Mutant clones in normal epithelium outcompete and eliminate emerging tumours.

Human epithelial tissues accumulate cancer-driver mutations with age1-9, yet tumour formation remains rare. The positive selection of these mutations suggests that they alter the behaviour and fitness of proliferating cells10-12. Thus, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less competitive neighbours11-14. However, little is known about how such dynamic competition in normal epithelia influences early tumorigenesis. Here we show that the majority of newly formed oesophageal tumours are eliminated through competition with mutant clones in the adjacent normal epithelium. We followed the fate of nascent, microscopic, pre-malignant tumours in a mouse model of oesophageal carcinogenesis and found that most were rapidly lost with no indication of tumour cell death, decreased proliferation or an anti-tumour immune response. However, deep sequencing of ten-day-old and one-year-old tumours showed evidence of selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased early tumour removal, whereas pharmacological inhibition of clonal competition reduced tumour loss. These results support a model in which survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the surrounding normal tissue. Mutant clones in normal epithelium have an unexpected anti-tumorigenic role in purging early tumours through cell competition, thereby preserving tissue integrity.

Long-term effects of gastric surgery for treating respiratory insufficiency of obesity.

The Pickwickian syndrome can be divided into two primary breathing disorders, which can affect patients alone or in combination: sleep apnea syndrome (SAS) and obesity hypoventilation syndrome (OHS). Between 1980 and 1990, 126 patients with respiratory insufficiency underwent gastric surgery for morbid obesity, 12.5% of the entire series. These patients weighed more (164 +/- 36 vs 135 +/- 25 kg, P less than 0.0001) and were more often men (62% vs 14%, P less than 0.001) than those without pulmonary dysfunction. Sixteen had OHS alone, 65 had SAS alone, and 45 had both. Of those with OHS, 38 have been followed for 5.8 +/- 2.4 y since surgery and 29 are currently asymptomatic. In the 12 patients in whom arterial blood gases were available greater than 5 y since surgery, the PaO2 increased from 54 +/- 10 to 68 +/- 20 mm Hg (P less than 0.0001) and PaCO2 fell from 53 +/- 9 to 47 +/- 11 mm Hg (P = 0.05). Of the 110 patients with SAS, 57 were available for follow-up an average of 4.5 +/- 2.3 y since surgery and 38 were completely asymptomatic, 15 had mild SAS, and 4 had both SAS and OHS. In 40 patients with pre- and post-weight reduction sleep polysomnograms, the sleep apnea index fell from 64 +/- 39 to 26 +/- 26 (P less than 0.0001). Although respiratory insufficiency of obesity patients had a higher operative mortality than did patients without pulmonary dysfunction (2.4% vs 0.2% after gastric bypass), weight loss was associated with significant improvements in sleep apnea, arterial blood gases, pulmonary hypertension, left ventricular dysfunction, lung volumes, and polycythemia.

Secondary arterial repair. The management of late failures in reconstructive arterial surgery.

The incidence and success of secondary operations after reconstructive arterial surgery were studied in a series of 4,247 cases of aneurysmal and occlusive arterial disease. Postoperative complications requiring secondary operations occurred, in order of frequency, as the result of defective healing (including infection), deterioration of the arterial implant, and degenerative arterial changes in the site of surgical intervention. A large variety of surgical techniques were used for correction, such as total replacement, segmental resection and replacement, remote bypass, thrombectomy, and partial excision and reanastomosis. Wth the exception of complications due to infection, the results of repair were good in 60% to 90% of the various categories; only 40% of the infected grafts could be managed without the loss of life or limb. The results appear to justify the trend noted in recent years to a more aggressive use of secondary, salvage operations.

Structure of the glycopeptidolipid antigen of serovar 20 of the Mycobacterium avium serocomplex, synthesis of allyl glycosides of the outer di- and tri-saccharide units of the antigens of serovars 14 and 20, and serology of the derived neoglycoproteins.

