| 2021 | Characterization of symptoms and determinants of disease burden in dementia with Lewy bodies: DEvELOP design and baseline results. | Alzheimers Res Ther | The DEmEntia with LEwy bOdies Project (DEvELOP) aims to phenotype patients with dementia with Lewy bodies (DLB) and study the symptoms and biomarkers over time. Here, we describe the design and baseline results of DEvELOP. We investigated the associations between core and suggestive DLB symptoms and different aspects of disease burden, i.e., instrumental activities of daily living (IADL) functioning, quality of life (QoL), and caregiver burden.We included 100 DLB patients (69 ± 6 years, 10%F, MMSE 25 ± 3) in the prospective DEvELOP cohort. Patients underwent extensive assessment including MRI, EEG/MEG, FP-CIT SPECT, and CSF and blood collection, with annual follow-up. Core (hallucinations, parkinsonism, fluctuations, RBD) and suggestive (autonomous dysfunction, neuropsychiatric symptoms) symptoms were assessed using standardized questionnaires. We used multivariate regression analyses, adjusted for age, sex, and MMSE, to evaluate how symptoms related to the Functional Activities Questionnaire, QoL-AD questionnaire, and Zarit Caregiver Burden Interview.In our cohort, RBD was the most frequently reported core feature (75%), while visual hallucinations were least frequently reported (39%) and caused minimal distress. Suggestive clinical features were commonly present, of which orthostatic hypotension was most frequently reported (64%). Ninety-five percent of patients showed EEG/MEG abnormalities, 88% of FP-CIT SPECT scans were abnormal, and 53% had a CSF Alzheimer's disease profile. Presence of fluctuations, lower MMSE, parkinsonism, and apathy were associated with higher IADL dependency. Depression, constipation, and lower IADL were associated with lower QoL-AD. Apathy and higher IADL dependency predisposed for higher caregiver burden.Baseline data of our prospective DLB cohort show clinically relevant associations between symptomatology and disease burden. Cognitive and motor symptoms are related to IADL functioning, while negative neuropsychiatric symptoms and functional dependency are important determinants of QoL and caregiver burden. Follow-up is currently ongoing to address specific gaps in DLB research. |
| 2021 | Dopaminergic Correlates of Orthostatic Hypotension in de novo Parkinson's Disease. | J Parkinsons Dis | Orthostatic hypotension (OH) at an early stage of Parkinson's disease (PD) predicts poor prognosis, which may suggest degeneration of dopaminergic neurons affects sympathetic function, causing OH.We tested the hypothesis that striatal dopaminergic depletion is associated with OH in PD.Out of 99 patients with newly diagnosed untreated PD, 81 patients were enrolled according to our selection criteria. All patients underwent head-up tilt-table testing and striatal 123I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) dopamine transporter single photon emission computed tomography (DAT-SPECT). DaTQUANT software (GE Healthcare) was used as a semi-quantitative tool to analyze DAT-SPECT data. The association between hemodynamic changes and 123I-FP-CIT uptake was examined.123I-FP-CIT uptake in the putamen, especially the anterior part and left side, was related not only to motor severity but also to OH. Change in systolic blood pressure correlated negatively with 123I-FP-CIT uptake in bilateral anterior putamen (left: p < 0.01, right: p < 0.05) and left posterior putamen (p < 0.05). Patients with OH had more severe dopamine depletion in left anterior (p = 0.008) and posterior (p = 0.007) putamen at a similar motor severity than did patients without OH even though both groups have similar baseline characteristics. An analysis of asymmetry index showed patients with OH had symmetrically decreased dopamine levels in anterior putamen when compared to those without OH (p = 0.024).OH is closely related to striatal dopamine depletion in PD. This relation may help to account for the prognostic value of OH. |
