followed by radiation and was characterised by extensive fibrosis around the tumour and nearly complete tumour necrosis. Liver cell regeneration was also noted in adjacent liver tissue. The advantages of regional infusion of MISO following hepatic-arterial embolisation are: (1) Selectivity increased radiosensitivity of liver cancer alongside very low drug concentration in the plasma. (2) Reduced or absent deleterious side effects of MISO with higher tumour/normal tissue ratios of drug concentration. (3) Reduced cost due to the lower dosage of MISO required for regional infusion.


Kaposi's sarcoma in England and Wales before the AIDS epidemic.

The epidemiological features of Kaposi's Sarcoma (KS) incidence in England and Wales in the period 1971-1980 are reviewed. The epidemiology of KS in England and Wales in this period is distinct from that associated with the AIDS epidemic. The incidence was probably very low compared to other Western countries, there was little male excess, and no indication, based on marital status data, of a raised incidence in male homosexuals. Half the cases registered were in people born outside the UK. The region of birth distribution in these migrants reflected the known pre-AIDS geographic distribution of KS and also pointed to high risks in those from Middle Eastern countries and the Caribbean. The very low incidence rates of KS in natives of England and Wales suggests that the background prevalence of the causative agent for KS was low in England and Wales prior to the AIDS epidemic.


Oestrogen receptor protein and mRNA in adenocarcinoma of the uterine cervix.

We have investigated the oestrogen receptor (ER) status of 20 cervical adenocarcinomas by immunocytochemistry for ER protein and non-isotopic in situ hybridisation for ER mRNA. Both methods, which are applicable to paraffin sections, were developed and validated in breast carcinomas with known ER content. Six cervical adenocarcinomas contained immunocytochemically demonstrable ER protein; all contained ER mRNA, but staining was less intense in poorly differentiated areas of four tumours. This disparity between protein and mRNA detection needs further investigation as does the possibility that oestrogens may play a role in the pathogenesis of cervical adenocarcinoma.


Outcome of children with resistant and relapsed Hodgkin's disease.

During the period 1974-89, 169 children with Hodgkin's disease were treated in the Paediatric Oncology Units of the Royal Marsden and St Bartholomew's Hospitals. The overall actuarial survival for the whole group was 81% at 10 years. Thirty-five of the 169 children either did not achieve a complete remission or subsequently relapsed. The estimated actuarial survival from initial relapse or failure of primary treatment was 60% at 5 years and 45% at 10 years. Over half of the patients requiring salvage therapy had declared themselves within 2 years and only 3 relapses occurred more than 3 years from diagnosis. Very few patients remain disease free long term after failure of primary and initial salvage therapy. Patients relapsing within a year of diagnosis or not achieving a complete response to primary therapy and those with disseminated relapse had a poor response to salvage therapy. A significant subgroup of patients had prolonged survival despite multiple relapses. Neither initial histology nor stage affected survival from relapse although numbers in each subgroup were small.


Beta-carotene supplementation in smokers reduces the frequency of micronuclei in sputum.

beta-carotene has been hypothesised to reduce lung cancer risk. We studied the effect of 14 weeks of beta-carotene supplementation (20 mg d-1) on the frequency of micronuclei in sputum in 114 heavy smokers in a double-blind trial. Micronuclei reflect DNA damage in exfoliated cells and may thus provide a marker of early-stage carcinogenesis. Pre-treatment blood levels of cotinine, beta-carotene, retinol and vitamins C and E were similar in the placebo group (n = 61) and the treatment group (n = 53). Plasma beta-carotene levels increased 13-fold in the treatment group during intervention. Initial micronuclei counts (per 3,000 cells) were higher in the treatment group than in the placebo group (5.0 vs 4.0, P < 0.05). During intervention, the treatment group showed a 47% decrease, whereas the placebo group showed a non-significant decrease (16%). After adjustment for the initial levels, the treatment group had 27% lower micronuclei counts than the placebo group at the end of the trial (95% CI: 9-41%). These results indicate that beta-carotene may reduce lung cancer risk in man by preventing DNA damage in early-stage carcinogenesis.


Is liver to lung shunting in colorectal liver metastasis the cause of toxicity following treatment with cytotoxic microsphere aggregates?

Incorporation of cytotoxic drugs into microspheres reduces but does not eliminate systemic toxicity. The extent of liver to lung shunt was measured in 26 patients with colorectal liver metastasis. Liver to lung shunting correlated with proportion of liver replacement but did not exceed 4.4% and therefore is unlikely to cause systemic toxicity.


