Diabetes mellitus (DM) is recognised as an important risk factor to tuberculosis (TB). India has high TB burden, along with rising DM prevalence. There are inadequate data on prevalence of DM and pre-diabetes among TB cases in India. Aim was to determine diabetes prevalence among a cohort of TB cases registered under Revised National Tuberculosis Control Program in selected TB units in Tamil Nadu, India, and assess pattern of diabetes management amongst known cases.827 among the eligible patients (n = 904) underwent HbA1c and anthropometric measurements. OGTT was done for patients without previous history of DM and diagnosis was based on WHO criteria. Details of current treatment regimen of TB and DM and DM complications, if any, were recorded. A pretested questionnaire was used to collect information on sociodemographics, habitual risk factors, and type of TB.2 vs <18.5 kg/m2) ; for pre-diabetes, risk factors were age  , waist circumference  [3.05 (1.35–6.9) (p = 0.007)], smoking [1.92 (1.12–3.28) (p = 0.017)] and monthly income  [0.59 (0.37–0.94) (p = 0.026)]. DM risk was higher among pulmonary TB [3.06 (1.69–5.52) (p<0.001)], especially sputum positive, than non-pulmonary TB.DM prevalence was 25.3% (95% CI 22.6–28.5) and that of pre-diabetes 24.5% (95% CI 20.4–27.6). Risk factors associated with DM among TB patients were age  , positive family history of DM [3.08 (1.73–5.5) (p<0.001)], sedentary occupation [1.69 (1.10–2.59) (p = 0.016)], and BMI (18.5–22.9, 23–24.9 and ≥25 kg/mNearly 50% of TB patients had either diabetes or pre-diabetes. Mycobacterium tuberculosis and about 10% of them are at risk of developing active form of the disease in their lifetime depending upon the interaction of the epidemiological triad The global burden of diabetes mellitus (DM) and tuberculosis (TB) is huge. Nearly one-third of world’s population is infected with India has the largest number of TB cases estimated globally to be 2 million per annum and accounts for more than 60 million people with type 2 diabetes Many studies reported that subjects with diabetes were at three-fold higher risk of developing TB. In addition, studies that screened for DM among TB patients reported a wide range of DM prevalence among TB patients, ranging from 1.9% to as high as 35% Therefore, it is necessary to consider the increasing prevalence of diabetes since diabetes is associated with an increased risk of TB treatment failure and death during tuberculosis treatment, as well as an increased risk of relapse. A study from Jaipur, Rajasthan, which followed up TB cases taking Category I and II treatment for 2 years, reported diabetes as one of the associated factors for relapse of TB cases Screening for DM in TB patients could improve DM case detection and early treatment and indirectly lead to better TB-specific treatment outcomes Ethics Committee of Prof. M. Viswanathan Diabetes Research Centre approved the study and written consent was obtained from all study subjects. Tamil Nadu state RNTCP also gave permission to conduct the study.The study population was selected from Tamil Nadu state in South India. Five TUs – two from urban (Jaibeem Nagar and Medavakkam), two from rural (Budur and Beerakuppam), and one from semi-urban (Nandivaram) areas of Chennai, Thiruvallur, and Kanchipuram districts, respectively, of Tamil Nadu were randomly selected for this study . Each TBAfter identification of the sampling frame, cluster random sampling technique was used to recruit the study subjects. A sample size of 800 was required, assuming the prevalence of diabetes as 20% amongst the TB subjects, with 95% confidence interval, precision ±5%, non-response rate of 10% and with the inclusion of design effect of 2. The assumption of prevalence of 20% (for 50.8 million people with diabetes in 2010) was based on the prevalence of DM among TB patients estimated by Stevenson et al. as 18.4% for 20 million people with diabetes in India in 2000 2) was calculated. Two blood pressure measurements were taken using sphygmomanometer with the subject in sitting posture, and average of the two readings was recorded.A trained investigator recorded anthropometric measurements viz., height, weight, and waist circumference by standard procedure. BMI  (categorised as <18.5 (reference), 18–22.9, 23.0–24.9, ≥25.0)]), waist circumference , type of TB (pulmonary vs extrapulmonary), family history of DM, smoking, alcohol consumption, and tobacco use. The model fit information was significant for multinomial logistic regression analysis  and also the fit was good . A P value of <0.05 was considered statistically significant.SPSS version 16.0 was used for statistical analysis. Prevalences are reported with 95% confidence intervals calculated considering the design effect. Mean and standard deviation for continuous variables and proportions for categorical variables are reported. Independent sample ‘t’ test and ANOVA were used to test continuous variables and Chi-square test was used to compare categorical variables. Multinomial logistic regression analysis was performed to identify the factors associated with diabetes and pre-diabetes – the dependent variable being either diabetes or pre-diabetes and the independent variables were age , sex, occupation (sedentary vs non-sedentary), locality , monthly income [(INR) ], BMI  had diabetes and prevalence of diabetes was significantly higher in men compared to women [27.5 (95% CI 22.8–31.2) vs 20.2% (95% CI 15.4–26.2); p = 0.031). Diabetes was newly detected in 9.3% (n = 77) of TB patients and 15.96% (n = 132) were known cases of diabetes. The prevalence of pre-diabetes was 24.5% (95% CI 20.4–27.6). Subjects were undiagnosed previously and the screening process identified that they had pre-diabetes. The prevalence of isolated Impaired Fasting Glucose (IFG) was 2.7% (95% CI 1.4–3.9) and isolated Impaired Glucose Tolerance (IGT) was 16.3% (95% CI 13.2–18.1) and both IFG and IGT were present in 5.6% (95% CI 4.0–7.5) of the subjects. There was no significant difference noted between men and women in the prevalence of different categories of pre-diabetes .Among the newly registered TB cases (695), 172 patients had diabetes and another 172 had pre-diabetes. A higher proportion of patients with TB DM were smear positive (55.8%) compared to pre-diabetes (50.6%) or those with normoglycaemia (42.5%). Extrapulmonary TB on the other hand was more common among TB patients with normoglycaemia (27.9%) compared to patients with pre-diabetes (16.3%) and diabetes (12.8%) as shown in 2, positive family history of diabetes, sedentary occupation and presence of PTB were significantly associated with diabetes among TB patients. Age category >50 years had a great influence with odds ratio of 24.7 , followed by positive family history of diabetes with OR 3.08 (95% CI 1.73–5.5). PTB compared to non-PTB was associated with a higher risk of diabetes with an odds ratio of 3.06 , [Multinomial logistic regression analysis showed that increasing age, BMI category 18.5–22.9 kg/m<0.001), . Age, wa<0.001), .Out of 209 DM subjects, 71 (34%) had HbA1c <7%, 25 (12%) had HbA1c 7.0–7.9%, 29 (13.9%) had HbA1c 8.0–8.9%, 15 (7.2%) had HbA1c 9.0–9.9%, and 69 (33%) had HbA1c ≥10.0%. Moreover, there was no significant difference in the proportion of new and relapsed cases between the HbA1c categories (p = 0.634).The median period of duration of diabetes among known cases was 2.3 years (0.5–24 years). Among the known cases of DM, 92.4% (n = 122) subjects reported regular compliance to treatment for diabetes, the remaining reported intermittent treatment or irregular compliance to diabetes treatment. Among those who were on regular treatment, 84 (68.9%) were on oral hypoglycemic agents, 29 (23.8%) were only on insulin, and nine (7.4%) were taking both oral hypoglycemic agents and insulin. About 59% (n = 72) were undergoing treatment in government health centres and 41% (n = 50) were undertaking treatment in private healthcare settings. Complications and comorbid conditions reported amongst subjects with pre-existing diabetes were nine cases (6.8%) of cardiovascular disorders, 12 cases (9.1%) of hypertension, three cases with (2.3%) foot ulcers, and one case (0.7%) of retinopathy.The association between DM and TB is well documented and there is substantial evidence to support the fact that diabetes is an important risk factor for TB Studies conducted in regions with dual burden had reported that the prevalence of DM ranged from 14–40% Alisjahbana et al. In the present study, among the TB patients identified with diabetes, more than 60% of them had been diagnosed with diabetes previously. It is known that long-term diabetes can impair the innate and adaptive immune responses necessary to counter the proliferation of TB 2 were double the time at risk of developing diabetes compared to the patients with BMI <18.5 kg/m2. The