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Clinical Progression (clinical + progression)
Selected AbstractsCurrent Experimental Perspectives on the Clinical Progression of Alcoholic Liver DiseaseALCOHOLISM, Issue 10 2009Katja Breitkopf Chronic alcohol abuse is an important cause of morbidity and mortality throughout the world. Liver damage due to chronic alcohol intoxication initially leads to accumulation of lipids within the liver and with ongoing exposure this condition of steatosis may first progress to an inflammatory stage which leads the way for fibrogenesis and finally cirrhosis of the liver. While the earlier stages of the disease are considered reversible, cirrhotic destruction of the liver architecture beyond certain limits causes irreversible damage of the organ and often represents the basis for cancer development. This review will summarize current knowledge about the molecular mechanisms underlying the different stages of alcoholic liver disease (ALD). Recent observations have led to the identification of new molecular mechanisms and mediators of ALD. For example, plasminogen activator inhibitor 1 was shown to play a central role for steatosis, the anti-inflammatory adipokine, adiponectin profoundly regulates liver macrophage function and excessive hepatic deposition of iron is caused by chronic ethanol intoxication and increases the risk of hepatocellular carcinoma development. [source] Changes in quality of life and sexual health are associated with low-dose peginterferon therapy and disease progression in patients with chronic hepatitis CALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 7 2010K. K. SNOW Aliment Pharmacol Ther,31, 719,734 Summary Background, Primary analysis of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) Trial showed long-term peginterferon therapy did not reduce complications in patients with chronic hepatitis C and advanced fibrosis or cirrhosis. Aim, To assess the effects of long-term peginterferon therapy and disease progression on health-related quality of life (HRQOL), symptoms and sexual health in HALT-C patients. Methods, A total of 517 HALT-C patients received peginterferon alfa-2a (90 ,g/week); 532 received no additional treatment for 3.5 years. Patients were followed up for outcomes of death, hepatocellular carcinoma and hepatic decompensation. Sexual health, SF-36 scores and symptoms were serially assessed by repeated-measures analyses of covariance. Results, Patients with cirrhosis (n = 427) reported lower general well-being and more fatigue (P < 0.001) than patients with fibrosis (n = 622). Physical scores declined significantly over time, independent of treatment, and patients with cirrhosis reported lower scores. Vitality scores were lower in those with cirrhosis, and treated patients experienced a greater decline over time than untreated patients; HRQOL rebounded after treatment ended. Patients with a clinical outcome had significantly greater declines in all SF-36 and symptom scores. Among men, Sexual Health scores were significantly worse in treated patients and in those with a clinical outcome. Conclusion, Clinical progression of chronic hepatitis C and maintenance peginterferon therapy led to worsening of symptoms, HRQOL and, in men, sexual health in a large patient cohort followed up over 4 years (NCT00006164). [source] Clinical progression in Parkinson disease and the neurobiology of axonsANNALS OF NEUROLOGY, Issue 6 2010Hsiao-Chun Cheng PhD Despite tremendous growth in recent years in our knowledge of the molecular basis of Parkinson disease (PD) and the molecular pathways of cell injury and death, we remain without therapies that forestall disease progression. Although there are many possible explanations for this lack of success, one is that experimental therapeutics to date have not adequately focused on an important component of the disease process, that of axon degeneration. It remains unknown what neuronal compartment, either the soma or the axon, is involved at disease onset, although some have proposed that it is the axons and their terminals that take the initial brunt of injury. Nevertheless, this concept has not been formally incorporated into many of the current theories of disease pathogenesis, and it has not achieved a wide consensus. More importantly, in view of growing evidence that the molecular mechanisms of axon degeneration are separate and distinct from the canonical pathways of programmed cell death that mediate soma destruction, the possibility of early involvement of axons in PD has not been adequately emphasized as a rationale to explore the neurobiology of axons for novel therapeutic targets. We propose that ongoing degeneration of axons, not cell bodies, is the primary determinant of clinically apparent progression of disease, and that future experimental therapeutics intended to forestall disease progression will benefit from a new focus on the distinct mechanisms of axon degeneration. ANN NEUROL 2010;67:715,725 [source] Double-outlet right ventricle in a 10-month-old Friesian fillyAUSTRALIAN VETERINARY JOURNAL, Issue 5 2009LC Fennell A 10-month-old Friesian filly had a presentation that was consistent with chronic left- and right-sided congestive heart failure. Clinical pathology findings included abnormal haematological and biochemical variables, abnormal blood gas values and increased serum concentration of cardiac troponin I. Echocardiography revealed cardiac chamber dilation and dextropositioning of the aorta. Radiography revealed a