The tetrasaccharide hapten released from the glycopeptidolipid (GPL) antigen of Mycobacterium avium serovar 20 has been characterized as O-(2-O-methyl-alpha-D-rhamnopyranosyl)-(1----3)-O-(2-O-methyl-alpha-L- fucopyranosyl)-(1----3)-alpha-L-rhamnopyranosyl-(1----2)-6-deoxy-L-talos e. Syntheses are reported of allyl glycosides of the outer disaccharide unit of this hapten, O-(2-O-methyl-alpha-D-rhamnopyranosyl)-(1----3)-2-O-methyl-alpha-L-fu copyranose , and also of the outer di- and tri-saccharide units of the GPL antigen of M. avium serovar 14, O-(N-formyl-alpha-L-kansosaminyl)-(1----3)-2-O-methyl-alpha-D-rham nopyranose and O-(N-formyl-alpha-L-kansosaminyl)-(1----3)-O-(2-O-methyl-alpha-D- rhamnopyranosyl)-(1----3)-2-O-methyl-alpha-L-fucopyranose. The key steps in the latter synthesis involve the preparation of allyl 4-azido-4,6-dideoxy-3-C-methyl-2-O-methyl-alpha-L-mannopyranoside as a precursor for the N-formylkansosamine unit, followed sequentially by conversion into and use of a trichloroacetimidate as glycosyl donor for di- and tri-saccharide formation, O-deacylation, reduction, and N-formylation. The allyl glycosides, representative of the haptens from both serovars, have been converted into neoglycoproteins (NGPs) and their serological activities have been compared in the light of the structural relationship between them.

Structures of the glycopeptidolipid antigens of serovars 25 and 26 of the Mycobacterium avium serocomplex, synthesis of allyl glycosides of the outer disaccharide units and serology of the derived neoglycoproteins.

The pentasaccharide hapten released from the glycopeptidolipid (GPL) antigen of M. avium serovar 26 has been characterized as O-(2,4-di-O-methyl-alpha-L-fucopyranosyl)-(1-->4)- O-beta-D-glucopyranosyluronic acid-(1-->4)-O-(2-O-methyl-alpha-L-fucopyranosyl)-(1-->3)-alpha-L- rhamnopyranosyl-(1-->2)-6-deoxy-L-talose. The allyl glycosides of the outer glycosyl and glycobiosyl units of this hapten have been synthesized, the latter by a route involving oxidation of the corresponding D-glucopyranose derivative. Conjugation of allyl glycosides to protein by ozonolysis and reductive coupling afforded neoantigens (neo 26-1 and 26-2), both of which interacted with antibodies to M. avium serovar 26. The terminal sugar residue of the pentasaccharide hapten of the serovar 25 GPL had been shown to have the galacto configuration on the basis of 1H-13C NMR correlation spectroscopy, but absolute configurational assignment for the sugar awaited the synthesis, as for neo 26, of two glycobiosyl NGPs bearing the terminal sugar in the D and L enantiomeric forms, respectively. Only the glycobiosyl NGP bearing the terminal sugar as the D-enantiomer interacted with antibodies to M. avium serovar 25, thus providing evidence for the absolute configuration of the sugar, and showing that the complete oligosaccharide hapten has the structure, O-(4-acetamido-4,6-dideoxy-2-O-methyl-alpha-D- galactopyranosyl)-(1-->4)-O-beta-D-glucopyranosyluronic acid-(1-->4)-O-(2-O-methyl-alpha-L-fucopyranosyl)-(1-->3)-O-alpha-L- rhamnopyranosyl-(1-->2)-6-deoxy-L-talose.

Non-aqueous cerimetric determination of phenylhydrazides.