lesser distribution of TB patients in the overweight and obese categories, as per Asian Indian guidelines can be explained for the non-significant association with DM among these categories. Positive family history of diabetes was significantly associated with DM with an odds ratio of 3.08. Age, waist circumference, smoking habit and monthly income category 5000–10,000 INR emerged as independent risk factors significantly associated with pre-diabetes among TB patients. The highest odds ratio was shown for age category 41–45 years (6.96), waist circumference (OR 3.05), and smoking (OR 1.92) for pre-diabetes among TB patients.As in the general population age, BMI, positive family history of DM and sedentary occupation were the common risk factors associated with diabetes among TB patients, in the present study. The DM-associated risk factors among general population which were not seen in the current study were urban dwelling and income status. TB patients with DM were older compared to the non DM counterparts and while still underweight compared to the general population they had higher BMI relative to non DM TB patients. In the multinomial logistic regression analysis, odds ratio for age group >50 years was higher compared to those aged <30 years. There was a gradual increase in the odds ratio as the age increased in terms of five units. A sudden decrease in the odds ratio was observed in the age group 46–50 years, which could be attributed to the less number of patients in this age group. The TB patients with BMI 18.5–22.9 kg/mAssociation of DM with PTB  particularly for smear positive cases in this study was similar to that of the findings of Stevenson et al. TB treatment outcome among TBDM patients is still not clear. Few studies reported that TB treatment outcome amongst DMTB subjects was good compared with non-DMTB subjects with the existing treatment An earlier report stated that prevalence of diabetes might be overestimated in TB since TB can cause transient hyperglycaemia Several recent reports indicate the need to consider the increasing trend in prevalence of diabetes in countries like India, which will impact the TB burden as well The study reports prevalence of DM among TB patients registered in the RNTCP. Since there is no active case detection under RNTCP, a community-based study would provide a better representative sample. This is one of the limitations of the present study.Moreover, there is a need for greater collaboration between RNTCP and National Program for Prevention and Control for Cancer, Diabetes, Cardiovascular Diseases and Stroke (NPCDCS) in India to ensure that protocols and guidelines are in place to address the dual burden. Given the high association between TB and dysglycemia  and that more than a third of DM cases amongst people with TB were newly detected, a recommendation for universal screening for diabetes amongst people with TB would not seem out of place in a country like India with a high double burden. The limited resources and infrastructure for diabetes prevention and care at the primary setting make it even more necessary that the health resources and infrastructure for TB control should be further strengthened and serve the purpose of promoting prevention, early detection, and treatment of diabetes among TB patients particularly in India. Although such services can be offered for a limited time–during the course of TB treatment–the intensive contact through DOTS initiative may lay a strong foundation for lifelong good control through self-care training in diabetes while at the same time reduce risk of treatment failure, re-infection, and relapse.In conclusion, this study revealed that about half of TB patients had either diabetes or pre-diabetes. Moreover, those with TBDM were more likely to have the infective form of TB. These findings pose a great challenge for TBDM control in India.


To study the evolution of CD4 count of HIV-infected patients in follow-up as an indicator of quality of care.3 after 1 year in HIV care, or an increasing rate exceeding 50 cells/mm3 per year, and this regardless of antiviral therapy. The proportion of patients with optimal CD4 evolution was measured and factors associated with outcome were identified by logistic regression.Adult patients newly diagnosed with HIV in 2007 who entered in care in the AIDS Reference Centres (ARC) and remained in care for at least one year were studied until end 2009. Optimal CD4 evolution was defined as having a CD4 count above 350 cells/mm482 patients were included. Median age was 37 years, 31.1% were females, 51.7% Belgians, 32.2% from Sub-Saharan Africa, 50.5% heterosexual, 48.7% MSM. 59.5% had a CD4 count above 350 at entry in care, 11.2% did not have a regular retention in care (at least 1 consultation/6-month period). 401 (83.2%) patients had an optimal CD4 evolution after 1 year in care. 60.5% of patients with non-optimal evolution had a CD4 count below 350 at entry in care. Although the proportion of female sex, heterosexual transmission, Sub-Saharan nationality and low retention in care was higher in the non-optimal CD4 evolution group compared to the optimal group, none of these characteristics showed a significant association with non-optimal CD4 count evolution.83.2% of patients had an optimal CD4 evolution after at least 1 year in HIV care. This indicator, analysed together with indicators of entry and retention in care, could contribute to a better monitoring of the HIV epidemic and to identify more precisely the steps in care system that could be improved. These indicators should be fully integrated in HIV surveillance.


ARSA gene. Based on epidemiological surveys the incidence of MLD per 100 000 live births varied from 0.6 to 2.5. Our purpose was to estimate the birth prevalence of MLD in Poland by determining population frequency of the common pathogenic ARSA gene mutations and to compare this estimate with epidemiological data.Metachromatic leukodystrophy (MLD) is a severe neurometabolic disease caused mainly by deficiency of arylsulfatase A encoded by the ARSA gene mutations: c.459+1G>A, p.P426L, p.I179S (cohort 1) and c.459+1G>A, p.I179S (cohort 2).We studied two independently ascertained cohorts from the Polish background population (N∼3000 each) and determined carrier rates of common ARSA gene mutation distribution among 60 Polish patients, the expected MLD birth prevalence in the general population (assuming no selection against homozygous fetuses) was estimated as 4.0/100 000 and 4.1/100 000, respectively for the 1st and the 2nd cohort with a pooled estimate of 4.1/100 000 (CI: 1.8–9.4) which was higher than the estimate of 0.38 per 100 000 live births based on diagnosed cases. The p.I179S mutation was relatively more prevalent among controls than patients .Taking into account The observed discrepancy between the measured incidence of metachromatic leukodystrophy and the predicted carriage rates suggests that MLD is substantially underdiagnosed in the Polish population. The underdiagnosis rate may be particularly high among patients with p.I179S mutation whose disease is characterized mainly by psychotic symptoms. ARSA gene located on chromosome 22q13. The overall incidence of MLD varies from 1 in 40 000 to 1 in 170 000 in different populations ARSA gene – c.459+1G>A, p.P426L, and p.I179S are responsible together for approximately 50% of mutated alleles in MLD patients from Poland Metachromatic leukodystrophy  is a severe demyelinating disease inherited in an autosomal recessive fashion. MLD is caused by deficient activity of lysosomal hydrolase arylsulfatase A  which leads to sulfatide storage. Apart from an MLD type caused by saposin B deficiency all clinical forms of MLD are due to mutations in the The aim of this study was to estimate the birth incidence of MLD in Poland by determining the population frequency of the common MLD causing mutations and compare this estimate with epidemiological data.ARSA gene mutations could be estimated as 0.28% (CI: 0.18–0.45) and joint population frequency of all pathogenic mutations in ARSA gene as 0.63%  with CI from 1.7 to 9.6.During the initial screening performed among subjects undergoing paternity testing results were obtained for 3 320, 3 467, and 3 159 samples, respectively for mutations c.459+1G>A, p.P426L, and p.I179S. Five heterozygous carriers for c.459+1G>A, seven heterozygous carriers for p.P426L, and 11 heterozygous carriers for p.I179S were identified  yieldingARSA gene mutations between MLD patients and controls. Among the patients the c.459+1G>A mutation was the most prevalent accounting for 42.4% or 28/66 of the three tested variants whereas p.I179S had lower frequency (28.8% or 19/66 of the tested variants). Among controls this correlation was reversed: c.459+1G>A was the least prevalent (21.7% or 5/23) whereas p.I179S had the highest frequency (47.8% or 