Multiple drug combination of anti-diabetic agents as a predictor for poor clinical response to liraglutide.

AIM: Aim of the study was to retrospectively analyze the clinical parameters that contribute to the therapeutic outcome of GLP-1 analogues. METHODS: We enrolled 106 patients with type 2 diabetes mellitus (T2DM), treated with liraglutide (N.=69) or exenatide (N.=37) for longer than three months. The patients were divided into two groups: good responders and poor responders to GLP-1 analogues, based on pretreatment and post-treatment HbA1c levels. Good responders were those whose HbA1c level had decreased by 1% or more, or maintained at less than 7%. All other patients were categorized as poor responders. We used univariate and multivariate analyses to assess pretreatment parameters between the two groups. RESULTS: Approximately 35% of the patients were poor responders. Our analysis of the pretreatment clinical parameters revealed that number of anti-diabetic agents and use of sulfonylurea were significantly associated with poor response to liraglutide (P=0.02 and P=0.03, respectively) in a multivariate analysis. We were not able to find any candidate related to clinical response to exenatide. CONCLUSION: Our study showed that the therapeutic effects of GLP-1 analogues on T2DM patients were heterogeneous. T2DM patients who require multiple anti-diabetic agents, especially sulfonylurea, do not benefit from liraglutide treatment.

Association between anti-ZnT8 autoantibody specificities and SLC30A8 Arg325Trp variant in Japanese patients with type 1 diabetes.

AIMS/HYPOTHESIS: We analysed the association between humoral autoreactivity to zinc transporter-8 (ZnT8) and the SLC30A8 rs13266634 polymorphism (Arg325Trp), which is located at the most distal loop in the ZnT8 protein. METHODS: Autoantibodies to ZnT8 were determined by RIA in 270 patients with type 1 diabetes using ZnT8 carboxy-terminal constructs (amino acids 268-369) carrying 325Trp(CW) and 325Arg(CR) and a hybrid construct (CW-CR). Forty-four ZnT8 autoantibody-positive sera with genomic DNA were used to examine the association between reactivity to ZnT8 constructs and the rs13266634 genotype. RESULTS: Seventy-five patients reacted to the CW-CR hybrid construct, whereas 37 and 36 patients reacted to the CW and CR constructs, respectively. All sera positive for either CW or CR autoantibodies were positive for CW-CR autoantibodies. Among 19 patients with a 325Arg(CC) genotype, 5% had CW-specific autoantibodies, 42% had CR-specific autoantibodies and 32% had dual reactivity. Conversely, 73% of 15 patients with the 325Trp(TT) genotype had CW-specific autoantibodies, no patients had CR-specific autoantibodies and 13% had dual reactivity. Nine of the ten patients (90%) with the CT genotype reacted with either CR or CW constructs. The titre of CR autoantibodies in patients carrying the C allele was significantly higher than that in TT homozygotes (p < 0.0001). In contrast, the titre of CW autoantibodies in patients carrying a T allele was significantly higher than that in CC homozygotes (p < 0.005). No evidence of an association between rs13266634 and type 1 diabetes was observed. CONCLUSIONS/INTERPRETATION: These results indicate that variant residue at amino acid 325 is a key determinant of humoral autoreactivity to ZnT8 and that the SLC30A8 genotype is an important determinant of autoantibody specificity.

Cervical dystonia in dentatorubral-pallidoluysian atrophy.

Hereditary dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal-dominant neurodegenerative disease characterized by variable clinical phenotypes. Its characteristic clinical manifestations include ataxia, choreoathetotic movements, seizures, myoclonus and dementia, but cervical dystonia has been rarely reported. Here we report a family with DRPLA who presented with cervical dystonia. The proband was a 66-year-old woman. Cervical dystonia was the initial and the most prominent symptom, and mild cerebellar signs and choreic movements were also observed. DNA analysis revealed expanded trinucleotide repeats within the DRPLA gene. The daughter of the proband, a 29-year-old woman, also had cervical dystonia for 3 years. Cranial magnetic resonance imaging showed a mild atrophy of the brainstem and the cerebellum in both of these patients. DRPLA should be considered in the differential diagnosis of patients presenting with cervical dystonia.