| 2021 | The fate of patients with REM sleep behavior disorder and mild cognitive impairment. | Sleep Med | To investigate clinical and dopaminergic pre-synaptic brain imaging characteristics of subjects with idiopathic rapid eye movement (REM) behavior disorder (iRBD) and mild cognitive impairment (MCI), and to evaluate the combined predictive value of risk factors for short-term conversion to synucleinopathy.In sum, 44 polysomnography (PSG)-confirmed iRBD patients (68.5 ± 7.2 years; 38 males) underwent I-FP-CIT-SPECT, comprehensive neuropsychological evaluation, clinical examination and clinical follow-up every six months (30.6 ± 21.5 months). Step-wise logistic regression was applied to identify those features discriminating iRBD patients with (iRBD-MCI; n = 14) and without MCI (normal cognition [NC], iRBD-NC; n = 30). The risk of neurodegeneration was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional-hazards analysis, adjusting for age, gender and education. A generalized linear model (GLM) was applied to define the best combination of risk factors predicting conversion at follow-up.At baseline, patients with iRBD-MCI showed reduced striatal dopamine transporter (DAT) specific to non-displaceable binding ratio (SBR) and more constipation compared with iRBD-NC patients (p < 0.0001). During the follow-up, 10 patients (22.7%) develop an overt synucleinopathy. GLM analysis showed that patients with orthostatic hypotension, non-motor experiences of daily living, reduced putaminal DAT-SPECT SBR, and cognitive impairment in verbal memory/visuoconstruction abilities were at higher risk of phenoconversion (Hazard Ratio [HR] 26.05; Sensitivity 90%; Specificity 100%; Accuracy 97.73%; Positive Predictive Value 100%; Negative Predictive Value 97.14%).iRBD-MCI patients showed a more severe dopaminergic neuroimaging and clinical phenotype. Combining clinical and neuroimaging markers allowed to achieve excellent ability in identifying iRBD patients at high risk of developing a synucleinopathy within about three years from diagnosis. |
| 2020 | Relationship between the washout rate of I-123 MIBG scans and autonomic function in Parkinson's disease. | PLoS One | We have evaluated the clinical significance of the washout rate (WR) on I-123 MIBG scans through the analysis of the relationship between the I-123 MIBG scans and autonomic status in patients with Parkinson's disease (PD).Sixty patients with clinical PD who had decreased HMR were enrolled. An autonomic symptom was evaluated using a head-up tilt test and the Composite Autonomic Severity Score (CASS). An I-123 MIBG scan and F-18 FP-CIT positron emission tomography (PET) were performed. All of the patients were classified into three groups according to the WR. The differences in patient characteristics and the imaging parameters among the three groups were evaluated, and a correlation analysis was also performed.The frequency of orthostatic hypotension was significantly different among the three groups. The difference in systolic pressure (dSysPr) and the difference in diastolic pressure (dDiaPr) of group 3 was significantly larger than those of groups 1 and 2. From the correlation analysis, it can be seen that age, Hoehn and Yahr (H&Y) stage, dSysPr, and dDiaPr had a weak positive correlation with the WR. The total CASS score was significantly higher in group 3 compared with groups 1 and 2. The WR had a moderate positive correlation with the cardiosympathetic score and the total CASS score.The WR is related to autonomic dysfunction. An I-123 MIBG cardiac scan is considered to be a good method to evaluate not only the differential diagnosis of Parkinson's disease but also the degree of autonomic dysfunction. |
