CALCINOSIS CUTIS - A SERIES OF 59 CONSECUTIVE CASES CONFINED AMONG WOMEN.

BACKGROUND: Calcinosis cutis is the cutaneous deposition of calcium salts. Tumoral Calcinosis is a condition consisting of massive subcutaneous deposits of calcium salts often overlying large joints in otherwise healthy patients. OBJECTIVE: To describe the characteristics of a series of patients with Tumoral Calcinosis in the Gurage Zone of Central Ethiopia. METHODOLOGY: Data was collected from 59 patients who presented with clinical diagnosis of calcinosis cutis around hip region between January 2005 and January 2009. RESULTS: All cases were females, with a mean (standard deviation) age at diagnosis of 50.7(10.8). The duration of illness ranged from one to eighteen years. The cases were distributed in the different villages of Gurage Zone without any sign of clustering of cases. The lesions were localized around hip region on both sides. The patients did not have any related co-morbidity or any history of similar illness among close family members. None of the patients gave history of evident trauma to the site of the lesions. Significant proportion of the patients (53.4%) confirmed to carry water container and/or other goods on their side. Serum Phosphate and Calcium levels in selected patients were with in normal limit. Histo-pathological examinations of five cases revealed Calcium deposits in collagenous connective tissue. CONCLUSION: The lesion was found to be relatively common in the study area and specifically confined to females. The probable factor associated with the cases is carrying objects on their side (hip area). Further research with in-depth clinical and laboratory evaluation is of paramount importance.

Design, methodological issues and participation in a multiple sclerosis case-control study.

OBJECTIVES: This study was conducted to determine whether the risk of developing multiple sclerosis (MS) was associated with certain environmental exposures or genetic factors previously reported to influence MS risk. This paper describes the methodological issues, study design and characteristics of the study population. MATERIALS AND METHODS: Individuals with definite MS were identified from a prevalence study conducted in three geographic areas. The target number of cases was not reached, so an additional study area was added. Identifying clinic controls was inefficient, so controls were recruited using random digit dialing. All study participants completed a detailed questionnaire regarding environmental exposures using computer-assisted telephone interviewing, and blood was collected for genetic analysis. RESULTS: In total, 276 cases and 590 controls participated, but participation rates were low, ranging from 28.4% to 38.9%. Only one-third (33.6%) of individuals identified in the prevalence study agreed to participate in the case-control study. Cases were more likely to be non-Hispanic white and older than their source populations as identified in the preceding prevalence study (P < 0.05). Most participants provided a blood sample for genotyping (91%; n = 789). CONCLUSIONS: Epidemiological studies play a key role in identifying genetic and environmental factors that are associated with complex diseases like MS. Methodological issues arise in every study, and investigators need to be able to detect, respond to and correct problems in a timely and scientifically valid manner.

The role of a maternity waiting area (MWA) in reducing maternal mortality and stillbirths in high-risk women in rural Ethiopia.

OBJECTIVE: To describe maternal mortality and stillbirth rates among women admitted via a maternity waiting area (MWA) and women admitted directly to the same hospital (non-MWA) over a 22-year period. DESIGN: Retrospective cohort study. SETTING: Hospital in rural Ethiopia, which provided comprehensive emergency obstetric care and has an established MWA. POPULATION: All women admitted for delivery between 1987 and 2008. METHODS: Data on maternal deaths, stillbirths, caesarean section and uterine rupture were abstracted from routine hospital records. Sociodemographic characteristics, antenatal care and other data were collected for 2008 only. Rates and 95% confidence intervals were calculated for maternal mortality and stillbirth. MAIN OUTCOME MEASURES: Maternal mortality and stillbirth. RESULTS: There were 24, 148 deliveries over the study period, 6805 admitted via MWA and 17, 343 admitted directly. Maternal mortality was 89.9 per 100, 000 live births (95% CI, 41.1-195.2) for MWA women and 1333.1 per 100, 000 live births (95% CI, 1156.2-1536.7) for non-MWA women; stillbirth rates were 17.6 per 1000 births (95% CI, 14.8-21.0) and 191.2 per 1000 births (95% CI, 185.4-197.1), respectively; 38.5% of MWA women were delivered by caesarean section compared with 20.3% of non-MWA women, and none had uterine rupture, compared with 5.8% in the non-MWA group. For the 1714 women admitted in 2008, relatively small differences in sociodemographic characteristics, distance and antenatal care uptake were found between groups. CONCLUSIONS: Maternal mortality and stillbirth rates were substantially lower in women admitted via MWA. It is likely that at least part of this difference is accounted for by the timely and appropriate obstetric management of women using this facility.

