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PubMed1996

Relation of stressors and depressive symptoms to clinical progression of viral illness.

OBJECTIVE: The aim of this research was to determine whether and in whom stressors and depressive symptoms facilitate clinical recurrence of herpes simplex virus (HSV) and progression of HIV. METHOD: Meta-analytic techniques were used to review the relations of stressors and depressive symptoms to clinical recurrence of HSV in 16 published studies and to indicators of HIV progression in 19 published studies. The authors calculated average effect sizes, performed fixed effect and random effect inferential analyses, tested for heterogeneous findings, and identified potential moderating variables. RESULTS: Depressive symptoms were associated with a slightly increased risk of HSV recurrence and increased reports of HIV-related symptoms, whereas stressors were not. However, depressive symptoms were not associated with objective indicators of accelerated HIV progression. Stressor studies, especially those that ascertained population-specific life events, found numerical and functional decrements in circulating natural killer cell populations. The candidate moderators identified include, for HSV recurrence, age, sex, and medication status, and for HIV-related symptoms, age, race, disease stage, and co-infection with HSV. CONCLUSIONS: Depressive symptoms, but not stressors, increase the risk of HSV recurrence generally. Depressive symptoms do not appear to accelerate HIV progression ubiquitously, although they are associated with increased reporting of HIV-related symptoms. Future studies that ascertain population-specific stressors should determine whether reductions in cytotoxic lymphocytes influence HIV disease progression. Moreover, researcher should investigate the role of the identified moderators and recognize psychoimmune moderators in existing and novel study groups. These analyses could confirm that certain individuals are especially susceptible to the effects on disease progression of stressors, depressive symptoms, or both.

Adult↗
PubMedDate not supplied

Information and awareness of diagnosis and progression of cancer in adult and elderly cancer patients.

AIMS AND BACKGROUND: The present study examines the effects of physicians' attitudes towards providing information about diagnosis and progression of disease to cancer patients. The aims of the study were to: a) establish how many patients (subdivided into an adult and an elderly group) were informed and how many were aware of the diagnosis and progression of disease; b) identify possible significant differences between the two groups as regards information and awareness of disease; c) determine possible significant differences between information about diagnosis and disease progression and between awareness of diagnosis and progression within each group, and d) identify the patients' real needs. METHODS AND STUDY DESIGN: A total of 311 adults and 92 elderly cancer patients were enrolled in the study. A semi-structured clinical interview was employed to assess the "information" and "awareness" variables and the patients' needs. Statistical analyses were made with the chi squared test. RESULTS: Significant differences were observed between the two groups as regards information and awareness of diagnosis. Within each group, we found significant differences between information about diagnosis and progression and between awareness of diagnosis and progression. The principle needs expressed in both groups were to have clear information and emotional containment. CONCLUSIONS: The results of the study showed that physicians informed a greater number of adult than elderly patients and more often during the early rather than in the more advanced stages of the disease.

Adult↗
PubMed2026

Multiomic study of cutaneous T-cell lymphoma reveals single-cell clonal evolution in progression and therapy resistance.

Cutaneous T-cell lymphoma (CTCL) remains a challenging disease due to its significant heterogeneity, therapy resistance, and relentless progression. Multiomics technologies offer the potential to provide uniquely precise views of disease progression and response to therapy. Here, we present a comprehensive multiomics view of CTCL clonal evolution, incorporating exome, whole-genome, epigenome, bulk, single-cell T-cell receptor, and single-cell RNA sequencing of 99 clinically annotated serial skin, peripheral blood, and lymph node samples from 34 patients with CTCL. We leveraged this extensive data set to define the molecular underpinnings of CTCL progression in individual patients at single-cell resolution with the goal of identifying clinically useful biomarkers and therapeutic targets. Our studies identified recurrent progression-associated clonal genomic alterations; we highlight mutation of CCR4, phosphoinositide 3-kinase inhibitor signaling, and programmed cell death protein 1 (PD-1) checkpoint pathways as evasion tactics deployed by malignant T cells. We identified a gain-of-function mutation in STAT3 (D661Y) and demonstrated, using cleavage under targets and release using nuclease (CUT&RUN) and RNA sequencing, that it enhances binding to and transcription of genes in Rho GTPase pathways. With our previous work implicating this pathway in histone deacetylase inhibitor-resistant CTCL, these data provide further support for a previously unrecognized role for Rho GTPase pathway dysregulation in CTCL progression. Recurrent progression-associated mutations were common in the epigenetic modifier EZH2, suggesting that EZH2 inhibition may benefit patients with CTCL. Our findings support an approach in which genomic analysis is widely used for improved disease monitoring, biomarker-informed clinical trial design, and genome-guided therapeutic decision-making. Moreover, these molecular changes present new opportunities for therapeutic targeting in this challenging and incurable cancer.

