Concurrent light chain amyloidosis and proximal tubulopathy: Insights into different aggregation behavior-A case report.

Due to differences in the protein folding mechanisms, it is exceedingly rare for amyloid light chain (AL) amyloidosis and monoclonal gammopathy of renal significance (MGRS) to coexist. We herein report the first case of concurrent AL amyloidosis and a subclass of MGRS, light chain proximal tubulopathy (LCPT). The 53-year-old female was diagnosed with smoldering myeloma immunoglobulin G kappa and AL amyloidosis with deposits in fat and gastrointestinal tissue. The kidney biopsy did not show amyloid deposits but electron microscopy revealed the presence of LCPT with crystal formation in proximal tubular epithelial cells. This case illustrates the complex pathophysiology of protein deposition in monoclonal gammopathies.

Readmissions of patients with diabetes mellitus and foot ulcers after infra-popliteal bypass surgery - attacking the problem by an integrated case management model.

BACKGROUND: Patients with neuroischemic diabetic foot syndrome (DFS) may need arterial revascularization, minor amputations, débridements as well as meticulous wound care. Unfortunately, postoperative outpatient care is frequently inadequate. This is especially true for Germany, where the in- and outpatient sectors are funded and managed separately, with poor communication between the two. Thus, many patients may be readmitted to the hospital following successful treatment and discharge. In an attempt to overcome these problems, we looked at whether an integrated case management (CM) system for outpatient care according to in-hospital standards might improve patients care and avoid readmissions. In addition we analyzed the length of hospital stay (LOS) as well as hospital costs. PATIENTS AND METHODS: In this retrospective cohort study patients with DFS, bypass surgery and foot surgery after implementation of the CM (study group; n = 376) were compared with a matched historic control group (HCG; n = 190) including the flat rate revenues (G-DRG K01B). Following a standardized assessment, integrated trans-sectoral CM care was offered to 116 patients (CMP). RESULTS: The proportion of patients who were readmitted to hospital was reduced in CMP compared to HCG (8.8 vs. 16.4 %; p < 0.01), with consequent reduction of case consolidations (9.7 % versus 17.8 %, p < 0.001). Although initially, the mean LOS was higher in the CMP patients, the reduction in readmissions meant that this integrated CM program improved the hospital's economic situation. CONCLUSIONS: A hospital-based integrated CM system significantly reduces the hospital readmissions in patients with neuroischemic DFS following bypass surgery, with lower hospital costs.

Photodissociation of group-6 hexacarbonyls: observation of coherent oscillations in an antisymmetric (pseudorotation) vibration in Mo(CO)(5) and W(CO)(5).

On dissociation of M(CO)(6), M = Cr, Mo and W, by a femtosecond UV laser (<270 to 360 nm), pronounced coherent oscillations are observed in the pentacarbonyl products on probing by long-wavelength (810 nm) ionization in the gas phase. They are vibrations in the ground state, driven by the slope from a conical intersection on relaxation from the initially formed excited state (S(1)). Surprisingly, with M = Mo and W we also find a fundamental of an antisymmetric (b(2) in C(4v)) vibration. From positive and negative displacements along such a coordinate one would expect the same signal, so that there should be only overtones. Vibrational selection rules are therefore considered for time-resolved spectroscopy. The reason for the symmetry breaking is suggested to result from the fact that the phase in superposition of wave functions is established by the pump process and this phase is conserved in probing, independently of the probe delay. An antisymmetric fundamental can be observed, if there is a small tunneling splitting in a state involved in the probe process. The observations also imply some conclusions on the dissociation and relaxation processes and the potentials: with longer wavelengths, the wave packet enters on the same surface but from a different direction to S(1). Only a very minor fraction of the available energy appears as coherent oscillation. There is no equipartition at the end, and a second CO is cleaved off in few picoseconds, even if there is only very little excess energy. Triplets do not contribute, even in the tungsten system and at longest wavelengths. The dissociation mechanism involves passage of the wave packet from all initial states over an avoided crossing to a repulsive ligand-field surface. It predicts that in some other molecules, the barrier caused thereby is larger and for long photolysis wavelength the lifetime is long enough for intersystem crossing to take place; it also predicts wavelength dependences in these cases. It is again emphasized that there is no vertical internal conversion; instead, the molecule is controlled by slopes and intersections of potentials. Also lifetimes can be considered as a control parameter in photochemistry.

Prognostic value of tumour endothelial markers in patients with endometrial cancer.