11/23). When frequency of the p.I179S mutation was expressed relative to frequency of the c.459+1G>A mutation a trend with borderline statistical significance of P = 0.051  was observed in a comparison between controls (11/5) vs. patients . Results were obtained for 3 019 and 2 937 samples for c.459+1G>A and p.I179S, respectively. Four heterozygous carriers of c.459+1G>A and 11 heterozygous carriers of p.I179S were identified yielding the respective estimates of gene frequency of 0.07% (CI: 0.03–0.17) and 0.19%  between population cohort 2 (11/4) and patients 19/28, .Since there were no statistically significant differences between mutation frequency estimates based on the two population cohorts (P>0.8 in both comparisons) we also analyzed the data after pooling. This analysis was based on 6 339 subjects tested for c.459+1G>A, nine of whom were positive and 6 096 subjects tested for p.I179S of whom 22 were positive yielding the estimates of gene frequencies equal to 0.07% (CI: 0.04–0.13) and 0.18% (CI: 0.12–0.27), and carrier frequencies per 10 000 equal to 14 (CI: 7–27) and 36 (CI: 24–55), respectively for c.459+1G>A and p.I179S .ARSA gene mutations among patients the gene frequency of all pathogenic mutations was estimated as 0.64 with CI from 0.42 to 0.97 and carriage rate per 10 000 as 126  with CI from 1.8 to 9.4  between pooled population cohorts (22/9) and patients 19/28, .Analysis of the graph showing cumulative number of MLD cases diagnosed per year plotted against year of birth showed that the curve was linear from year 1975 to 2004  indicatiARSA gene mutations: c.459+1G>A, p.P426L, and p.I179S. After taking into account the frequency of these mutations among MLD patients, the carriage rate of all pathogenic ARSA gene mutations was estimated as 125/10 000 or 1/80 whereas disease prevalence among conceived fetuses was 4.0 per 100 000. These estimates were closely confirmed by analysis of an independently ascertained population cohort . An analysis using a pooled cohort of > 6 000 subjects yielded carriage rate per 10 000 equal to 126 or 1 in 79 and prevalence of fetuses conceived with two pathogenic MLD causing mutations of 4.1 per 100 000 (CI: 1.8–9.4). We also observed that the p.I179S mutation was relatively more frequent among controls than patients. In particular when p.I179S frequency was expressed relative to c.459+1G>A a statistically significant difference was observed between controls vs. patients .In the present study we determined the general population carriage rates of three pathogenic ARSA mutations in Poland (4.1 per 100 000) is substantially higher than the birth prevalence of MLD based on diagnosed cases (0.38 per 100 000 live births as determined by us or 0.53 per 100 000 (1 in 189 000) as previously reported in Poland The expected prevalence of fetuses conceived with two pathogenic The birth prevalences of MLD were higher only in small, geographically or ethnically isolated communities like in Habbanite Jews in Israel (1 in 75) ARSA gene resulting in the severe phenotype can lead to prenatal or perinatal loss of affected fetuses thus decreasing prevalence among live born children. Whereas in Poland prenatal screening for MLD has not been performed, prenatal diagnosis in families with MLD probands is available which is likely to decrease number of affected individuals born. We also cannot fully exclude that some patients are diagnosed abroad and thus not referred to the Institute of Psychiatry and Neurology in Warsaw. However, this should not be frequent since in the Polish health system referral to foreign centers occurs only in exceptional cases.This discrepancy between our estimate and observed incidence of MLD in Poland may have several causes. It should be emphasized that all birth prevalence values reported so far were based on direct diagnoses whereas our estimations are the first based on the mutation carrier rates in general population. It is possible that mutations in the Our findings may also be influenced by a distinct phenotype associated with the p.I179S and possibly other yet unknown mutations. Since patients with the p.I179S mutation suffer initially mainly from psychotic manifestations it is possible, that some individuals from this group are misdiagnosed as affected with atypical schizophrenia The close similarity of carriage rates of c.459+1G>A and p.I179S in a population coming mainly from Central Poland  and population representative of the whole country  supports ethnic homogeneity of Polish population and strengthens our conclusions which rely also on data from patients coming from the whole Polish territory. Homogeneity of contemporary Polish population is consistent with studies on distribution of Y chromosome markers which are particularly sensitive to population substructure A limitation of our study is caused by lack of appropriate molecular testing allowing to rigorously exclude related individuals from the population cohorts studied. Further, whereas our determination of background population carriage rates is apparently robust the data on mutation distribution among patients may not be so reliable as they come from a single group of limited size. Although our statistical approach takes this into account it would be interesting to verify our conclusions in another population and MLD patients groups.ARSA mutations of 4.1 in 100 000 and heterozygote frequency of 1 in 79 negate this statement. One possible reason for the discrepancy between observed and expected prevalence of MLD may be related to disease underdiagnosis, especially among patients with p.I179S mutation.In conclusion, MLD and other lysosomal disorders are considered to be orphan diseases but the expected incidence of fetuses conceived with two pathogenic Three thousand five hundred DNA samples were obtained from anonymous DNA samples collection of Department of Forensic Medicine WUM which has been described previously This cohort consisted of three thousand one hundred subjects randomly selected from the participants of WOBASZ study ARSA gene among MLD patients was determined based on 60 unrelated probands who were all typed for these variants for diagnostic purposes as described previously The distribution of the c.459+1G>A, p.P426L and p.I179S mutations in the Assay on Demand from Life Technologies and real time PCR apparatus ABI Prism 7500. In all TaqMan experiments at least three positive samples verified by PCR-RFLP were used as controls. For all mutations positive results were verified by re-analysis of samples from the original stock.In population cohort 1 the screening for the c.459+1G>A, p.P426L, and p.I179S mutations was performed by PCR-RFLP methods tested_pop.f) was estimated by summing individual frequencies. The population frequency of mutations which were not tested including those which are unknown (n.tested_pop.f) was estimated from the prevalence of the tested mutations among MLD patients from our center (tested_pat.f). Assuming similar penetrance for all MLD mutations their relative frequencies among patients and population controls should be the same. Thus, n.tested_pop.f  =  tested_pop.f (1- tested_pat.f)/ tested_pat.f. Similarly, population frequency of all pathogenic mutations all_popf  =  tested_popf / tested_pat.f Based on data available from patients tested_pat.f was estimated as 66/120 or 55% for Population cohort 1 and 47/120 or 39.2% for Population cohort 2 as well as the pooled cohorts. The expected population frequencies of (i) carriers of pathogenic mutations and (ii) of affected individuals (i.e. those with two pathogenic ARSA gene mutations) were estimated from Hardy-Weinberg law as (i) 2× all_popf ×  and (ii) all_popf2.Joint population frequency of tested mutations . Analogous approach was used for Population cohort 2 and pooled cohort. Computations of CI were done using spreadsheet downloaded from (accessed 20.01.2007):http://www.cardiff.ac.uk/medicine/epidemiology_statistics/research/statistics/ODDSRATIOANDRR.xls. Frequency of the p.I179S mutation expressed relative to frequency of the c.459+1G>A in the general population and among patients was compared by a chi square test with one degree of freedom using Statistica software package.Ninety five percent confidence intervals (CI) for mutation frequencies were calculated according to Wilson Incidence  of MLD in Poland was determined by the method proposed by Claussen et al. www.stat.gov.pl/gus).In Poland lysosomal disorders including MLD are diagnosed exclusively in the Department of Genetics at the Institute of Psychiatry and Neurology in Warsaw and it was assumed that all Polish patients with the suspicion of MLD were referred to our laboratory. The numbers of births per year were obtained from Polish Central Statistical Office (Table S1Demographic data vs. numbers of MLD patients born in Poland.(DOC)Click here for additional data file.