Multiomics↗
PubMed2005

The progressive nature of Wallerian degeneration in wild-type and slow Wallerian degeneration (WldS) nerves.

BACKGROUND: The progressive nature of Wallerian degeneration has long been controversial. Conflicting reports that distal stumps of injured axons degenerate anterogradely, retrogradely, or simultaneously are based on statistical observations at discontinuous locations within the nerve, without observing any single axon at two distant points. As axon degeneration is asynchronous, there are clear advantages to longitudinal studies of individual degenerating axons. We recently validated the study of Wallerian degeneration using yellow fluorescent protein (YFP) in a small, representative population of axons, which greatly improves longitudinal imaging. Here, we apply this method to study the progressive nature of Wallerian degeneration in both wild-type and slow Wallerian degeneration (WldS) mutant mice. RESULTS: In wild-type nerves, we directly observed partially fragmented axons (average 5.3%) among a majority of fully intact or degenerated axons 37-42 h after transection and 40-44 h after crush injury. Axons exist in this state only transiently, probably for less than one hour. Surprisingly, axons degenerated anterogradely after transection but retrogradely after a crush, but in both cases a sharp boundary separated intact and fragmented regions of individual axons, indicating that Wallerian degeneration progresses as a wave sequentially affecting adjacent regions of the axon. In contrast, most or all WldS axons were partially fragmented 15-25 days after nerve lesion, WldS axons degenerated anterogradely independent of lesion type, and signs of degeneration increased gradually along the nerve instead of abruptly. Furthermore, the first signs of degeneration were short constrictions, not complete breaks. CONCLUSIONS: We conclude that Wallerian degeneration progresses rapidly along individual wild-type axons after a heterogeneous latent phase. The speed of progression and its ability to travel in either direction challenges earlier models in which clearance of trophic or regulatory factors by axonal transport triggers degeneration. WldS axons, once they finally degenerate, do so by a fundamentally different mechanism, indicated by differences in the rate, direction and abruptness of progression, and by different early morphological signs of degeneration. These observations suggest that WldS axons undergo a slow anterograde decay as axonal components are gradually depleted, and do not simply follow the degeneration pathway of wild-type axons at a slower rate.

Animals↗
PubMed2026

Targeting super-enhancer-driven SKIL transcription by CDK7 inhibitor THZ1 to suppress gastric cancer progression.

BACKGROUND: Gastric cancer (GC) is a lethal malignancy characterized by high incidence, mortality, and limited treatment options. Transcriptional addiction is a key cancer hallmark that drives tumor pathogenesis, making its inhibition a promising therapeutic strategy for GC. The study aims to investigate the roles and mechanisms of super-enhancer (SE)-driven oncogenic transcriptional addiction in GC progression and to identify novel targetable vulnerabilities. METHODS: We utilized cellular and animal models to assess the effects of THZ1 treatment and CDK7 knockdown on GC progression. RNA sequencing was employed to elucidate the potential molecular mechanism of THZ1 treatment. ChIP-seq was performed to establish SE landscape in GC. Integrative analysis of transcriptomic and SE profiling was used to identify THZ1-targeted oncogenic genes. Rescue experiments were conducted to confirm that THZ1 treatment suppresses GC malignant progression by targeting SE-driven SKIL transcription. RESULTS: GC cells exhibited pronounced sensitivity to THZ1 compared to normal gastric mucosa cells, and the treatment potently suppressed tumor growth and migration in both cellular and animal models. CDK7 was significantly upregulated in GC tissues, and its knockdown inhibited malignant progression in vitro and in vivo, whereas its overexpression accelerated tumor progression. Mechanistically, SE-driven oncogenic transcriptional amplification underlies GC cell susceptibility to THZ1, supported by the identification of novel oncogenic genes such as SKIL. SKIL, a key Hippo pathway regulator, was highly expressed in GC cells, and its elevated expression predicted poor patient prognosis. SKIL silencing attenuated malignant phenotypes, while its overexpression diminished THZ1’s suppression of GC cell proliferation and migration. CONCLUSION: Our findings demonstrate that THZ1 inhibits GC progression by disrupting SE-driven oncogenic transcription, thereby offering CDK7 inhibition as a promising therapeutic intervention for GC.