| 2020 | Pulmonary embolism with clot in transit: An analysis of risk factors and outcomes. | Thromb Res | Clot in transit (CIT) represents a rare and life-threatening manifestation of venous thromboembolism of which we have limited understanding. This study describes the risk factors, clinical characteristics, and outcomes associated with the development of CIT as well as death following CIT diagnosis.We analyzed patients enrolled in our institutional Pulmonary Embolism Response Team (PERT) registry and compared 57 patients who had a CIT to 608 pulmonary embolism (PE) patients who did not have a CIT. We performed univariate and multivariate logistic regression to identify factors associated with CIT (vs PE without CIT) among patients who had an echocardiogram, as well as factors associated with 7-day death after CIT diagnosis.CIT was present in (57) 8.6% of patients who had an echocardiogram. Multivariate analysis showed heart failure (OR 2.8, 95% CI 1.2-6.5, P = 0.01), a pre-existing central venous catheter (OR 2.5, 95% CI 1.1-5.7, P = 0.03), and hypotension (OR 2.1, 95% CI 1.1-3.7, P = 0.02) to be independently associated with CIT. All-cause mortality by 7 days was higher in CIT patients (12.5% vs 5.1%, P = 0.02). CIT patients who died were more likely to have presented with hemodynamic collapse (57.1% vs 14.0%, P = 0.02), mental status change (100% vs 22.0%, P < 0.001), and to be intubated (100% vs 36.0%, P = 0.001).The presence of heart failure, a central venous catheter, and hypotension should alert physicians to patients who may require an echocardiogram to diagnose CIT. The mortality of CIT is high, even relative to a population with severe PE. |
| 2019 | Distinct clinical features of predominant pre-synaptic and trans-synaptic nigrostriatal dysfunction in multiple system atrophy. | J Neurol Sci | The severity of parkinsonism and response to levodopa vary in patients with multiple system atrophy (MSA) because of the heterogeneity of nigrostriatal neuropathology.To investigate the difference in clinical features between MSA patients with predominantly pre-synaptic nigrostriatal dysfunction and those with trans-synaptic nigrostriatal dysfunction.We retrospectively analyzed clinical data of 61 patients with MSA who underwent both [F]FP-CIT-PET and [F]FDG-PET within 3 months of clinical evaluation, and who had ≤3 years of disease duration. Tracer uptake of the striatum on [F]FP-CIT-PET and glucose metabolism of the striatum on [F]FDG-PET were analyzed using eight striatal subregional volumes-of-interest templates. The patients were classified into two subgroups according to the predominant pre-synaptic tracer uptake loss of the posterior putamen on [F]FP-CIT-PET (MSA-SNpc, n = 21) and trans-synaptic dopaminergic dysfunction reflected by both [F]FP-CIT-PET and [F]FDG-PET (MSA-STR, n = 40).Parkinsonian features were significantly more severe in the MSA-STR group than in the MSA-SNpc group (P = .005) and cerebellar ataxia was significantly more severe in the MSA-SNpc group (P = .036). The cerebellar type of MSA was significantly more common in the MSA-SNpc group (P = .001). There was no difference in age at onset, disease duration at the time of study, or Mini-Mental Status Examination scores between the groups.Patients with MSA showed distinct clinical features depending on whether the pattern of nigrostriatal dysfunction was predominantly pre-synaptic or trans-synaptic. |
| 2016 | Functional neuroimaging and clinical features of drug naive patients with de novo Parkinson's disease and probable RBD. | Parkinsonism Relat Disord | The association between Parkinson Disease (PD) and REM sleep behavior disorder (RBD) has been related to a specific, malignant clinical phenotype. Definite RBD diagnosis requires video-polysomnography that is often unfeasible. A malignant clinical PD-RBD phenotype could be expected also in PD patients with probable RBD. Aim of this cross-sectional study was to evaluate whether a more severe neuropsychological and functional neuroimaging phenotype can be identified in PD patients with probable RBD.Thirty-eight de novo, drug naïve PD patients underwent a first-line clinical assessment and a second-line multimodal assessment, including neuropsychological evaluation, (123)I-FP-CIT-SPECT and (18)F-FDG-PET, which were compared between PD patients with (PD + RBD+) and without (PD + RBD-) probable RBD.On first-line assessment, PD + RBD + patients had significantly more constipation (p = 0.02) and showed worse olfaction (p = 0.01) compared with PD + RBD-while the two groups were similar as for age, presence of orthostatic hypotension, UPDRS-III and MMSE scores. On second-line assessment, PD + RBD + patients showed a worse neuropsychological test profile, more severe nigro-striatal dopaminergic impairment, mainly at caudate level in the less affected hemisphere (p = 0.004) and impaired brain glucose metabolism, with relative hypometabolism in posterior cortical regions and relative hypermetabolism mainly in anterior regions of the more affected hemisphere (p = 0.015).PD patients with probable RBD are likely to have a more severe neuropsychological and functional brain-imaging phenotype already at the time of diagnosis. |