Parasitaemia on Day 3 has been proposed as a useful alert of potential artemisinin resistance, however, the normal variation of parasite clearance observed in artemisinin-based combination therapy clinical trials is poorly documented.The trends in early parasitological response following treatment with an artemisinin anti-malarial regimen were reviewed. A PubMed literature search identified all studies using an artemisinin regimen for uncomplicated falciparum malaria published between January 2000 and December 2011. Data from clinical studies were extracted for analysis using a standardized questionnaire.vs 0%, p=0.007), but increased in Asia . In 95% of studies the proportion of patients with peripheral parasitaemia was less than 6% at 72 hours.In total 65,078 patients were enrolled into 213 clinical trials with 413 treatment arms containing either an artemisinin derivative alone (n=26) or in combination with a partner drug (n=387). The proportion of patients remaining parasitaemic at 24, 48 and 72 hours was documented in 115 (28%), 167 (40%) and 153 (37%) treatment arms, respectively. Excluding resistance studies in Cambodia, the median proportion of patients still parasitaemic was 53.8%  on Day 1, 6%  on Day 2 and 0  on Day 3. Comparing studies from 2000 to 2005 and 2006 to 2011, the median proportion of patients reported to remain parasitaemic at 72 hours decreased in Africa (1.2% These results highlight the normal distribution of early parasitological responses following ACT, and the influence that heterogeneity in study design, host and parasite factors have in confounding a surveillance system based on Day 3 parasite positivity. Greater understanding of factors influencing parasite clearance is crucial, but will require analysis of pooled data from individual patient records. Plasmodium falciparum malaria recommended by the World Health Organization (WHO)  for PPRday2 was 2.72 [1.90-3.92] for regimens with less than two days of artemisinin derivative therapy (four arms with 588 patients) and was 6.19 [3.43-11.17] for PPRday3 for treatments with shorter than three days  compared to regimens with longer courses of artemisinin derivatives. In Asia, all treatments included at least three days of artemisinin derivatives, except for 182 patients in two study arms who received only two days. Further analyses of PPRday2 were restricted to patients who received at least two days of artemisinin derivatives and of PPRday3 to patients who received at least three days of artemisinin derivatives.In African studies, the median age of the patient was associated with a reduced risk of parasitaemia at Day 1 (OR 0.97 [95% CI 0.95 - 0.99]), but not on subsequent days Table . IncreasIn Asian studies, there were no significant differences in initial parasite clearance between treatment regimens at 48 or 72 hours Table . HoweverIn African studies, univariate factors were confirmed in multivariate analysis of parasitaemia at Day 1 and Day 2 Table . After cIn the multivariate analysis of the Asian studies, baseline parasitaemia, age and treatment regimen also remained significantly associated with delayed parasite clearance Table . After cIn the studies conducted in Asia, there was a temporal trend for an increased risk of parasite positivity at Day 1 (AOR = 0.90 [95% CI 0.81-0.99] per year), but not at other time points. In African studies, the reverse was observed, with a linear trend for decreased positivity at all days, but only statistically significant on Day 1 and Day 3 .Temporal trends in parasitological response were assessed in studies conducted from 2000 to 2005 and compared with 2006 to 2011. In African studies, the median reported proportion of patients remaining parasitaemic during follow up decreased at Day 1 (64% to 43%), Day 2 (10% to 4.6%) and Day 3 (1.2% to 0%). However these changes, adjusted for confounding factors, were not statistically significant in the logistic regression model. In contrast, in Asian studies the median proportion of patients parasitaemic at Day 3 rose from 0.4% in 2000 to 2005 to 6.5% in 2006 to 2011. However after adjusting for confounding factors, and exclusion of Cambodian studies, these temporal trends were no longer statistically significant.The parasite prevalence rates and 95% confidence intervals are presented in the forest plots at Day 3 Figures  and 7 anAmong 153 treatment arms reporting parasite positivity rate at Day 3, nine (5.9%) recorded a PPRday3 of 10% or higher. Of them, six treatment regimens were evaluated in Western Cambodia and one study was of a single dose of artesunate  of these data points were estimated from figures presented to depict parasitological response rather than the text itself. From the data available, 91% of patients had cleared their parasitaemia within two days and 97.9% within three days, however there was marked heterogeneity in clearance rates between studies and regions . Heterogeneity between studies I2 : AL = 92.3%; AS+AQ = 92.9%; AS+MQ = 91.7%; AS+SP = 95.6%; PIP+DHA = 60.9%.Click here for fileForest plots of Day 2 parasite positivity rates in Asia. Estimates and 95% CI are shown by treatment, sorted by year in descending order (most recent first). Heterogeneity between studies I2 : AL = 90.3%; AS+AQ = 93.8%; AS+MQ = 95.3%; AS+SP = 42.1%; PIP+DHA = 96.0%.Click here for fileStudies with Day 3 parasitaemia positivity rates ≥10%.Click here for file


INK4B methylation, longer survival expectancy and less AML transformation. In summary, the younger patients with MDS in China may show more benign disease features than the older ones. Enhanced immunological response may be involved in the pathogenesis of MDS in the patients younger than 60 years.Myelodysplastic syndromes (MDS) mainly occur in elderly individuals in Western countries. However, MDS is commonly found in young individuals (<60 years) in Asia. The reason for the high incidence in younger individuals is still unclear, and the differences in disease features between young and elderly patients with MDS have been not well recognized. To explore these issues, in this study, we analyzed the clinical and experimental characteristics of MDS in the patients younger and older than 60 years old and characterized the potential age-associated differences. The results showed that over half of the patients with MDS (61.9%) were younger than 60 years old upon the first diagnosis. The younger patients were more likely to be female, who have lower risk and less advanced MDS. The occurrence of trisomy 8 and bone marrow failure were more frequent in the younger patients than the older ones. The marrow CD34+ cells in the younger patients showed lower proliferation and higher apoptosis in comparison with that in the older ones. Obvious amplification of T cells and low CFU formation could be found in the younger patients. CFU formation was significantly increased in the younger patients after the removal of activated T cells. In addition, the younger patients had a lower frequency of p15 In Western countries, myelodysplastic syndromes (MDS) occur more frequently in older individuals INK4b methylation, were also integrated into this study. Through this study, we could deepen the insight into the age-associated pathogenesis of MDS.In this study, we performed a retrospective analysis to investigate whether a difference in disease features do exist between young and elderly patients with MDS. In addition, through this study, we sought to investigate whether different disease characteristics in younger patients imply distinct pathogenesis. The choice of the cut-off age between young and elderly patients is an important issue. WHO and UN recommended that the cut-off age of the elderly could be 60 years old 502 patients with MDS between January, 2006 and April, 2011 were included in this study. The MDS diagnoses were made in accordance with the minimum diagnostic criteria All subjects provided written informed consent. The written informed consent was obtained from patient himself . The study was approved by the Ethics Committee of the Sixth Hospital affiliated with Shanghai Jiao Tong University, and Chinese Academe of Medical