Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation.

Aurora-A/STK15/BTAK, which encodes a centrosome-associated kinase, is amplified and overexpressed in multiple types of human tumors, including breast cancer. However, the causal relationship between overexpression of Aurora-A and tumorigenesis has not been fully established due to contradictory data obtained from different experimental systems. To investigate this, we generated a mouse strain that carries an MMTV-Aurora-A transgene. We showed that all the MMTV-Aurora-A mice displayed enhanced branch morphogenesis in the mammary gland and about 40% developed mammary tumors at 20 months of age. The tumor incidence was significantly increased in a p53(+/-) mutation background with about 70% MMTV-Aurora-A;p53(+/-) animals developed tumors at 18 months of age. Of note, overexpression of Aurora-A led to genetic instability, characterized by centrosome amplification, chromosome tetraploidization and premature sister chromatid segregation, at stages prior to tumor formation. Most notably, the severe chromosomal abnormality did not cause cell death owing to the activation of AKT pathway, including elevated levels of phosphorylated AKT and mammalian target of rapamycin, and nuclear accumulation of cyclin D1, which enabled continuous proliferation of the tetraploid cells. These data establish Aurora-A as an oncogene that causes malignant transformation through inducing genetic instability and activating oncogenic pathways such as AKT and its downstream signaling.

Primary posterior continuous curvilinear capsulorhexis combined with diffractive multifocal intraocular lens implantation.

PurposeTo evaluate the effect of mild posterior capsule opacity (PCO) on visual acuity (VA) in eyes implanted with a diffractive multifocal intraocular lens (IOL) compared with a monofocal IOL, and the effect of posterior continuous curvilinear capsulorhexis (PCCC) combined with diffractive multifocal IOL implantation.MethodsFor the initial evaluation, we compared charge-coupled device (CCD) camera photographs taken through both a monofocal IOL-loaded model eye and a diffractive IOL-loaded model eye under the conditions of both with and without an opaque filter for the simulation of mild PCO. The clinical evaluation involved 20 patients who underwent bilateral implantation of the same diffractive multifocal IOL. In all 20 cases, PCCC was performed in 1 eye (PCCC group) and not performed in the fellow eye (NCCC group). Postoperative clinical results were then compared between the two groups.ResultsThe CCD photographs revealed that the diffractive IOL-loaded eye was more strongly affected by the simulated PCO than was the monofocal IOL-loaded eye. In the clinical setting, the PCCC group registered better results than NCCC group in distance and near VA, low-contrast VA, and contrast sensitivity testing.ConclusionsDiffractive multifocal IOLs tend to be more influenced by mild PCO than do monofocal IOLs, and PCCC prior to IOL implantation can contribute to the avoidance of this effect.

Implantation of refractive multifocal intraocular lens with a surface-embedded near section for cataract eyes complicated with a coexisting ocular pathology.

PURPOSE: To evaluate the postoperative outcomes of cataract eyes complicated with coexisting ocular pathologies that underwent implantation of a refractive multifocal intraocular lens (MIOL) with a surface-embedded near section. METHODS: LENTIS MPlus (Oculentis GmbH) refractive MIOLs were implanted in 15 eyes with ocular pathologies other than cataract (ie, six high-myopia eyes with an axial length longer than 28 mm, two fundus albipunctatus eyes, two branch retinal-vein occlusion eyes, four glaucoma eyes (one with high myopia), and two keratoconus eyes). Uncorrected or corrected distance and near visual acuity (VA) (UDVA, UNVA, CDVA, and CNVA), contrast sensitivity, and defocus curve were measured at 1 day and 6 months postoperatively, and each patient completed a 6-month postoperative questionnaire regarding vision quality and eyeglass use. RESULTS: Thirteen eyes (87%) registered 0 or better in CDVA and 12 eyes (73%) registered better than 0 in CNVA. Contrast sensitivity in the eyes of all patients was comparable to that of normal healthy subjects. No patient required eyeglasses for distance vision, but three patients (20%) required them for near vision. No patient reported poor or very poor vision quality. CONCLUSION: With careful case selection, sectorial refractive MIOL implantation is effective for treating cataract eyes complicated with ocular pathologies.

Purification and properties of a cytochrome b560-d complex, a terminal oxidase of the aerobic respiratory chain of Photobacterium phosphoreum.