| 2013 | Changing pattern of donor selection criteria in deceased donor liver transplant: a review of literature. | J Clin Exp Hepatol | During the last couple of decades, with standardization and progress in surgical techniques, immunosuppression and post liver transplantation patient care, the outcome of liver transplantation has been optimized. However, the principal limitation of transplantation remains access to an allograft. The number of patients who could derive benefit from liver transplantation markedly exceeds the number of available deceased donors. The large gap between the growing list of patients waiting for liver transplantation and the scarcity of donor organs has fueled efforts to maximize existing donor pool and identify new avenues. This article reviews the changing pattern of donor for liver transplantation using grafts from extended criteria donors (elderly donors, steatotic donors, donors with malignancies, donors with viral hepatitis), donation after cardiac death, use of partial grafts (split liver grafts) and other suboptimal donors (hypernatremia, infections, hypotension and inotropic support). |
| 2013 | Pramipexole in patients with early Parkinson's disease (PROUD): a randomised delayed-start trial. | Lancet Neurol | In models of dopaminergic neuronal loss, the dopamine agonist pramipexole has exhibited neuroprotective properties. The Pramipexole On Underlying Disease (PROUD) study was designed to identify whether early versus delayed pramipexole initiation has clinical and neuroimaging benefits in patients with Parkinson's disease (PD).Between May 24, 2006, and April 22, 2009, at 98 centres, we recruited patients with PD diagnosed within 2 years and aged 30-79 years. We randomly assigned eligible patients (ratio 1:1), by a centralised, computerised randomisation schedule, to receive double-blind either placebo or pramipexole (1·5 mg a day) and followed them up for 15 months. At 9 months, or as early as 6 months if considered necessary, placebo recipients were assigned to pramipexole. In a neuroimaging substudy, striatal dopamine-transporter binding was assessed by SPECT. All patients, investigators, and independent raters were masked to study treatment. The primary endpoint was the 15-month change from baseline in total score on the unified Parkinson's disease rating scale (UPDRS). This trial is registered with ClinicalTrials.gov, number NCT00321854.Of 535 patients, 261 were randomly assigned to receive pramipexole and 274 to receive placebo. At 15 months (n=411), adjusted mean change in UPDRS total score showed no significant difference between early and delayed pramipexole (-0·4 points, 95% CI -2·2 to 1·4, p=0·65). 62 patients in the early pramipexole group and 61 patients in the delayed pramipexole group were included in the neuroimaging substudy, for which the adjusted mean 15-month change in striatal (123)I-FP-CIT binding was -15·1% (SE 2·1) for early and -14·6% (2·0) for delayed pramipexole (difference -0·5 percentage points, 95% CI -5·4 to 4·4, p=0·84). Overall, 180 (81%) of patients given early pramipexole and 179 (84%) patients given delayed pramipexole reported adverse events (most frequently nausea), and 22 (10%) patients in the early pramipexole group and 17 (8%) in the delayed pramipexole group had serious events, two of which (hallucinations and orthostatic hypotension) were deemed related to study drug.By clinical and neuroimaging measures, pramipexole showed little evidence differentiating 15-month usage from usage delayed for 6-9 months. The results do not support the hypothesis that pramipexole has disease-modifying effects.Boehringer Ingelheim GmbH. |