Sciences, Tianjin, China. All patient-relevant research strictly abided by the Declaration of Helsinki.MDS was classified according to the WHO criteria (2008) Complete blood cell counts and bone marrow analysis were performed for each patient. At least 500 nucleated cells from bone marrow aspirates were counted and analyzed. The percentage of marrow blasts in all nucleated cells was calculated. In calculating, nucleated erythroid cells should be excluded when their percentage exceeded 50% in all nucleated cells A routine G-Banding analysis was conducted for all patients 2 (25 mM), 1 unit of Taq DNA polymerase , and 0.05 µg of DNA. The final volume was then adjusted to 20 ul with deionized water. PCR amplification was performed using a PTC-200 thermocycler . The PCR products were then analyzed with 2% agarose gel electrophoresis.In brief, as previously described 4Cl (hemolytic reagent) and total bone marrow nucleated cells were subsequently isolated. All samples underwent FCM within 6 hours. A flow cytometer  equipped with CellQuest software was used for logarithmic (Log) sampling, in which at least 105 total cells were acquired and analyzed. CD45/SSC gating was configured to delimit the population of leucocytes; CD34+ blasts with immunophenotypes of CD45intCD34int/highSSClow were screened to delimit, followed by the analysis of the expression of surface antigens . For apoptosis detection, BM cells were stained with anti-CD34- APC at room temperature for 20 minutes and then were labeled with 5 µL of Annexin V-FITC (BD Biosciences) in combination with 1 µL of PI for 15 minutes. After incubation, the cells were washed once and were analyzed within 2 hours.The following fluorescent-labeled antibodies were used: CD45, CD34, CD19, CD38, CD117 and CD7. The expression of CD19, CD38, CD117 and CD7 in CD34+ cells are considered to be related to differentiation and proliferation of HSCs In brief, as previously described 6 of BMMCs and 1.2×106 of BMMCs without CD8+CD57+ cells or CD4+CCR5+ cells were resuspended in 400 µL of a resuspension solution . In all cases, semi-solid culture were performed according to the manufacturer’s instructions (R&D Systems) for growing colony-forming units (CFUs). The culture was incubated at 37°C in a fully humidified, 5% CO2-containing atmosphere, and the colony formation was analyzed in the presence and absence of CD8+CD57+T or CD4+/CCR5+ cells after 14 days. Colonies were scored as aggregates with more than 40 cells.The CD8+CD57+ and CD4+CCR5+ cells were defined as activated CD8+ and CD4+ T cells, respectively A 1 µg DNA sample in a 100-µl volume was treated with bisulfite using the EZ DNA Methylation™ Kit  according to the manufacturer’s instructions. The modified DNA was subjected to two separate rounds of PCR. As previously described The comparison of overall survival and leukemia-free survival between the younger patients and the older ones were analyzed according to the IPSS prognosis, FAB/WHO classification and cytogenetic risk groups.All data were analyzed with the tool of SPSS 11.0 statistical software package. A cohort comparison was performed by use of Pearson’s χ2 or Fisher’s exact test for categorical data, and the paired measurement data were analyzed using Student’s t-test. Kaplan-Meier curves were used for analysis of overall survival (OS) and leukemia-free survival. The comparison of survival rate and AML transformation rate between the younger MDS patients (<60 years old) and the older ones (≥60 years old) was analyzed using the log rank test. Difference with a P-value of <0.05 was considered to be statistically significant.P = 0.011, compared with the younger group). Apparently, over half of MDS patients were younger than 60 years, and male-to-female ratio in MDS patients gradually increases from the young to the old (As shown in  the old .P<0.001). On the contrary, the percentage of the older patients is significantly higher than that of the younger ones in advanced MDS (P<0.001). As far as single MDS subtype was concerned, the percentage of the younger patients is significantly higher than that of the older ones in MDS with RCMD (P<0.001), whereas the percentage of the older patients is significantly higher than that of the younger ones in MDS with RARS, 5q− syndromes or CMML . There was no obvious difference between the younger and the older patients in other subsets of MDS.FAB and WHO 2008 classification were used to classify MDS. RCUD (RA/RN/RT), RARS, RCMD and 5q− syndrome were defined as less advanced MDS; RAEB-1, RAEB-2, RAEB-T and CMML were defined as advanced MDS. Less advanced MDS accounted for 70.4% and 52.4% of the cases in the younger and the older group, respectively, while advanced MDS accounted for 29.6% and 47.6% of the cases in the younger and the older group, respectively . The perP = 0.005). On the contrary, the percentage of the older patients is obviously higher than that of the younger ones in higher-risk MDS    .P<0.001). Among these common chromosome abnormalities, trisomy 8 was observed more frequently in the younger patients than the older ones . Abnormalities of chromosome 5 or 20 was less found in the younger patients compared with the older ones . Incidence of abnormalities of chromosome 7 or complex karyotypes showed no significant difference between the younger and older patients. Trisomy 8 was the most frequent chromosomal abnormality in the younger patients, whereas −5 and 5q− were the most frequent abnormalities in older ones.As shown in P = 0.002; P<0.001) (P = 0.019). In addition, the younger patients showed more frequent BM hypocellularity (hematopoietic tissue less than 30%) in marrow biopsies than the older ones   . The per= 0.001) . In brieAmong the 316 patients with HLA-DR15 available, 212 younger patients and 104 older ones were examined for the HLA-DR15 allele. 58 cases of 212 (27.4%) younger patients and 29 cases of 104 (27.9%) older ones have positive HLA-DR15 allele. No significant difference was found between the two groups .INK4B methylation analysis available, 236 cases of younger patients and 146 cases of older patients were determined for p15INK4B methylation. As shown in INK4B methylation was documented in 64.4% and 82.2% of the younger and older patients, respectively. The difference was of statistical significance (P = 0.005).Among the 382 patients with p15P = 0.045). The percentage of CD34+CD19+ cells was significantly higher in the younger patients than the older ones . The younger patients showed lower expression of CD117 in CD34+ cells than the older ones . The expression of CD38 and CD7 in CD34+ cells showed no significant difference between the younger and the older ones. In addition, apoptosis of CD34+ cells was also analyzed by FCM. The younger patients showed significantly higher apoptosis of CD34+ cells (Annexin V+) than the older ones . In brief, besides lower percentage in BM, CD34+ cells in the younger patients have better B-cell differentiation, lower proliferation, and higher apoptotic rate.To investigate the proliferation, differentiation and apoptosis of CD34+ cells between the MDS younger patients and the older ones, some surface antigens that reflect proliferation, differentiation and apoptosis were entailed in this study. As presented in P = 0.067) (P = 0.038)   . The per= 0.038) . However= 0.001) . The per= 0.001) .P = 0.154). After removal of activated CD4+T cells, the younger patients showed significantly higher colony formation than the older ones . Similarly, the younger patients showed significantly higher colony formation than the older ones after removal of activated CD8+T cells . Although the older patients showed increased ratio of lymphocytes subsets (high percentage of Tc1 and NK cells) which may target towards tumor cells than that in the younger patients, the removal of activated T lymphocytes did not caused increased colony formation of hematopoietic cells in the older patients.Colony formation of BMMCs was studied in 70 cases with younger patients and 55 cases with older ones . In vitrP = 0.043) (P<0.001) (P = 0.021) (P<0.001) (P<0.001) (P = 0.321) , and the probability for survival at 48 months was 