Head tremor in dentatorubral-pallidoluysian atrophy.

Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal-dominant neurodegenerative disorder characterized by variable combination of clinical manifestations including ataxia, myoclonus, seizures, dementia, and choreic movements. Head tremor has been rarely reported. We report a 66-year-old-woman with genetically determined DRPLA who presented with head tremor. A "no-no" type head tremor was the initial and the most prominent symptom, and mild cerebellar signs and choreic movements were also observed later. Neither hand tremor nor dystonia was noted. The patient did not show dementia, myoclonus, or seizures. Surface electromyogram (EMG) revealed 3.5-4 Hz rhythmic EMG bursts in both sternocleidomastoid muscles. DNA analysis disclosed expanded trinucleotide repeats (n = 54) in the DRPLA gene. We suggest that isolated head tremor can be a clinical manifestation of DRPLA.

Thermoregulatory responses to low-intensity prolonged swimming in water at various temperatures and treadmill walking on land.

The purpose of the present study was to examine the effect of water temperature on the human body during low-intensity prolonged swimming. Six male college swimmers participated in this study. The experiments consisted of breast stroke swimming for 120 minutes in 23 degrees C, 28 degrees C and 33 degrees C water at a constant speed of 0.4 m.sec-1 in a swimming flume. The same subjects walked on a treadmill at a rate of approximately 50% of maximal oxygen uptake (VO2max) at the same relative intensity as the three swimming trials. Rectal temperature (Tre) in 33 degrees C water was unchanged during swimming for 120 minutes. Tre during treadmill walking increased significantly compared to the three different swimming trials. Tre, mean skin temperature (Tsk) and mean body temperature (Tb) in 23 degrees C and 28 degrees C water decreased significantly more than in both the 33 degrees C water and walking on land. VO2 during swimming in 23 degrees C water increased more than during swimming in the 28 degrees C and 33 degrees C trials; however, there were no significant differences in VO2 between the 23 degrees C swimming trial and treadmill walking. Heart rate (HR) during treadmill walking on land increased significantly compared with HR during the three swimming trials. Plasma adrenaline concentration at the end of the treadmill walking was higher than that at the end of each of the three swimming trials. Noradrenaline concentrations at the end of swimming in the 23 degrees C water and treadmill walking were higher than those during the other two swimming trials. Blood lactate concentration during swimming in 23 degrees C water was higher than that during the other two swimming trials and walking on land. These results suggest that the balance of heat loss and heat production is maintained in the warm water temperature. Therefore, a relatively warm water temperature may be desirable when prolonged swimming or other water exercise is performed at low intensity.

Sweet's syndrome associated with encephalitis.

The involvement of the central nervous system (CNS) in Sweet's syndrome (acute febrile neutrophilic dermatosis) is rare. We report a 47-year-old woman who presented with acute encephalitis and was subsequently diagnosed as having Sweet's syndrome. She developed altered consciousness following fever and erythematous skin plaques in the extremities. Cerebrospinal fluid (CSF) examination disclosed neutrophilic pleocytosis without decreased glucose level. Brain magnetic resonance imaging (MRI) showed abnormal signal intensity lesions in the basal ganglia and the hippocampus. Skin biopsy revealed a dense dermal infiltration of neutrophils, which is compatible with Sweet's syndrome. Treatment with acyclovir and antibiotics failed, but the subsequent corticosteroid therapy was effective. Awareness of neurological complication in Sweet's syndrome may avoid unnecessary empiric therapy for meningoencephalitis and will lead to a successful treatment with corticosteroids.

Physiological responses to water-walking in middle aged women.