Prevalence of human papilloma virus infection in women in rural Ethiopia.

In Ethiopia cervical carcinoma is the most frequent cancer in women. HPV infection is a prerequisite for this disease. However, to date there have been no data on human papilloma virus (HPV) prevalence in Ethiopia. Outpatients attending Attat hospital in rural Ethiopia were examined for the presence of HPV DNA using the Digene HPV test. 15.9% of patients were found to be HPV positive. The proportion of HPV high risk types was 13.2% [age-standardised rates: HPV: 14.4% (95% CI: 8.5-20.2); HPV high risk: 11.6% (95% CI: 6.3-16.9)]. Compared to other countries HPV prevalence is high, especially of high risk types. Until vaccination programmes take effect, screening programmes should not be based on HPV testing alone as this will lead to significant overtreatment of healthy women.

Differential regulation of the expression of transporters associated with antigen processing, TAP1 and TAP2, by cytokines and lipopolysaccharide in primary human macrophages.

OBJECTIVE: Using microarray technique we analysed global changes in gene expression of interferon-y treated primary macrophages. Among the differential expressed genes identified we focussed on the expression of the transporters associated with antigen processing, TAP1 and TAP2, which are involved in the antigen presentation via MHC class 1. Patients suffering from TAP deficiency syndrome have clinical manifestations including recurrent bacterial infections of the respiratory tract and chronic necrotizing granulomatous skin lesions. This is one reason why the regulation of TAP gene expression in antigen presenting cells such as macrophages might provide important general insights into the generation of cellular immune response to multiple pathogens. Additionally IFN-alpha is important in adjuvant tumortherapie although the working mechanisms are unknown. Because of the possibility of the TAPs to be involved in these mechanisms we studied the expression of these transporters in human macrophages after stimulation with pro-inflammatory mediators. MATERIAL AND TREATMENT: Monocyte derived macrophages were treated for 24 h with either interferon-gamma, interferon-alpha, interleukin-1 (each 100 U/ml) or lipopolysaccharide (1 microg/ml). METHODS: IFN-gamma induced gene expression was analysed using microarray technique. TAP expression was investigated by RT-PCR, northern blot- and western blot analysis. RESULTS: TAP1 and TAP2 were constitutively expressed at a low level. IFN-gamma upregulated the expression of both transporters. LPS caused an increase similar to the effect of IFN-gamma. Treatment with IFN-a stimulated also the expression, however, less than IFN-y. In contrast, IL-1beta stimulation had no effect. CONCLUSION: Our data show that the transporters associated with antigen presentation are differentially regulated by pro-inflammatory mediators in human macrophages. The finding that IFN-alpha stimulates the expression of proteins involved in cytotoxic effector functions of macrophages contributes to the understanding of the immunoregulatory role of type 1 interferons and may help to explain the efficacy of IFN-alpha in the treatment of tumors.

Dementia: the University of Oklahoma autopsy experience.

The brain from 98 consecutive patients with the clinical diagnosis of dementia were examined at autopsy in a standardized fashion. Alzheimer's Disease was present in 79 of the cases, 76%, but represented the only diagnosis in 41%. Thus, almost 60% had another associated pathologic disorder. Cerebral amyloid angiopathy (CAA) represented the single largest subset, present in 25 cases. 40% were accompanied by either 1) small, microscopic infarcts or cortical scars, or 2) small collections of macrophages containing hemosiderin or small hemorrhages. CAA occurred with both atherosclerotic cortical infarcts and arteriolosclerotic subcortical pallor or lacunar infarcts. Alzheimer's Disease occurred with Diffuse Lewy Body (DLB) Disease in 13 cases. DLB Disease did not occur as a distinct entity, and thus may represent the second largest subset of Alzheimer's Disease. Both Alzheimer's Disease and DLB Disease accounted for dementia in Parkinson's Disease. Almost 25% of all cases had a disorder other than Alzheimer's Disease.