73.8% and 34.3% respectively in the younger group and the older one . The lif= 0.043) . AccordiP<0.001) . The you= 0.021) . AccordiP<0.001) . The youP<0.001) . However= 0.321) .P = 0.003; P = 0.024). Whether classifying according to less advanced or advanced MDS, the AML transformation rate at 24 months was significantly lower in the younger group than the older ones (5.2% VS 20.8% and 44.2% VS 69.8%) (P = 0.006), and the AML transformation rate at 24 months was significantly lower in the younger group than the older one (5.4% VS 24.6%) (P = 0.191), and the AML transformation rate at 24 months was 49.7% and 58.2% respectively in the younger group and the older one . Whether classifying according to good or poor karyotype, the AML transformation rate at 24 months was lower in the younger group than the older one (7.7% VS 37.1% and 17.5% VS 58.8%) (P = 0.406), and the AML transformation rate at 24 months was 40.2% and 51.1% respectively in the younger group and the older one , and the AML transformation rate at 24 months was 12.1% and 44.2% respectively in the younger group and the older one . The LFSS 69.8%) . AccordiS 24.6%) . Howeverlder one . AccordiS 58.8%) . Howeverlder one .INK4B methylation. All these distinct findings provided some important clues to explore the pathogenesis of the younger MDS patients.The purpose of this study is to explore whether there are some different clinical/experimental characteristics between the younger MDS patients and the older ones and whether these characteristics imply distinct age-associated pathogenesis of MDS. The large-sample data in this study indeed presented distinct clinical and experimental characteristics of the younger MDS patients compared with the older ones. As shown in this study, besides the similar features reported by Kuendgen et al in vitro, suggesting that younger MDS patients have a stronger self-immune surveillance reaction during the development and progression of MDS. The formation of initial MDS clones in the younger patients may induced a strong T-cell response, which in turn suppressed the MDS clones but simultaneously resulted in severe BM failure and an autoimmune-like clinical presentation. Lower incidence of abnormal chromosomes and better differentiation of CD34+ cells observed in the younger patients, may contribution to the existence of the initial MDS clones in conditions of strong T-cell attack. The stronger T-cell self-immune surveillance and performance of TSGs function (less p15INK4B methylation) suppressed the development of clonal cells in younger patients, which yielded more low-risk patients, less AML transformation, and ultimately, significantly longer overall survival. On the contrary, the MDS malignant clones in the older patient might not be controlled by the weaker T-cell response (demonstrated by the presence of fewer CFUs compared with the younger patients after the deletion of the activated CD4 or CD8 cells) and the activated TSGs, although some of the tumor-targeted T cells (such as Tc1 and NK) number expanded. Predominantly malignant clones such as 5q−/−5 that were more frequently observed in older patients could be selected and expanded preferentially due to the weaker T-cell response in those patients. Weaker T-cell surveillance, poor differentiation of CD34+ cells and frequent activation of TSGs may result in more higher risk diseases, more rapid AML transformation, and ultimately, obviously shorter OS.These characteristics suggested a trend towards bone marrow failure rather than disease progression for younger patients with MDS. What are the reasons for such distinct features in younger MDS patients? To put in another way, whether these characteristics imply some distinct age-associated pathogenesis in MDS is worth discussing We present the following hypothesis based on our observations . Both thMatsuda et al In summary, MDS in China is diagnosed at an earlier age than in Western countries. Young patients present with less advanced disease, more slowly progress and significantly longer survival than older patients. We interpret these data as an indication that the self-immune surveillance mechanism may play a role in pathogenesis of younger patients with MDS.


In a retrospective review of patients with acquired demyelinating disorders of the central nervous system, 133 patients (5.6%) whose diseases started in childhood, were selected from 2369 patients, who had medical records in the Neurology Department of Dokuz Eylul University. Out of 133, 98 had relapsing remitting multiple sclerosis, 21 had secondary progressive multiple sclerosis, 8 had clinically isolated syndrome, 3 had neuromyelitis optica, 2 had Marburg disease, and 1 had radiologically isolated syndrome. In 55 patients (41.3%), disease onset was before age 16. Polysymptomatic presentation (22.6%) was the most common initial feature. The EDSS scores ranged from 0 to 9 with a median of 2.0 (2.22 ± 1.88) for 126 patients. MRI records of 111 patients were obtained. 97 patients had clinically definite multiple sclerosis. 11 MS patients (11.3%) did not initially present the diagnostic MRI features. All of the remaining multiple sclerosis patients fulfilled Barkhof-Tintore criteria (100%) and 88.7% fulfilled KIDMUS criteria. Cranial MRI of NMO patients was normal. Our findings demonstrate some important clinical and paraclinical features that can help the literature on acquired demyelinating disorders of childhood by utilizing data from Western Turkey. It was only in the late 1950s that multiple sclerosis (MS) in the pediatric population resurfaced in the literature . The latIn this study, we aim to define the demographic, clinical, and laboratory features of patients affected from inflammatory demyelinating central nervous system diseases before the age of 18. n = 84) of the patients were women, and 36.8% (n = 49) were men. The following data were analyzed on the basis of age at onset, sex, initial symptoms, course of disease, magnetic resonance imaging (MRI) features, presence of oligoclonal bands (OCBs), time of followup, treatment, and disability.All data were collected from medical records of the patients who were being followed up at the Adult Neurology Department of Dokuz Eylül University Hospital. Patients, whose first acute inflammatory event of demyelination had started after the age of 18 were excluded from the study. Children that had been diagnosed with definite MS , 9 and NMRIs, that was obtained within six months of the disease, was evaluated according to Barkhof-Tintore , 10 and Disability was measured by Expanded Disability Status Scale (EDSS) scores. EDSS score 3 represents mild-to-moderate disability without limitation in ambulation and 4 as moderate disability with an ability to walk at least 500 m unaided, score 6 walking with unilateral aid and score 7 wheelchair bound. We focused on score 4, that is, the walking ability of the patient is limited but they can walk without aid or resting for more than 500 m .All analyses were performed with Statistical Package For Social Sciences (SPSS version 15.0). Statistical significance was defined by an alpha level of 0.05. Descriptive statistics summarize clinical and demographic data. About 5.6% (133/2369) of the patients, with complete disease histories, experienced initial symptoms consistent with a demyelinating event under 18 years of age. The mean age at onset was 15.07 ± 2.72 (4–18), and it was 15.19 ± 2.78 (4–18) for females and 14.86 ± 2.62 (9–18) for males. The female/male ratio in the cohort was 1.7 : 1.Of the patients, only 15 experienced onset below the age of 12 years and 118 experienced onset at and above the age of 12 years. The female/male ratio was 1.1 : 1 for under the age of 12. The youngest case was a 4-year-old girl with a polysymptomatic presentation after Mumps (ADEM-like onset). In 55 patients (41.4%), disease onset was before the age of 16, and in 78 patients it was after the age of 16 (58.6%). The female/male ratio was 1.3 : 1 for ages below 16, while it was 2.1 : 1 for ages above 16.Patients experienced their first events with a myriad of neurologic symptoms including ON (19.4%), brainstem dysfunction (18.5%), sensory impairment (11.3%), ATM (10.5%), and motor dysfunction (10.5%) . Polysymn = 98) had RRMS, 15.8% (n = 21) SPMS, 6% (n = 8) CIS, 2.3% (n = 3) NMO, 1.5% (n = 2) Marburg, and 0.8% (n = 1) radiologically isolated syndrome (RIS). None of our cases experienced primary progressive (PP) MS course. And all our cases who presented like ADEM, a multifocal presentation with encephalopathy, were found to have MS in the course of their disease. Overall, 119 out of 2369 had MS: 5% of the total population in our center. Three patients meeting the inclusion criteria for NMO [Of the 133 patients, 73.7% (The mean disease duration of the demyelinating disease at the end of the follow-up period (which was March 2012 for the present study) was 9.48 ± 8.43 (range 1–44) years. At some point during the course of the disease, 68 cases (51.1%) received disease-modifying and immunosuppressant drugs: interferon beta (27.1%), glatiramer acetate (8.3%), and azathioprine (10.5%) . The EDSMRI records of 111 patients were obtained. 