A non-aqueous oxidimetric method is described for the determination of some carboxylic acid phenylhydrazides with ammonium hexanitratocerate(IV) in acetonitrile. The end-points have been detected visually with chemical indicators (diphenylamine, diphenylbenzidine, Methyl Red, Malachite Green, Janus Green, Gentian Violet) and potentiometrically. The compounds are smoothly, rapidly and quantitatively oxidized with a two-electron change per hydrazino group. The method is simple, accurate, reliable and widely applicable.

Determination of mercaptopyrimidines with copper(II) in acetonitrile.

A non-aqueous oxidimetric method is described for the determination of mercaptopyrimidines with copper(II) perchlorate in acetonitrile, diphenylamine being used as indicator. A bright platinum wire is used as indicator electrode and a modified calomel or an antimony electrode as reference for potentiometric titrations. The method, based on the oxidation of the mercapto group to the disulphide, is simple, accurate and reliable.

Determination of thiuram disulphides and analysis of thiuram disulphide-dithiocarbamate mixtures.

Potassium trithiocarbonate is used as reluctant for the titrimetric determination of thiuram disulphides in dimethylformamide-water media. The method is based on reductive cleavage of the disulphide linkage to yield the corresponding dithiocarbamates. In visual titrations, the end-point is marked by appearance of a yellow colour with the first drop of reagent added in excess. The method is simple, accurate, reliable and of wide applicability. It has been successfully extended to the analysis, in the same sample solution, of thiuram disulphide-dithiocarbamate mixtures.

A new colorimetric method for the determination of carbon disulphide and its application to the analysis of some dithiocarbamate fungicides.

A new and convenient colorimetric method for determination of carbon disulphide, based on its transformation into bright yellow potassium benzyl trithiocarbonate through reaction with benzyl mercaptan and potassium hydroxide in tert.-butyl alcohol, has been successfully applied to determination of some dithiocarbamate fungicides in their formulations. The method possesses a distinct advantage in that it is free from all sources of errors/problems which are associated with the xanthate method for the analysis of these materials. The proposed method is precise and accurate and hence recommended for routine analysis of technical formulations containing dithiocarbamate fungicides.

Breast metastasis from a pharyngeal carcinoma.

The reported incidence of metastatic disease in head and neck cancer is increasing. The most common site of metastatic involvement in squamous carcinoma of the head and neck is the lung followed by liver, mediastinal nodes and bone. The breast is rarely infiltrated by metastatic disease, 2 per cent or less of clinically detected breast lumps being of non-mammary origin, most frequently malignant melanoma, lymphoma/leukaemia and primary lung carcinoma. A 73-year-old female presented with a primary posterior pharyngeal wall squamous carcinoma and bilateral enlarged neck nodes. She developed an isolated breast metastasis while receiving palliative radiotherapy and died seven months after presentation. Clinically detected breast metastasis in head and neck squamous cell carcinoma was first documented by Toombs and Kalisher in 1977. This is the first report of such a case originating in the posterior pharyngeal wall. The prognosis is invariably poor.

Age during breast feeding and timely suckling.

A cross sectional study of 398 mothers and infants was conducted to assess the age at first breast feeding, and its determinants, in Shimla. We found that the timely first suckling rate was 0.10 in urban group and 0.11 in rural group. The median age at initiation of breast feeding was five hours among urban cases and four hours among rural cases. Most of the infants were breast fed by the age of 24 hours which is a positive sign and is higher than previous studies. Absence of definite trend vs mother's education may be due to other factors. A community-based educational programme to promote early breast feeding is required, along with training on lactation management counselling for health workers. This will help in achieving healthy child development through prevention of childhood malnutrition.

An epidemiological study of obesity in Shimla Town.

A cross sectional study of 888 randomly selected subjects in Shimla town was done to determine prevalence of obesity, its relation to age and physical activity. The prevalence of obesity was 21.5% using cut off levels of BMI 25. The prevalence of obesity rose significantly with age. Obesity was less in those having moderate physical activity as compared to those with low and high activity. Primary prevention is required to tackle this disease risk factor through health education focussing on promotion of moderate regular physical activity.