Recurrent neural network-based approach for early recognition of Alzheimer's disease in EEG.

OBJECTIVE: We explored the ability of specifically designed and trained recurrent neural networks (RNNs), combined with wavelet preprocessing, to discriminate between the electroencephalograms (EEGs) of patients with mild Alzheimer's disease (AD) and their age-matched control subjects. METHODS: Twomin recordings of resting eyes-closed continuous EEGs (as well as their wavelet-filtered subbands) obtained from parieto-occipital channels of 10 early AD patients and 10 healthy controls were input into RNNs for training and testing purposes. The RNNs were chosen because they can implement extremely non-linear decision boundaries and possess memory of the state, which is crucial for the considered task. RESULTS: The best training/testing results were achieved using a 3-layer RNN on left parietal channel level 4 high-pass wavelet subbands. When trained on 3 AD and 3 control recordings, the resulting RNN tested well on all remaining controls and 5 out of 7 AD patients. This represented a significantly better than chance performance of about 80% sensitivity at 100% specificity. CONCLUSION: The suggested combined wavelet/RNN approach may be useful in analyzing long-term continuous EEGs for early recognition of AD. This approach should be extended on larger patient populations before its clinical diagnostic value can be established. Further lines of investigation might also require that EEGs be recorded from patients engaged in certain mental (cognitive) activities.

Expression of multiple cytochrome p450 enzymes and multidrug resistance-associated transport proteins in human skin keratinocytes.

Cytochrome P450 enzymes metabolize various endogenous and exogenous small molecular weight compounds. Transport-associated proteins, such as P-glycoprotein, multidrug resistance-associated protein and lung resistance protein are overexpressed in drug-resistant cell lines, as well as in human tumors from various histologic origins, including malignant melanoma. Little is known about the expression and function of cytochrome enzymes and multidrug resistance-associated transport proteins in human skin; therefore, the aim of this study was to analyze the expression pattern of cytochrome enzymes and multidrug resistance-associated transport proteins in proliferating human epidermal keratinocytes under constitutive conditions and after induction with various inducers. Reverse transcription-polymerase chain reaction revealed constitutive expression of cytochromes 1A1, 1B1, 2B6, 2E1, and 3A5 in keratinocytes and showed expression of cytochrome 3A4 after incubation with dexamethasone. The expression of cytochrome 1A1 was enhanced on the mRNA level after induction with benzanthracene. Reverse transcription-polymerase chain reaction analysis of the multidrug resistance-associated transport proteins revealed constitutive expression of multidrug resistance-associated proteins 1 and 3-6, and lung resistance protein in human epithelial keratinocytes and was negative for multidrug resistance 1 and 2. Expression of 1 was seen after induction with dexamethasone. Reverse transcription-polymerase chain reaction results were confirmed by immunoblots which showed expression of cytochromes 1A1, 2B6, 2E1, and 3A, multidrug resistance-associated proteins 1, 3, and 5 as well as multidrug resistance 1 after induction with dexamethasone. Immunohistology showed positive immunofluorescence in skin specimens for cytochromes 1A1, 2B6, 2E1, and 3A and multidrug resistance-associated protein 1 and multidrug resistance 1. Constitutive activity of cytochrome 1A1, 2B, 2E1, and 3A enzymes was measured by catalytic assays. These results show that keratinocytes of the human skin express various transport-associated enzymes and detoxifying metabolic enzymes. Previous studies have revealed that cytochrome enzymes and transport-associated proteins play complementary parts in drug disposition by biotransformation (phase I) and anti-transport (phase III) and act synergistically as a drug bioavailability barrier.

Inflammatory response to a porcine membrane composed of fibrous collagen and elastin as dermal substitute.

