(12) HIRAI: Zikahassi, 1923. (Quoted by Suzuki and Kaneko.)

(13) SUZUKI, T., AND KANEKO, J.: Serous meningitis in infants from lead poisoning. Jour. Oriental Medicine, Dairen, Manchuria, 1924, ii, 55-67. (14) TURNER, A. J.: On lead poisoning in childhood. Brit. Med. Jour., 1909, i, 895-897.

(15) THOMAS, H. M., AND BLACKFAN, K. D.: Recurrent meningitis, due to lead, in a child of five years. Amer. Jour. Dis. Child., 1914, viii, 377-380. (16) STRONG, R. A.: Meningitis caused by lead poisoning in a child of 19 months. Arch. Ped., 1920, xxxvii, 532-537.

(17) MOTT, F. W.: Examination of the

nervous system in a case of chronic lead encephalitis. Arch. Neurol. and Psych., 1909, iv, 117–130.

(18) MCCORD, C. P., MINSTER, D. K., and REHM, M.: The basophilic aggregation test in lead poisoning. Jour. Amer. Med. Assoc., 1924, lxxxii, 1759-1763.

(19) FAIRHALL, L. J.: The microchemical detection of lead. Jour. Biol. Chem., 1923, lvii, 455–461.

(20) LYMAN, H. M.: Chronic meningoencephalitis complicated with leadpoisoning. Intern. Clin., Philadelphia, 1891, ii, 252–262. (21) PINARD, M.: Étude clinique de la méningite saturnine. Gaz. des Hôpitaux, Paris, 1908, lxxxi, 963-968.

lead-colic type, were very frequently observed symptoms. Since his observations were made upon the same group of people over such a long period, Kretschmer came to the conclusion that those who showed the latter symptoms possessed an especial individual predisposition of the vegetative nervous system. Arthralgia and neuritis were never observed, and no lead-paralysis occurred. No study was made of the blood-pressure or of the occurrence of hematoporphyrin in the urine. According to the rules laid down for the protection of the workers the occurrence of basophile granulations in the red blood cells was made the chief criterion for the early recognition of lead-poisoning. This sign, first described by Behrend, in 1899 as characteristic of lead-poisoning, occurs usually very early, especially when the affected worker is exposed to a massive inhalation of lead-dust or lead-vapor, as is the case in the accumulator factory in the so-called "Schmierern" or "pasting." According to many authors the number of cells showing basophile granulation varies greatly from day to day, so that on some days many are present, at other times almost none. It has also been emphasized by many that the number of cells with basophile granulation does not run parallel with the severity of the symptoms of lead-poisoning. Kretschmer could occasionally determine a certain degree of variation in the number in certain laborers, but this was usually in workmen who had been changed to a less exposed form of labor. He noted also in many cases the lack of correlation between the severity of symptoms and the number of cells with basophile

granulation. Some laborers observed for a long time showed numerous granular cells in the blood without any decisive symptoms of intoxication. He could not confirm the statement of many investigators that the granular cells quickly disappear when the individual is no longer exposed to lead. In one laborer free from exposure to lead for one year the blood still showed numerous granular cells. He noted, however, that when the basophile granulation appeared quickly in great numbers, in laborers exposed but a short time to lead, that, either through individual predisposition or through disregard of the preventive regulations they quickly developed other symptoms of intoxication. The technique employed by Kretschmer was fixation of the smears in absolute alcohol and staining according to Hamel with Löffler's methylene-blue, or according to Schmidt with Azur II. As a positive criterion for the action of lead the lead-regulations take the occurrence of more than one granular erythrocyte in 50 fields averaging 200 red cells. Kretschmer, however, recommends the method of Schwarz in estimating the number of granular red cells in unfixed thick drops, although Engel has affirmed that a comparison of the stained smears and the thick drop preparations shows that the latter may contain great numbers of basophilic granular reds while the stained smears will show fewer than the one granular cell in fifty fields. The divergence between the two methods depends, according to Schwartz and Hefke, upon variations in the fixation and staining. Kretschmer used both unfixed and fixed smears and also the thick drop