Stomach Neoplasms↗
PubMed2004

Effect of drugs in secondary disease progression in patients with multiple sclerosis.

Secondary progressive multiple sclerosis (SPMS) is a form of MS characterized by continuously worsening disability with or without superimposed relapses that occurs after a variable period of relapsing remitting disease and results in limited ambulation for almost all patients. The use of interferon beta (IFN beta) for immunomodulation in patients with SPMS has been evaluated in four recent clinical trials: The European multicentre trial on IFN beta-1b in SPMS (EUSPMS), the Secondary Progressive Efficacy Trial of Rebif (IFN beta-1a) in MS (SPECTRIMS), the North American Study of IFN beta-1b in SPMS (NASPMS), and the International MS Secondary Progressive Avonex Clinical Trial (IMPACT). EUSPMS was the only trial to demonstrate a significant positive effect of therapy on disease progression as measured by the expanded disability status scale (EDSS). However, results from all studies demonstrated significant positive effects of treatment on relapse, T2 lesion load, and gadolinium enhancement. Immunomodulation with IFN beta has the potential to significantly slow disease progression and improve quality of life for patients with SPMS. While results with monthly i.v. Ig were disappointing, positive effects on disease progression have been reported with the application of immunosuppressants, especially Mitoxantrone. The risk-benefit ratio of these cytostatic agents remains controversial. New strategies addressing the important neurodegenerative aspects of the disease are urgently needed.

Adjuvants, Immunologic↗
PubMed2005

Apo E in multiple sclerosis and optic neuritis: the apo E-epsilon4 allele is associated with progression of multiple sclerosis.

OBJECTIVE: To investigate the association between apolipoprotein E (Apo E) genotype in multiple sclerosis (MS) and acute monosymptomatic optic neuritis (ON) in a genetically homogeneous population with a high frequency of the Apo epsilon4 allele. BACKGROUND: The association between heterozygosity of Apo epsilon4 and the development of MS is thoroughly investigated, while the association between homozygosity of Apo epsilon4 and the development of MS is insufficiently studied. The association between Apo E genotype and disease progression remains controversial. METHODS: 475 patients were included, 385 with MS and 90 with ON, consecutively seen in the MS clinic in the County of Copenhagen. Clinical data were obtained from medical records and degree of disability was determined prospectively using the Kurtzke expanded disability status scale (EDSS). Blood samples were used for Apo E genotyping. Disease progression was evaluated by the progression index (PI = EDSS/disease duration). Apo E genotype distribution was compared with 361 healthy controls. RESULTS: The Apo epsilon genotype distribution in the MS and ON groups was similar to the controls. The rate of disease progression in the group of MS patients with a disease duration of 10 years or less was significantly faster in the Apo epsilon4 positive group (heterozygosity and homozygosity for Apo epsilon4) (PI = 1.41) compared to the Apo epsilon4 negative group (PI =0.92) (P =0.009). Observing the MS subgroups, we found that the group of patients with RRMS had a faster rate of disease progression in the Apo epsilon4 positive group (PI =1.12) compared to the Apo epsilon4 negative group (P =0.77) (P =0.024). CONCLUSIONS: Apo E genotypes do not influence the development of MS and ON. The Apo epsilon4 allele seems to predispose carriers with MS to a faster progression of disease.

Adult↗
PubMed2004

Association of preoperative plasma levels of vascular endothelial growth factor and soluble vascular cell adhesion molecule-1 with lymph node status and biochemical progression after radical prostatectomy.