| 2010 | Cardiac sympathetic denervation precedes nigrostriatal loss in the E46K mutation of the alpha-synuclein gene (SNCA). | Clin Auton Res | Here we report the case of an asymptomatic carrier of the E46K substitution in alpha-synuclein gene where we have documented that cardiac sympathetic denervation precedes nigrostriatal dopaminergic loss.She has been followed up regularly with standard neurological examination, UPDRS, neuropsychological formal testing, parkinson disease sleep scale-PDSS, Epworth scale, Hamilton-D scale, SCOPA Aut, orthostatic hypotension test, brief smell identification test, polysomnography, cerebral 123-I-FP-CIT SPECT, and, 123I-MIBG cardiac scintigraphy.She shows no presence of orthostatic hypotension. Olfactory test results demonstrate normal limits. In the PSG the nocturnal sleep shows mild abnormalities although the sleep efficiency and stage proportion remain under normal limits. The 123-I-FP-CIT SPECT is normal; in contrast, the 123I-MIBG cardiac scintigraphy shows a complete lack of isotopic uptake compatible with a severe sympathetic myocardial denervation.This example of monogenic autosomal dominant parkinsonism due to an alpha-synuclein mutation favours the hypothesis that peripheral autonomous nervous system involvement occurs earlier than the CNS degeneration. |
| 2008 | Per-operative changes and related factors during simultaneous pancreas-kidney transplantation: first experience at a Brazilian university hospital. | Ann Transplant | Several factors influence ischemic/reperfusion injury in simultaneous pancreas-kidney transplantation (SPKT). Per-operative period is full of intense changes in systemic parameters related to pancreatic reperfusion (PR). This work aims to study these changes evaluating fluid reposition, need of vasopressors and other related factors.Sixteen SPKT enduring patients mean age 32.4+/-4.76 had metabolic, electrolyte and hemodynamic data evaluated and compared at three times. Arterial blood gases, glucose, hematocrit; Na, K; MAP, HR and PAP were monitored after skin incision (T1), before and after PR (T2-T3). Fluid reposition, vasopressors, endocrine graft recovery and other related factors as donors, grafts, surgery team and receptors were also considered.Glucose, PaO2, PaCO2 and electrolytes didn't vary along the times. From T1v.T2 there was significant metabolic acidosis; T2v.T3 identified tachycardia and pulmonary hypertension; T1v.T3 confirmed metabolic acidosis, hemodilution and arterial hypotension. Use of crystalloids (8500+/-2909.75 mL), colloids (647.05+/-492.59 mL), human albumin (8.57+/-2.44 U), fresh frozen plasma (1.06+/-1.91 U), platelets (1.86+/-4.16 U) and red packed cells (5.75+/-3.25 U), needs of noradrenalin and dobutamin: 37,5% and 6,25%. Endocrine graft recovery median was 4.15 h. Related factors to donor's: 25.43+/-8.14 years, BMI 23.24+/-1.66, serum creatinine 1.1+/-0.47mg/dl, hemodynamically stable and trauma as cause of 50% donors brain death; graft storage: cold ischemia time (CIT) median of 12.5 h; surgery team: warm ischemia time (WIT) median of 60min; receptors: ASA4, type 1 diabetes mellitus and end stage renal disease medias of 18.87+/-5.64 and 2+/-1.3 years.Our experience confirmed the intense instability related in literature caused by PR in SPKT. |
| 2002 | Postoperative pain relief following intrathecal bupivacaine combined with intrathecal or oral clonidine. | Acta Anaesthesiol Scand | The purpose of the present study was to evaluate the postoperative analgesic and adverse effects of equal doses of oral or intrathecal clonidine in spinal anaesthesia with bupivacaine plain.Forty-five ASA I-III orthopaedic patients scheduled for osteosynthesis of a traumatic femur fracture were randomised in a double-blind fashion to one of 3 groups. Patients received 15 mg of plain bupivacaine intrathecally (group B) or an intrathecal mixture of bupivacaine 15 mg and clonidine 150 mg (group CIT). In group CPO oral clonidine 150 mg was administered 60 min before intrathecal injection of bupivacaine 15 mg.Oral and intrathecal clonidine prolonged the time until the first request for analgesics, 313 +/- 29 and 337 +/- 29 min, respectively, vs. 236 +/- 27 min in