97 patients had clinically definite multiple sclerosis. 11 MS patients (11.3%) did not initially present the diagnostic MRI features. All of the remaining multiple sclerosis patients fulfilled Barkhof-Tintore criteria (100%) and 88.7% fulfilled KIDMUS criteria. Cranial MRI of NMO patients was normal. For of those patients whose MRI did not meet both criteria, we employed Callen criteria . Six of Among 133 patients, 35 OCB results were obtained from the medical records. OCBs were positive in 24 MS patients, one Marburg disease patient, and one CIS patient. OCB was negative in two of three NMO patients and in the RIS patient. Six patients (4.6%) had a positive family history of MS. In five case, first-degree relatives and in one case, third-degree relatives had MS.The most frequent coexisting conditions were psychiatric disorders (depression and bipolar disorders) and migraine. Psychiatric disorders ascertained by Structured Clinical Interview for DSM-IV (SCID-I)  were seeP > 0.05). We obtained 10 of 15 patients MRIs. 5 MRIs were of MS patients, and all the MRIs met both Barkhof-Tintore and KIDMUS criteria. We reached the EDSS score of 14 of 15 cases, and of 85.7% had EDSS score of <4 with a median of eight years of disease duration. Fifteen patients experienced onset below the age of 12 years. Polysymptomatic presentation and brainstem involvement were the most common initial features, and the findings did not differ from patients above age 12  ADD patients seen in our center experienced their first symptoms under 18 years of age: 15/2369 (0.63%) had an onset below the age of 12 years, 55/2369 (2.3%) below the age 16, and 78/2369 (3.3%) above the age 16. The most common initial event was polysymptomatic presentation in the present study. Some studies suggest that children are more commonly polysymptomatic (50–70%) than adults, although a monosymptomatic (30–50%) presentation is not uncommon –18.Approximately 20% of the children ultimately diagnosed with MS were reported to demonstrate polysymptomatic features, encephalopathy, and widespread magnetic resonance imaging (MRI) lesions indistinguishable from ADEM . On the Childhood MS was found to be about 5% of our total patient population. This finding is consistent with several retrospective studies which have estimated the overall prevalence of MS, with onset before 18 years, to range from 1.6% to 10.5% of the total MS populations , 23–25.  More than half of our patients had been receiving immunomodulatory or immunosuppressive treatment at the time of enrollment. However, patients, who are still in childhood, constitute the minority of our treated patients. Prospective studies of immunomodulatory therapies to increase the recognition of the safety and tolerability of the agents –30 will Although we did not apply a Kaplan Meier analysis for the time duration that passed to reach EDSS score 4 or greater, we found the median disease duration of patients, with EDSS score >4, to be 15 years. This result seems to be a little long, compared to that of a study in which 30 of 197 children (15%) documented EDSS score ≥4 after a median observation of 4.8 years (from second demyelinating attack)  and compn = 97) fulfilled Barkhof criteria (100%). Out of 97, 85 fulfilled KIDMUS criteria (88.7%). 12.6% of MS patients did not present the diagnostic MRI features initially; however in this group we found that 54.5% of them met the proposed Callen criteria, yet the criteria remain to be studied in larger pediatric cohorts. Several diagnostic imaging criteria are being described and examined in pediatric multiple sclerosis. An increased risk of MS is associated with the presence of three out of four Barkhof criteria ; namely,n = 35), was low, but OCBs analyzed by isoelectric focusing were positive in 24 MS patients. OCBs were positive in 92% of 136 children studied in a German cohort, although CSF OCBs were not always in the CSF obtained at first attack [The number of patients, whose medical records of OCBs were achieved  of the patients had a positive family history of MS in first-degree relatives (n = 5) and a third-degree relative (n = 1).It is reported that an estimated 6 to 21% of children with MS have a first, second, or third-degree relative with MS –38. In oThe most frequent coexisting conditions were psychiatric disorders (depression and bipolar disorders) (5.2%) in our study. Depression is a common comorbidity in adults with MS, estimated to affect 50–70% of adults at some point in the course of their diseases. Preliminary data from pediatric MS cohorts suggest that the rate of depression is similar, if not higher , using aAll children presenting symptoms consistent with acute demyelination should be of particular interest as they require accurate evaluation aiming to decrease the burden of the disease when they reach adulthood. For this purpose, all features, such as demographic, immunologic, genetic, prognostic, and therapeutic, of early onset acute demyelinating diseases should be clarified, thus offering more specific treatment options.


Atopic dermatitis (AD) is a common chronic skin disease that can vary in degree of severit. The factors affecting the severity of AD are not known well. In this study, the clinical features of patients with different disase severity were compared if there is any significant difference between patients with mild, moderate and severe atopic dermatitis.The patients with AD admitted to outpatient clinic of pediatric allergy department from 1 January 2010 to 30 June 2010 were enrolled to the study. The disease severity and risk factors of the patients were assesed according to the SCORAD index. Skin prick test (SPT) for common food and inhalent allergens were performed to all patients with atopic dermatitis. The food specific IgE blood tests  were performed to only selected patients who had symptoms on the basis of clinical history.Total of 134 patients were evaluated with average age of 31.4±3.5 months, 58.2% of patients were male. The mean age of the start of symptoms and the duration of breast-feeding were 8.2±1.2 and 8.8±0.5 months, respectively. The frequency of taking cow's milk in the first year of life was 29.1% (n=39). The 29.9% of patients had family history of atopy. Peripheral blood eosinophil ratio was 3.3% (2.0 -5.0)  and total blood IgE level was 32.6 (10.4-100.0) kU/L. The 70.1% of patients was higher than the normal range for age. The SCORAD index was 36.1 (26.4-45.6). The frequency of mild, moderate and severe atopic dermatitis among the patients were 19.4, 62.7 and 17.9%, respectively. The 42.5% of patients were sensitized to the allergens tested. The most frequent sensitized allergens were egg white (26.9%), cow’s milk (10.4%), wheat (6.0%). Among the patients with different severity, there were no significant difference according to gender, the status of atopy, age, the beginning age of symptoms, the percent of peripheral blood eosinophil, family history of atopy, serum IgE level.The most common form was moderate AD. There were no differences of clinical features among mild, moderate and severe atopic dermatitis.