Peripheral blood lymphocyte number and phenotype prior to therapy correlate with response in subcutaneously applied rIL-2 therapy of renal cell carcinoma.

The phenotype of peripheral blood lymphocytes of 27 renal cell carcinoma patients before and at the end of subcutaneously given rIL-2 therapy was determined by two colour flow cytometry. Therapy induced changes in peripheral blood leucocyte composition and phenotypes were comparable to those reported for intravenously given rIL-2. The present paper shows a correlation between the 'activation status' of the patient before therapy and eventual response.


The combination of radiotherapy, adjuvant chemotherapy (cyclophosphamide-doxorubicin-ftorafur) and tamoxifen in stage II breast cancer. Long-term follow-up results of a randomised trial.

Two hundred patients with node positive stage II breast cancer were randomised to four groups after radical mastectomy and axillary evacuation: (1) Postoperative radiotherapy, (2) Adjuvant chemotherapy with eight courses of CAFt (cyclophosphamide 500 mg m-2 + doxorubicin 40 mg/m-2 + ftorafur 20 mg kg-1 orally day 1-14) every fourth week, (3) Postoperative radiotherapy and adjuvant chemotherapy and (4) postoperative radiation, adjuvant chemotherapy and tamoxifen 40 mg daily for 2 years. Thirty-two per cent of the patients discontinued treatment due to GI-toxicity, while 26% required dose reductions due to leukopenia. Radiation pneumonitis was more frequent after the combination of postoperative radiotherapy with chemotherapy. There was a better relapse-free survival in the groups receiving chemotherapy compared to radiotherapy alone (P = 0.05), which was highly significant in a multivariate Cox analysis (P = 0.004). No significant survival differences were seen. Tamoxifen had no clear overall effect but there were better relapse-free (P = 0.04) and overall (P = 0.004) survival with tamoxifen in estrogen receptor positive patients, while estrogen receptor negative patients had a somewhat poorer survival (P = 0.07) after tamoxifen. Local control was better (NS) after the combination (93%) radiotherapy and chemotherapy compared to either treatment alone (76% with radiotherapy and 74% with chemotherapy at 5 years).


The association of body size, reproductive factors and thyroid cancer.

A population-based case-control study of the association of diet and other factors and thyroid cancer was conducted between 1980 and 1987 on Oahu, Hawaii. Study participants included 51 men and 140 women with thyroid cancer, and 113 male and 328 female controls matched on age (+/- 5 years) and sex. A significant, positive monotonic dose-response relation of weight in late adulthood (5 years prior to interview) and the risk for thyroid cancer was found for men and women. A greater than five-fold increase in the risk for thyroid cancer among men, and more than a two-fold increase in risk among women, was found for subjects in the highest compared with the lowest quartile of weight in late adulthood. Height was significantly related to the risk for thyroid cancer among men, but not women. Among men, there was a significant dose-response relation of weight in early adulthood (20-29 years of age) and the odds ratios (ORs) for thyroid cancer, although the trend was not significant after adjustment for height. Among women, there was also a positive relation of adult weight gain and thyroid cancer, with an OR of 2.6 associated with more than a 14% increase in weight. The effects of relative weight and weight gain on thyroid cancer risk were stronger in post-menopausal women than in premenopausal women. There was a significant positive interaction between fertility drug use and early adult weight and the risk for thyroid cancer in women. Odds ratios were also significantly elevated for women above the median weight in early adulthood who experienced a miscarriage or stillbirth at first pregnancy. In summary, these data show an association of weight, particularly in late adulthood, and the risk for thyroid cancer in men and women, and further suggest a positive interaction between weight in young adulthood and fertility drug use on thyroid carcinogenesis in women.


Interleukin 2 therapy in cancer: identification of responders.

C-reactive protein (CRP) levels in serum were measured in fifteen patients with metastatic colorectal carcinoma, prior to and during treatment with a continuous intravenous infusion of rIL.2. Patients were subsequently classified as responders or non-responders to this therapy. Baseline serum CRP levels, prior to treatment, were significantly lower in the responders (range < 2-8 mg l-1) when compared with the non-responders (range 7.5-116 mg l-1), P = 0.004. Furthermore, the responding patients demonstrated significantly and grossly elevated CRP stimulation indices (SI) compared with non-responders at different time intervals during the rIL2 infusion. At the cessation of rIL2 therapy, the CRP stimulation index was 31.3 +/- 9.3 in the responders, and only 1.6 +/- 0.3 in the non-responders (means +/- s.e.m, P = 0.014). These findings suggest that it is possible to predict those cancer patients who are most likely to respond to and benefit from rIL2 therapy, either prior to the commencement of or during the first course of rIL2.