PURPOSE: Angiogenesis is a critical process for cancer progression. We tested whether elevated circulating levels of the angiogenesis-related markers vascular endothelial growth factor (VEGF) and/or soluble vascular cell adhesion molecule-1 (sVCAM-1) are associated with prostate cancer diagnosis, stage, progression, and metastasis. PATIENTS AND METHODS: Plasma levels of VEGF and sVCAM-1 were measured on frozen, archival plasma obtained preoperatively from 215 consecutive patients who underwent radical prostatectomy for clinically localized disease, nine men with untreated prostate cancer metastatic to bones, and 40 healthy men without cancer. RESULTS: Plasma levels of both VEGF and sVCAM-1 were highest in patients with bone metastases (P <.001). VEGF levels were higher in patients with clinically localized disease than in healthy controls (P <.001). VEGF levels were elevated in patients with biopsy and final Gleason sum > or = 7 (P =.036 and P =.020, respectively) and extraprostatic extension (P =.047). Higher preoperative VEGF was independently associated with metastases to lymph nodes (P <.001). Both VEGF and sVCAM-1 were independently associated with biochemical progression after adjustment for the effects of standard preoperative features (P =.014 and P =.039, respectively). VEGF remained independently associated with biochemical progression after adjustment for standard postoperative features (P =.019). CONCLUSION: Plasma levels of VEGF increased incrementally from healthy controls to patients with clinically localized disease to patients with lymph node and skeletal metastases. Higher preoperative VEGF was independently associated with metastases to lymph nodes and biochemical progression after surgery in both pre- and postoperative models. Plasma sVCAM-1 was elevated in men with bone metastases and was associated with biochemical progression in a preoperative model.

Adult↗
PubMed2005

Inferring a tumor progression model for neuroblastoma from genomic data.

PURPOSE: The knowledge of the key genomic events that are causal to cancer development and progression not only is invaluable for our understanding of cancer biology but also may have a direct clinical impact. The task of deciphering a model of tumor progression by requiring that it explains (or at least does not contradict) known clinical and molecular evidence can be very demanding, particularly for cancers with complex patterns of clinical and molecular evidence. MATERIALS AND METHODS: We formalize the process of model inference and show how a progression model for neuroblastoma (NB) can be inferred from genomic data. The core idea of our method is to translate the model of clonal cancer evolution to mathematical testable rules of inheritance. Seventy-eight NB samples in stages 1, 4S, and 4 were analyzed with array-based comparative genomic hybridization. RESULTS: The pattern of recurrent genomic alterations in NB is strongly stage dependent and it is possible to identify traces of tumor progression in this type of data. CONCLUSION: A tumor progression model for neuroblastoma is inferred, which is in agreement with clinical evidence, explains part of the heterogeneity of the clinical behavior observed for NB, and is compatible with existing empirical models of NB progression.

Child↗
PubMed2006

Fulvestrant in women with advanced breast cancer after progression on prior aromatase inhibitor therapy: North Central Cancer Treatment Group Trial N0032.

PURPOSE: Fulvestrant is an antiestrogen that leads to estrogen receptor degradation and has demonstrated efficacy in breast cancer patients who have had disease recurrence or progression after tamoxifen. This study was designed to examine the efficacy and toxicity of fulvestrant in patients with disease progression on a third-generation aromatase inhibitor (AI). PATIENTS AND METHODS: A one-stage phase II trial was conducted in postmenopausal women with measurable disease by Response Evaluation Criteria in Solid Tumors criteria who experienced disease progression after treatment with a third-generation AI and, at most, one additional hormonal agent. Tumors must have been estrogen receptor and/or progesterone receptor positive. The primary end point was objective response rate, and secondary end points were time to disease progression, survival, duration of response, and toxicity. RESULTS: Eighty patients were enrolled, and three were ineligible. Characteristics of the 77 eligible patients included median age of 68 years, performance score of 0 or 1 in 91% of patients, visceral dominant disease in 88% of patients, two prior hormonal treatments in 73% of patients, and prior chemotherapy for metastatic disease in 32% of patients. Eleven patients (14.3%) achieved a partial response, and 16 patients (20.8%) had stable disease for at least 6 months, for a clinical benefit rate of 35%. Antitumor activity seemed to be higher in women with prior treatment with AI alone compared with women whose prior treatment also included tamoxifen. Median time to progression was 3 months, and median survival time was 20.2 months. Fulvestrant was well tolerated. CONCLUSION: Fulvestrant is a well-tolerated treatment and has efficacy against breast cancers that have progressed after therapy with a third-generation AI.