Endometrial cancer is one of the more frequent and most lethal gynaecological cancer types. Since it occurs more frequently in elderly and overweight patients, a pre-operative staging method would be beneficial. The growth of solid neoplasms is always accompanied by neovascularisation. Tumour endothelial markers (TEMs) are a group of recently described endothelial cell surface markers that appear to be specific to neoplastic tissue. This study aimed to investigate the potential usefulness of TEM assessment in the endometrium by comparing the transcriptional expression of TEMs in the normal endometrium with endometroid adenocarcinoma tissue. Tissues were lysed and the RNA was extracted, assessed and reverse transcribed in one batch. Real-time quantitative PCR was performed for TEM-1, -2, -6, -7, -7r and -8. GAPDH, ß-actin and ribosomal protein L13A (RPL13A) were used as control genes. TEM-8 showed the highest expression level in all of the groups. TEM-1 showed higher expression levels in the normal endometrium than in the tumour tissues. For the remaining TEMs, we found a higher expression in the cancer samples than in the normal endometria. Statistical significance of this difference was achieved for TEM-1, -2 and-7. No clear correlation was noted between the tumour stage and the level of TEM-1, -6 and -8 expression. Apart from TEM-6, the highest expression in FIGO I cancer stages was noted in the remaining TEMs. Our results showed that for most of these tumour endothelial markers, gene expression was slightly higher in the endometrial carcinoma tissue samples than in the endometrium of normal cycling women. However, with the possible exception of TEM-8 and -6, absolute expression levels were generally low, indicating that most TEMs may only be specifically expressed in a restricted number of cancer types (e.g., colorectal). Therefore, TEMs may not be useful in the context of endometrial cancer.

A remote control for intraoperative ultrasound--is it really necessary?

BACKGROUND: A remote control, which can be used to manipulate the scanner functions remotely from within the sterile field, is designed to save time during IOUS. This study was designed to evaluate whether the time saved by using a remote control should be a decisive factor in buying a special system. METHODS: During 50 intracranial operations, the temporary arrest of the operative procedure caused by the use of ultrasound was measured. In 25 arbitrarily chosen operations, the remote control was draped and used (group 1); in the other group (group 2), it was not used. In addition, we analyzed the use of vascular duplex sonography in 12 of the operations with remote control (group 1a) and 14 of the operations without remote control (group 2a). RESULTS: The average time spent for ultrasound use including draping was 390 seconds in group 1, compared to 388 seconds in group 2 (without remote control). During examinations including duplex sonography, the average time spent for IOUS including draping was 464 seconds for group 1a and 466 seconds for group 2a. CONCLUSION: Based on results, the neurosurgeon does not save much time by using a remote control. The time used for draping the additional remote control is equal to the length of time that is saved. However, the surgeon's frustration in attempting to instruct a layperson to operate the ultrasound keyboard and its impact on the operative procedure cannot be measured.

Predisposing conditions and risk factors for development of symptomatic meningioma in adults.

BACKGROUND: Risk factors and predisposing factors for the development of symptomatic meningioma during adult life are not well known. METHODS: Data from 306 consecutive patients with primary meningioma were collected retrospectively in a hypothesis-generating study. Factors studied included localisation of tumours, blood group typing, and risk factors, such as diabetes mellitus, coronary arterial disease, hypertension, rheumatoid arthritis, bronchial asthma, smoking, obesity, and second primary tumour. Case-control analysis of putative risk factors was carried out using a control data set from the German East-West Health Survey (n=7466, age range 25-69 years). Patients and controls were matched for age, gender, geographic area, and time of data collection. RESULTS: Rh(D) positive cases were significantly less frequent in the patient group compared to controls (p=0.01). Pre-existing diabetes was associated with meningioma in middle-aged (40-69 years) patients (odds ratio, OR 13.94-4.30, p=0.001-0.05). In female patients, arterial hypertension was significantly associated with occurrence of meningioma in the age group 60-69 years (OR=2.23, p=0.041). Rheumatoid arthritis had a negative association with meningioma in both males and females in the age groups above 50 years (OR 0.19-0.27, p=0.02-0.034). Bronchial asthma, smoking, and obesity were not significantly associated with meningioma. A second primary tumour was present in 12 cases. The most frequent combination was meningioma and breast cancer (5/12). CONCLUSIONS: This study shows statistically significant association of some co-morbidities with symptomatic meningioma in adults. Areas of interest have been identified where further research would be necessary.