Expression of metalloproteinases and their inhibitors in primary pulmonary carcinomas.

Nine primary pulmonary carcinomas, one metastatic carcinoma, and two malignant pleural mesotheliomas have been analysed for the expression at the mRNA level of metalloproteinases (MPs) and tissue inhibitors of MPs (TIMPs). In situ hybridisation showed TIMP-1 and TIMP-2 transcripts predominantly over tumour stroma and gelatinases evenly distributed over both stromal and tumour cells. While both TIMP-1 and TIMP-2 were expressed in non-neoplastic lungs (NNL) as well as in carcinomas, stromelysin 3 (ST3), 92 kDa gelatinase and interstitial collagenase were expressed only by carcinomas. Expression of these MPs by carcinomas was independent of histologic type and such tumour features as fibrosis or necrosis. The consistent expression of ST3 by all of the carcinomas examined and absence of its expression in NNL indicates that ST3 production is likely associated with the malignant phenotype. However, since 92 kDa gelatinase and interstitial collagenase transcripts were found in some but not all tumour samples, their expression is not a uniform feature of pulmonary carcinomas. The possible prognostic significance of the expression of the latter two enzymes by carcinomas remains to be established.


IL2 treatment for cancer: from biology to gene therapy.

In this review we shall discuss the biological rationale and the clinical findings obtained using Interleukin 2 (IL2)-based immunotherapy in the management of cancer patients. Objective and long-lived clinical responses have been documented in a proportion of cases, particularly renal cell carcinoma, melanoma and acute myeloid leukaemia. Though encouraging, the clinical use of IL2 has so far been limited by toxicity, as well as by the heterogeneous and unpredictable responses and by the lack of specific anti-tumour effect. These considerations have led to the belief that more sophisticated technologies aimed at introducing the IL2 gene into the neoplastic cells may potentially overcome some of the limitations coupled to the in vivo infusion of high doses of IL2. The data accumulated in animal models and, more recently, also with human tumour cells indicate that the IL2 gene may be successfully inserted into neoplastic cells. The constitutive secretion of IL2 by the tumour cells leads to a reduced or abrogated tumorigenicity in several different tumour models. The evidence that in some experimental tumours the transduction of the IL2 gene into the neoplastic cells may elicit a specific cytotoxic response and confer anti-tumour memory, suggests that vaccination protocols based on this innovative strategy may represent a potential new tool in the management of cancer patients.


Intrathecal chemotherapy with ACNU for meningeal gliomatosis.

ACNU [1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride], one of the chloroethylnitrosoureas (CENUs), is believed to be effective against malignant glioma when intravenously or intrathecally administered. A rat model with meningeal gliomatosis (MG) induced by an intracisternal inoculation of rat C6 or 9L glioma cells was intrathecally and intravenously treated with ACNU in order to test the feasibility of intrathecal chemotherapy with ACNU in the treatment of meningeal gliomatosis. The median survival time (MST) of the animals was significantly prolonged when ACNU was intrathecally administered at dosages of 0.5 to 1.5 mg kg-1 in the early stages of MG, i.e. within 3 days after the tumour inoculation, whereas intravenous therapy with ACNU at a dose of 15 mg kg-1 did not exhibit any efficacy in the rats inoculated with C6 glioma cells (C6-MG). Intrathecal ACNU, however, at dosages of up to 1.5 mg kg-1 failed to demonstrate any therapeutic effect in the late stage of MG, i.e. 5 days after the tumour inoculation, except in the rats inoculated with 9L brain tumour cells (9L-MG). Intravenous chemotherapy with ACNU at a dose of 15 mg kg-1 extended the MST of the 9L-MG rats more significantly in the late stage of MG than in its early stage. This points to the feasibility of intrathecal ACNU in the treatment of meningeal gliomatosis in its early stages, but not in its late stages in which intravenous ACNU might be more effective than intrathecal treatment against MG of which the parenchyma has already been deeply invaded by the tumour.


Fibrous dysplasia of the skull in children.

