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proper.8 Thus, tissue confined mosaicism can occur duringearly cell lineage. Furthermore, in tissues with a highproliferation rate of cells an increased chromosomal insta-bility of Y derived marker chromosomes might lead to acomplete loss of a second cellline.2

Suspecting Y mosaicism I would recommend conven-tional cytogenetics complemented by fluorescence in situhybridisation (FISH) in several tissues. FISH technology,with Y-specific centromeric probes, permits localising andscoring 100 or so metaphases per hour, a number which maybe increased by screening additional interphase nuclei.Until PCR-based techniques are confirmed they should beconsidered an adjunctive rather than an independent test.

K R HeldInstitut für Humangenetik, Hamburg, Germany

1 De la Chapelle A. Sex chromosome abnormalities. In: Emery AEH,Rimoin DL, eds. Principles and practice of medical genetics.Edinburgh: Churchill Livingstone, 1990: 273-99.

2 Held KR, Kerber S, Kaminsky E, Singh S, Goetz P, Seemanova E,Goedde HW. Mosaicism in 45,X Turner syndrome: does survival inearly pregnancy depend on the presence of two sex chromosomes?Hum Genet 1992; 88: 288-94.

3 Hook EB, Warburton D. The distribution of chromosomal genotypesassociated with Turner’s syndrome: live-birth prevalence and evidencefor diminished fetal mortality and severity in genotypes associated withstructural X abnormalities or mosaicism. Hum Genet 1983; 64: 24-27.

4 Hassold T, Benham F, Leppert M. Cytogenetic and molecular analysisof sex-chromosome monosomy. Am J Hum Genet 1988; 42: 534-41.

5 Ostrer H, Clayton CM. Y chromosome mosaicism in 45,X Turnersyndrome. Am J Med Genet 1989; 34: 294-96.

6 Witt M, Michalczak K, Latos-Bielenska A, Jaruzelska J, Kuczora I,Lopez M. An improved, non-isotopic method of screening cells frompatients with abnormalities of sexual differentiation for Ychromosomal DNA content. J Med Genet 1993; 30: 304-07.

7 Cooper C, Crolla JA, Laister C, Johnson DI, Cooke P. Aninvestigation of ring and dicentric chromosomes found in threeTurner’s syndrome patients using DNA analysis and in situhybridisation with X and Y chromosome specific probes. J Med Genet1991; 28: 6-9.

8 Bianchi DW, Wilkins-Haug LE, Enders AC, Hay ED. Origin ofextraembryonic mesoderm in experimental animals: relevance tochorionic mosaicism in humans. Am J Med Genet 1993; 46: 542-50.

Tight glucose control and diabeticcomplicationsThe long-awaited results of the Diabetes Control andComplications Trial (DCCT) were announced at theAmerican Diabetes Association meeting in Las Vegas onJune 12. This randomised study sponsored by the NationalInstitute of Diabetes and Digestive and Kidney Diseasesconfirms the conclusion of our meta-analysis published inThe Lancet a few weeks earlier,! demonstrating once againthat a good meta-analysis is an excellent alternative to alarge multicentre trial. The DCCT examined the effects ofintensive therapy in 1441 patients with type 1 diabetes in theUS and Canada. In patients with minimal retinopathy andalbuminuria, intensive therapy reduced the risk of retino-pathy progression by 22-54% and the risk of nephropathyprogression by nearly 60%. A similar effect or trend wasfound in patients without retinopathy and nephropathy atthe start of study. In addition, intensive therapy signifi-cantly reduced the prevalence of neuropathy. Althoughthere was no significant difference in cardiovascular events,neurobehavioural and psychological measurements, or

quality of life, the incidence of severe hypoglycaemiatripled in patients treated intensively (62 vs 19 per 100

person-years). One episode of severe hypoglycaemic reac-tion caused a serious car accident.Decades of debates over whether attainment of a normal

blood glucose may prevent or retard diabetic complicationsshould come to an end with the results of this trial and the

meta-analysis. At least in type 1 diabetic patients, the risk ofmicrovascular complications can be reduced by tighteningblood glucose control. The increased risk of severe hypo-glycaemia should not be neglected and the risk/benefit ratiohas to be worked out for patients individually. For example,a highly motivated medical student with new-onset type Idiabetes could be a good candidate for intensive therapywhereas a 65-year-old diabetic man with a history ofischaemic heart disease and hypoglycaemia unawarenesswould not. The risk/benefit ratio for each individual will bemore precisely defined in the future as we gain furtherexperience of intensive control in the general diabeticpopulation. Until now, intensive therapy has been limitedto a small fraction of diabetic patients, but the demand forintensive therapy is likely to rise. Physicians and nurses willface an increasing challenge as the number of patients onintensive therapy swells. The cost of diabetic care willprobably increase too.The benefit of intensive therapy in type 2 diabetes is less

certain, but the Wisconsin study suggests that hypergly-caemia may cause microvascular damage similar to that seenin type 1.2 There is no firm evidence against giving intensivetherapy to these patients. However, it is unclear whether ornot the weight gain3 and hyperinsulinaemia that can beassociated with intensive therapy offset the beneficialeffects. The ongoing UK Prospective Diabetes Study ontype II diabetes5 should provide more conclusive data. TheUS Veterans Affairs Study had shown that the pattern ofsevere hypoglycaemic reactions may not be the same in type1 and type 2 patients. In that study, the incidence of severehypoglycaemia was similar in the conventional control andintensive therapy groups in type 2 diabetic patients.6 Sincethe beneficial effects of intensive therapy have already beenshown in type 1 patients and only minor side-effects havebeen documented in type 2 diabetic patients thus far, morephysicians may choose to treat their type 2 patientsintensively.As we enter the new era of intensive glucose control

physicians will under pressure to treat all patients in thisway if there is no contraindication. This new standard willhave notable impact not only on health-care professionalsand patients but also on health-service budgets, healthinsurance provision, and malpractice liability.

Ping H Wang

Joslin Diabetes Center, Harvard Medical School, Boston, USA

1 Wang PH, Lau J, Chalmers TC. Meta-analysis of effects of intensiveblood-glucose control on late complications of type I diabetes. Lancet1993; 341: 1306-09.

2 Klein R, Klein BEK, Moss S. Epidemiology of proliferative diabeticretinopathy. Diabetes Care 1992; 15: 1875-91.

3 The DCCT research group. Weight gain associated with intensivetherapy in the Diabetes Control and Complications Trial. DiabetesCare 1988; 11: 567-73.

4 Reaven GM. Relationship between insulin resistance andhypertension. Diabetes Care 1991; 14 (S4): 33-38.

5 UK Prospective Diabetes Study Group. UK Prospective DiabetesStudy VIII: study design, progress and performance. Diabetologia1991; 34: 877-90.

6 Sawin CT, Johnson NL, Silbert CK, et al. Hypoglycemia in the VAfeasibility trial on glycemic control and complications in type IIdiabetes mellitus. Proc Endoc Soc 1993: 230 (abstr).