A cytochrome b560-d complex, a terminal oxidase in the respiratory chain of Photobacterium phosphoreum grown under aerobic conditions, was purified to near homogeneity. The purified oxidase complex is composed of equimolar amounts of two polypeptides with molecular weights of 41,000 and 54,000, as determined by gel electrophoresis in the presence of sodium dodecyl sulfate. It contains 10.2 nmol of protoheme and 22.5 nmol of iron/mg of protein. The enzyme is a "cytochrome bd-type oxidase," showing absorption peaks at 560 and 625 nm in its reduced minus oxidized difference spectrum at 77K. This oxidase combined with CO, and its CO difference spectrum at room temperature in the Soret region showed a peak at 418 nm and a trough at 434 nm. In addition, a trough at 560 nm (cytochrome b), and a trough at 620 nm and a peak at 639 nm (cytochrome d) were observed in the CO-binding spectrum. This cytochrome b560-d complex catalyzed the oxidation of ubiquinol-1 and ascorbate in the presence of N,N,N',N'-tetramethyl-p-phenylenediamine dihydrochloride or phenazine methosulfate. The oxidase activity required phospholipids and was inhibited by the respiratory inhibitors, KCN and NaN3, and the divalent cation, ZnSO4. Formation of a membrane potential by the cytochrome b560-d complex reconstituted into liposomes was observed with the fluorescent dye, 3,3'-dipropylthiodicarbocyanine iodide, on the addition of ubiquinol-1, showing that the enzyme provided a coupling site for oxidative phosphorylation.

Optic disk pallor and retinal atrophy in Sotos syndrome (cerebral gigantism).

PURPOSE: To report a case of Sotos syndrome (cerebral gigantism) with megalophthalmos, optic disk pallor, and retinal atrophy. METHODS: Case report. RESULTS: A 22-year-old man was diagnosed with Sotos syndrome with optic atrophy. His corneal diameters were 13 mm horizontally, and his optic disks were pale. His retinal vessels were attenuate in diameter, and small white spots were found on the retina. The results of a Goldmann visual field test were normal. His visually evoked potential to flash stimuli showed extended latent times and normal amplitudes. Keratometry was 40.5 diopters (8.33 mm) in both eyes. The axial length was 25.9 mm in the right eye and 25.4 mm in the left eye. CONCLUSION: Sotos syndrome may be associated with optic disk pallor and retinal atrophy.

Problems of trace elements and vitamins during long-term total parenteral nutrition: a case report of idiopathic intestinal pseudo-obstruction.

An 8-year-old girl with chronic idiopathic intestinal pseudo-obstruction (CIIP), who is the first case of CIIP in Japan, has been receiving total parenteral nutrition (TPN) for more than 6 years. During this time, she experienced deficiencies of copper, zinc, vitamin A, vitamin B12, folic acid, and biotin, and an excess of vitamin A; she exhibited a series of signs and symptoms due to these deficiencies and vitamin A overdosage. Nevertheless, careful monitoring of serum levels of trace elements and vitamins and appropriate therapy have almost solved these problems. She has achieved normal physical and mental development and goes to school, while receiving home parenteral nutrition with an ambulatory infusion system.

Extraction equilibria of various metal picrates with 19-crown-6 between benzene and water. Effect of the extra methylene group on extraction ability and selectivity.

The overall extraction equilibrium constants (K(ex)) of picrates of Li(+), Na(+), K(+), Rb(+), Cs(+), Ag(+), Tl(+), and Sr(2+)with 19-crown-6 (19C6) were determined between benzene and water at 25 degrees C. The K(ex) values were analyzed into the constituent equilibrium constants, i.e. the extraction constant of picric acid, the distribution constant of the crown ether, the formation constant of the metal ion-crown ether complex in water, and the ion-pair extraction constant of the complex cation with the picrate anion. The effects of an extra methylene group of 19C6 on the extraction ability and selectivity are discussed in detail by comparing the constituent equilibrium constants of 19C6 with those of 18-crown-6 (18C6). The K(ex) value of 19C6 for each metal ion is lower than that of 18C6, which is mostly attributed to the higher lipophilicity of 19C6. The extraction ability of 19C6 for the univalent metal ions decreases in the order Tl(+)>K(+)>Rb(+)>Ag(+)>Cs(+)>Na(+)Li(+), which is the same as that observed for 18C6. The difference in logK(ex) between the univalent metals is generally smaller for 19C6 than for 18C6. The extraction selectivity of 19C6 is governed by the selectivity in the ion-pair extraction, whereas that of 18C6 depends on both the selectivities in the ion-pair extraction and in the complexation in water.