group B (P < 0.01). The total 24- h PCA morphine dose was significantly lower in group CIT(19.3 +/- 1.3 mg) compared to groups B and CPO(33.4 +/- 2.0 and 31.2 +/- 3.1 mg). MAP was decreased significantly during the first hour after intrathecal clonidine(14%) and during the first 5 h after oral clonidine(14-19%). HR decreased in CIT during the 5th and 6th postoperative hours(7-9%) and during the first 2 h(9%) in CPO (P < 0.01). The degree of sedation was more pronounced in group CPO during the first 3 h. Four patients had pruritus in group B.Addition of intrathecal clonidine prolonged analgesia and decreased morphine consumption postoperatively more than oral clonidine. Hypotension was more pronounced after oral than after intrathecal clonidine. Intrathecal clonidine is therefore recommended. |
| 2001 | The 1.6 A crystal structure of E. coli argininosuccinate synthetase suggests a conformational change during catalysis. | Structure | Argininosuccinate synthetase (AS) is the rate-limiting enzyme of both the urea and arginine-citrulline cycles. In mammals, deficiency of AS leads to citrullinemia, a debilitating and often fatal autosomal recessive urea cycle disorder, whereas its overexpression for sustained nitric oxide production via the arginine-citrulline cycle leads to the potentially fatal hypotension associated with septic and cytokine-induced circulatory shock.The crystal structure of E. coli AS (EAS) has been determined by the use of selenomethionine incorporation and MAD phasing. The structure has been refined at 1.6 A resolution in the absence of its substrates and at 2.0 A in the presence of aspartate and citrulline (EAS*CIT+ASP). Each monomer of this tetrameric protein has two structural domains: a nucleotide binding domain similar to that of the "N-type" ATP pyrophosphatase class of enzymes, and a novel catalytic/multimerization domain. The EAS*CIT+ASP structure clearly describes the binding of citrulline at the cleft between the two domains and of aspartate to a loop of the nucleotide binding domain, whereas homology modeling with the N-type ATP pyrophosphatases has provided the location of ATP binding.The first three-dimensional structures of AS are reported. The fold of the nucleotide binding domain confirms AS as the fourth structurally defined member of the N-type ATP pyrophosphatases. The structures identify catalytically important residues and suggest the requirement for a conformational change during the catalytic cycle. Sequence similarity between the bacterial and human enzymes has been used for providing insight into the structural and functional effects of observed clinical mutations. |
| 1997 | Brain perfusion scintigraphy with 99mTc-HMPAO or 99mTc-ECD and 123I-beta-CIT single-photon emission tomography in dementia of the Alzheimer-type and diffuse Lewy body disease. | Eur J Nucl Med | Dementia of the Alzheimer-type (DAT) is characterized by progressive cognitive decline, variably combined with frontal lobe release signs, parkinsonian symptoms and myoclonus. The features of diffuse Lewy body disease (DLBD), the second most common cause of degenerative dementia, include progressive cognitive deterioration, often associated with levodopa-responsive parkinsonism, fluctuations of cognitive and motor functions, psychotic symptoms (visual and auditory hallucinations, depression), hypersensitivity to neuroleptics and orthostatic hypotension. A recent report suggests that positron emission tomography studies in patients with degenerative dementia may be useful in the differential diagnosis of DAT and DLBD. However, the diagnostic role of single-photon emission tomography (SPET) studies remains to be established. The aim of this study was therefore to evaluate regional cerebral perfusion [with either technetium-99m hexamethylpropylene amine oxime (99mTc-HMPAO) or 99mTc-ethyl cysteinate dimer (99mTc-ECD) SPET] and striatal dopamine transporter density [using iodine-123 2 beta-carboxymethoxy-3 beta-[4-iodophenyl]tropane (123I-beta-CIT) SPET] in patients with DAT and DLBD. Six patients with probable DAT and seven patients with probable DLBD were studied. Blinded qualitative assessment by four