UPDATE ON THE USE OF METHOTREXATE IN THE MANAGEMENT OF RHEUMATOID ARTHRITIS.

Rheumatoid arthritis (RA) is an auto-immune disorder described by permanent inflammation of the articular synovial membrane. Non-treated RA can cause gradual joint damage, ending in complaint, poor lifestyle, and an upright ratio of death. Approximately one percent of the people are involved, and the disorder begins, in general, appears during the third and fifth decades of age, with more occurrences in females. The treatment is complicated as well as involves various stages of medications with variable methods of application as well as non-pharmacologic methods. The extra prevalent are disease person's culture, then, sports and mechanical and behavioral therapy. Due to more chance of ischemic heart disease, trials should be increased to lessen the assisting behaviors such as cigarette smoking, high lipid profile, elevation of blood pressure, and high body mass index.

Higher beta-hydroxybutyrate ketone levels associated with a slower kidney function decline in ADPKD.

BACKGROUND AND HYPOTHESIS: Dysregulated energy metabolism is a recently discovered key feature of Autosomal Dominant Polycystic Kidney Disease (ADPKD). Cystic cells depend on glucose and are poorly able to use other energy sources such as ketone bodies. Raising ketone body concentration reduced disease progression in animal models of polycystic kidney diseases. Therefore, we hypothesized that higher endogenous plasma beta-hydroxybutyrate concentrations are associated with reduced disease progression in patients with ADPKD. METHODS: We analyzed data from 670 patients with ADPKD participating in the DIPAK cohort, a multi-center prospective observational cohort study. Beta-hydroxybutyrate was measured at baseline using nuclear magnetic resonance spectroscopy. Participants were excluded if they had type 2 diabetes, were using disease-modifying drugs (e.g. tolvaptan, somatostatin analogs), were not fasting, or had missing beta-hydroxybutyrate levels, leaving 521 participants for the analyses. Linear regression analyses were used to study cross-sectional associations and linear mixed-effect modeling for longitudinal associations. RESULTS: Of the participants, 61% were female, with an age of 47.3 ± 11.8 years, a height-adjusted total kidney volume (htTKV) of 834 (IQR 495-1327) ml/m, and an estimated glomerular filtration rate (eGFR) of 63.3 ± 28.9 mL/min/1.73m2. The median concentration of beta-hydroxybutyrate was 94 (IQR 68-147) µmol/L. Cross-sectionally, beta-hydroxybutyrate was neither associated with eGFR nor with htTKV. Longitudinally, beta-hydroxybutyrate was positively associated with eGFR slope (B = 0.35 ml/min/1.73m2 (95% CI 0.09 to 0.61), p = 0.007), but not with kidney growth. After adjustment for potential confounders, every doubling in beta-hydroxybutyrate concentration was associated with an improvement in the annual rate of eGFR by 0.33 ml/min/1.73m2 (95% CI 0.09 to 0.57, p = 0.008). CONCLUSION: These observational analyses support the hypothesis that interventions that raise beta-hydroxybutyrate concentration could reduce the rate of kidney function decline in patients with ADPKD.

Toxicity, arsenic speciation and characteristics of hyphenated techniques used for arsenic determination in vegetables. A review.

Arsenic (As) speciation is an interesting topic because it is well recognized that the toxicity of this metalloid ultimately depends on its chemical form. More than 300 arsenicals exist naturally. However, As can be present in four oxidation states: As-III, As0, AsIII and AsV. Long-term exposure to As from different sources, such as anthropogenic processes, or water, fauna and flora contaminated with As, has put human health at risk for decades. There are many side-effects correlated with exposure to InAs species, such as skin problems, respiratory diseases, kidney problems, cardiovascular diseases and even cancer. There are different levels and types of As in foods, particularly in vegetables. Furthermore, different chemical methods and techniques have been developed. Therefore, this review focuses on the general properties of various approaches used to identify As species in vegetation samples published worldwide. This includes various approaches (different solvents and techniques) used to extract As species from the matrix. Then, versatile chromatographic and non-chromatographic systems to separate different forms of As are reviewed. Finally, the general properties of the most common instruments used to detect As species from samples of interest are listed.