Superior mesenteric artery aneurysm secondary to infectious endocarditis.

A case of superior mesenteric artery aneurysm secondary to infectious endocarditis is presented. Although selective angiography was necessary to detect the shape and precise location of the aneurysm, non-invasive diagnostic techniques including ultrasonography and computed tomography were also useful in detecting the aneurysm and planning the management of this unusual condition. Mitral valve replacement and aneurysmorrhaphy with bypass grafting of the superior mesenteric artery were successfully performed.

The effect of age on cadmium retention in organs of hamsters.

Age difference of cadmium retention was investigated in hamsters after a short term cadmium exposure. Three types of organs were identified in relation to cadmium retention, i. e., the liver and testes retained an increasing amount of cadmium with increasing age, the kidney and heart showed a gradual decrease in the retention after a transient increase in young ages and the bone showed no retention. These changes seemed to be related to the de novo synthesis of metallothionein in the organ.

Analysis of swinepox virus antigens using monoclonal antibodies.

Seventeen monoclonal antibodies (MAbs) against swinepox virus (SPV) were produced and characterized. These MAbs were classified into eight groups (A through H) on the basis of the molecular weight of the polypeptides which they recognized and the staining patterns of antigens in SPV-infected cells by the indirect immunofluorescent (IF) technique. The MAbs belonging to groups A, B, C and G recognized late antigens in cytoplasmic inclusion bodies with molecular weights of 97 kD, 65 kD, 48 kD and 15 kD, respectively. The MAbs belonging to groups D and H respectively recognized 35 kD and 12 kD late antigens, which first appeared in cytoplasmic inclusion bodies and spread to the cytoplasms and surface membranes of the infected cells. The MAb of group F recognized an 18 kD late antigen with granular distribution in the cytoplasm. The MAbs of group E recognized a 32 kD early antigen. Although all the MAbs belonging to the six groups (A, D through H) were specific for SPV, some of those belonging to groups B and C showed cross-reactivity with members of the other genera of poxviridae. An MAb in group B, SP14, cross-reacted with orf and rabbit fibroma viruses. Two MAbs in group C, SP24 and SP32, cross-reacted with vaccinia, cowpox, ectromelia, and rabbit fibroma viruses. These findings indicate that at least two SPV antigens contain cross-reactive epitopes with different genera of poxviridae.

Asymptomatic pyuria in diabetic women.

The aim of the present study was to determine the prevalence of and the host factors for asymptomatic pyuria (ASP) in women with type 2 diabetes. The study included 179 type 2 diabetic women and consecutive 455 non-diabetic women attending as out-patients in 1996. Patients with symptoms of a urinary tract infection were excluded. ASP was defined as the presence of more than 10 leukocytes/high-power field in a random urine sample. Diabetic women more often had ASP than non-diabetic women (27.9 vs. 15.8%, P<0.001). The prevalence of ASP was significantly increased in patients with a duration of diabetes exceeding 15 years (0 approximately 4 years; 20.3%, 5 approximately 9 years; 24.3%, 10 approximately 14 years; 23.8%, and > or =15 years; 46.3%). No differences were evident in HbA(1C) between diabetic patients without ASP and those with ASP. Diabetic women with ASP more often had diabetic retinopathy, neuropathy, nephropathy, cerebrovascular disease, ischemic heart disease, and hyperlipidemia than those without ASP. However, no statistically significant differences were evident in the prevalence of hypertension, constipation, or dementia. As the degree of neuropathy increases, it is accompanied by an increasing prevalence of ASP (none, 21.4%; blunt tendon reflexes, 24.5%; symptomatic, 50.0%; and gangrene, 66.6%). The prevalence of ASP was significantly increased in the patients with proliferative diabetic retinopathy (none, 23.2%; background, 29.4%; pre-proliferative, 18.2%; and proliferative, 50.0%). As the degree of nephropathy increases, it is accompanied by an increasing prevalence of ASP (none, 20.0%; microalbuminuria, 31.9%; macroalbuminuria, 37.0%; and renal failure, 60.0%). Thus, the prevalence of ASP is increased in women with diabetes and increased with longer duration of diabetes but was not affected by glucose control. The incidence of ASP increases significantly as diabetic microangiopathy becomes severer.