generally enlarged heart and pulmonary interstitial infiltration. These findings were supported at necropsy and the diagnosis of double-outlet right ventricle was confirmed. The pathological changes and physiological responses subsequent to double-outlet right ventricle have not previously been described in detail in horses. Clinical progression closely resembles that seen in humans, in whom antemortem diagnosis relies on echocardiography. In horses, complex cardiac disease presents a diagnostic challenge to the clinician. Appropriate therapy must be based on an accurate diagnosis. [source] Direct preputial hernia associated with a ventral abdominal wall defect in a two-year-old geldingEQUINE VETERINARY EDUCATION, Issue 7 2010T. O'Brien Summary The case of a 2-year-old gelding with acute onset of preputial swelling and prolapse is presented. After initiating conservative management using a penile repulsion device, the horse repeatedly displayed signs of mild abdominal discomfort with sudden deterioration to an episode of violent colic after 5 days of hospitalisation. Ultrasonographic examination of the preputial swelling at that time demonstrated the presence of small intestine between the internal and external laminae of the prepuce and led to the diagnosis of a direct preputial hernia. The contents of the hernia were readily reduced through a defect in the ventral abdominal wall after the anaesthetised horse was placed in dorsal recumbency. The historical information, clinical progression and surgical findings were supportive of an acquired ventral abdominal wall defect. To the authors' knowledge, this is the first reported case of a direct preputial hernia associated with an acquired ventral abdominal wall defect. [source] Coenzyme Q10 and vitamin E deficiency in Friedreich's ataxia: predictor of efficacy of vitamin E and coenzyme Q10 therapyEUROPEAN JOURNAL OF NEUROLOGY, Issue 12 2008J. M. Cooper Background and purpose:, A pilot study of high dose coenzyme Q10 (CoQ10)/vitamin E therapy in Friedreich's ataxia (FRDA) patients resulted in significant clinical improvements in most patients. This study investigated the potential for this treatment to modify clinical progression in FRDA in a randomized double blind trial. Methods:, Fifty FRDA patients were randomly divided into high or low dose CoQ10/ vitamin E groups. The change in International Co-operative Ataxia Ratings Scale (ICARS) was assessed over 2 years as the primary end-point. A post hoc analysis was made using cross-sectional data. Results:, At baseline serum CoQ10 and vitamin E levels were significantly decreased in the FRDA patients (P < 0.001). During the trial CoQ10 and vitamin E levels significantly increased in both groups (P < 0.01). The primary and secondary end-points were not significantly different between the therapy groups. When compared to cross-sectional data 49% of all patients demonstrated improved ICARS scores. This responder group had significantly lower baseline serum CoQ10 levels. Conclusions:, A high proportion of FRDA patients have a decreased serum CoQ10 level which was the best predictor of a positive clinical response to CoQ10/vitamin E therapy. Low and high dose CoQ10/vitamin E therapies were equally effective in improving ICARS scores. [source] Comparison of biomechanical gait parameters of young children with haemophilia and those of age-matched peersHAEMOPHILIA, Issue 2 2009D. STEPHENSEN Summary., Quality of life for children with haemophilia has improved since the introduction of prophylaxis. The frequency of joint haemorrhages has reduced, but the consequences of reduced bleeding on the biomechanical parameters of walking are not well understood. This study explored the differences in sagittal plane biomechanics of walking between a control group (Group 1) of normal age-matched children and children with haemophilia (Group 2) with a target ankle joint. A motion capture system and two force platforms were used to collect sagittal plane kinematic, kinetic and temporal,spatial data during walking of 14 age-matched normal children and 14 children with haemophilia aged 7,13 years. Group differences in maximum and minimum flexion/extension angles and moments of the hip, knee and ankle joints, ground reaction forces and temporal,spatial gait cycle parameters were analysed using one-way anova. Significant changes (P < 0.05) in kinematic and kinetic parameters but not temporal,spatial parameters were found in children with haemophilia; greater flexion angles and external moments of force at the knee, greater ankle plantarflexion external moments and lower hip flexion external moments. These results suggest that early biomechanical changes are present in young haemophilic children with a history of a target ankle joint and imply that lower limb joint function is more impaired than current clinical evaluations indicate. Protocols and quantitative data on the biomechanical gait pattern of children with haemophilia reported in this study provide a baseline to evaluate lower limb joint function and clinical progression. [source] Structured treatment interruption in patients with alveolar echinococcosisHEPATOLOGY, Issue 2 2004Stefan Reuter In human alveolar echinococcosis (AE), benzimidazoles are given throughout life because they are only parasitostatic. It has been a longstanding goal to limit treatment, and recent reports suggest that, in selected cases, benzimidazoles may be parasitocidal. Previously, we showed that positron ,emission tomography (PET) using [18F]fluoro-deoxyglucose discriminates active from inactive lesions in AE. We have now performed a 3-year prospective study in 23 patients and conducted a structured treatment interruption in those without signs of PET activity. Disease progression was further assessed by ultrasound, computerized tomography, laboratory parameters, and clinical examination. We found PET-negative lesions in 15 of 23 patients and benzimidazoles were discontinued in these patients. After 18 months, patients were reevaluated, and, of the 15 initially PET-negative patients, 8 showed either new activity on PET (n = 6) or signs of clinical progression (n = 2). Reinitiation of benzimidazoles halted parasite growth again. No further progression was detected after 36 months. PET had a sensitivity of 91% for the detection of active lesions. In conclusion, despite successful suppression of metabolic activity, in most cases benzimidazoles do not kill the parasite. PET is a reliable tool for assessing metabolic activity and for timely detection of relapses. Neither duration of treatment, kind of treatment, lesion size, calcifications, or regressive changes reliably indicate parasite death. We discourage the discontinuation of benzimidazoles in inoperable AE even after many years of treatment. However, patients with a poor compliance of benzimidazole intake or patients suffering from side effects to benzimidazoles might be assessed for PET negativity. If permanent discontinuation of benzimidazoles is attempted, the course of disease should be followed by PET. (HEPATOLOGY 2004;39:509,517.) [source] Alteration of subcellular and cellular expression patterns of cyclin B1 in renal cell carcinoma is significantly related to clinical progression and survival of patientsINTERNATIONAL JOURNAL OF CANCER, Issue 4 2006Stephen O. Ikuerowo Abstract Cyclin B1, identified as a regulator of late cell cycle, is involved in the development and progression of a variety of human malignancies. To clarify the role of cyclin B1 in the pathogenesis and prognosis of renal cell carcinoma (RCC), protein expression was compared with clinicopathological characteristics of patients as well as the long-term survival after surgical therapy. Expression analysis was carried out by immunohistochemistry and tissue microarray analysis. The microarrays that represented the primary tumors, their invasion front and normal peritumoral renal parenchyma contained 753 tissue cores obtained from 251 randomly selected nephrectomy specimens. Immunopositivity within the primary tumors was significantly associated with tumor stage (pT) (p < 0.01), lymph node status (pN) (p < 0.01) as well as the presence of systemic metastatic disease (p = 0.01). Subcellular expression in the cytoplasm of tumor cells significantly correlated with pT (p = 0.02) and pN (p = 0.03). When peritumoral tissue samples exhibited a relative amount of <10% of positively reacting epithelial cells, cyclin B positivity was identified to predict long-term survival of patients in univariate analysis (p < 0.01) whereas borderline significance was observed in multivariate statistical analysis (p = 0.05). Increased intratumoral cyclin B1 positivity and aberrant localization of signals within the cytoplasm of tumor cells is positively correlated with the tendency towards tumor progression, indicating the significant role of cyclin B1 in the development and pathogenesis of RCC. The result of uni- and multivariate statistical analysis suggests the prognostic value of cyclin B1 for RCC patients. © 2006 Wiley-Liss, Inc. [source] Quantification of red blood cell fragmentation by the automated hematology analyzer XE-2100 in patients with living donor liver transplantationINTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 5 2005S. BANNO Summary The fragmented red cell (FRC) is a useful index for diagnosing and determining the severity of thrombotic thrombocytopenic purpura (TTP), thrombotic microangiopathy (TMA) and other similar conditions, as it is found in peripheral blood in patients with these diseases. The FRC expression rate has conventionally been determined by manual methods using smear samples. However, it is difficult to attain accurate quantification by such methods as they are time consuming and prone to a great margin of error. With cases of living donor liver transplantation, the current study examined the possibility of using a multi-parameter automated hematology analyzer, the XE-2100 (Sysmex Corporation) for FRC quantification. While there was a notable correlation between the manual and automated measurements, the manual measurement resulted in higher values. This suggested remarkable variations in judgment by individuals. The FRC values had a significant correlation with the reticulocyte count, red blood cell distribution width (RDW), fibrin/fibrinogen degradation products (P-FDP) and lactate dehydrogenase (LDH) among the test parameters, and this finding was consistent with the clinical progression in patients. The automated method can offer precise measurements in a short time without inter-observer differences, meeting the requirement for standardization. The determination of FRC count (%) by the XE-2100 that enables early diagnoses and monitoring of TTP or TMA will be useful in the clinical field. [source] Per-operative frozen section examination of pelvic nodes is unnecessary for the majority of clinically localized prostate cancers in the prostate-specific antigen eraINTERNATIONAL JOURNAL OF UROLOGY, Issue 8 2000Yoshiyuki Kakehi Abstract Background: The incidence of unsuspected lymph node metastasis seems to be decreasing in the prostate-specific antigen (PSA) era. It remains controversial as to whether routine pelvic lymph node dissection and per-operative frozen section examination should be performed. In addition, it is still unclear whether an aggressive approach to local disease by surgery or irradiation confers survival benefits on stage D1 patients. Methods: Eighty-eight consecutive patients with clinically localized prostate cancer who underwent pelvic lymph node dissection prior to radical prostatectomy during the period between 1985 and 1998 were analyzed. The incidence of lymph node metastases after 1992 was compared with that before 1992. Sensitivity and specificity of frozen section examination was assessed. Progression-free survival and cause-specific survival curves of node-positive patients who underwent radical prostatectomy were estimated by the Kaplan,Meier method. Results: Six of 17 patients (35.3%) treated before 1992 and five of 71 patients (7.0%) treated after 1992 showed unsuspected lymph node metastasis (P = 0.0059). Eight of 11 node-positive patients underwent radical prostatectomy and two have so far demonstrated clinical progression and cancer death with a median follow-up period of 63 months. The 5 year progression-free rate and the cause-specific survival rate for these patients were 71.4 and 85.7%, respectively. Sensitivity of frozen section examination for micrometastasis and gross-metastasis cases, respectively, was 3/6 (50%) and 4/4 (100%), while specificity was 85/85 (100%). Conclusions: The incidence of unsuspected lymph node metastases has been significantly decreased in the PSA era. Frozen section examination of pelvic nodes can be omitted and radical prostatectomy is an acceptable choice of treatment in patients without macroscopically apparent nodal metastases. [source] Magnetic resonance imaging measures of brain atrophy in multiple sclerosisJOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 5 2006Valerie M. Anderson BSc Abstract Magnetic resonance imaging (MRI) has been widely used to diagnose and monitor multiple sclerosis (MS). Although MRI-visible lesions are a key feature of MS, they are thought to correlate poorly with clinical progression. Neurodegeneration is increasingly being recognized as an important factor in the pathogenesis of MS, and MRI measures of brain atrophy have been suggested as surrogate markers of neuroaxonal loss and disease progression. This pathology may be more relevant to the progression of disability than focal inflammation. A number of MRI-based methods have been developed for the measurement of global and regional brain atrophy. Natural-history studies of MS and clinically isolated syndromes suggestive of MS have observed atrophy in these subjects above that seen in controls, over periods ranging from three months to years. Brain atrophy has also been incorporated as an outcome measure in therapeutic trials of disease-modifying treatments. This paper considers neuroaxonal loss and the pathological basis of brain atrophy, methods developed to quantify brain atrophy, the findings of natural-history and therapeutic studies, the relationship of brain atrophy to disability and cognition, and the future research directions and clinical applications of brain atrophy measurements. J. Magn. Reson. Imaging 2006. © 2006 Wiley-Liss, Inc. [source] Clinical outcome after 4 years follow-up of HIV-seropositive subjects with incomplete virologic or immunologic response to HAARTJOURNAL OF MEDICAL VIROLOGY, Issue 2 2005Emanuele Nicastri Abstract The duration of the clinical, virologic, and immunologic response to HAART, is not well defined. In this observational multi-center study 2,143 patients were enrolled classified according to virologic suppression (<500 cp/ml) and immune recovery (>100 CD4+ cells/,l from baseline) at month 12 of HAART as complete responders, virologic only responders, immunologic only responders and non-responders. Kaplan Meyer curves, multivariate and politomous regression analysis were used. Complete responders patients were 781 (36.4%), immunologic only responders 441 (20.6%), virologic only responders 336 (15.7%), and non-responders 585 (27.3%). Using multivariate analysis, being antiretroviral-naïve increased the probability of having both a virologic only or a complete response and reduced the probability of an immunologic only response (P,<,0.001 for all tests). Older age was associated directly with a virologic only response and inversely associated with an immunologic only response (P,=,0.027 and P,=,0.035, respectively). Using politomous analysis, patients baseline HIV-RNA level more than 5 log cp/ml had a 1.9-fold higher probability of an immunologic response than of a complete response (P,=,0.001). After 4 years, the clinical progression rate was six times greater in non-responders, 1.9 times greater in virologic only responders, and 2.3 times greater in immunologic only responders than for responders. However, patients with virologic only response or with immunologic only response had a significantly reduced risk for clinical progression than non-responders (P,<,0.001). After 4 years of HAART, the risk of clinical progression in patients with immunologic only or virologic only response is low but still higher than in complete responder patients. J. Med. Virol. 