Directed delivery of terahertz frequency radiation from quantum cascade lasers within a dry 3He dilution refrigerator.

We present a scheme for the full integration of terahertz (THz) frequency quantum cascade lasers (QCLs) within a dilution refrigerator in order to provide a directed delivery of THz power into the sample space. We describe a successful operation of a 2.68 THz QCL located on the pulse tube cooler stage of the refrigerator, with its output coupled onto a two-dimensional electron gas (2DEG) located on a milli-kelvin sample stage via hollow metal waveguides and Hysol thermal isolators, achieving a total loss from QCL to the sample of ∼-9 dB. The thermal isolators limit heat leaks to the sample space, with a base temperature of ∼210 mK being achieved. We observe cyclotron resonance (CR) induced in the 2DEG by the QCL and explore the heating impact of the QCL on all stages of the refrigerator. The CR effect induced by the THz QCL is observable at electron temperatures as low as ∼430 mK. The results show a viable route for the exploitation of THz QCLs within the environment of a dilution refrigerator and for the THz power delivery in very low-temperature (<0.5 K) condensed matter experiments.

Large Rhinophyma Treated by Surgical Excision and Electrocautery.

Rhinophyma is a benign condition characterized by a large, bulbous nose with prominent pores. It is commonly associated with untreated cases of rosacea. The disease can carry a substantial psychological impact that causes patients to seek advice about how to improve their physical appearance. Many treatment options are available for rhinophyma, but there is no standard treatment protocol. Here, we describe the case of a 65-year-old man with a large rhinophyma that caused him cosmetic and psychosocial embarrassment. The condition was treated by surgical excision and bipolar electrocautery. No complications occurred after the procedures, and healing was completed 2 weeks later by secondary intention and reepithelialization. A simple surgical removal using a scalpel to shave off the abnormal tissue with electrocauterization of the bleeding points can be considered as a good treatment option for rhinophyma, as it results in an excellent cosmetic outcome and has short recovery time.

Clinical predictors of escalating care in hepatic and renal cyst infection in autosomal dominant polycystic kidney and liver disease.

BACKGROUND: Cyst infection may occur in autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant polycystic liver disease (ADPLD). Antimicrobial agents often fail to control infection, leading to invasive action. We aimed to identify factors predicting escalation of care. METHODS: ADPKD and ADPLD patients were identified from local/national databases (2001-2013). Records were screened for patients meeting criteria for cyst infection (positive cyst aspirate and/or clinical findings). Factors that predict escalated care were identified with multivariate modified Poisson regression. RESULTS: We screened 1773 patients. A total of 77 patients with cyst infection (4.3%) were included for analysis (hepatic 36%; male 49%; age 54 ±; 13 years; ADPKD 95%; dialysis 9%, diabetes 18%, renal transplant 56%, eGFR [IQR 24-78] ml/min/1.73 m2 (excluding patients with a history of renal transplant or receiving dialysis)). A pathogen was identified in 71% of cases. Escherichia coli was the most common pathogen and accounted for 69% of cases. Initial treatment was limited to antibiotics in 87% of patients (n = 67), 40% included a fluoroquinolone. Ultimately, 48% of patients underwent some form of invasive action (escalation of care). Increasing white blood cell count (WBC) (RR 1.04 95%-CI 1.01-1.07, p = 0.008) was associated with escalating care, whereas an increase in time between transplant and infection (RR 0.92 95% CI 0.86-0.97, p = 0.005) and E. coli isolation (RR 0.55 95% CI 0.34-0.89, p = 0.02) were protective. CONCLUSION: High serum WBC, isolation of atypical pathogens and early infection after transplantation are factors that increase the risk of escalation of care in hepatic and renal cyst infection patients.

GLI3-related polydactyly: a review.

GLI3 mutations are known to be associated with nine syndromes/conditions in which polydactyly is a feature. In this review, the embryology, pathogenesis, and animal models of GLI3-related polydactyly are discussed first. This is followed by a detailed review of the genotype-phenotype correlations. Based on our review of the literature and our clinical experiences, we recommend viewing GLI3-related syndromes/conditions as four separate entities; each characterized by a specific pattern of polydactyly. These four entities are: the preaxial polydactyly type IV-Greig-acrocallosal spectrum, postaxial polydactyly types A/B, Pallister-Hall syndrome (PHS), and oral-facial-digital overlap syndrome. We also provide illustrative clinical examples from our practice including a family with a novel GLI3 mutation causing PHS. The review also introduces the term 'Forme Fruste' preaxial polydactyly and gives several conclusions/recommendations including the recommendation to revise the current criteria for the clinical diagnosis of PHS.