Aged↗
PubMed2001

Role of PI3K signaling in survival and progression of LNCaP prostate cancer cells to the androgen refractory state.

The mechanisms by which prostate cancer (PCa) cells progress to a hormone refractory state are poorly understood. The progression process under androgen ablation conditions involves the survival of at least a portion of malignant cells and their eventual proliferation in an androgen-independent manner. The goal of this study was to investigate the role of PI3K signaling in such a progression. Using an in vitro model of androgen ablation, we show that after removal of androgen support, the human PCa cell line LNCaP initially arrested in G(1) and trans-differentiated into neuroendocrine-like cells that eventually resumed androgen-independent proliferation. Both acute and chronic androgen ablation resulted in an increase in basal levels of PI3K and Akt activity, which were sustained throughout the progression process. Under these conditions, inhibition of PI3K, pharmacologically or with ectopic expression of PTEN, arrested cell proliferation and blocked progression to the androgen-independent state. In contrast, LNCaP cells in the presence of androgens were marginally sensitive to PI3K inhibition. During the chronic stage of androgen deprivation, androgen-independent proliferation correlated with diminished p27(kip1) protein levels, whereas PI3K and Akt activity remained elevated. At this stage, PI3K inhibition rapidly triggered accumulation of p27(kip1), cell cycle arrest, and cell death. PI3K modulated p27(kip1) levels at least in part by regulating its rate of degradation. Taken together, these data show that androgen ablation alone can increase PI3K-Akt activation, which supports survival after acute androgen ablation and proliferation during chronic androgen deprivation. Successful progression to the androgen-independent state in the LNCaP cell line model requires intact PI3K signaling.

Androgen Antagonists↗
PubMed2003

Differences in patterns of progression in demyelinating and axonal Guillain-Barré syndromes.

BACKGROUND: Immune treatments are recommended for patients with Guillain-Barré syndrome (GBS) who cannot walk independently, but a considerable number of GBS patients are in the progressive phase at the first examination. OBJECTIVE: To investigate whether progression patterns differ in demyelinating and axonal subtypes of GBS. METHODS: Clinical, laboratory, and electrophysiologic data on 131 consecutive patients with GBS were reviewed. Patients were classified as having acute inflammatory demyelinating polyneuropathy (AIDP) or acute motor axonal neuropathy (AMAN) based on electrodiagnostic criteria. RESULTS: Forty-one patients had AIDP, 62 AMAN, and 28 were unclassified. Age, sex, and Hughes Functional Grading Scale score at the first medical examination did not differ for the AIDP and AMAN patients. Mean periods between neurologic onset and first examination (5.3 vs 4.2 days; p = 0.01) and neurologic onset and nadir (18.0 vs 11.5 days; p = 0.001) were longer for the AIDP group. In the subgroup of those with mild disability (able to walk independently at the first neurologic examination), 88% of the AMAN patients had reached the nadir, whereas 65% of the AIDP patients had reached it. The remaining 35% progressed to it over the next 1 to 2 weeks and were unable to walk at nadir. CONCLUSIONS: The patterns and speeds of progression differ in AMAN and AIDP, AMAN having a rapid progression and an early nadir. AIDP patients frequently have a significantly long progression after the first examination; therefore, they need to be carefully monitored.

Acute Disease↗
PubMed2000

Defective regulation of IFNgamma and IL-12 by endogenous IL-10 in progressive MS.

