Long-term followup of patients treated with total lymphoid irradiation for lupus nephritis

OBJECTIVE: To describe the long-term survival, renal condition, and morbidity outcomes in patients who received total lymphoid irradiation (TLI) for the treatment of lupus nephritis. METHODS: Twenty-one patients with biopsy-proven, diffuse membranoproliferative glomerulonephritis and significant proteinuria of >2.5 grams/day received TLI from 1980 to 1987 at Stanford University Medical Center. All patients had previously failed to respond to treatment with high-dose corticosteroids or therapy with corticosteroids plus immunosuppressive agents (azathioprine, cyclophosphamide, or chlorambucil). RESULTS: The mean duration of followup since TLI was 10.7 years. Fifteen of 21 patients (71%) remained alive at the time of this assessment. Nine of the 21 patients (43%) survived without developing end-stage renal disease (ESRD). The probability of long-term survival without ESRD and without need for additional immunosuppressive agents after TLI was 19% (4 of 21). Factors predicting renal failure at the time of TLI included elevated creatinine levels, increased interstitial fibrosis on renal biopsy, and increased fractional excretion of immunoglobulin and albumin. Malignancies were found in 4 patients, and opportunistic infections occurred in 7 patients. CONCLUSION: Overall, patients with lupus nephritis treated with TLI do not appear to have better 10-year survival with lower incidence of ESRD compared with patients in published series treated with conventional immunosuppressive therapies. However, in this series of patients, treatment with conventional immunosuppressive therapies had been unsuccessful and given the limited number of adverse events and the efficacy seen in some patients, TLI appears to be a reasonable therapeutic option for the treatment of severe lupus nephritis among patients who fail to respond under standard cytotoxic regimens.     

Differential killing of mismatch repair-deficient and -proficient cells: towards the therapy of tumors with microsatellite instability

DNA mismatch repair (MMR) defects bring about a strong mutator phenotype and microsatellite instability (MSI). In an attempt to exploit MSI in cancer therapy, we constructed expression vectors carrying a thymidine kinase/blasticidin deaminase fusion gene downstream from a (C)(12) or an (A)(26) microsatellite and stably transfected these constructs into human cells in which the MMR status could be regulated by doxycycline. We now show that ganciclovir-resistant clones arising through frameshifts in the (C)(12) microsatellite were 20 times more frequent in cells in which MMR was inactivated. This difference may be exploited in gene therapy of tumors with MSI, which represent a substantial proportion of cancers of many different tissues.     

Identification of hearing loss in newborns by transient otoacoustic emissions

OBJECTIVE: More than 90% of congenital hearing loss cases are of cochlear origin. There are two methods for newborn hearing screening: the transient otoacoustic emission (TEOAE) or (ABR) screening. When TEOAE is used for hearing screening patients, newborn with a neural hearing loss are not discovered. MATERIALS: In the present study TEOAEs were obtained from 3,048 newborns from both ears in patients with and without risk factors for hearing loss in the history. All newborns who did not pass TEOAE in the 2nd screening (uni or bilaterally) underwent additional audiologic tests. RESULTS: In the first screening 150 (4.5%) of the newborns newborn did not pass the screening and 30 (0.98%) did not pass in the second screening. In nine newborns with unilateral absent TEOAE and in two newborns a deafness was confirmed, with one side cochlear and on the other side retrocochlear. Both patients received cochlear implants before the 2nd year of age. In 21 newborns with absent TEOAE bilaterally, five had moderate sensorineural hearing loss bilaterally and in nine patients profound hearing loss (90-100 dB) or deafness was confirmed. Of 3,048 newborns there were 1,355 with a risk of hearing loss and in 12 (0.88%) newborns bilateral hearing loss or deafness was confirmed; of the 1663 newborns without risk of hearing loss in the history, in four (0.24%) newborn deafness or bilateral sensorineural hearing loss in the range of 45-65 dB were confirmed. CONCLUSION: When the newborn has an absent TEOAE uni or bilaterally, we need to inform the parents and to recommend additional screening and other audiologic tests to confirm or exclude hearing loss.     

