Development of endometrioid adenocarcinoma despite Levonorgestrel-releasing intrauterine system: a case report with discussion and review of the RCOG/BSGE Guideline on the Management of Endometrial Hyperplasia.

Obesity is a significant risk factor for the development of endometrial hyperplasia and cancer. More conservative prevention and management strategies are attractive due to the increased surgical risk and complication rates associated with obesity. The Levonorgestrel-releasing intrauterine system (LNG-IUS, Mirena) has been shown to reduce the risk of developing endometrial cancer. The recent joint Green Top Guideline on the Management of Endometrial Hyperplasia published by the Royal College of Obstetricians and Gynaecologists (RCOG) with the British Society for Gynaecological Endoscopy (BSGE) recommends the LNG-IUS for the medical management of endometrial hyperplasia without atypia. This case study reports on the development of endometrioid adenocarcinoma despite the presence of an LNG-IUS following a negative hysteroscopy in a 56-year-old woman with morbid obesity. This report highlights the need for patients and clinicians to remain vigilant to the early warning signs of developing endometrial cancer, especially in those at an increased risk secondary to obesity.

A nonlinear effect of hyperglycemia and current cigarette smoking are major determinants of the onset of microalbuminuria in type 1 diabetes.

Cigarette smoking and poor glycemic control are risk factors for diabetic nephropathy in type 1 diabetes. However, the specifics of the relation of these risk factors to the onset of this complication have not been elucidated. To investigate these issues, we followed for 4 years 943 Joslin Clinic patients aged 15-44 years with type 1 diabetes who had normoalbuminuria during the 2-year baseline period. Microalbuminuria developed in 109 of the 943 individuals, giving an incidence rate of 3.3/100 person-years. The risk of onset of microalbuminuria was predicted somewhat more precisely by the measurements during the 1st and 2nd years preceding onset than by all the measurements during the longer (4-year) interval, suggesting attenuation of the impact of past hyperglycemia over time. Point estimates of the incidence rate (per 100 person-years) according to quartiles of HbA(1c) during the 1st and 2nd years preceding the outcome were 1.3 in the 1st, 1.5 in the 2nd, 3.1 in the 3rd, and 6.9 in the 4th (P = 1.3 x 10(-9)). Point estimates of the incidence rate (per 100 person-years) according to smoking status were 7.9 for current smokers, 1.8 for past smokers, and 2.2 for those who had never smoked (P = 2.0 x 10(-7)). In a multiple logistic model, the independent effects of HbA(1c) level and cigarette smoking remained highly significant, but their magnitudes were reduced. Using the same covariates in a generalized additive model, we examined the shape of the relationship between HbA(1c) and onset of microalbuminuria and found significant nonlinearity in the logarithm of odds scale (P = 0.04). The slope was steeper with HbA(1c) >8% than <8%. Furthermore, the change in the slope was magnified among current smokers. In conclusion, patients with type 1 diabetes who smoke and have an HbA(1c) >8% have the highest risk of onset of microalbuminuria.

Segregation analysis of urinary albumin excretion in families with type 2 diabetes.

Elevated urinary albumin excretion (UAE) is a predictor of the development of nephropathy and cardiovascular mortality. To study whether genetic factors may determine UAE, we examined familial aggregation of UAE in 96 large multigenerational pedigrees ascertained for type 2 diabetes. A total of 1,269 subjects had UAE measured as the urinary albumin-to-creatinine ratio (ACR). This included 630 subjects with type 2 diabetes and 639 subjects without diabetes. A significant correlation (Spearman's correlation 0.34, P < 0.001) was found between the median ACR values determined separately in nondiabetic and diabetic members of the same family. To determine whether this familial aggregation of ACR could be explained by the transmission of 1 or more major genes and thus be suitable for gene mapping studies, segregation analyses were performed. In these analyses, ACR was modeled as a continuous trait with the inclusion of age, sex, and duration of diabetes as covariates. Likelihood ratio tests were performed to test competing hypotheses, and Akaike's information criterion was used to determine the most parsimonious models. The Mendelian model with multifactorial inheritance was supported more strongly than Mendelian inheritance alone. These analyses suggested that the best model for ACR levels was multifactorial with evidence for a common major gene. When the analyses were repeated for diabetic subjects only, the evidence for Mendelian inheritance was improved, although a single major locus with additional multifactorial effects was more strongly supported. The results from the current study suggest that levels of UAE are determined by a mixture of genes with large and small effects as well as other measured covariates, such as diabetes.