Early diagnosis of skull fibrous dysplasia in children is relatively easy, based on a history of painless progressive bony bulging. The therapeutic approach is still controversial, due to the benignity of the lesion. However, the clinical course may be unpredictable, with sudden appearance of symptoms, some of which can be important and irreversible. In pediatric patients, the possibility that an early surgical correction might positively interfere with the natural history of the lesion has to be evaluated by taking into account the obvious difficulties that will be encountered in reconstructing the skull after a wide excision of the pathologic bone. In the present report, we describe our personal experience on the surgical treatment of 9 children, ranging in age between 7 and 14 years. The patients were subdivided into two groups, according to the localization and extent of the disease. Patients in group 1 presented an involvement of the hair-covered cranium and/or the fronto-orbital region. Group 2 patients presented with a multizonal involvement of the skull, including the central cranial base (pterygoid, sphenoid, petrous and mastoid bone). The different surgical options, chosen for the two groups of patients, are discussed, together with the technical methodologies utilized, the cosmetic results and the long-term follow-up.


Time course of intraventricular pressure change in a canine model of hydrocephalus: its relationship to sagittal sinus elastance.

Hydrocephalus was induced in adult greyhounds by intracisternal kaolin. Intraventricular pressure (IVP) was monitored in the conscious animal for 2 weeks using a small implantable sensor, and the time-course of IVP change was characterized. Intraventricular pressure increased significantly within 36 h of kaolin infusion and gradually subsided to normal values within 1 week. Enlargement of the lateral ventricles was not observed during the early phase of intracranial hypertension (less than 2 days). Evolving hydrocephalus and intracranial hypertension increased the elasticity (dP/dV) of the sagittal sinus. This effect was statistically significant (p < 0.05) and is possibly reversible in the acute stage. Normotensive hydrocephalus (1 and 2 weeks after kaolin) was associated with an irreversible increase in resistance to outflow (i.e., increased sagittal sinus elasticity). Sagittal sinus venography of animals with obvious ventricular enlargement (at least 1 week after kaolin) showed development of venous collaterals and atypical outflow pathways.


Biopsy diagnosis of familial Alexander's disease.

A 26-year-old woman presented with headaches, incoordination and a cerebellar mass (1982). The CT scan revealed dilated ventricles and a hypodense space-occupying lesion adjacent to the fourth ventricle. Neuronal loss, gliosis and masses of Rosenthal fibers were seen in biopsy. There was no evidence of neoplasm. A second biopsy 2 years later was similar to the original specimen. A diagnosis of Alexander's disease was suggested. Later that year the patient's 11-year-old brother manifested a clinical picture initially diagnosed as brainstem glioma, but whose biopsy was characteristic of Alexander's disease. There has been a gradual deterioration of these siblings over the past 6 years (1986-1991). No evidence of neoplasm has appeared.


The Vater association and spinal dysraphia.

We here present a hereto previously undescribed association of occult spinal disorders of the distal spinal cord/filum in the Vater association. We present 6 patients who were diagnosed as having the Vater association who subsequently presented with occult spinal disorders, primarily lipomas of the filum/conus complex with or without subcutaneous lipomas. Uniformly the spinal cord was tethered to the lipoma/filum complex. Progressive neurological dysfunction was noted in those in whom the diagnosis was made late in the disease. The importance of neuroimaging of the distal spinal canal, in children in whom the diagnosis of the Vater association has been made, is emphasized to prevent insidious neurological damage if not already present.


Perinatal spinal cord injury: clinical, radiographic and pathologic features.

Perinatal spinal cord injury is a relatively uncommon, but a frequently misdiagnosed disorder. Often, the injury is not suspected and an erroneous diagnosis is made. We present five cases of perinatal spinal cord injury. In four, the referring physicians (including pediatric neurologists) misdiagnosed the condition. In view of these diagnostic difficulties, we review the clinical, radiographic and pathologic aspects of these injuries. Serious spinal injuries occasionally occur in the perinatal period. With improving medical care, many infants with less severe injuries are surviving the neonatal period. Therefore, the prompt recognition of neonatal spinal cord damage is essential and allows for optimal treatment of the injured child.


Osteoplastic laminotomy in children.

The article reviews 180 cases of osteoplastic laminotomies, 1 year after operation. The patients were predominantly children undergoing selective dorsal rhizotomies. Also included were a few pediatric patients who received laminotomies for spinal cord tumors. Spinal X-rays were reviewed at 1 and 3 years of follow-up. There was complete to partial bridging of the laminar roof in all cases. This experience confirms that the procedure is well tolerated and is associated with reossification of the replaced bony segment.