[Screening for antagonistic agents to the lethal toxicity of neocarzinostatin. II. Effects of various drugs in inhibiting the toxicity of neocarzinostatin in vivo].

In clinical chemotherapy with neocarzinostatin (NCS) against cancers, side effects such as leukopenia, anorexia, vomiting and nausea were mainly observed when parenteral administration was used. To prevent these adverse side effects without changing the anticancer activity of the drug, we attempted to apply the two-route-infusion chemotherapy using NCS and antidotes for the NCS treatment devised by Baba. This report presents the results of our study on effects of some antidotes on the acute toxicity of NCS in mice and also on the antitumor activity of NCS against Sarcoma-180 in mice (ICR-JCL strain) when used with tiopronin. The results are summarized as follows. 1. LD50 values of NCS administered via intravenous route increased 2.3- to 3.2-fold when 150, 300, 500 or 1,000 mg/kg of tiopronin was administered subcutaneously together with NCS, 1.3- to 1.4-fold when 50 or 100 mg/kg of sodium thioglycolate was used. When antidotes were given prior to the administration of NCS, 1.8- to 5.4-fold increase in LD50 values of NCS resulted with 300, 500 or 1,000 mg/kg of tiopronin administered 1 hour prior to NCS, 2.3-fold increase resulted with 2,000 mg/kg reduced glutathione, 1.2-fold increase with 100 mg/kg of sodium thioglycolate and 1.9-fold increase with 1,000 mg/kg of L-cysteine monohydrochloride monohydrate. Furthermore, 4.8- to 13.1-fold increase in LD50 of NCS occurred when 150, 300, 500 or 1,000 mg/kg of tiopronin was administered 15 minutes prior to NCS. When these antidotes were administered 1 hour after the administration of NCS, however, no changes in the LD50 value occurred. 2. The LD50 value of NCS given intraperitoneally increased 1.6- to 5.8-fold when 150, 300, 500 or 1,000 mg/kg of tiopronin was administered intravenously at the same time as NCS, 1.4- to 1.6-fold when tiopronin was given 1 hour prior to NCS, intraperitoneally and 1.3- to 1.7-fold when it was given 1 hour after NCS. 3. It was recognized that the acute toxicity of NCS was the most effectively reduced by tiopronin, but only slightly by glutathione, sodium thioglycolate or L-cysteine monohydrochloride monohydrate. The action of tiopronin was the most effective when it was given subcutaneously 15 minutes prior to NCS administered intravenously. 4. The combination chemotherapy on Sarcoma-180 in mice using NCS intraperitoneally and tiopronin intravenously was markedly effective when these agents were given simultaneously.

[Screening for the antagonizing agents against lethal toxicity of neocarzinostatin. I. Inhibitory effects of various drugs on the toxicity of neocarzinostatin in vitro and in vivo].

Neocarzinostatin (NCS) used for the chemotherapy of leukemia and cancers such as stomach, pancreas and bladder, has been pointed out to have the side effects mainly causing leukopenia. In order to prevent these side effects of NCS by systemic administration, we have attempted to inject NCS directly into the tumor tissues and to inactivate NCS leaked from the tissues by the treatment of antidotes for NCS. The present report deals with the influence of some antidotes on the toxicity of NCS in vitro and in vivo. The results demonstrated that; Four SH-compounds, such as thiopronin, glutathione (reduced form), sodium thioglycolate and L-cysteine monohydrochloride monohydrate were effective to inactivate antibacterial activity of NCS against M. luteus ATCC 9341 in vitro. It was recognized that acute toxicity of NCS was reduced by pretreatment of these SH-compounds and its action was dose related. The LD50 values of NCS intravenous administration in mice increased 5.8- to 24-fold when 150, 300, 500 and 1,000 mg/kg of thiopronin were administered intravenously 2 minutes prior to NCS. And 2.3- to 4.2-fold by 500 and 1,000 mg/kg of glutathione (reduced form), 1.6- to 4.2-fold by 50, 100 and 200 mg/kg of sodium thioglycolate, 1.9- to 4.2-fold by 100, 200 and 400 mg/kg of L-cysteine monohydrochloride monohydrate respectively. On the other hand, pretreatment of NCS didn't affect the acute toxicity of thiopronin.