In vitro characterization of five humanized OKT3 effector function variant antibodies.

Orthoclone OKT 3 (mOKT3) is a highly effective agent for the reversal of steroid-resistant renal allograft rejection. However, its wider use has been limited by the development of a human anti-mouse antibody response (HAMA) and by the "cytokine release syndrome" (CRS). CRS has been associated with T cell/monocyte activation and, secondarily, with activation of the complement cascade. These processes are mediated through Abs' Fc regions by their abilities to cross-link T cells and mononuclear cells and to activate complements. To alleviate these problems, a group of five huIgG1- and huIgG4-based OKT3 wild-type antibodies and their corresponding Fc mutants with altered residues at amino acids 234, 235, and 318, reported to be required for FcgammaRI and FcgammaRII binding and complement fixation, were constructed. Characterization of these humanized OKT3 Abs, denoted huOKT3gamma1, huOKT3gamma4, huOKT3gamma1(A(234), A(235)), huOKT3gamma4(A(234), A(235)), and huOKT3gamma1(A(318)), has demonstrated that huOKT3gamma1(A(234), A(235)) and huOKT3gamma4(A(234), A(235)), and have at least a 100-fold reduced binding to FcgammaRI and FcgammaRII. As expected, they are much less potent in the induction of T cell activation and cytokine release, yet retain in vitro immunosuppressive effects as potent as those of mOKT3. Unexpectedly, while huOKT3gamma1(A(318)) did not show any reduction in its ability to bind C1q and to fix a complement, huOKT3gamma1(A(234), A(235)) was completely inactive. The in vitro characteristics of huOKT3gamma1(A(234), A(235)) are consistent with recent in vivo studies, in which this Ab showed greatly reduced HAMA and CRS with the retention of its ability to reverse ongoing graft rejection in man.

Progression of microalbuminuria to proteinuria in type 1 diabetes: nonlinear relationship with hyperglycemia.

While small clinical trials have shown that improved glycemic control reduces the risk of progression of microalbuminuria to proteinuria, two recent clinical trials did not confirm this finding. We sought to reconcile the contradictory evidence by examining the dose-response relationship between hyperglycemia and progression of microalbuminuria to proteinuria in individuals with type 1 diabetes and microalbuminuria (n = 312) who were followed for 4 years with repeated assessments of urinary albumin excretion. Since 33 patients did not participate in follow-up (10.6%), data for 279 patients were analyzed. Urinary albumin excretion level worsened to proteinuria in 40 (4.1 per 100 person-years). To examine the dose-response relationship, baseline HbA1c was divided into four roughly equal groups using the cut points 8, 9, and 10%. The incidence rate varied significantly among the four groups (P = 0.008). Among those with HbA1c <8.0%, the incidence rate of progression was only 1.3 per 100 person-years, while it was 5.1, 4.2, and 6.7 per 100 person-years in the three other groups. We used generalized additive models to examine the dose-response curve using HbA1c as a continuous variable and found that the risk of progression rises steeply between an HbA1c of 7.5-8.5% and then remains approximately constant across higher levels. In conclusion, the results of this study suggest that, in patients with microalbuminuria, the risk of progression to overt proteinuria can be reduced by improved glycemic control only if the HbA1c is maintained below 8.5%. Moreover, below that value, the risk declines as the level of HbA1c decreases.

Risk of advanced diabetic nephropathy in type 1 diabetes is associated with endothelial nitric oxide synthase gene polymorphism.