How to reduce the morbidity of wound closure following extensive and complicated laminectomy and tethered cord surgery.

Prior irradiation and surgery predispose laminectomy wounds to a higher than usual incidence of wound problems. Likewise the tightness or absence of local fascia in the tethered cord patient make wound closure more complicated. To reduce morbidity, i.e., CSF leak or pseudomeningocele formation, specific techniques are required. These methods are outlined below.


Removal of adherent ventricular catheter.

The technique for freeing adherent ventricular catheters is described in which a Bugbee wire, insulated except for the tip, is used to deliver a monopolar coagulating current to the tissue adherent to the drainage holes of the catheter. This may have some advantage over the use of an uninsulated metal cannula for delivery of a unipolar diathermy cutting current. The technique described has permitted effective and safe removal of adherent ventricular catheters.


IGF-2 stimulates growth and metabolism of early mouse embryos.

Recent reports indicate that the insulin gene family plays a significant role in early development. Both insulin and IGF-1 stimulate growth and metabolism in preimplantation mouse embryos, however, little is known of the physiological effects of IGF-2. In this study, addition of IGF-2 to defined culture medium for the culture of 2-cell embryos stimulated blastocyst formation by 15%, ICM mitogenesis by 37%, and protein synthesis by 35%. EC50s of 12-63 pM IGF-2 for these responses were in the range for mediation by IGF-2 receptors. These results coupled with the previously demonstrated presence and expression of the IGF-2 receptor from the 2-cell stage supports a role for this third member of the insulin gene family in early development.


Over-expression of fibroblast growth factors in Xenopus embryos.

A number of forms of fibroblast growth factor (FGF) were over-expressed within Xenopus embryos by injection of synthetic FGF mRNAs into fertilized eggs. Injected embryos showed abnormalities in development which were mainly secondary to a disruption of gastrulation movements. The effects observed after injection of bFGF mRNA, however, were much less severe than those observed after injection of an altered form of bFGF mRNA which differs only by the addition of a signal sequence for secretion, or of another member of the FGF family, kFGF, which is normally efficiently secreted. All forms of FGF caused the induction of mesoderm in animal cap explants isolated from blastulae, but the amount of bFGF mRNA required to induce the formation of significant levels of mesoderm was higher by a factor of over a hundred than that of the FGFs which contain a signal sequence for secretion. Over-expressed bFGF accumulated in the nuclei of blastulae but did not necessarily cause mesoderm formation. These results show that FGFs must be secreted from the cells in which they are synthesised in order to act efficiently as mesoderm inducing factors and suggest that bFGF itself, which does not contain a signal sequence for secretion, is unlikely to be directly involved in mesoderm induction during early embryonic development.


Ectopic expression of the Drosophila tramtrack gene results in multiple embryonic defects, including repression of even-skipped and fushi tarazu.

The tramtrack (ttk) gene of Drosophila encodes 69-kDa and 88-kDa proteins through alternative splicing of the primary ttk transcript. The two proteins share a common amino-terminal sequence, but contain different carboxy-terminal portions, each of which has a distinct zinc finger domain with a unique DNA binding specificity. The 69-kDa ttk protein has been shown to bind multiple sites within important regulatory elements of the pair-rule genes even-skipped (eve) and fushi tarazu (ftz), and it has been suggested that this protein may function as a repressor of ftz transcription. Here we present evidence that the 69-kDa ttk protein can indeed repress expression not only of ftz, but also of eve. Ectopic expression of the 69-kDa protein, but not of the 88-kDa form, was found to nearly abolish the striped patterns of expression of both eve and ftz in transgenic embryos. These findings, coupled with our detection of significant levels of ttk protein in ovaries and 0-2-h embryos, support the idea that maternally supplied ttk protein serves to prevent premature activation of eve and ftz, thereby helping to establish the timing of the onset of zygotic expression of these two genes. Furthermore, gross defects in the larval cuticle resulting from misexpression of the 69-kDa protein suggest that this protein performs additional functions in the early embryo.


Comparative analysis of Pax-2 protein distributions during neurulation in mice and zebrafish.