76:153,160, 2005. © 2005 Wiley-Liss, Inc. [source] Variations in the serum concentrations of soluble Fas and soluble Fas ligand in Vietnamese patients infected with hepatitis B virusJOURNAL OF MEDICAL VIROLOGY, Issue 2 2004Le H. Song Abstract Earlier studies of both chronic hepatitis B and C virus (HBV and HCV) patients have shown a strong correlation between the soluble membrane Fas (sFas) and Fas protein expression on hepatocytes. The serum concentrations of sFas and soluble Fas ligand (sFasL) was examined in both healthy and HBV-infected Vietnamese patients to determine their relationship with the outcome of HBV infection. Patients with chronic rather than acute HBV had significantly higher amounts of sFas and sFasL, whilst the highest concentrations of both molecules were detected in those with malignant forms of HBV infection. sFas and sFasL concentrations tended to increase with a profile that paralleled the progression from asymptomatic to acute through chronic to malignant states, most markedly in the case of sFas. The sFas:sFasL ratio highlighted the relative predominance of sFas in those with acute and chronic HBV compared with asymptomatic or severe forms. In patients with hepatocellular carcinoma (HCC) a significant correlation was also observed between sFasL and alpha-feto protein (AFP) levels. The results indicate that sFas and to a lesser extent sFasL levels are to some degree associated with clinical progression in HBV infection. J. Med. Virol. 73:244,249, 2004. © 2004 Wiley-Liss, Inc. [source] Preliminary evaluation of hemostasis in neonatal foals using a viscoelastic coagulation and platelet function analyzerJOURNAL OF VETERINARY EMERGENCY AND CRITICAL CARE, Issue 1 2009Barbara L. Dallap Schaer VMD, DACVECC, DACVS Abstract Objectives , To compare coagulation and platelet function parameters measured using a viscoelastic analyzer in 3 groups: foals presenting to a neonatal intensive care unit with presumed sepsis, normal foals, and adult horses. Design , Preliminary prospective trial. Setting , Veterinary teaching hospital. Animals , Ten clinically healthy foals, 13 clinically healthy adult horses, and 17 foals sequentially admitted for suspected sepsis. Intervention , A single citrated (3.8%) blood sample collected at admission was submitted for coagulation evaluation using a viscoelastic analyzer. Measurements and Main Results , Time to initial clot formation (ACT), clot rate (CR), platelet function, and time to peak parameters were collected from the signature generated with the associated software. Peak clot strength was collected manually from signature tracings. Signalment, presenting complaint, blood culture results, clinical progression, and outcome were collected from the medical record. Kruskal-Wallis testing was used to determine differences in coagulation parameters between groups, as well as to identify any associations between coagulation variables, foal variables, and outcome. Normal foals were more likely to have increased platelet function (P=0.04) compared with normal adult horses. Prolonged ACT (P=0.004) and decreased CR (P=0.03) were associated with foals with positive blood culture. There was a trend toward prolonged ACT and increased likelihood of death (P=0.06). Conclusions , Healthy foals differ in values measured by the viscoelastic coagulation and platelet function analyzer compared with healthy adult horses. ACT and CR abnormalities were more likely to be observed in foals with positive blood cultures. The viscoelastic coagulation and platelet function analyzer may be useful in identifying early hemostasic and platelet dysfunction in critically ill foals, particularly those that are septic. [source] Meningioangiomatosis in Young Dogs: A Case Series and Literature ReviewJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 4 2004Todd M. Bishop Meningioangiomatosis (MA) is a proliferative disorder of the central nervous system (CNS) that has been reported rarely in humans and sporadically in dogs. Meningioangiomatosis may occur in the brainstem or cervical spinal cord of young dogs and can be identified tentatively by magnetic resonance imaging. The histopathologic hallmark of MA is a leptomeningeal plaque that extends along the CNS microvasculature and invades the adjacent neural parenchyma. This case series describes the neurologic signs, clinical progression, diagnostic imaging, and neuropathology of 4 dogs with MA. The 4 dogs with MA are compared and contrasted with 4 previously reported cases in dogs as well as with their human counterpart. [source] Clinical measures of progression in Parkinson's disease,MOVEMENT DISORDERS, Issue S2 2009Werner Poewe MD Abstract Despite all recent advances in symptomatic therapy Parkinson's disease (PD) continues to be a relentlessly progressive neurodegenerative disorder. Therefore therapies that will slow or hold disease progression are a major medical unmet need in PD. Clinical measures of disease progression that have been used in disease modification trials so far have focused on indices of progression of cardinal motor features like bradykinesia, rigidity, and tremor as captured by the UPDRS and the emerging need for effective dopaminergic symptomatic therapy. Progression of global disability in PD, however, is driven by additional factors beyond progressive nigrostriatal denervation leading to increasing severity of cardinal motor features. Progressive pathology in extranigral sites in the brain or peripheral autonomic nervous system contribute to poorly levodopa responsive motor symptoms like postural instability, freezing and falls or nonmotor symptoms. In addition treatment-induced motor