UNLABELLED: Risk of advanced diabetic nephropathy in type 1 diabetes is associated with endothelial nitric oxide synthase gene polymorphism. BACKGROUND: Polymorphisms in the endothelial nitric oxide synthase gene (eNOS) may be implicated in the development of nephropathy in patients with type 1 or insulin-dependent diabetes mellitus (IDDM). METHODS: Three groups of IDDM patients were selected to study this hypothesis: cases with advanced diabetic nephropathy (N = 78), cases with overt proteinuria but normal serum creatinine (N = 74), and controls with normoalbuminuria despite 15 years of diabetes (N = 195). Parents of 132 cases and 53 controls were also examined and were used for the transmission disequilibrium test, a family-based study design to test association. RESULTS: We examined four eNOS polymorphisms, and two were associated with diabetic nephropathy in the case-control comparisons: a T to C substitution in the promoter at position -786 and the a-deletion/b-insertion in intron 4. For the former, the risk of developing advanced nephropathy was higher for C allele homozygotes than for the other two genotypes (odds ratio 2.8, 95% CI, 1.4 to 5.6). For the latter polymorphism, it was the a-deletion carriers that had the higher risk (odds ratio 2.3, 95% CI, 1.3 to 4.0) in comparison with noncarriers. Both polymorphisms were analyzed together as haplotypes in a family-based study using the transmission disequilibrium test. The C/a-deletion haplotype was transmitted from heterozygous parents to cases with advanced diabetic nephropathy with a significantly higher frequency than expected (P = 0.004). CONCLUSION: The findings of the case-control and family-based studies demonstrate clearly that DNA sequence differences in eNOS influence the risk of advanced nephropathy in type 1 diabetes.

Tuberculosis meningitis, Abbassia Fever Hospital-Naval Medical Research Unit No. 3-Cairo, Egypt, from 1976 to 1996.

A total of 1,430 patients with the presumptive diagnosis of tuberculous meningitis were admitted to the U.S. Naval Medical Research Unit No. 3/Abbassia Fever Hospital in Cairo, Egypt from January 1976 to January 1996. Diagnosis was confirmed by culture of the mycobacteria from the cerebrospinal fluid CSF of 857 patients and these patients are included in the final analysis. There were 497 males and 360 females. The patients ranged in age from five months to 55 years. The number of patients admitted during the months of March, April, and May were more than double those admitted during October, November, and December. The duration of symptoms prior to admission ranged from seven to 90 days (mean = 29.5 days). Upon admission, 4% of the patients were alert, 34% were drowsy, and 62% were in a coma. Of the 857 patients studied, 490 (57%) died, 256 (30%) recovered completely, and 11 (13%) recovered with sequelae. The mortality and neurologic sequelae were directly related to the stage of disease and duration of symptoms prior to admission. Mortality was significantly lower in patients admitted in stage II and or with short duration of disease compared with those in stage III and or with prolonged duration of symptoms prior to admission. The use of dexamethasone in patients with tuberculous meningitis significantly reduced the ocular complications that occur in these patients and also significantly reduced the fatality rate.

Schistosoma mansoni: egg granuloma reduction in challenged mice after vaccination with irradiated-attenuated cercariae.

Response of Swiss albino mice vaccinated with irradiated-attenuated cercariae or repeatedly infected with normal cercariae of Schistosoma mansoni were known to develop resistance to reinfection. The mean (+/- SD) of the hepatic granuloma numbers and diameters for vaccinated-challenged group (I) were 2 +/- 0.89/1mm2 and 116 +/- 11.5 microns, for repeatedly infected group (II) were 2 +/- 0.63/1mm2 and 2 +/- 0.89/1mm2 and 195 +/- 11.8 microns and for control group (III) were 4 +/- 1.36/1mm2 and 140 +/- 12.3 microns respectively. Mean of the diameter of the granulomas were significantly smaller in the group vaccinated with irradiated cercariae than the other two groups. Most of the granulomas in groups I and II were fibro-cellular while all granulomas in group III were cellular. Predominent cell types of the granulomas were lymphocytes in groups I and II and eosinophils in group III. The incidence of focal hydropic and fatty degenerations, necrosis and prominent kupffer cell hyperplasia were lower in group I. These results supported that granuloma size reduction in all vaccinated animals were apparently effective in sequestering egg toxins and reduced hepatocytes damage. The present study gives encouragement that a vaccine to enhance protection against disease in human schistosomiasis is possible.