The inflammatory response to a collagen/elastin membrane was studied by measuring the expression of cytokines and function associated antigens in human macrophages. Additionally the angiogenic and inflammatory activity in the chorioallantoic membrane of the chick embryo (CAM-assay) was investigated. Macrophages cultured on the membrane expressed IL-1beta mRNA as early as after 4 hours. During prolonged culturing IL-1beta mRNA levels decreased. Messenger RNA for IL-8 was detectable over the whole culture period. The anti-inflammatory cytokine IL-10 was expressed up to one day only. Phenotypic analysis revealed a decrease in the number of chronic inflammatory 25F9 positive macrophages not migrating into the membrane but a presence of these cells together with the acute inflammatory 27E10 macrophages within the membrane whereas the anti-inflammatory subtype RM3/1 was absent. In the CAM-assay the membrane stimulated angiogenesis and induced the formation of granulation tissue. Histological analysis showed that the membrane was infiltrated with macrophages, fibroblasts and endothelial cells and locally with granulocytes. These data show that the collagen/elastin membrane causes activation of macrophages, angiogenesis and the formation of inflammatory tissue. Although these processes are essential for wound healing the type of inflammation points to a chronic process which might counteract an efficient scar formation.

A multiple sclerosis cluster associated with a small, north-central Illinois community.

The authors investigated a reported incidence cluster of multiple sclerosis (MS) cases in a small, north-central Illinois community to determine validity and statistical significance. DePue, Illinois--a small, north-central Illinois community--has previously been the site of significant environmental heavy-metal exposure from a zinc smelter. Significant contamination of soil and water with zinc and other metals has been documented in this community during the time period of interest. In the mid-1990s, several cases of MS were reported to the Illinois Department of Public Health within the geographic limits of this community. Available medical records from purported MS cases reported to the Illinois Department of Public Health were reviewed, and living individuals were seen and examined. Statistical analyses were conducted with clinically definite MS cases; onset dates were determined by first symptom, and expected incidence rates were determined from published epidemiologic studies. Nine new cases of clinically definite MS occurred among residents of DePue, Illinois, during the period between 1971 and 1990. Seven of the 8 living subjects included in the final analyses were examined by one author (RS). The computed incidence rate deriving from these cases within DePue Township, Illinois, represented a statistically significant excess of new MS cases over expected. During the period from 1971 through 1990, a significant excess of MS cases occurred within the population of DePue, Illinois. Significant exposure of this population to mitogenic trace metals, including zinc, was also documented during this time period.

Parkinson's disease: a preliminary study of yohimbine challenge in patients with anxiety.

In this pilot study, we performed an oral yohimbine challenge in 6 patients with Parkinson's disease (PD) and anxiety or depression, 2 parkinsonian patients without psychiatric illness, and 2 healthy control subjects to determine whether patients with Parkinson's disease and anxiety respond to this adrenergic agent in the same way patients with idiopathic anxiety disorders respond. Given the atypical nature of depression in Parkinson's disease (characterized by prominent anxiety), we also wanted to see if patients with Parkinson's disease and depression (but no history of anxiety) are susceptible to yohimbine-induced panic. Parkinsonian patients with anxiety developed panic attacks at frequencies comparable to primary psychiatric patients with panic disorder. The one patient with PD and a history of major depression alone developed a panic attack. Regardless of their history of anxiety or depression, parkinsonian patients demonstrated a vulnerability to yohimbine-induced somatic symptoms.

Neuropsychologic status in multiple sclerosis after treatment with glatiramer.