method, and found that the lastnamed worked perfectly well in determining quickly whether basophile granulation cells were occasional, scarce, numerous or very abundant, appropriate measures to be taken accordingly. He considers this criterion much more practical than the Schmidt of one granular cell in fifty fields. He, therefore, thinks it would be an advantage for the national health regulations to be altered in respect to this point. Kretschmer also occupied himself with the question of the nature of the basophilic stippling. The earlier workers, Ehrlich and others regarded the basophile stippling as remains of the nucleus and as signs of a degenerative change. This view has been abandoned by all of the haematologists of the present day, and basophilic stippling is now regarded as a sign of blood-regeneration. An especial point of view is that of Schilling, who, on the basis of his investigations by means of the thick drop method, believes that the basophilic granulation and the polychromasia of the red blood cells are substantially identical morphological modifications of the same basic young net-substance of the erythrocyte. The basic net-substance is only another appearance of polychromasia produced by the technique of unfixed staining, and clinically the two are of equal value. Basophilic stippling (physiologic in the embryo) on the contrary represents in later life a pathological condensation or clumping of a degenerative character which clinically is, almost without exception the result of a toxic injury to erythropoësis, and is to be separated from the physiological polychromasia of the anaemias. Schilling's view of the degenerative

nature of basophilic stippling is not accepted by the majority of workers, and is apparently contradicted by the facts. The majority of haematologists have attacked the problem only from the standpoint of haematological and staining properties, and have neglected the colloid chemistry aspects of the problem. Based on Bechhold's studies of haemolysis and conclusions that the erythrocytes possess a netlike covering of albumin the meshes of which are filled with a colloidal solution of lecithin and cholesterin, all chemical and physical agents which will act upon any one of the constituents of the erythrocyte envelope will produce haemolysis. According to Bechhold's investigations there is no internal skeleton net-work in the erythrocyte; the basophile granulation and the net-like structure are elements of the erythrocyte covering. Kretschmer's studies, he thinks, confirm those of Bechhold. Comparative investigations of fixed and unfixed blood-preparations from lead-workers show that the basophile stippling and the net-like substance (Substantia reticulofilamentosa) do not belong to a spongioplastin or inner network of the erythrocyte but represent elements of the erythrocyte surface, which are precipitated either as a net-like substance or as a basophilic stippling, according to the manner of fixation and staining. The number of basophile granules, therefore, depends upon the quantitative relation and the colloid-chemical binding of the albumins and lipoids in the erythrocyte envelope, which is influenced by the age of the individual red cells, by intoxications, especially lead, and other pathological factors.

In this country McCord, Minster

and Rehm (Jour. Amer. Med. Assoc., 1924, lxxxii, 1759) employ a basophilic aggregation test in examining for evidences of lead poisoning. Their method is as follows: Blood smears are made in the usual way, thick ones preferable to thin smears. HaemolyHaemolysis is produced with distilled water or hypotonic salt solution and the haemolyzed smear stained with Manson's methylene blue. This is made by dissolving 5 gm. borax in 100 cc. boiling water, to which is then added 2 gm. of methylene blue. This stain deteriorates within a month. Instead of haemolyzing the smear before staining, the stain may be diluted with distilled water until the stain is transparent, and the unfixed slide is then stained with this for ten minutes. Under these conditions the staining is so slow that haemolysis precedes staining. After air-drying the slides are examined microscopically, using oilimmersion. In cases of lead-poisoning, twenty-five or more basophilic aggregations may be seen in a single field, while preparations from the same patient at the same time, and stained with Wright's stain may show only a few preformed stipple cells in the entire slide. The writers believe that the minute, invisible basophilic particles are aggregated into coarser masses as a result of haemolysis. This view is borne out by the results of fractional haemolysis with diminishing concentrations of hypotonic sodium chloride solutions, the weaker concentrations yielding a greater proportion of stipple cells. When fractional haemolysis is carried out the red cells become much swollen, and the basophilic substance is definitely arranged at the periphery giving a beaded ap

pearance. In some of the preparations stained by the methylene blue method the basophilic granulations are seen within the red cell membrane; in other preparations the red cell membrane is not visible, but the granules tend to arrange themselves at the periphery. The size of the granules varies greatly in different preparations and in the single cells. When the red blood cells are definitely larger than normal the basophilic aggregations are definitely arranged at the periphery. The basophilic aggregation test is not pathognomonic of lead poisoning; it is a measure of the precocious introduction of red cells into the circulation. The blood of healthy persons contains a few basophilic aggregations; and in a variety of conditions associated with anaemia they are found in larger numbers. On a quantitative basis clinical cases of lead poisoning show regularly a high basophilic aggregation content of the blood. As a result of their experience the writers believe that the majority of lead-exposed workers quickly come to have a higher basophilic aggregation count than is found among normal persons. They regard this as evidence of a preclinical plumbism. When the number of stipple cells in every field is ++++++ and higher the workers should be placed on lead-eliminating or lead-controlling treatment. With clinical evidence of plumbism treatment is begun when the basophilic aggregations are ++++. In workers with an increasing basophilic aggregation count, with or without clinical plumbism, in the absence of other diseases, antilead measures should be adopted.