Predictors of knowledge level and awareness towards breast cancer among Turkish females.

BACKGROUND: Breast cancer (BC) is the most-common malignancy of women worldwide. Though there are differences among developed and developing countries, BC remains the most common cancer type of women in Turkey. OBJECTIVE: This study aimed to identify the level of knowledge, awareness, and their potential predictors towards BC in Ankara, Turkey. MATERIALS AND METHODS: The present descriptive study was conducted on 376 females attending a breast health outpatient clinic. A self-administered questionnaire was designed to evaluate knowledge level about BC and predictors effecting its level. Data analysis was performed using the chi-square test. A value of p<0.05 was considered statistically significant. RESULTS: Mean age of the participants was 46.2±9.93 (22-75). The majority (92.6 %) were married; 41.5% were educated less than nine years. Most of the women were housewives (82.7%) and, were living in an urban region (86.4%). Predictors of effecting responses to seven knowledge and awareness questions about BC varied from demographic features including older age groups, higher educational levels, being married, living in an urban area, being employee, smoking, having greater BMI to additional attributes associated breast health such as the increased number of births, applying for the purpose of control, positive family history of breast diseases, any diagnoses of breast diseases and performing BSE practice. CONCLUSIONS: It was determined that females in Turkey have better knowledge of BC than other developing countries even though it is not at the desired level. These findings revealed that females should be more informed about BC risk factors, prognosis and treatments by primary health-care providers to counteract the ascending burden of this disease.

Pellagra-like condition is xeroderma pigmentosum/Cockayne syndrome complex and niacin confers clinical benefit.

An extremely rare pellagra-like condition has been described, which was partially responsive to niacin and associated with a multisystem involvement. The condition was proposed to represent a novel autosomal recessive entity but the underlying mutation remained unknown for almost three decades. The objective of this study was to identify the causal mutation in the pellagra-like condition and investigate the mechanism by which niacin confers clinical benefit. Autozygosity mapping and exome sequencing were used to identify the causal mutation, and comet assay on patient fibroblasts before and after niacin treatment to assess its effect on DNA damage. We identified a single disease locus that harbors a novel mutation in ERCC5, thus confirming that the condition is in fact xeroderma pigmentosum/Cockayne syndrome (XP/CS) complex. Importantly, we also show that the previously described dermatological response to niacin is consistent with a dramatic protective effect against ultraviolet-induced DNA damage in patient fibroblasts conferred by niacin treatment. Our findings show the power of exome sequencing in reassigning previously described novel clinical entities, and suggest a mechanism for the dermatological response to niacin in patients with XP/CS complex. This raises interesting possibilities about the potential therapeutic use of niacin in XP.

Predictors affecting breast self-examination practice among Turkish women.

BACKGROUND: Breast cancer (BC) is the most common cancer among females in Turkey. Predictors affecting the breast self-examination (BSE) performance vary in developing countries. OBJECTIVE: To determine the frequency of BSE performance and predictors of self-reported BSEs among women in the capital city of Turkey. MATERIALS AND METHODS: This cross-sectional study was conducted on 376 Turkish women using a self- administered questionnaire covering socio-demographic variables and BSE-related features. RESULTS: Of the participants, 78.7% (N=296) reported practicing BSE, whereas 9.5% (N=28) were implementing BSE regularly on a monthly basis, and only 5.7% (N=17) were performing BSE regularly within a week after each menstrual cycle. Multivariate logistic regression modeling revealed that BSE performance was more likely in younger age groups [20-39 years] (p=0.018, OR=3.215) and [40-49 years] (p=0.009, OR=3.162), women having a family history of breast disease (p=0.038, OR=2.028), and housewives (p=0.013, OR=0.353). CONCLUSIONS: Although it appears that the rates of BSE performers are high, the number of women conducting appropriate BSE on a regular time interval basis is lower than expected. Younger age groups, family history of breast diseases and not being employed were identified as significant predictors of practicing BSE appropriately. Older age and employment were risk factors for not performing BSE in this sample.