Oxidative stress in patients with COPD and pulmonary hypertension

OBJECTIVE: Oxidative stress plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Oxidant/antioxidant imbalance has also been reported in various forms of pulmonary hypertension. The present study aimed to assess systemic oxidative stress, as reflected by serum malondialdehyde (MDA) concentrations and activities of antioxidant enzymes in erythrocytes [glutathione peroxidase (GPX), superoxide dismutase (SOD) and catalase (CAT)] in patients with and without pulmonary hypertension secondary to COPD. PATIENTS AND METHODS: Seventy-five patients (58 male) with COPD (mean age 65.1 +/- 1.2 years; mean smoking history 35.6 +/- 3.8 pack-years) were studied. Twenty-one healthy non-smokers served as a control group. Pulmonary function was evaluated with body plethysmography; mean and systolic pulmonary artery pressures (Ppa) were assessed with Doppler echocardiography. Serum concentrations of MDA and activities of GPX, SOD and CAT in washed red blood cells were measured using spectrophotometry. RESULTS: Pulmonary hypertension was present in 28 patients with COPD (systolic Ppa: 46.4 +/- 2.3 mmHg; mean Ppa: 26.0 +/- 1.9 mmHg) and absent in 47 (systolic Ppa: 22.9 +/- 0.8 mmHg; mean Ppa: 13.4 +/- 0.6 mmHg). Compared with the healthy control group, all the patients (with or without pulmonary hypertension) had higher serum MDA concentrations (1.5 +/- 0.1 versus 2.3 +/- 0.1 versus 2.3 +/- 0.1 nmol/mL, ANOVA, P < 0.001) and lower erythrocyte GPX activity (51.3 +/- 3.2 versus 42.2 +/- 2.0 versus 41.3 +/- 2.5 U/g Hb, P = 0.029), whereas SOD (1121.1 +/- 29.0 versus 1032.6 +/- 21.8 versus 1032.7 +/- 36.2 U/g Hb, P = 0.063) and CAT activities (4.9 +/- 0.2 versus 4.6 +/- 0.1 versus 4.7 +/- 0.2 U/g Hb; P= 0.454) were similar. No differences were observed in serum MDA concentrations or activities of GPX, SOD and CAT in erythrocytes between COPD patients with and without pulmonary hypertension. CONCLUSION: The study demonstrates the presence of oxidative/antioxidative imbalance in the systemic circulation in patients with COPD: compared with healthy subjects, COPD patients had higher serum MDA concentrations and lower GPX activity in erythrocytes. The magnitudes of the increase in MDA and reduction in GPX activity were similar in COPD patients with pulmonary hypertension and in those with normal pulmonary artery pressures.     

A prognostic impact of separation of refractory cytopenia with multilineage dysplasia and 5q- syndrome from refractory anemia in primary myelodysplastic syndrome

A prognostic impact of WHO classification of myelodysplastic syndrome (MDS) was studied in a group of 103 primary MDS patients with refractory anemia (RA) according to French-American-British (FAB) classification. Median survival of 37 patients with RA according to WHO criteria of 85.2 months was significantly different from that in both 37 patients with refractory cytopenia with multilineage dysplasia (RCMD) (47.0 months, P=0.002) and 29 patients with 5q- abnormality diagnosed by routine chromosome banding (36.2 months, P=0.0002). A more detailed karyotype analysis with fluorescent in situ hybridization (FISH) techniques confirmed 5q deletion as a sole cytogenetic abnormality in only 12 out of 29 patients, in 4 patients 5q- was associated with complex abnormalities involving 5q region, 13 patients had 5q deletion combined with further karyotype abberations outside 5q. No difference in median survival and estimated 3 years survival was observed between RA patients, patients with 5q- syndrome according to WHO morphology criteria and patients with 5q- as a single abnormality confirmed by FISH in contrast to patients with either additional 5q abberations or further karyotype changes not involving 5q. The same difference was also observed in time to 25% of patients evolving to acute myeloid leukemia (AML). Our study confirmed usefulness of separation of RCMD from RA. RCMD represents a poor prognostic subgroup of MDS clearly distinct from pure RA mainly due to short survival connected with progressive bone marrow failure and increased risk of leukemic transformation. We also suggest to define 5q- syndrome as primary MDS of FAB type RA with 5q deletion as a sole cytogenetic abnormality confirmed by FISH analysis. This definition enabled us to discriminate 5q- patients with favorable prognosis similar as in RA from those with poor outcome associated with 5q- combined with complex abnormalities involving either 5q or regions outside 5q.     