complications also impact on PD disability. Although it is widely accepted that clinical progression of PD is multidimensional and in addition includes effects of aging, there is no consensus how to best implement more clinically meaningful endpoints for disease progression trials that would reflect these complex interactions impacting on the evolution of global disability in PD. There is an urgent need for biomarkers for disease progression that would faithfully reflect advancing neurodegeneration and resulted clinical disability in PD and that could be used in shorter term clinical trials testing putative disease modifying agents. © 2009 Movement Disorder Society [source] Severe acute respiratory syndrome in childrenPEDIATRIC PULMONOLOGY, Issue 4 2003Gary W.K. Wong MD Abstract Severe acute respiratory syndrome (SARS) is a newly described and highly contagious respiratory infection. Many adult patients will develop progressive hypoxia, and a large proportion will develop respiratory distress syndrome (RDS), possibly related to massive and uncontrolled activation of the immune system. The mortality has been reported to be quite high, especially in the elderly with comorbid conditions. The causative agent has been identified as a novel coronavirus, and children appear to acquire the infection by close-contact household exposure to an infected adult. However, the severity is much milder and the clinical progression much less aggressive in young children. The exact pathophysiology of SARS is still unclear, and the medical treatment of SARS remains controversial. The main treatment regime used in Hong Kong is a combination of ribavirin and steroid. To date, there have been no reported case fatalities in children with this disease. The success of reducing the burden of this infection in children will depend on proper isolation of infected adults early in the course of illness. Strict public health policy and quarantine measures are the key in controlling the infection in the community. Pediatr Pulmonol. 2003; 36:261,266. © 2003 Wiley-Liss, Inc. [source] Pelizaeus,Merzbacher,Like disease presentation of MCT8 mutated male subjects,ANNALS OF NEUROLOGY, Issue 1 2009Catherine Vaurs-Barrière PhD Pelizaeus,Merzbacher Disease is an X-linked hypomyelinatiing leukodystrophy. We report mutations in the thyroid hormone transporter gene MCT8 in 11% of 53 families affected by hypomyelinating leukodystrophies of unknown aetiology. The 12 MCT8 mutated patients express initially a Pelizaeus,Merzbacher-Like disease phenotype with a latter unusual improvement of magnetic resonance imaging white matter signal despite absence of clinical progression. This observation underlines the interest of determining both free T3 and free T4 serum concentrations to screen for MCT8 mutations in young patients (<3 y) with a severe Pelizaeus,Merzbacher-Like disease presentation or older severe mentally retarded male patients with "hypomyelinated" regions. Ann Neurol 2009;65:114,118 [source] Biomarkers for Parkison's disease: Tools to assess Parkinson's disease onset and progression,ANNALS OF NEUROLOGY, Issue S2 2008Kenneth Marek MD Reliable and well-validated biomarkers for PD to identify individuals "at risk" before motor symptoms, accurately diagnose individuals at the threshold of clinical PD, and monitor PD progression throughout its course would dramatically accelerate research into both PD cause and therapeutics. Biomarkers offer the potential to provide a window onto disease mechanism, potentially generating therapeutic targets for disease. In particular, biomarkers enable investigation of the premotor period of PD before typical symptoms are manifest, but while degeneration has already begun. Given the multiple genetic causes for PD already identified, the marked variability in the loss of dopaminergic markers measured by imaging at motor symptom onset and the clear heterogeneity of clinical symptoms in PD onset and clinical progression, it is likely many biomarkers with a focus ranging from clinical symptoms to PD pathobiology to molecular genetic mechanisms will be necessary to fully map PD risk and progression. Biomarkers are also critical in new drug development for PD, both in early validation studies to assess drug dosing and to determine drug penetrance into the brain, and in later efficacy studies to complement PD clinical outcomes. During the past two decades, much progress has been made in identifying and assessing PD biomarkers, but as yet, no fully validated biomarker for PD is currently available. Nonetheless, there is increasing evidence that molecular genetics, focused -omic (proteomic, metabolomic, and transcriptomic) assessment of blood and cerebrospinal fluid, and advanced in vivo brain imaging will provide critical clues to assist in the diagnosis and medical management of PD patients. Ann Neurol 2008;64 (suppl):S111,S121 [source] Alveolar adenoma of the lung,APMIS, Issue 12 2007Immunohistochemical, a review of the literature, flow cytometric characteristics of two new cases Alveolar adenoma is a rare and benign tumour of the lung that usually presents in asymptomatic patients as a coin lesion on chest radiography. Only 25 cases have been reported in the English medical literature. Alveolar adenoma has a characteristic multicystic histology and often resembles the normal lung parenchyma. Ultrastructural studies indicate that the epithelial cells lining the cysts are type-II pneumocytes. Immunohistochemical analysis may aid in the characterization of alveolar adenoma