Cholesterol 25-hydroxylase on chromosome 10q is a susceptibility gene for sporadic Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia. It is characterized by beta-amyloid (A beta) plaques, neurofibrillary tangles and the degeneration of specifically vulnerable brain neurons. We observed high expression of the cholesterol 25-hydroxylase (CH25H) gene in specifically vulnerable brain regions of AD patients. CH25H maps to a region within 10q23 that has been previously linked to sporadic AD. Sequencing of the 5' region of CH25H revealed three common haplotypes, CH25Hchi2, CH25Hchi3 and CH25Hchi4; CSF levels of the cholesterol precursor lathosterol were higher in carriers of the CH25Hchi4 haplotype. In 1,282 patients with AD and 1,312 healthy control subjects from five independent populations, a common variation in the vicinity of CH25H was significantly associated with the risk for sporadic AD (p = 0.006). Quantitative neuropathology of brains from elderly non-demented subjects showed brain A beta deposits in carriers of CH25Hchi4 and CH25Hchi3 haplotypes, whereas no A beta deposits were present in CH25Hchi2 carriers. Together, these results are compatible with a role of CH25Hchi4 as a putative susceptibility factor for sporadic AD; they may explain part of the linkage of chromosome 10 markers with sporadic AD, and they suggest the possibility that CH25H polymorphisms are associated with different rates of brain A beta deposition.

Complement C2 receptor inhibitor trispanning: a novel human complement inhibitory receptor.

The complement system presents a powerful defense against infection and is tightly regulated to prevent damage to self by functionally equivalent soluble and membrane regulators. We describe complement C2 receptor inhibitor trispanning (CRIT), a novel human complement regulatory receptor, expressed on hemopoietic cells and a wide range of tissues throughout the body. CRIT is present in human parasites through horizontal transmission. Serum complement component C2 binds to the N-terminal extracellular domain 1 of CRIT, which, in peptide form, blocks C3 convertase formation and complement-mediated inflammation. Unlike C1 inhibitor, which inhibits the cleavage of C4 and C2, CRIT only blocks C2 cleavage but, in so doing, shares with C1 inhibitor the same functional effect, of preventing classical pathway C3 convertase formation. Ab blockage of cellular CRIT reduces inhibition of cytolysis, indicating that CRIT is a novel complement regulator protecting autologous cells.

A peptide derived from the parasite receptor, complement C2 receptor inhibitor trispanning, suppresses immune complex-mediated inflammation in mice.

Complement C2 receptor inhibitor trispanning (CRIT) is a Schistosoma protein that binds the human complement protein, C2. We recently showed that peptides based on the ligand binding region of CRIT inhibit the classical pathway (CP) of complement activation in human serum, using hemolytic assays and so speculated that on the parasite surface CRIT has the function of evading human complement. We now show that in vitro the C2-binding 11-aa C terminus of the first extracellular domain of CRIT, a 1.3-kDa peptide termed CRIT-H17, inhibits CP activation in a species-specific manner, inhibiting mouse and rat complement but not that from guinea pig. Hitherto, the ability of CRIT to regulate complement in vivo has not been assessed. In this study we show that by inhibiting the CP, CRIT-H17 is able to reduce immune complex-mediated inflammation (dermal reversed passive Arthus reaction) in BALB/c mice. Upon intradermal injection of CRIT-H17, and similarly with recombinant soluble complement receptor type 1, there was a 41% reduction in edema and hemorrhage, a 72% reduction in neutrophil influx, and a reduced C3 deposition. Furthermore, when H17 was administered i.v. at a 1 mg/kg dose, inflammation was reduced by 31%. We propose that CRIT-H17 is a potential therapeutic agent against CP complement-mediated inflammatory tissue destruction.

Antioxidant treatment of therapy-resistant idiopathic membranous nephropathy with probucol: a pilot study.

BACKGROUND: Proteinuria in Heymann's nephritis, an experimental rat model disease corresponding to membranous nephropathy, has been shown to be due to lipid peroxidation. Since the pathophysiology might be similar to idiopathic membranous nephropathy in humans, we performed a prospective multicenter trial to investigate the efficacy of the lipid peroxidation scavenger, probucol. METHODS: Fifteen patients with biopsy-proven idiopathic membranous nephropathy resistant to conventional immunosuppressive therapy (n = 7) and/or ACEI treatment (n = 12) were recruited. Probucol (1 g/d orally) was administered for three months, followed by a washout period of four weeks, whereon lovastatin (10-20 mg/d orally) was administered for additional three months. RESULTS: A significant reduction in proteinuria was seen during the probucol treatment (median (range): 6.4 (3.8-9.1) g/d vs. 4.7 (1.3-16) g/d; P < 0.05), with partial remission achieved in four patients. Three of these patients had previously been resistant to immunosuppressive therapy. Median protein excretion increased to pretreatment values during the washout period (6.2 (1.9-15) g/d; P < 0.05) and was not significantly different after the intake of lovastatin (4.9 (1.8-19) g/d; P = NS). None of the patients achieved partial remission during lovastatin therapy (P < 0.05 vs. probucol). CONCLUSION: The present study led us to conclude that proteinuria can be reduced by probucol in some patients with idiopathic membranous nephropathy. A randomized multicenter study to further elucidate the influence of lipid peroxidation scavengers on membranous nephropathy is warranted.