BACKGROUND: MS is a chronic inflammatory disease of the CNS postulated to be a Th1 type cell-mediated autoimmune disease. There is increased interferon-gamma (IFNgamma) secretion in MS, and IFNgamma administration induces exacerbations of disease. IFNgamma expression is closely regulated by a number of cytokines produced by different cells of the immune system. Interleukin-12 (IL-12) is a major factor leading to Th1-type responses, including IFNgamma secretion, and there is increased secretion of IL-12 in MS. IL-10 is a potent inhibitor of both IL-12 and IFNgamma expression. METHODS: The authors investigated cytokine production and proliferative responses of peripheral blood mononuclear cells stimulated with soluble anti-CD3 in healthy controls and patients with stable relapsing-remitting MS or progressive MS. RESULTS: The authors found that T cell receptor-mediated IFNgamma and IL-10 secretion were increased in progressive MS, whereas IL-4 and IL-2 secretion and lymphocyte proliferative responses were normal. Anti-IL-12 antibody suppressed raised IFNgamma in progressive MS but did not affect raised IL-10. In addition, neutralization of endogenous IL-10 upregulated IFNgamma in controls but not progressive MS. IL-10 was produced by CD4+ cells whereas IFNgamma was produced by both CD4+ and CD8+ cells. There were no differences in IL-10 receptor expression in MS patients. CONCLUSIONS: These abnormalities in IL-10 regulation were not seen in the relapsing-remitting form of MS. Thus, the defect in regulation of both IL-12 and IFNgamma production by endogenous IL-10 in progressive MS could be an important factor involved in the transition of MS from the relapsing to the progressive stage and has implications for treating MS patients with exogenous IL-10.

Adult↗
PubMed2006

Acute traumatic intraparenchymal hemorrhage: risk factors for progression in the early post-injury period.

OBJECTIVE: To characterize the natural course of traumatic intraparenchymal contusions and hematomas (IPHs) and to identify risk factors for IPH progression in the acute post-injury period. METHODS: A retrospective analysis was performed on a prospective observational database containing 113 head trauma patients exhibiting 229 initially nonoperated acute IPHs. The main outcome variable was radiographic evidence of IPH progression on serially obtained head computed tomographic (CT) scans. Secondary outcomes included the actual amount of IPH growth and later surgical evacuation. Univariate and multivariate analyses (using a generalized estimate equation) were applied to both demographic and initial radiographic features to identify risk factors for IPH progression and surgery. RESULTS: Overall, 10 IPHs (4%) shrank, 133 (58%) remained unchanged, and 86 (38%) grew between the first and second head CT scan. IPH progression was independently associated with the presence of subarachnoid hemorrhage (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.12-2.3), presence of a subdural hematoma (OR, 1.94; 95% CI, 1.1-3.43), and initial size (OR, 1.11; 95% CI, 1.02-1.21, for each cm volume). Size of initial IPH proportionately correlated with the amount of subsequent growth (linear regression, P < 0.001). Worsened Glasgow Coma Score between initial and follow-up head CT scan (OR, 8.6; 95% CI, 1.5-50), IPH growth greater than 5 cm (OR, 7.3; 95% CI, 1.6-34), and effacement of basal cisterns on initial CT scan (OR, 9.0; 95% CI, 1.5-52) were strongly associated with late surgical evacuation. CONCLUSION: A large proportion of IPHs progress in the acute post-injury period. IPHs associated with subarachnoid hemorrhage, a subdural hematoma, or large initial size should be monitored carefully for progression with repeat head CT imaging. Effacement of cisterns on the initial head CT scan was strongly predictive of failure of nonoperative management, thereby leading to surgical evacuation. These findings should be important factors in the understanding and management of IPH.

Acute Disease↗
PubMed2004

Pharmacy-based assessment of adherence to HAART predicts virologic and immunologic treatment response and clinical progression to AIDS and death.

Although adherence to HAART at a level above 95% has been associated with optimal viral suppression, the impact of different levels of adherence on long-term clinical outcomes has not been determined. We used an objective pharmacy-based measure to examine the association between three levels of adherence to HAART and disease progression among a population-based cohort of HIV-infected patients attending an urban HIV specialty clinic. Higher levels of adherence to HAART were significantly associated with longer time to virologic failure (P < 0.001), greater increase in CD4 cell count (P = 0.04), and lower risk of progression to clinical AIDS or death (P < 0.007). After controlling for other factors, patients with low adherence had over five times the risk of disease progression than patients with moderate adherence (P = 0.007) or patients with high adherence (P = 0.001). There was no significant difference in the risk of progression between patients with moderate and high levels of adherence (P > 0.2). Patients who progressed to AIDS or death had significantly higher viral loads (P = 0.01) and lower CD4 cell counts (P = 0.03) than patients who experienced virologic failure, but did not progress.