and discriminate this condition from other types of benign lesions of the lung. An indolent clinical progression and absence of recurrence and metastasis after complete resection are the most important characteristics indicative of the benign nature of alveolar adenoma. Few studies have been conducted at the molecular level, such as by flow cytometry, with the objective of characterizing the biological nature of alveolar adenoma. Differential diagnoses include sclerosing hemangioma, papillary adenoma, lymphangioma, atypical adenomatous hyperplasia and bronchioloalveolar carcinoma. In this article we describe the immunohistochemical and flow cytometric features of this neoplasm in two male patients. Both the tumours showed a diploid DNA pattern with a low proliferation index. p53 test was found to be negative, and post-operative follow-up examinations at 22 and 32 months proved uneventful. [source] Treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia in relation to the patient's risk profile for progressionBJU INTERNATIONAL, Issue 2005John Trachtenberg SUMMARY Lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) is a slowly progressing disease, with some patients progressing more rapidly than others. In 80% of patients who progress this is caused by the worsening of symptoms. The physician can predict the risk of progression from the patient's clinical profile; increased symptom severity, a poor maximum urinary flow rate (Qmax), and a high postvoid residual urine volume (PVR), are major risk factors for overall clinical progression of LUTS/BPH. A large baseline prostate volume and a high serum prostate-specific antigen (PSA) level are the predominant risk factors for developing acute urinary retention. After predicting risk, the most appropriate treatment should be established by balancing the benefits of treatment against the possible risks and bother resulting from adverse events. From the Medical Therapy Of Prostatic Symptoms study it can be concluded that monotherapy with an ,1 -adrenoceptor (AR) antagonist is an appropriate treatment for many patients with LUTS/BPH. However, for those at high risk of progression (those with a large prostate volume and high PSA level), it appears more appropriate to add a 5,-reductase inhibitor to the ,1 -AR antagonist to obtain maximum relief of symptoms, and ideally to halt the progression of the disease. This was confirmed by the RAND Appropriateness Method study, in which 12 urologists determined the most appropriate treatment for patients with LUTS/BPH based on their clinical profile, combination of clinical variables and/or risk factors. This study also indicates that patients at very high risk of progression, with severe obstruction (poor Qmax and high PVR), are potential candidates for immediate surgery. [source] Doxazosin for treating lower urinary tract symptoms compatible with benign prostatic obstruction: a systematic review of efficacy and adverse effectsBJU INTERNATIONAL, Issue 9 2004Roderick MacDonald The first paper in this section is a systematic review of the efficacy and adverse effects of doxazosin for treating LUTS compatible with benign prostatic obstruction. The criteria for inclusion were met by 13 studies involving 6033 men. The authors found evidence that doxazosin was effective and well tolerated in patients with LUTS. Combined therapy was superior to doxazosin alone in reducing the risk of clinical progression and other long-term complications of this condition. Authors from the UK reviewed the long-term results they achieved with an endourethral stent for treating BPH; quite a large proportion of patients had either died from unrelated causes or had had the stent removed. They stressed the necessity for careful case selection, but showed that it was a safe treatment for BPH in poor-risk patients. OBJECTIVE To evaluate the efficacy and adverse effects of doxazosin for treating lower urinary tract symptoms (LUTS) compatible with benign prostatic obstruction (BPO). METHODS Randomized controlled trials were included in the meta-analysis if: the study duration was ,,1 month; the study involved men with symptomatic BPO; and doxazosin was compared with placebo or active controls. Study and patient characteristics and outcome data were extracted in duplicate onto standardized forms using a prospectively developed protocol. RESULTS Thirteen studies involving 6033 men with (mean age 64 years) met the inclusion criteria; 10 were placebo-controlled, including two with combined doxazosin/finasteride therapy and finasteride monotherapy arms. Three trials were a comparison with other ,-blockers. The study duration was 1,54 months. The mean baseline symptom scores and peak urinary flow (PUF) rates were indicative of moderate BPO. Doxazosin gave significant improvements in LUTS, assessed by symptom scores, vs placebo and finasteride in the short- to long-term. Two long-term studies (1 and 4 years) reported mean changes from baseline for the International Prostate Symptom Score of ,,8.3 and ,,6.6 points (,49% and ,,39%) for doxazosin and ,,5.7 and ,,4.9 points (,33% and ,,29%) for placebo, respectively. Doxazosin significantly increased PUF rates vs placebo. In pooled results from three studies, the weighted mean difference in the mean change from baseline vs placebo was 1.6 mL/s (95% confidence interval 1.2,2.1). Efficacy was comparable with other ,1,blockers. In the long-term (>4 years) doxazosin was no better then finasteride in improving PUF. Combined doxazosin and finasteride