The purpose of the present study was to examine the physiological responses to water-walking using the Flowmill, which has a treadmill at the base of a water-flume, in two groups of women. In the first group, the women were known to regularly swim and exercise in water (group A), while in the second, they did not routinely participate in water-exercise (group B). In both groups, twelve healthy female volunteers in their fifties participated in the study. All of the subjects walked in water using the Flowmill for the first time. Subjects completed four consecutive bouts of 4-minute duration at progressively increasing speeds (20, 30, 40, and 50 m.min-1), with 1-minute rests between each bout. In addition, water-velocity was adjusted to the walking speed of each bout. The water-depth of the Flowmill was the level of the xiphoid process. The water and room temperatures were 30.3 +/- 0.1 degrees C and 24.9 +/- 0.4 degrees C, respectively. In both groups, the relationship between walking speed and oxygen uptake (VO2) as well as that between walking speed and heart rate (HR) changed exponentially as the walking speed increased, and the relationship between HR and VO2 was linear. The relationship between HR and VO2 was similar in both groups, and there was no significant difference between the predicted maximal oxygen uptake (VO2max) of the two groups. VO2 and HR of group B during water-walking, however, were significantly higher than those of group A at all walking speeds. The results of this study clearly showed that experience in moving through the water strongly affects physiological responses to water-exercise, even when fitness levels are equivalent.

Endovascular photodynamic therapy using mono-L-aspartyl-chlorin e6 to inhibit Intimal hyperplasia in balloon-injured rabbit arteries.

BACKGROUND AND OBJECTIVE: Intimal hyperplasia (IH) leading to restenosis is a major complication of arterial revascularization. The purpose of this study was to investigate the effect of photodynamic therapy (PDT) using mono-L-aspartyl chlorin e6 (NPe6) as a photosensitizer and intraluminal radial irradiation for inhibition of IH experimentally. STUDY DESIGN/MATERIALS AND METHODS: Study of laser transmission through the blood indicated that exclusion of blood is a prerequisite for intraluminal PDT. For homogeneous radial laser irradiation to the vessel wall, we used a newly developed cylindrical diffusing balloon laser fiber. Injuries were induced by pulling a balloon catheter through the right iliac artery of rabbits. One and 6 hours after the NPe6 injection (5mg/kg i.v.), drug distribution was examined by fluorescence microscopy. Nineteen rabbits received NPe6 at the time of injuries and PDT was performed with 664-nm laser at 30 and 10 J/cm(2) (20, 30, 40 mW/cm(2)) 1 hour after the injuries. The arteries were harvested at 2 days. In a second group of rabbits, PDT was given at 30 mW/cm(2) (30 J/cm(2)). Two weeks after treatment, the arteries were removed and examined histologically. RESULTS: NPe6 was found to be distributed selectively in the injured media. Endovascular NPe6-PDT showed complete depletion of smooth muscle cells even with 10 J/cm(2) at 2 days. IH was significantly inhibited at 14 days after PDT. CONCLUSIONS: Endovascular PDT of injured artery using NPe6 can prevent IH in this model of arterial wall injury and may become clinically useful for the prophylaxis of IH.

[A quadriplegic patient with chronic inflammatory demyelinating polyneuropathy (CIDP) who responded well to corticosteroids and intravenous immunoglobulin therapy].

We report an elderly patient with chronic inflammatory demyelinating polyneuropathy (CIDP) presenting with complete quadriplegia who responded well to the treatment. A 74-year-old woman was transferred to our hospital from a hospital for the elderly patients. The patient had a history of progressive limb weakness over three years, and has been quadriplegic for the last six months. The patient was unable to move her extremities, but neither respiratory nor bulbar dysfunction was observed. Deep tendon reflexes were absent. Glove and stocking type sensory disturbance was noted. Nerve conduction studies showed slowed motor and sensory conduction velocities with diminished compound muscle action potentials (CMAP). Abnormal temporal dispersion and conduction blocks were also demonstrated. Cerebrospinal fluid examination revealed an elevated protein level of 78 mg/dl with normal cell counts. The patient was diagnosed as having CIDP. She was treated with methylprednisolone pulse therapy and oral prednisolone, followed by high dose intravenous immunoglobulin treatment. Significant recovery occurred during the first week, and she became able to walk four months later. Motor nerve conduction velocity (MCV) and CMAP were also improved. It is suggested that CIDP must be considered in patients with quadriplegia of unknown etiology: such patients may be seen in hospitals for elderly patients.