[A case report of the atypical tuberculosis associated with AIDS].

A 49-year-old Japanese male who had been imprisoned for five years then lived with other men complained of fever, constitutional symptoms and a 12 kg weight loss over four-month period. He was referred to us as his gastric washings were positive for acid-fast bacilli (AFB). Chest X-ray showed patchy, infiltrative small shadows primarily in the right upper lung field without hilar adenopathy. Before transfer to our hospital, tuberculosis chemotherapy composed of SM, INH, RFP and PZA was initiated. Over the next three weeks, fever dropped, and the above described abnormal shadows on the chest X-ray improved, leaving small cystic lesions. Although a sputum smear was negative for AFB, M. tuberculosis was isolated from cultured samples and sensitive to all standard anti-tuberculous drugs. AFB were also demonstrated on a touch imprint of biopsied cervical lymph nodes. Sputum samples turned negative one month later both on smear and culture. Moreover, high fever developed and another abnormal shadow indicative of Pneumocystis carinii (PCP) appeared in the left lung field one month after the admission. White plaque was noted in the oral cavity. Dark red nodules were observed on the upper extremities and chest wall, and diagnosed histologically as Kaposi's sarcoma. Serologic testing for HIV was positive both by PA and Western blot methods, thus AIDS was diagnosed according to the CDC surveillance case definition for AIDS with the diagnosis of tuberculosis. The patient died of wasting syndrome on the 90th hospital day. On autopsy, small thin-walled cavities were observed in the right upper lung, correlating with earlier X-ray and CT findings.(ABSTRACT TRUNCATED AT 250 WORDS)

[A case of anterior cerebral artery dissecting aneurysm].

The incidence of intracranial dissecting aneurysms is lower than that of berry aneurysms. Following the recent spread of the use of cerebral angiography, however, the number of patients identified as having this type of aneurysm has been increasing. In a majority of cases of intracranial dissecting aneurysms, the aneurysm afflicted the vertebral and basilar arteries. After these, the internal carotid artery and the middle cerebral artery are the next most frequently affected. It is very rare that this type of aneurysm develops in the anterior cerebral artery. According to our search of the literature, only 17 cases of dissecting aneurysm of the anterior cerebral artery have been reported to date (including the case to be presented here). The case we recently encountered was that of a 52-year-old male. On October 25, 1994, the man suddenly developed a headache and strong paresis of the left leg while performing clerical work. The plain head CT, taken next day, revealed low density in the area supplied by the right anterior cerebral artery. An angiogram taken 6 days after onset disclosed characteristic signs of dissecting aneurysm (i.e., double lumen, etc.) at the A2 segment of the right anterior cerebral artery, as well as the presence of non-ruptured berry aneurysms at the bifurcation of the right middle cerebral artery. The non-ruptured berry aneurysms were treated by neck clipping, while the dissecting aneurysms were treated conservatively. The patient was discharged on March 21, 1995, without needing any assistance to walk. We analyzed the 17 reported cases of dissecting aneurysms of the anterior cerebral artery. The cause of this aneurysm was often hypertension, and only 3 of the 17 cases were rated as being idiopathic cases. The site of this aneurysm was often the pericallosal artery (segments A2, A3, etc.). Of the 17 patients, 11 were middle-aged or elderly (over 40). The male-to-female ratio was 13: 4, indicating a predominance of males. The incidence did not differ significantly between the right and left hemispheres. The number of ischemic cases was more than double that of hemorrhagic cases. Most ischemic cases had a good prognosis, even when treated conservatively. All 3 patients with the hemorrhagic type, who were treated conservatively, died.

[Results and problems of thymectomy in myasthenia gravis over 65 years old].