significantly reduced the risk of overall clinical progression of BPO vs each drug separately in men followed for >4 years. Absolute risk reductions vs placebo were 11.3%, 6.9% and 6.4% for combined therapy, doxazosin and finasteride, respectively (P < 0.001). Improvements in symptom scores and PUF were also significantly greater with combined than monotherapy, and the former reduced the need for invasive treatment for BPO and the risk of long-term urinary retention, although the absolute reductions in risk vs placebo were small (<4%). Dizziness and fatigue were significantly more common with doxazosin than placebo (11% vs 7%, and 6% vs 3%, respectively). Adverse events reported for combined therapy were similar to those with each monotherapy. CONCLUSION The evidence indicates that doxazosin is effective and generally well tolerated for improving LUTS and PUF in men with symptomatic BPO. Combined therapy was better than doxazosin alone in reducing the risk of clinical progression of BPO and other long-term complications related to BPO. [source] IgV gene intraclonal diversification and clonal evolution in B-cell chronic lymphocytic leukaemiaBRITISH JOURNAL OF HAEMATOLOGY, Issue 1 2006Davide Bagnara Summary Intraclonal diversification of immunoglobulin (Ig) variable (V) genes was evaluated in leukaemic cells from a B-cell chronic lymphocytic leukaemia (B-CLL) case over a 2-year period at four time points. Intraclonal heterogeneity was analysed by sequencing 305 molecular clones derived from polymerase chain reaction amplification of B-CLL cell IgV heavy (H) and light (C) chain gene rearrangements. Sequences were compared with evaluating intraclonal variation and the nature of somatic mutations. Although IgV intraclonal variation was detected at all time points, its level decreased with time and a parallel emergence of two more represented VHDJH clones was observed. They differed by nine nucleotide substitutions one of which only caused a conservative replacement aminoacid change. In addition, one VLJL rearrangement became more represented over time. Analyses of somatic mutations suggest antigen selection and impairment of negative selection of neoplastic cells. In addition, a genealogical tree representing a model of clonal evolution of the neoplastic cells was created. It is of note that, during the period of study, the patient showed clinical progression of disease. We conclude that antigen stimulation and somatic hypermutation may participate in disease progression through the selection and expansion of neoplastic subclone(s). [source] The use of human immunodeficiency virus resistance tests in clinical practiceCLINICAL MICROBIOLOGY AND INFECTION, Issue 10 2010F. Ceccherini-Silberstein Clin Microbiol Infect 2010; 16: 1511,1517 Abstract Important progress has been made in recent years in the development and clinical use of drugs for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Nevertheless, when antiretroviral therapy fails to be fully suppressive, new viral variants emerge, thus allowing HIV-1 to escape from drug pressure by accumulating mutations. Between 50% and 70% of treated patients with virological rebound harbour some form of drug-resistant virus; transmitted drug resistance in drug-naïve populations has reached 5,20% in areas of the world with access to treatment. The emergence of drug-resistant viruses remains the limiting factor in HIV-1 management, being a major cause of treatment failure, and being associated with clinical progression and death. All international guidelines focus on the importance of tailoring antiretroviral therapy to the individual patient, on the basis onf HIV-1 genetic data, integrated with clinical, laboratory and therapeutic information. The aim of this review is to provide useful information to clinicians and virologists about how and when to use genotypic resistance testing in clinical practice, especially in the management of the first stages of HIV-1 patient care and treatment decisions. [source] Non-progressive congenital ataxia with cerebellar hypoplasia in three familiesACTA PAEDIATRICA, Issue 2 2005Z Yapici Abstract Aim: Non-progressive ataxias with cerebellar hypoplasia are a rarely seen heterogeneous group of hereditary cerebellar ataxias. Method: Three sib pairs from three different families with this entity have been reviewed, and differential diagnosis has been discussed. Results: In two of the families, the parents were consanguineous. Walking was delayed in all the children. Truncal and extremity ataxia were then noticed. Ataxia was severe in one child, moderate in two children, and mild in the remaining three. Neurological examination revealed horizontal, horizonto-rotatory and/or vertical nystagmus, variable degrees of mental retardation, and pyramidal signs besides truncal and extremity ataxia. In all the cases, cerebellar hemisphere and vermis hypoplasia were detected in MRI. During the follow-up period, a gradual clinical improvement was achieved in all the children. Conclusion: Inheritance should be considered as autosomal recessive in some of the non-progressive ataxic syndromes. Congenital non-progressive ataxias are still being investigated due to the rarity of large pedigrees for genetic studies. If further information on the aetiopathogenesis and clinical progression of childhood ataxias associated with cerebellar hypoplasia is to be acquired, a combined evaluation of metabolic screening, long-term follow-up and radiological analyses is essential. [source] | ||||||||||||||||||||||||||||