Schistosoma mansoni: IgG reactivity to soluble adult worm antigen preparation (SWAP) in sera of immunized mice with irradiated attenuated and virulent cercariae.

The aim of this work was to identify the antigens, that elicit a greater or unique immune response in the immunized host against Schistosoma mansoni (Egyptian strain) infection. Moreover the difference in immune response to this antigen between mice immunized with radiation-attenuated cercariae or immunized with virulent cercariae were investigated. Immunobloting technique was used to monitor the fine specificity of host IgG to SDS-PAGE separated SWAP in the sera of different test groups immunized with either radiation-attenuated cercariae or low doses of virulent cercariae compared to non-immunized group. Data from this study showed that groups immunized with virulent and irradiated-attenuated cercariae showed 74.7% and 68.3% reduction in worm burden respectively. Differences of humoral immune response of sera of different tested groups against SWAP proteins were definite. Sera of non-immunized mice precipitated non-immunogenic proteins of 87 and 83 KD. SWAP proteins of 106 and 97 KD were identified only by the sera of vaccinated animals with irradiated attenuated cercariae whether challenged or not. Resistant sera from animals immunized by either irradiated-attenuated cercariae or virulent cercariae recognized low molecular weight antigens that ranged from 34 to 52 KD in addition to 57 KD. This indicated that the 106 and 97KD may be the target antigens for protection by radiation-attenuated larvae, while the marker of resistance induced by attenuated or virulent larvae may be 34-52 and 75 KD antigens.

Crystallization and preliminary X-ray studies of recombinant human granulocyte-macrophage colony stimulating factor.

Human granulocyte-macrophage colony stimulating factor (hGM-CSF) is an important regulator of growth and differentiation for mononuclear and polymorphonuclear phagocytes. Here we report the crystallization and preliminary X-ray studies of Escherichia coli-expressed hGM-CSF. The crystals are orthorhombic, with the space group P212121, and have unit cell dimensions a = 46.62 A, b = 58.73 A and c = 126.42 A. Recombinant hGM-CSF crystals diffract X-rays to 2.4 A resolution and are thus suitable for X-ray structural studies.

Ocular complications in meningitis: "fifteen years study".

The incidence of ocular complications in 4102 patients with meningitis was studied during a 15 year period. Cranial nerve involvement was detected in 23% of patients (sixth cranial nerve in 16.5%; third and seventh nerve in 3.0% each; and fourth and fifth nerve in 0.1% each). Pupillary changes were detected in 82% and fundus changes in 5.2% of patients.

Comparison of structures of various human fibrinogens and a derivative thereof by a study of the kinetics of release of fibrinopeptides.

The kinetics of the thrombin-induced release of fibrinopeptides from several variants of human fibrinogen, and from the plasmin digestion fragment E thereof, have been studied by using an HPLC technique to separate the reaction products. The data were analyzed in terms of a Michaelis-Menten mechanism in which the A alpha and B beta chains compete for thrombin. Phosphorylation of Ser-3 of the A alpha chain appears to increase the rate of release of the corresponding phosphorylated peptide A from fibrinogen, due to enhanced binding of thrombin (lower value of the Michaelis-Menten constant KM). However, phosphorylation does not affect the rate of release of the unphosphorylated A or B peptides. Increase in the length of the gamma chain (at the C-terminus) does not affect the rate of release of any of the fibrinopeptides. The rate of release of the A peptide from fragment E (which is devoid of the B peptide) is similar to that for the complete fibrinogen molecule. These results are in agreement with an earlier conclusion [Martinelli, R. A., & Scheraga, H. A. (1980) Biochemistry 19, 2343] that the A alpha and B beta chains behave independently in their competition for thrombin; i.e., the hydrolyzable Arg-Gly bonds of the A alpha and B beta chains are both accessible to thrombin.