Long-term outcome of patients with antineutrophil cytoplasmic autoantibody-associated vasculitis with renal involvement

BACKGROUND: Despite treatment, renal involvement in antineutrophil cytoplasmic autoantibody (ANCA)-positive vasculitis is still associated with significant long-term mortality and remains an important cause of end-stage renal failure. METHODS: We retrospectively analyzed a series of 61 consecutive patients with newly diagnosed ANCA-associated renal vasculitis (54.1% Wegener's granulomatosis, 23% renal-limited vasculitis, 16.4% microscopic polyangiitis, 4.9% Churg-Strauss syndrome) diagnosed between 1986 and 1997. RESULTS: The median creatinine level at diagnosis was 221.5 (63-762) micromol/l, i.e. 2.5 (0.7-8.6) mg/dl, 32.8% were dialysis-dependent. All patients were treated with cyclophosphamide. Remission was achieved in 87% of patients. Relapses occurred in 44.7%. The median renal disease-free interval was 62.5 (0-138) months. The estimated patient survival at 5 and 10 years was 78.3 and 62.2%, respectively. Mortality was associated with age (p = 0.04 when age limit 50 years) and advanced renal failure (p = 0.038 when compared dialysis-dependent and independent patients). Estimated renal survival time at 5 and 10 years was 69.2 and 55.8%, respectively. At the end of follow-up, 50.8% of patients were in complete remission, 31% had died. The median serum creatinine level was 137.5 (77-469) micromol/l, i.e. 1.56 (0.87-5.3) mg/dl, 24.6% of patients were on regular dialysis treatment. CONCLUSION: Patient survival, relapse rate and mortality were comparable to similar reports. In view of the severity of the renal disease and the length of follow-up, renal survival was very good. Despite effective treatment, the long-term outcome of patients with ANCA-associated renal vasculitis remains unsatisfactory.     

The impact of sleep and mood disorders on quality of life in Parkinson’s disease patients

Sleep disturbances are common and often severe in patients with Parkinson’s disease (PD) and their symptoms can be present at any time of day. The purpose of our study was to examine how excessive daytime sleepiness or poor nocturnal sleep quality and mood disorders influence the quality of life (QoL) in PD patients. Ninety-three PD patients from eastern Slovakia were recruited (49.5% males, mean age 68.0 ± 9.5 years, mean disease duration 6.1 ± 5.9 years). Sleep disturbances were measured using the Epworth Sleepiness Scale (ESS) and the Pittsburgh Sleep Quality Index (PSQI); QoL with the Parkinson’s Disease Quality of Life Questionnaire (PDQ-39); depression and anxiety with the Hospital Anxiety and Depression Scale (HADS) and disease severity with the Unified Parkinson’s Disease Rating Scale (UPDRS). χ ² test, bivariate correlations and multiple linear regressions were performed. PSQI and ESS had significant correlations with worse QoL (p < 0.01, p < 0.05, respectively). HADS-D (p < 0.01), HADS-A (p < 0.01), UPDRS (p < 0.01) and disease duration (p < 0.05) were also significantly related to worse QoL. In the linear regression analysis, however, only PSQI (p < 0.01), anxiety (p < 0.001) and UPDRS (p < 0.001) remained significant. The model with PSQI explained 74% of the variance, and the model with ESS explained 63% of the variance in PDQ-39 when analyses were performed separately. In an overall model, however, only PSQI remained significant, accounting for 82% of the variance in PDQ-39. Nighttime poor sleep and anxiety are important contributors leading to a worse QoL. As these are treatable conditions, they should be recognized by clinicians and managed properly.     

Two novel fibrinogen variants in the C-terminus of the Bβ-chain: fibrinogen Rokycany and fibrinogen Znojmo

Hereditary dysfibrinogenemia is a rare disorder wherein an inherited abnormality in fibrinogen structure may result in defective fibrin function and/or structure. Congenital hypofibrinogenemia is a rare autosomal bleeding disorder, either recessive or dominant, characterized by a low fibrinogen plasma level. A 28-year-old asymptomatic woman (fibrinogen Rokycany) and a 54-year-old man with thrombosis and pulmonary embolism (fibrinogen Znojmo) were investigated for a suspected fibrinogen mutation after abnormal coagulation tests results were obtained. DNA sequencing showed the heterozygous point mutation Bβ Asn351Lys in fibrinogen Rokycany and the heterozygous point mutation Bβ Arg237Ser in fibrinogen Znojmo, respectively. The kinetics of fibrinopeptide release was found to be normal in both cases. Fibrinolysis was impaired in the Znojmo variant. The average fibril diameters of Znojmo fibrin was slightly increased, but not differing significantly from normal; formed by less fibrils with abrupt fibril terminations. Rheological studies revealed a softer clot. Rokycany fibrin was formed by significantly narrower fibrils than normal fibrin; and the clot was denser than the control clot. Rheological studies revealed a stiffer clot. Impaired fibrinolysis and abnormal clot morphology may be the cause of thrombotic episodes in the patient with Znojmo mutation. New cases of hypofibrinogenemia and dysfibrinogenemia, found by routine coagulation testing, were genetically identified as a novel fibrinogen variants Bβ Asn351Lys (fibrinogen Rokycany) and Bβ Arg237Ser (fibrinogen Znojmo), respectively.