BACKGROUND: Glatiramer acetate (Copaxone) therapy reduces clinical disease activity in relapsing-remitting multiple sclerosis (MS). OBJECTIVE: To study the effect of glatiramer therapy on neuropsychologic function as part of a randomized, placebo-controlled, multicenter trial. METHODS: Two hundred forty-eight patients with relapsing-remitting MS and mild to moderate disability (Expanded Disability Status Scale score, <5.0) were tested before and 12 and 24 months after randomization to administration of glatiramer acetate, 20 mg/d, or matching placebo. Neuropsychologic tests examined 5 cognitive domains most often disrupted in patients with MS: sustained attention, perceptual processing, verbal and visuospatial memory, and semantic retrieval. RESULTS: Baseline neuropsychologic test performance was similar in both treatment groups and was within normal range, except for impaired semantic retrieval. Mean neuropsychologic test scores were higher at 12 and 24 months than at baseline, and no differences were detected between treatment groups over time. No significant interactions were detected between treatment and either time or baseline impairment. CONCLUSIONS: Our 2-year longitudinal study showed no effect of glatiramer therapy on cognitive function in relapsing-remitting MS. Although it is possible that glatiramer therapy has no effect on cognitive function, the lack of measurable decline in cognitive function in both patient groups for 2 years limits the opportunity for glatiramer to demonstrate a therapeutic effect by minimizing such decline. Emerging treatments for MS should continue to be examined for their effect on cognitive impairment because it can be a critical determinant of disability. A greater understanding of the natural history of cognitive decline in MS is essential for a rational design of these drug trials.

The contact of human macrophages with extracellular matrix proteins selectively induces expression of proinflammatory cytokines.

The interaction of macrophages with proteins of the extracellular matrix (ECM) is important for the regulation of the immune and nonimmune functions displayed by these cells. Little, however, is known about the ability of different ECM proteins to transmit inflammatory signals into macrophages. Here we investigated the effect of the ECM proteins collagen type I, fibrin and fibronectin on the expression of the proinflammatory cytokines interleukin-1beta (IL-1beta) and IL-8 using RT-PCR, Northern and Western blot analysis and ELISA technique. It was found that collagen strongly induced IL-1beta and IL-8 expression in the macrophages. Fibronectin also stimulated cytokine expression, however, the amounts of the specific mRNAs were significantly lower compared to those induced by collagen. On the protein level IL-1beta revealed a close correlation to the mRNA expression. In contrast, fibrin did not elicit any IL-1beta and IL-8 response. These data show that different ECM proteins vary in their ability to induce proinflammatory cytokine expression in human macrophages suggesting that the protein composition of the ECM might be crucial in the initiation of inflammatory processes.

Lewy body disease: can we diagnose it?

The authors assessed the accuracy of published clinical criteria and their own modifications of those criteria in diagnosing Lewy body disease (LBD). Clinical diagnoses were made by two clinicians, blinded to neuropathologic diagnoses, using the Rochester Alzheimer's Disease Center database and traditional medical records. Neuropathologic diagnoses were made according to published guidelines. Results from 21 Alzheimer's disease and 18 LBD patients indicated that no set of clinical criteria was accurate in diagnosing LBD. The only significant predictor of LBD in this population was depression, which was more common in LBD than in Alzheimer's disease. The authors conclude that clinical identification of LBD is an important but unresolved neurological problem.

A review of Lewy body disease, an emerging concept of cortical dementia.

Dementia associated with cortical Lewy bodies on neuropathologic examination may comprise the second largest category of age-related cognitive impairment, after Alzheimer's disease. Despite its prevalence, a consensus has not yet been reached regarding the terminology, neuropathologic criteria, or clinical symptomatology of this postulated nosologic entity. Lewy body disease (LBD) is beginning to be diagnosed clinically in neuropsychiatric clinics, but universally accepted diagnostic criteria for LBD remain to be validated. In this article the authors review the literature on LBD, including both neuropathologic and clinical findings.

Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Copolymer 1 Multiple Sclerosis Study Group.

When 251 relapsing-remitting patients with multiple sclerosis were randomized to receive daily subcutaneous injections of glatiramer acetate, previously called copolymer 1 (Copaxone; n = 125) or placebo (n = 126) for 24 months, there were no laboratory abnormalities associated with glatiramer acetate treatment and it was well tolerated with few side effects. Patients receiving glatiramer acetate had significantly fewer relapses and were more likely to be neurologically improved, whereas those receiving placebo were more likely to worsen. This study was extended for 1 to 11 months (mean of 5.2 months for the glatiramer acetate group and 5.9 months for the placebo group). The blinding and study conditions used during the core 24-month study were unchanged throughout the extension. The results of this extension study confirm the excellent tolerance and safety profile of glatiramer acetate for injection. The clinical benefit of glatiramer acetate for both the relapse rate and for neurologic disability was sustained at the end of the extension trial.