NPHP4 mutation is linked to cerebello-oculo-renal syndrome and male infertility.

Nephronophthisis is the most common genetic cause of renal failure in children and young adults. It is genetically heterogeneous and can be seen in isolation or in combination with other ciliopathy phenotypes. Here we report an index case where nephronophthisis is associated with oculomotor apraxia and cerebellar abnormalities, consistent with the clinical diagnosis of cerebello-oculo-renal syndrome. Prompted by a family history of an uncle with early onset end stage renal failure and infertility, we performed semen analysis on the index. This revealed marked reduction in the count of motile sperms as well as multiple abnormalities in the head and tail. Autozygome-guided mutation analysis followed by exome sequencing and segregation analysis revealed a homozygous truncating mutation in NPHP4, indicating that mutations of this gene can on rare occasions cause cerebello-oculo-renal syndrome. Our finding of severe male infertility in a family with NPHP4 truncation is strongly supported by the mouse model and, to our knowledge, is the first reported male infertility phenotype in association with NPHP4 or any other nephrocystin in humans.

Enantioselective Ullmann ether couplings: syntheses of (-)-myricatomentogenin, (-)-jugcathanin, (+)-galeon, and (+)-pterocarine.

The first enantioselective Ullmann cross-coupling reactions to prepare diaryl ethers are reported. The reactions were used to prepare the diarylether heptanoid natural products (-)-myricatomentogenin, (-)-jugcathanin, (+)-galeon, and (+)-pterocarine.

Growth curve prediction from optical density data.

A fundamental aspect of predictive microbiology is the shape of the microbial growth curve and many models are used to fit microbial count data, the modified Gompertz and Baranyi equation being two of the most widely used. Rapid, automated methods such as turbidimetry have been widely used to obtain growth parameters, but do not directly give the microbial growth curve. Optical density (OD) data can be used to obtain the specific growth rate and if used in conjunction with the known initial inocula, the maximum population data and knowledge of the microbial number at a predefined OD at a known time then all the information required for the reconstruction of a standard growth curve can be obtained. Using multiple initial inocula the times to detection (TTD) at a given standard OD were obtained from which the specific growth rate was calculated. The modified logistic, modified Gompertz, 3-phase linear, Baranyi and the classical logistic model (with or without lag) were fitted to the TTD data. In all cases the modified logistic and modified Gompertz failed to reproduce the observed linear plots of the log initial inocula against TTD using the known parameters (initial inoculum, MPD and growth rate). The 3 phase linear model (3PLM), Baranyi and classical logistic models fitted the observed data and were able to reproduce elements of the OD incubation-time curves. Using a calibration curve relating OD and microbial numbers, the Baranyi equation was able to reproduce OD data obtained for Listeria monocytogenes at 37 and 30°C as well as data on the effect of pH (range 7.05 to 3.46) at 30°C. The Baranyi model was found to be the most capable primary model of those examined (in the absence of lag it defaults to the classic logistic model). The results suggested that the modified logistic and the modified Gompertz models should not be used as Primary models for TTD data as they cannot reproduce the observed data.

Is full colonoscopic examination necessary in young patients with fresh bleeding per rectum?