Cardiorespiratory response to low-intensity walking in water and on land in elderly women.

The purpose of the present study was to determine whether or not the exercise intensity of water-walking for elderly women could be accurately prescribed by heart rate data obtained during treadmill exercise on land. Six healthy female volunteers, with a mean age of 62.2 +/- 4.2 years, took part in this study. Walking on land was performed on a treadmill. Each subject completed three consecutive 4-minute walks at a progressively increasing velocity (40, 60 and 80 m.min-1), with a 1-minute rest after both the first and second walks. The room temperature and relative humidity were 24.5 +/- 0.2 degrees C and 54.8 +/- 4.0%, respectively. Walking in water was performed in a Flowmill, which is a treadmill positioned at the base of a water flume. Each subject completed three consecutive 4-minute walks at a progressively increasing belt and water-flow velocity (20, 30 and 40 m.min-1), with a 1-minute rest after both the first and second walks. The water depth was at the level of the xiphoid process of each subject. The water temperature was 30.7 +/- 0.1 degrees C. The exercise intensity at the highest workrate was equivalent to 44.2 +/- 10.3% of the heart rate reserve (HRR) during water-walking and 38.4 +/- 4.7% of the HRR during land-walking. There was a highly significant linear relationship between heart rate (HR) and oxygen uptake (VO2) during both water-walking and land-walking. The relationship between HR and VO2 in both exercise modes was similar. Thus, the relationship of HR to VO2 derived from a treadmill-graded walking test on land may be used to prescribe exercise intensity for water-walking in thermoneutral water.

Physiological responses and RPE during underwater treadmill walking in women of middle and advanced age.

The purpose of this study was to examine the physiological responses and RPE during water walking using the Flowmill, which has a treadmill at the base of a water flume, in order to obtain basic data for prescribing water walking for people of middle and advanced age. Twenty healthy female volunteers with an age of 59.1 +/- 5.2 years took part in this study. They belonged to the same swimming club and regularly swam and exercised in water. Walking in water took place in the Flowmill. Subjects completed four consecutive bouts of 4 min duration at progressively increasing speeds (20, 30, 40 and 50 m/min) with 1 min rest between each bout. In addition, water velocity was adjusted to the walking speed of each bout. Subjects were instructed to swing both arms in order to maintain their balance during walking in water. The water depth was to the level of the xiphoid process and the water temperature was 30.31 +/- 0.08 degrees C. Both heart rate (HR) and oxygen uptake (VO2) increased exponentially as walking speed increased. HR was 125 +/- 15 bpm, and VO2 was 18.10 +/- 2.72 ml/kg.min-1 during walking in water at 50 m/min, which was the highest speed. The exercise intensity at this speed was equivalent to 5.2 +/- 0.8 Mets. The relationship between HR and VO2 during walking in water showed a highly significant linear relationship in each subject. There was also a highly significant linear relationship in the mean HR and VO2 of all subjects. Blood lactate concentration (LA) measured at rest and immediately after each bout was 1.1 +/- 0.4 mmol/l at rest, 1.0 +/- 0.2 mmol/l at 20 m/min, 1.0 +/- 0.3 mmol/l at 30 m/min, 1.1 +/- 0.2 mmol/l at 40 m/min, and 2.4 +/- 0.7 mmol/l at 50 m/min. LA at 50 m/min was significantly higher than at rest and at the other speeds. The relationship between HR and RPE during walking in water showed a highly significant linear relationship. The relationship between walking speed and energy expenditure calculated from VO2 and the respiratory exchange ratio (R) showed a high significant exponential relationship. These results suggested that HR and RPE can be effective indices for exercise prescription during Flowmill walking as with land walking.

ME3277, a GPIIb/IIIa antagonist reduces cerebral infarction without enhancing intracranial hemorrhage in photothrombotic occlusion of rabbit middle cerebral artery.