independent raters of 99mTc-HMPAO or 99mTc-ECD SPET studies revealed bilateral temporal and/or parietal hypoperfusion in all DAT patients. There was additional frontal hypoperfusion in two patients and occipital hypoperfusion in one patient. In the DLBD group, regional cerebral perfusion had a different pattern. In addition to temporoparietal hypoperfusion there was occipital hypoperfusion resembling a horseshoe defect in six of seven patients. In the DAT group, the mean 3-h striatal/cerebellar ratio of 123I-beta-CIT binding was 2.5 +/- 0.4, with an increase to 5.5 +/- 1.1 18 h after tracer injection. In comparison, in the DLBD patients the mean 3-h striatal/cerebellar ratio of 123I-beta-CIT binding was significantly reduced to 1.7 +/- 0.3, with a modest increase to 2.1 +/- 0.4 18 h after tracer injection (P < 0.05, Scheffe test, ANOVA). These results suggest that 99mTc-HMPAO or 99mTc-ECD and 123I-beta-CIT SPET may contribute to the differential diagnosis between DAT and DLBD, showing different perfusion patterns and more severe impairment of dopamine transporter function in DLBD than in DAT. |
| 1995 | Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. | Diabetes Res Clin Pract | To examine whether intensive glycemic control could decrease the frequency or severity of diabetic microvascular complications, we performed a prospective study of Japanese patients with non-insulin-dependent diabetes mellitus (NIDDM) treated with multiple insulin injection treatment. A total of 110 patients with NIDDM was randomly assigned to multiple insulin injection treatment group (MIT group) or to conventional insulin injection treatment group (CIT group). Fifty-five NIDDM patients who showed no retinopathy and urinary albumin excretions < 30 mg/24 h at the baseline were evaluated in the primary-prevention cohort, and the other 55 NIDDM patients who showed simple retinopathy and urinary albumin excretions < 300 mg/24 h were evaluated in the secondary-intervention cohort. The appearance and the progression of retinopathy, nephropathy and neuropathy were evaluated every 6 months over a 6-year period. The worsening of complications in this study was defined as an increase of 2 or more steps in the 19 stages of the modified ETDRS interim scale for retinopathy and an increase of one or more steps in 3 stages (normoalbuminuria, microalbuminuria and albuminuria) for nephropathy. The cumulative percentages of the development and the progression in retinopathy after 6 years were 7.7% for the MIT group and 32.0% for the CIT group in the primary-prevention cohort (P = 0.039), and 19.2% for MIT group and 44.0% for CIT group in the secondary-intervention cohort (P = 0.049). The cumulative percentages of the development and the progression in nephropathy after 6 years were 7.7% for the MIT group and 28.0% for the CIT group in the primary-prevention cohort (P = 0.032), and 11.5% and 32.0%, respectively, for the MIT and CIT groups in the secondary-intervention cohort (P = 0.044). In neurological tests after 6 years, MIT group showed significant improvement in the nerve conduction velocities, while the CIT group showed significant deterioration in the median nerve conduction velocities and vibration threshold. Although both postural hypotension and the coefficient of variation of R-R interval tended to improve in the MIT group, they deteriorated in the CIT group. In conclusion, intensive glycemic control by multiple insulin injection therapy can delay the onset and the progression of diabetic retinopathy, nephropathy and neuropathy in Japanese patients with NIDDM. From this study, the glycemic threshold to prevent the onset and the progression of diabetic microangiopathy is indicated as follows; HbA1c < 6.5%, FBG < 110 mg/dl, and 2-h post-prandial blood glucose concentration < 180 mg/dl. |