BACKGROUND AND STUDY AIMS: Guidelines and practices differ regarding evaluation of young patients with fresh bleeding per rectum (FBPR). The aim of this study was to determine the frequency and site of endoscopic lesions in young patients with FBPR, and to thereby determine whether full colonoscopic examination is necessary in these patients. METHODS: Consecutive patients aged 18-50 years who were scheduled to undergo full colonoscopy for FBPR at Aga Khan University Hospital between May 2007 and October 2009 were enrolled in the study after giving informed consent. FBPR was defined as the passing of fresh blood per rectum with or without stools and/or noticing blood in the toilet bowl. Lesions were characterized as proximal or distal to the splenic flexure. Patients with positive family history of colorectal cancer, bleeding requiring blood transfusion, bleeding diathesis, or iron deficiency anemia were excluded. RESULTS: A total of 379 patients met the inclusion criteria and were analyzed. Of these, 248 patients (65.4%) were under 40 years of age and 131 (34.6%) were aged 40-50 years. Mean hemoglobin was 12.93 ± 1.78 g/dL. In patients < 40 years, seven (2.8%) adenomatous polyps and malignant lesions were found, all of which were located in the distal colon. In patients aged 40-50 years, 10 (7.6%) adenomatous polyps and malignant lesions were detected, one of which was located in the proximal colon. On univariate analysis, malignant and adenomatous lesions were significant in the 40-50 years age group (P = 0.031; OR, 2.84; 95% CI 1.05-7.65). CONCLUSION: Endoscopic lesions in patients younger than 40 years with FBPR are found mostly in the distal colon and hence flexible sigmoidoscopy seems to be a reasonable evaluation tool in young patients with no other alarm symptoms.

Rubber band ligation for 750 cases of symptomatic hemorrhoids out of 2200 cases.

AIM: To study the results for the treatment of symptomatic hemorrhoids using rubber band ligation (RBL) method. METHODS: A retrospective study for 750 patients who came to the colorectal unit from June, 1998 to September, 2006, data was retrieved from archived files. RBL was performed using the Mc Gown applicator on an outpatient basis. The patients were asked to return to out-patient clinic for follow up at 2 wk, 1 mo, 6 mo and through telephone call every 6 mo for 2 years). RESULTS: After RBL, 696 patients (92.8%) were cured with no difference in outcome for second or third degree hemorrhoids (P = 0.31). Symptomatic recurrence was detected in 11.04% after 2 years. A total of 52 patients (6.93%) had 77 complications from RBL which required no hospitalization. Complications were pain, rectal bleeding and vaso-vagal symptoms (4.13%, 4.13% and 1.33% of patients, respectively). At 1 mo there were a significant improvement in mean SF-36 scores over baseline in five items, while after 2 years there were improvement in all items over baseline, but not significant. No significant manometeric changes after band ligation. CONCLUSION: RBL is a simple, safe and effective method for treating symptomatic second and third degree hemorrhoids as an out patient procedure with significant improvement in quality of life. RBL doesn't alter ano-rectal functions.

A new form of childhood onset, autosomal recessive spinocerebellar ataxia and epilepsy is localized at 16q21-q23.

Childhood ataxias are a complex set of inherited disorders. Ataxias associated with generalized tonic-clonic epilepsy are usually included with the progressive myoclonus epilepsies (PME). Five disease entities, Unverricht-Lundborg disease, Lafora's disease, neuronal ceroid lipofuscinoses, myoclonic epilepsy with ragged red fibres and sialidoses, account for the majority of PME cases. Two rare forms of ataxia plus epilepsy, sensory ataxic neuropathy, dysarthria and ophthalmoparesis, and infantile onset spinocerebellar ataxia were described recently and found to be caused by defective mitochondrial proteins. We report here a large consanguineous family from Saudi Arabia with four affected children presenting with generalized tonic-clonic epilepsy, ataxia and mental retardation, but neither myoclonus nor mental deterioration. MRI and muscle biopsy of one patient revealed, respectively, posterior white matter hyperintensities and vacuolization of the sarcotubular system. We localized the defective gene by homozygosity mapping to a 19 Mb interval in 16q21-q23 between markers D16S3091 and D16S3050. Linkage studies in this region will allow testing for homogeneity of this novel ataxia-epilepsy entity.

Uranium and thorium series radionuclides in drinking water from drilled bedrock wells: correlation to geology and bedrock radioactivity and dose estimation.