Members of different vertebrate species share a number of developmental mechanisms and control genes, suggesting that they have similar genetic programs of development. We compared the expression patterns of the Pax-2 protein in Mus musculus and Brachydanio rerio to gain a better understanding of the evolution of developmental control genes. We found that the tissue specificity and the time course of Pax-2 expression relative to specific developmental processes are remarkably similar during the early development of the two organisms. The brain, the optic stalk, the auditory vesicle, the pronephros, and single cells in the spinal cord and the hindbrain express Pax-2 in both species. The Pax-2 expression domain in the prospective brain of E8 mouse embryos has not been described previously. Expression appears first during early neurulation at the junction between the midbrain and hindbrain. However, there are some differences in Pax-2 expression between the two species. Most notable, expression at the midbrain/hindbrain boundary is no longer detectable after E11 in the mouse. Using monoclonal antibodies, we could exclude that primary neurons express Pax-2 in the zebrafish spinal cord. Our results confirm that Pax genes are highly conserved both in sequences and in expression patterns, indicating that they may have a function during early development that has been conserved during vertebrate evolution.


An early molecular component of the wound healing response in rat embryos--induction of c-fos protein in cells at the epidermal wound margin.

The spreading of epithelial sheets plays a pivotal role in normal embryonic morphogenesis but the cellular and molecular mechanisms underlying these processes are not very well understood. One way of directly examining epithelial spreading in the embryo is to excise a piece of tissue and follow the epithelial wound healing process. In this paper we report our studies of the healing of a simple excisional lesion to the E12.5 rat embryo hindlimb. The wounded, living embryo is cultured in a roller bottle and under such conditions the lesion is completely re-epithelised by 24 h. We find that epidermal cells specifically at the margin of the wound rapidly (within 15 min of wounding) and transiently express the nuclear transcription factor c-fos. This induction occurs whether or not serum is included in the culture medium. We speculate that local induction of c-fos at the wound site may play a role in regulating transcription of genes involved in the healing process.


Computer-aided classification of malignancy in astrocytomas. I. The value of nuclear parameters obtained by automated black and white image analysis.

Ninety-three selected cases of astrocytomas including glioblastomas (astrocytomas grades 1-4) were evaluated by means of Feulgen-stained microscopic slides for nuclear parameters obtained by automated black and white image analysis (ABWIA). The goal was to determine to what extent nuclear features evaluated by ABWIA were applicable as classifiers for the computer-aided numerical classification of malignancy in astrocytomas. Before the automated evaluation, all tumours had been subjectively graded according to the Mayo Clinic grading rules as delineated by Ringertz. Twenty-three nuclear parameters were evaluated and tested for their classification impact. With a model of five parameters (number of nuclei per area, mean of the convex form factor, extinction sum, extinction variation, and full-width-half-maximum of the extinction distribution) the highest reclassification rate of 75% correctly reclassified cases was obtained. Although this is a good result for a classification using only nuclear parameters, it is too poor for practical application. Thus, nuclear parameters evaluated by ABWIA alone are insufficient for numerical classification models assessing the malignant expression of astrocytomas.


Computer-aided classification of malignancy in astrocytomas. II. The value of categorically evaluated histologic and non-histologic features for a numerical classifier.

The present study was carried out in order to obtain a numerical classifier for the assessment of the malignancy in astrocytomas including glioblastomas ('astrocytomas grade 4'). The attempt resulted in 'TESTAST 268', a classifier based on a reference sample of 268 tumours, 67 in each of four malignancy classes. TESTAST 268 aids the identification of astrocytomas with one of four malignancy classes by means of eight classification variables, five histologic and three non-histologic. Identification is achieved with the aid of linear discriminant functions, both according to Bayes' decision rule (BAYTEST) and by canonical discriminant analysis (CANTEST) using the squared Mahalanobis distance. The discriminant functions with the calibration of the reference sample of the 268 tumours may be implemented on personal and even small pocket computers for practical application.


Can chromatin texture predict structural karyotypic changes in diploid cells from thyroid cold nodules?

To assess the effect of a single chromosomal translocation on the nuclear phenotype of human cells, seven diploid adenomas and five diploid carcinomas of the thyroid gland were studied using quantitative nuclear morphometry. Four adenomas and three carcinomas were cytogenetically normal, whereas three adenomas and two carcinomas had a unique chromosomal translocation. A densitometric parameter discriminated adenomas from carcinomas (skewness of the optical density histogram, SODH), and tumours with and without chromosomal translocation (standard deviation of the optical density, SDODH). These results demonstrate that single chromosomal structural rearrangements produce quantifiable alterations of nuclear organisation, but that other nuclear features which do not express an aneuploid DNA content or an abnormal karyotype differentially characterise benign and malignant conditions.