GPIIb/IIIa antagonists are expected to have a beneficial effect on acute cerebral infarction, however, the occurrence of intracranial hemorrhage has not been as widely investigated. A rabbit focal thrombotic occlusion model of the middle cerebral artery was established by creating a photochemical reaction between green light and Rose Bengal. Hemorrhagic transformation was common in the area of cerebral infarction. Using this model, the effect of a GPIIb/IIIa antagonist, ME3277 (low dose, (L); 0.15 mg/kg + 0.125 mg/kg x h, middle dose, (M); 0.3 mg/kg + 0.25 mg/kg x h and high dose, (H); 0.6 mg/kg + 0.5 mg/kg x h), aspirin (20 mg/kg) and sodium ozagrel (thromboxane A2 synthase inhibitor, 1 mg/kg + 2 mg/ kg x h) were evaluated. Drugs were intravenously administrated 30 minutes after the photochemical reaction for 24 hours. Aspirin inhibited the ex vivo platelet aggregation induced by arachidonic acid and collagen but not by adenosine diphosphate (ADP), while sodium ozagrel only inhibited the arachidonic acid-induced aggregation. ME3277 dose-dependently inhibited the platelet aggregation induced by all the inducers (approximately 60% in L, 80% in M, and 90% in H). At 24 hours of middle cerebral artery (MCA) occlusion, infarct volume was significantly reduced by aspirin and each dose of ME3277. These agents improved neurologic deficits, with ME3277 being more potent than aspirin. Sodium ozagrel did not alter the infarct volume nor neurologic deficits. No drug was found to worsen hemorrhage volume despite increasing bleeding time (2-3 fold) in the skin. In this model, the occluded artery was spontaneously recanalized and re-thrombosed frequently. One mechanism by which antiplatelet agents reduced infarct volume was inhibition of rethrombosis of the MCA. These results suggest that treatment with a GPIIb/IIIa antagonist is a useful intervention for acute cerebral infarction prolonging dose bleeding time to 3 times the basal value.

[Effects of amrinone, an inhibitor of c-AMP-specific phosphodiesterases, on neointimal hyperplasia after balloon injury in rats].

Amrinone(5-amino(3,4'-bibyridin)6-(1H)-one), an inhibitor of c-AMP-specific phosphodiesterases, has been used clinically as an inodilator. We have investigated the effect of amrinone on neointimal hyperplasia in rat carotid artery after balloon injury. When amrinone was administered subcutaneously to rats at a dose of 10 mg/kg/day for 14 days, significant reduction of neointimal thickness was noted. Four days treatment with amrinone, however, failed to reduce the intimal thickness. To investigate the mode of action to reduce intimal thickness, we tried to study the effects of amrinone on platelet aggregation and the proliferation of aortic smooth muscle cells. Amrinone produced a dose-dependent inhibition of ADP-induced rat platelet aggregation in vitro as well as ex vivo in rats. The proliferation of human aortic smooth muscle cells in culture stimulated with FBS or PDGF was also inhibited by amrinone. These results indicate that amrinone may have potential to prevent vascular neointimal hyperplasia in clinical balloon injury through inhibition of vascular smooth muscle cell growth and platelet aggregation.

Human thermoregulatory responses during prolonged walking in water at 25, 30 and 35 degrees C.