Natural radioactivity in drinking water from 328 drilled wells was studied in correlation to source parameters. Poor correlation to both aquifer geology and bedrock radioactivity was observed. Concentrations of 238U, 226Ra, 228Ra, 222Rn and 210Po in groundwater samples was in the ranges <0.027-5.3, <0.016-4.9, <0.014-1.24, 5-8105 and <0.05-0.947 Bq.l(-1) respectively. In about 80% of the sites the radon concentration exceeds the Nordic recommended exemption level for radon in drinking water and 15% of the sites exceed the action limit. The effective doses from ingestion were calculated and presented in association with geology. Doses due to ingestion ranged between 0.05 and 20.4 mSv.y(-1), where the average contribution from 222Rn amounted to 75%. In comparison, the effective doses from inhalation of indoor 222Rn ranged between 0.2 and 20 mSv.y(-1). The average contribution from inhalation of 222Rn in air to the total effective dose (ingestion+inhalation) was 58 +/- 22%, 73 +/- 18% and 77 +/- 16% (1 SD) for the age categories 1 y, 10 y and adults respectively.

Alternative splicing in intracellular loop connecting domains II and III of the alpha 1 subunit of Cav1.2 Ca2+ channels predicts two-domain polypeptides with unique C-terminal tails.

Novel splice variants of the alpha(1) subunit of the Ca(v)1.2 voltage-gated Ca(2+) channel were identified that predicted two truncated forms of the alpha(1) subunit comprising domains I and II generated by alternative splicing in the intracellular loop region linking domains II and III. In rabbit heart splice variant 1 (RH-1), exon 19 was deleted, which resulted in a reading frameshift of exon 20 with a premature termination codon and a novel 19-amino acid carboxyl-terminal tail. In the RH-2 variant, exons 17 and 18 were deleted, leading to a reading frameshift of exons 19 and 20 with a premature stop codon and a novel 62-amino acid carboxyl-terminal tail. RNase protection assays with RH-1 and RH-2 cRNA probes confirmed the expression in cardiac and neuronal tissue but not skeletal muscle. The deduced amino acid sequence from full-length cDNAs encoding the two variants predicted polypeptides of 99.0 and 99.2 kDa, which constituted domains I and II of the alpha(1) subunit of the Ca(v)1.2 channel. Antipeptide antibodies directed to sequences in the second intracellular loop between domains II and III identified the 240-kDa Ca(v)1.2 subunit in sarcolemmal and heavy sarcoplasmic reticulum (HSR) membranes and a 99-kDa polypeptide in the HSR. An antipeptide antibody raised against unique sequences in the RH-2 variant also identified a 99-kDa polypeptide in the HSR. These data reveal the expression of additional Ca(2+) channel structural units generated by alternative splicing of the Ca(v)1.2 gene.

Alternative splicing, expression, and genomic structure of the 3' region of the gene encoding the sarcolemmal-associated proteins (SLAPs) defines a novel class of coiled-coil tail-anchored membrane proteins.

The sarcolemmal associated proteins (SLAPs) are encoded by multiple mRNAs that are presumably generated by alternative splicing mechanisms. The amino acid sequence of the SLAP1 isoform exhibited 76% identity with TOP(AP), a topographically graded antigen of the chick visual system. The regions of coiled-coil structure including an 11-heptad acidic amphipathic alpha-helical segment was conserved with a major divergence in sequence noted in the hydrophobic C termini predicted to be transmembrane domains in the two polypeptides. The genomic organization of the 3' region of the SLAP gene indicated that SLAP1 and TOP(AP) are generated by alternative splicing mechanisms, which are conserved among mammalian and avian species. SLAP1/TOP(AP) were encoded by 11 exons distributed over a minimum of 35 kilobase pairs of continuous DNA; 9 of the exons were constitutively expressed, and 2 were alternatively spliced. The exons range in size from 60 to 321 base pairs, and the predicted functional domains within the polypeptides were encompassed by single exons. The introns vary from 0.2 to 10 kilobase pairs and conform to consensus dinucleotide splicing signals. Reverse transcriptase-polymerase chain reaction studies demonstrated that alternative exons (IV and X) of SLAP were expressed in a tissue-specific fashion and developmentally regulated. The alternatively spliced exon X, which encodes the putative transmembrane anchor in TOP(AP), and a constitutively expressed exon XI, which encodes the putative transmembrane domain in SLAP, were found to target these polypeptides to membrane structures. The presence and conservation of termination codons in exons X and XI render expression of the two SLAP1/TOP(AP) transmembrane domains mutually exclusive. These data reveal that TOP(AP) and SLAP are alternatively spliced products of a single gene that encodes a unique class of tail-anchored membrane proteins.