| 1994 | Influence of donor criteria on postoperative graft function after orthotopic liver transplantation. | Transpl Int | Evaluation of graft quality remains a major problem in liver transplantation. The aim of this retrospective analysis was to examine the impact of donor criteria on postoperative graft function. Between June 1986 and September 1993 324 liver transplantations were performed at our institution. Criteria for exclusion from analysis were postoperative thrombosis of graft vessels, retransplantation, death prior to the 5th postoperative day or missing donor criteria. For the eligible 255 transplantations the impact of the following donor criteria were examined: age (range 1-62 years, median 28 years), size/body weigt index, duration of intensive care, cause of death, circulatory condition, need for vasopressive support and liver function tests (bilirubin, GOT, GPT, GGT, LDH, ALP, prothrombin time (PT), creatinine, sodium). The following intraoperative factors were also assessed: type of protective solution, cold ischaemic time (CIT), anhepatic period and blood transfusions. Graft function during the first 5 postoperative days was categorized into four groups: (1) good function (GOT max < 1000 U/l, spontaneous PT > 50%, bile production > 100 ml/day); (2) fair function (GOT 1000-2500 U/l, clotting factor support < 2 days, bile < 100 ml/day); (3) poor function (GOT > 2500 U/l, clotting factor support > 2 days, bile < 20 ml/day); (4) primary non-function (retransplantation required within 7 days). A univariate analysis revealed duration of intensive care (P = 0.001), circulatory condition (P = 0.005), anhepatic period (P = 0.0004), blood transfusions (P = 0.03) and CIT (P = 0.039) as significant risk factors for postoperative graft function. Entering these factors in a multivariate regression model we identified creatinine (P = 0.007), duration of intensive care (P = 0.009) and the size/body weight index (P = 0.03) as donor-related factors of high significance. Analysis of the intraoperative data revealed the anhepatic period as the factor of highest significance (P = 0.0004) together with CIT (P = 0.02) and intraoperative blood transfusions (P = 0.008). A doubling of the number of days of intensive care resulted in a threefold increased risk of postoperative graft failure. Prolonged intensive care is a variable representing multiple risk factors. Accepting donors with a longer history of hypotension or who show signs such as elevated creatinine should be carefully considered. In patients with expected surgical difficulties resulting in an extended anhepatic period and a higher blood loss, transplantation of organs retrieved from donors with a long duration of intensive care and a long CIT should be avoided. |
| 1988 | Toxicity of citreoviridin. | Res Commun Chem Pathol Pharmacol | The mycotoxin citreoviridin (CIT) isolated from Penicillium citreoviride was studied to elucidate the mechanism of its toxic actions. In CF#1 mice, near lethal doses of CIT decreased motor activities, body temperature and had cataleptic effects. Male mice appeared to be more susceptible to CIT and had lower subcutaneous (sc) LD50 values and longer CIT-induced hypothermia and hypokinesia. In CIT-treated mice the weights and histology of liver, kidneys and adrenals were normal one week after sc treatment, except for the increased adrenal weights in female mice. Single doses of CIT (sc), given on either day 4 or 5 of pregnancy (perinidation period), had no adverse effect on the rates of pregnancy, implantation of ova and embryonal resorptions in those mice examined on day 12 of pregnancy. CIT (40 mg/kg ip) produced a brief electro-encephalographic (EEG) activation, cardiac sinus arrhythmias and tachypnea in the rabbit. Intravenous (iv) lethal doses of CIT (greater than or equal to 5 mg/kg) caused an EEG activation followed by high voltage delta waves, increased the T wave in the electrocardiogram (ECG) and depressed the respiratory amplitude. The death caused by iv CIT started with the respiratory arrest, followed by isoelectric EEG and ECG was the last to stop. In urethane-anesthetized rabbits CIT decreased the blood pressure, and in succession it lowered, flattened and inverted the T wave of ECG suggesting heart ischemia. These observations indicated that the toxic effects of CIT resulted from respiratory and cardiovascular failures (apnea, delta EEG waves, sinus arrhythmia, hypotension) leading to central nervous system depression due to systemic hypoxia. |