From June 1975 to March 1999, 300 cases of myasthenia gravis (MG) have undergone thymectomy. Twenty-eight patients over 65 years old were examined, focusing on the relationship between clinical appearances and microscopic findings of the thymuses. Among these cases, six were classified as ocular type (one case with thymoma) and 22 generalized type (eight cases with thymoma). According to the thymoma registering stages defined by Masaoka and colleagues, those nine cases with thymoma associated with stages I (n = 7), II (n = 1) and III (n = 1), respectively. The case of stage III (74 year old female) died four years and eight months after surgery. The case of stage II died of old age two years after the surgery. Complete remission was achieved in two cases of stage I. The follicular hyperplasia were seen in eight cases, and all resulted in improvement. Nine cases with no particular findings of thymuses classified into four ocular type and five generalized type including one fulminating type. Post-operative course of all these cases were uneventful. Although one recurrent of the thymoma and one death of the tumor were observed, post-operative outcomes of these elderly patients were generally satisfactory. We concluded that there is an operative indication of thymectomy for MG of even elderly patients, if no particular findings were recognized in the thymus.

[Clinico-immunological evaluation of T cells bearing IgG Fc receptors in brain tumor patients].

T cells bearing IgG Fc receptors (Tr cells) were determined in 40 cases of brain tumor using the double rosette method, and compared with the changes of PHA reaction, immunoglobulin (IgG A M), performance status, and mass effect on CT in 20 pre-and post-operative and/or radio-clinico-immunotherapeutic patients. The proportion of control Tr cells was 8-19% in 20 healthy adults. Values of Tr cells over 20% were correlated with a poor grade of performance status, and large mass effects on CT. Post-therapeutic change in the value was well correlated with change in performance status, mass effects, and IgG. Our results suggest a correlation between the value of Tr cells and clinico-radiological findings. Immunological analysis of Tr cells serves as a parameter of tumor expansion or prognosis, and could be of significant importance clinically.

Effect of allergen sensitization on external root resorption.

In orthodontic tooth movement (OTM), we should be concerned about external root resorption (ERR) as an undesirable iatrogenic problem, but its mechanisms are not fully understood. Since our previous epidemiologic studies found that patients with allergic diseases showed higher rates of ERR during orthodontic treatment, we explored the possible effect of allergic sensitization on ERR. In ovalbumin (OVA)-sensitized Brown-Norway rats, the amounts of ERR and OTM were greater than those in animals subjected to orthodontic force alone. The expression levels of RANKL and pro-inflammatory cytokines were increased in the periodontal tissues of sensitized rats with OTM, compared with control rats. Furthermore, leukotriene B4 (LTB4), a potent lipid mediator of allergic inflammation, and enzymes of the 5-lipoxygenase pathway, the biosynthetic pathway of leukotrienes, were also up-regulated. We found that low doses of aspirin suppressed ERR in allergen-sensitized rats, as well as the expressions of RANKL, pro-inflammatory cytokines, and LTB4. The present findings indicate that allergen sensitization has adverse effects on ERR under OTM, and that aspirin is a potential therapeutic agent for combating ERR.

Effects of sex and age on serum 1,5-anhydroglucitol in nondiabetic subjects.

The aim of this study was to demonstrate the effects of sex and age on serum levels of 1,5-AG in nondiabetic subjects.A total of 1 134 nondiabetic subjects aged 16-96 years with HbA1c less than 6.8% were recruited and divided into 4 HbA1c groups (Q1: HbA1c≤5.3; Q2: 5.4-5.8; Q3: 5.9-6.3; and Q4: 6.4-6.8 [%]). 38 elderly subjects (65 years or older) in the Q3 and Q4 groups (13 men and 25 women) underwent a 75-g oral glucose tolerance test (OGTT).The Q4 group had significantly lower 1,5-AG levels than did the Q1 group among nonelderly males, nonelderly females, and elderly men. In elderly women, 1,5-AG levels did not differ among the 4 HbA1c groups. In both nonelderly and elderly subjects, the 1,5-AG level of the Q1 group was significantly higher in males than in females. Stepwise multivariate regression analysis showed that age was significantly associated with 1,5-AG level in both sexes. HbA1c was significantly associated with the 1,5-AG level in males, while there was no significant association between HbA1c and the 1,5-AG level in females. In the elderly OGTT group, although the glucose levels of both sexes during OGTT were identical, the mean urinary glucose levels and the percentages of subjects with glucosuria were significantly higher in elderly men than in elderly women.Serum 1,5-AG levels were significantly associated with age and sex. The sensitivity of the 1,5-AG level for identifying postprandial hyperglycemia in elderly women with near-normoglycemia is less reliable because they have a higher renal threshold for glucose.