Eight healthy and physically well-trained male students exercised on a treadmill for 60 min while being immersed in water to the middle of the chest in a laboratory flowmill. The water velocity was adjusted so that the intensity of exercise correspond to 50% maximal oxygen uptake of each subject, and experiments were performed once at each of three water temperatures: 25, 30, 35 degrees C, following a 30-min control period in air at 25 degrees C, and on a treadmill in air at an ambient temperature of 25 degrees C. Thermal states during rest and exercise were determined by measuring rectal and skin temperatures at various points, and mean skin temperatures were calculated. The intensity of exercise was monitored by measuring oxygen consumption, and heart rate was monitored as an indicator for cardiovascular function. At each water temperature, identical oxygen consumption levels were attained during exercise, indicating that no extra heat was produced by shivering at the lowest water temperature. The slight rise in rectal temperature during exercise was not influenced by the water temperature. The temperatures of skin exposed to air rose slightly during exercise at 25 degrees C and 30 degrees C water temperature and markedly at 35 degrees C. The loss of body mass increased with water temperature indicating that both skin blood flow and sweating during exercise increased with the rise in water temperature. The rise in body temperature provided the thermoregulatory drive for the loss of the heat generated during exercise. Heart rate increased most during exercise in water at 35 degrees C, most likely due to enhanced requirements for skin blood flow. Although such requirements were certainly smallest at 25 degrees C water temperature, heart rate at this temperature was slightly higher than at 30 degrees C suggesting reflex activation of sympathetic control by cold signals from the skin. There was a significantly greater increase in mean skin and rectal temperatures in subjects exercising on the treadmill in air, compared to those exercising in water at 25 degrees C.

Nonpeptide angiotensin II receptor antagonist recognizes inter-species differences in angiotensin AT1 receptors.

Oral administration of the angiotensin AT1 receptor antagonist 3-methyl-2,6-dimethyl-4-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-yl ]methoxy] pyridine (ME3221) inhibited the pressor response to angiotensin II at doses of 0.3-1.0 mg/kg in rats. A higher dose of ME3221 (3-10 mg/kg) was required to obtain the same inhibitory potency in dogs. The antagonistic potency of ME3221 for angiotensin II-induced contraction in the rabbit aorta (pA2 = 8.82) was about five times higher than that in the canine aorta (pA2 = 8.18). The inhibition constant of ME3221 for displacing [125I]angiotensin II binding to membrane fractions from the rabbit aorta (Ki = 3.84 nM) and rat liver (Ki = 2.55 nM) was significantly lower than that for the canine aorta (Ki = 84.5 nM), canine liver (Ki = 122 nM) and bovine adrenal cortex (Ki = 21.5 nM). In contrast, [Sar1, Ala8]angiotensin II had a similar inhibition constant (Ki = 0.85-4.67 nM) in the species investigated. Treatment with 5 mM dithiothreitol significantly (P < 0.01) reduced the angiotensin II-induced contractile response to 1.2% in the rabbit aorta, but it did not significantly reduce the response in the canine aorta (83.2%). Dithiothreitol reduced [125I]angiotensin II binding to membrane fractions from the rabbit aorta and the rat liver but partially inhibited binding in preparations that had a low affinity for ME3221. These data indicate a species difference in the angiotensin AT1 receptor: the canine and bovine angiotensin AT1 receptor has a relatively low affinity for ME3221 and is slightly resistant to dithiothreitol. The species difference in the angiotensin AT1 receptor reflects the in vivo efficacy of ME3221 in rats and dogs.

[Effects of amrinone on renal blood flow and cardiac function, in comparison with those of milrinone and olprinone, in anesthetized dog].

Amrinone, one of the phosphodiesterase III inhibitors, is clinically used for acute heart failure and possesses diuretic action, which is not observed in other phosphodiesterase III inhibitors. To clarify the mechanism of the diuretic action of amrinone, we investigated its effects on renal blood flow and some other hemodynamic parameters in comparison with the effects of milrinone and olprinone in anesthetized dogs. Amrinone increased both renal and femoral blood flow in a dose-dependent manner. On the other hand, milrinone and olprinone increased only femoral blood flow and had no effect on renal blood flow. Amrinone, milrinone and olprinone dose-dependently increased left ventricular max dp/dt, and the estimated slope of the dose-response curve for olprinone was significantly sharper than that of amrinone. Furthermore, these three drugs increased the cardiac index and decreased systemic vascular resistance (SVR) significantly. The action of amrinone on SVR was more potent than those of milrinone and olprinone. These results suggest that the diuretic action of amrinone is involved in augmentation of renal blood flow and may support useful effects on acute heart failure.