Adult↗
PubMed2004

Progression of diabetic nephropathy enhances the plasma osteopontin level in type 2 diabetic patients.

Osteopontin (OPN) is thought to play multiple roles in the progression of atherosclerotic plaque including diabetic vascular complications. However, it still remains unclear whether the level of OPN in vivo is indeed clinically associated with the progression of diabetic complications. This study evaluated whether the levels of OPN in plasma and urine are correlated with the progression of diabetic complications, such as retinopathy, neuropathy, and nephropathy in patients with type 2 diabetes. In 229 patients with type 2 diabetes, OPN level in plasma and urine was evaluated by both the severity of diabetic complications, such as retinopathy, neuropathy, and nephropathy, and the clinical characteristics and the substantial laboratory findings. Plasma OPN level increased significantly with aging and the progression of diabetic nephropathy, especially at the stage of renal failure (p<0.05). However, the level was not related to the progression of retinopathy or neuropathy, or to laboratory findings, such as HbA1c or serum lipids. In contrast, urinary OPN level was not associated with diabetic complications in any of the subjects. There was no correlation between the plasma and urinary values of OPN. The results established that the plasma OPN was elevated in proportion to the progression of diabetic nephropathy, indicating that the plasma concentration may be a potential diagnostic predictor of diabetic end-stage renal disease.

Aged↗
PubMed2001

Obstructive nephropathy in children: long-term progression after relief of posterior urethral valve.

BACKGROUND: Approximately one third of children with end-stage renal disease have the illness because of urinary tract malformations, obstructive uropathy, and hypoplasia/dysplasia. The significant drop in infant mortality from obstructive uropathies in recent decades, attributable to prenatal diagnosis with renal ultrasonography and coordinated surgical and medical care, necessitated a reevaluation of the long-term outcome. METHODS: To that end, we examined the long-term progression of obstructive nephropathy after neonatal relief of posterior urethral valves in our center over a span of 21 years, with diagnosis and care being provided by the same pediatric and urology team. RESULTS: The 10 consecutive cases of posterior urethral valves represented 7% of all patients with congenital malformative uropathies seen over this period. The following procedures were performed: primary valve ablation (90%) and vesicostomy (40%). Seventy percent of patients progressed to end-stage renal disease over a (mean +/- standard error of the mean) follow-up of 11.3 +/- 2.1 years. The linear plot of the log of the inverse of serum creatinine versus time suggested unrelenting progression. The rate of progression was rapid after serum creatinine exceeded 5 mg/dL but the rate was slow and steady from serum creatinine of 1.5 to 5 mg/dL. CONCLUSIONS: To test the effect of a therapeutic intervention to ameliorate the rate of progression, this steady and prolonged progression of 0.5 mg/dL per year between serum creatinine concentration of 1.5 to 5 mg/dL would seem the optimal study.

Adolescent↗
PubMed2005

Essential hypertension, progressive renal disease, and uric acid: a pathogenetic link?

Hypertension and hypertension-associated ESRD are epidemic in society. The mechanisms responsible for renal progression in mild to moderate hypertension and those groups most at risk need to be identified. Historic, epidemiologic, clinical, and experimental studies on the pathogenesis of hypertension and hypertension-associated renal disease are reviewed and an overview/hypothesis for the mechanisms involved in renal progression is presented. There is increasing evidence that hypertension may exist in one of two forms/stages. The first stage, most commonly observed in early or borderline hypertension, is characterized by salt-resistance, normal or only slightly decreased GFR, relatively normal or mild renal arteriolosclerosis, and normal renal autoregulation. This group is at minimal risk for renal progression. The second stage, characterized by salt-sensitivity, renal arteriolar disease, and blunted renal autoregulation, defines a group at highest risk for the development of microalbuminuria, albuminuria, and progressive renal disease. This second stage is more likely to be observed in blacks, in subjects with gout or hyperuricemia, with low level lead intoxication, or with severe obesity/metabolic syndrome. The two major mechanistic pathways for causing impaired autoregulation at mild to moderate elevations in BP appear to be hyperuricemia and/or low nephron number. Understanding the pathogenetic pathways mediating renal progression in hypertensive subjects should help identify those subjects at highest risk and may provide insights into new therapeutic maneuvers to slow or prevent progression.

Disease Progression↗