Kinetic analysis of nicotinate phosphoribosyltransferase from yeast using high pressure liquid chromatography.

A new procedure has been designed for the purification of nicotinate phosphoribosyltransferase and orotate phosphoribosyltransferase from the same baker's yeast extract. Using purified nicotinate phosphoribosyltransferase, the enzyme-catalyzed formation of nicotinate mononucleotide was analyzed using a new high pressure liquid chromatographic assay (Hanna, L., and Sloan, D. L. (1980) Anal. Biochem. 103, 230-234). Initial velocity measurements and product inhibition studies, with pyrophosphate, were performed. In addition, this assay procedure was used to demonstrate that purified nicotinate phosphoribosyltransferase possesses an ATPase activity in the presence of either product (pyrophosphate or nicotinate mononucleotide (NaMN] but in the absence of 5-phosphoribosyl alpha-1-pyrophosphate (P-Rib-PP). Moreover, exchanges of radioactivity between specific substrate/product pairs [( 14C]nicotinate/NaMN and [32P]PPi/P-Rib-PP) in the absence of other substrates were not observed when these pairs were incubated with nicotinate phosphoribosyltransferase, and binding of [14C] nicotinate to nicotinate phosphoribosyltransferase was not detected in the presence of ATP. In contrast, an exchange of label between ATP and [14C]ADP was characterized in the absence of other substrates and in the presence of either P-Rib-PP or PPi. These results indicate that nicotinate phosphoribosyltransferase proceeds through the use of an ordered Uni Uni Bi Ter Ping Pong kinetic mechanism during which ATP reacts with nicotinate phosphoribosyltransferase to form ADP and a previously described phosphorylated enzyme (Kosaka, A., Spivey, H. O., and Gholson, R. K. (1977) Arch. Biochem. Biophys. 179, 334-341). Thereafter, P-Rib-PP and nicotinate bind in order to the active site, to produce PPi and NaMN which are released in a random order followed by Pi. The Km values for ATP, P-Rib-PP, and nicotinate were calculated to be 70 +/- 10, 24 +/- 3, and 23 +/- 4 microM, respectively, whereas a value for Ki(PRPP) of 5 +/- 1 microM was determined.

Effect of urinary bilharzial infection on male pubertal development and endocrine functions.

One hundred seventy-five males aged 9-20 years were selected. The subjects comprised two groups; controls and patients infected with urinary bilharziasis not associated with any other parasite. Pubertal development was assessed. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and progesterone were determined by radioimmunoassay procedure. Delay in pubertal development was evident in the normal control group as indicated by higher chronological age mean values at the various stages as compared to other world norms. Urinary bilharziasis exaggerated the delay in pubertal development as compared to that in the control group. In relation to the control group, the group with urinary bilharziasis had higher levels of serum FSH and LH, which were significant only at stages III and IV. No significant difference was noted between the two groups for serum testosterone and progesterone levels, except for the high progesterone mean value at stage V in the group with urinary bilharziasis.

The use of dexamethasone in preventing ocular complications in tuberculous meningitis.

Twenty-seven patients with tuberculous meningitis (TBM) were treated with ethambutol, isonicotinic acid hydrazide, streptomycin and dexamethasone and 28 were treated with triple anti-tuberculous drugs only. Only two of the patients to whom steroids were given developed ocular complications as compared to seven of those not receiving dexamethasone. High dose dexamethasone apparently prevents optic atrophy in TBM. Controlled double-blind studies with and without dexamethasone are needed to confirm this postulation.