This paper demonstrates multiple benefits of intravitreal bevacizumab (IVB) on diabetic retinopathy (DR) including diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) at 24 months of followup. This is a retrospective multicenter interventional comparative case series of intravitreal injections of 1.25 or 2.5 mg of bevacizumab for DME, PDR without tractional retinal detachment (TRD), and patients who experienced the development or progression of TRD after an intravitreal injection of 1.25 or 2.5 mg of bevacizumab before vitrectomy for the management of PDR. The results indicate that IVB injections may have a beneficial effect on macular thickness and visual acuity (VA) in diffuse DME. Therefore, in the future this new therapy could complement focal/grid laser photocoagulation in DME. In PDR, this new option could be an adjuvant agent to panretina photocoagulation so that more selective therapy may be applied. Finally, TRD in PDR may occur or progress after IVB used as an adjuvant to vitrectomy. Surgery should be performed 4 days after IVB. Most patients had poorly controlled diabetes mellitus associated with elevated HbA1c, insulin administration, PDR refractory to panretinal photocoagulation, and longer time between IVB and vitrectomy. Diabetic retinopathy remains the major threat to sight in the working age population in the developed world. Furthermore, it is increasing as a major cause of blindness in other parts of the world especially in developing countries . DiabetiVascular endothelial growth factor has been shown to be an endothelial cell-specific mitogen and an angiogenic inducer in a variety of in vitro and in vivo models . VEGF, aBevacizumab  is a complete full length humanized antibody that binds to all subtypes of VEGF and is successfully used in tumor therapy as a systemic drug . Recent In an open label uncontrolled clinical study of 4303 injections in human eyes with 1.25 mg or 2.5 mg IVT bevacizumab, our group  found syRecently, it has been reported that intravitreal injection of bevacizumab may be also useful for early vitreous hemorrhage in PDR in order to decrease the risk of new hemorrhages while clearing occurs and to minimize the indications of vitrectomy . In addi The purpose of this paper is to describe the anatomic and functional outcomes, and the effectiveness of intravitreal bevacizumab (IVB) in patients with diabetic retinopathy at 24 months of followup.Diabetic macular edema is a manifestation of diabetic retinopathy that produces loss of central vision. DME is caused by excessive vascular permeability, resulting in the leakage of fluid and plasma constituents, such as lipoproteins into the retina, leading to thickening of the retina.Although the Early Treatment Diabetic Retinopathy Study (ETDRS)  demonstrGiven that most eyes with DME that are treated with laser photocoagulation do not have an improvement in visual acuity, there has been an interest in other treatment modalities such as pharmacologic therapy with oral protein kinase C inhibitors and the use of intravitreal corticosteroids , 33. TheIt was recently demonstrated that retinal hypoxia plays a role in DME  and VEGFWe have recently reported the 24-month anatomic and BCVA response after primary intravitreal bevacizumab (IVB) in patients with DME . We condμm in central macular thickness) and/or FA, after complete or partial resolution in previous followup visits.Exclusion criteria included patients (eyes) with DME previously treated with laser photocoagulation or intravitreal triamcinolone, macular ischemia, and the presence of an epiretinal membrane or vitreomacular traction syndrome. Patients received reinjections whenever there was a recurrence of DDME. Recurrence was defined as a decrease of BCVA associated with an increase of intraretinal fluid due to macular edema on OCT (≥50 P < .001) (P = .0001). This improvement in BCVA was maintained throughout the 3-, 6-, 12-, and 24-month followup, (P < .001) a statistically significant difference from baseline BCVA. Twenty-four month BCVA analysis by subgroups demonstrated that 62 (44.6%) eyes remained stable, 72 (51.8%) eyes improved two or more ETDRS lines of BCVA, and 5 (3.6%) eyes decreased two or more ETDRS lines of BCVA.Within one month after the initial bevacizumab injection, improvements in BCVA and central macular thickness (CMT) measurements were observed and these significant changes continued throughout the 24-month followup. At one month BCVA improved from log MAR = 0.90 to 0.76, a difference that was statistically significant , and this overall improvement continued throughout the 24-month followup, . Optical coherence tomography results were available for all 139 eyes at 1-, 3-, 6-, 12-, and 24-month followups. At one month, the mean 1-mm CMT measurements decreased from 446.4 μm. The patient underwent an intravitreal injection of bevacizumab at a dose of 2.5 mg in this eye. In μm. Visual acuity (VA) improved to 20/400. In μm). VA improved to 20/200. In μm. She received a second injection of intravitreal bevacizumab at a dose of 2.5 mg at this point. In Figures μm, 318 μm, and 173 μm, resp.). VA also improves progressively . In μm, and visual acuity was 20/125. In μm. She received a fourth injection of intravitreal bevacizumab at dose de 2.5 mg. In μm and VA was 20/160. In μm). VA improved to 20/125. In μm. She received a fifth injection of intravitreal bevacizumab at a dose of 2.5 mg at this point. In μm. VA improved to 20/200. In μm, and VA improved to 20/160 (Reprinted with permission from [In ion from ).P = .511 for BCVA and P = .483 for CMT).We wished to compare the response to treatment between patients with PDR and previous PRP to those with nonproliferative diabetic retinopathy and DDME to see if there was any difference. However, when we ran the repeated measures ANOVA to compare mean values to statistically analyze mean retinal thickness and logMAR VA adjusting for the grade of diabetic retinopathy as a covariate, we found no statistical significance  at a mean interval of 12.2 ± 10.4 weeks. Seventy-four (53.2%) cases were treated with an intravitreal injection of 1.25 mg of bevacizumab and sixty-five (46.8%) cases with at a dose of 2.5 mg of IVB. Adverse events included transient high blood pressure in one (0.9%) patient, cerebrovascular accident in one (0.9%) patient, heart attack in one (0.9%) patient, transient increased intraocular pressure in seven (5%) eyes, cataract in five (3.6%) eyes, and tractional retinal detachment in one (0.7%) eye. There were no episodes of inflammation or severe decrease of vision immediately after an injection. Our results indicate that primary IVB at doses of 1.25 mg or 2.5 mg seems to provide stability and improvement in BCVA, OCT, and FA in DDME at 24 months. We identified no difference in outcomes between IVB at doses of 1.25 mg or 2.5 mg. Therefore, doses lower than 2.5 mg should be preferred. These results indicate that IVB injections may have a beneficial effect on macular thickness and BCVA in DDME.Panretinal photocoagulation (PRP) has been the mainstay for the treatment of PDR, and its suppressive effect on RN has been well documented –39. HoweNeovascularization on and around the optic disc (NVD) and vitreous hemorrhage were found to be more frequently associated with severe visual loss despite PRP in the Diabetic Retinopathy Study (DRS) and ETDRS , 43. LonAlthough RN actually may be due to more than one cytokine, VEGF is an important, if not the most important cytokine involved . ActivatWe conducted a retrospective study in 43 eyes of 39 patients with PDR that had retinal neovascularization (RN), who were treated with off-label intravitreal bevacizumab between September 2005 and July 2007 at 7 institutions in Venezuela, Costa Rica, Brazil, Argentina, Spain, and Peru. Patients were followed for 24 months. Our patients had a mean age of 54 ± 12.5 years old (range from 28 to 79 years), and twenty-three (59%) patients were male. Eleven (28.2%) diabetic patients were insulin dependent. The mean duration of diabetes was 17.2 years (range from 1 to 33 years). Twenty-four (55.8%) eyes were treated with an intravitreal injection of 1.25 mg and 19 (44.2%) eyes were treated with 2.5 mg of bevacizumab. Of the total of 43 eyes, 31 (72.1%) eyes had been previously treated with scatter photocoagulation at least 6 months before IVB, no eyes had prior focal/grid laser photocoagulation, and no eyes had a previous intravitreal triamcinolone injection. All eyes had clinical significant macular edema (CSME) at biomicroscopic noncontact fundus examination with a 66- or a 78-diopter lens. P < .0005). Final BCVA analysis by subgroups demonstrated that 35 (81.4%) eyes remained stable, 5 (11.6%) eyes improved two or more ETDRS lines of BCVA, and 3 (7%) eyes decreased two or more ETDRS lines of BCVA. The mean baseline BCVA was log MAR = 0.94 ± 0.38 ETDRS (20/176) and the mean 24-month BCVA was log MAR = 0.67 ± 0.39 ETDRS (20/94) (μm ± 169.5 μm to 311.51 μm ± 116 μm (P < .05) (P = .01), and this overall improvement continued throughout the 24-month follow-up. At 3-, 6-, 12-, and 24-month follow-ups, mean CMT were 319.6 μm ± 95.7 μm, 297.1 μm ± 102.5 μm, 297.5 μm ± 91.2 μm and 270.3 ± 75.9 respectively, which were significantly different from baseline (P = .0001). Optical coherence tomography results were available for all 43 eyes at 1-, 3-, 6-, 12-, and 24-month follow-up time points. At 1 month, the mean 1-mm central macular thickness (CMT) measurements decreased from 430.9  Of the total of 43 eyes, 17 (39.5%) eyes treated showed total regression of RN on fundus examination with absence of fluorescein leakage, , 15 34..When divided by type of RN, of the total of 43 eyes, 15 (34.9%) eyes showed total regression of NVE (neovascularization elsewhere) on fundus examination with absence of fluorescein leakage, , 10 (23.P = .02) and (P = .0001), respectively. When divided by IVB dose utilized, we observed that 9 (37.5%) eyes treated with 1.25 mg dose showed no regression of NVE and 13 (54.2%) eyes showed no regression of NVD at the end of followup, while only 3 (15.8%) eyes treated with 2.5 mg dose showed no regression of NVE, and 3 (15.8%) eyes showed no regression of NVD at 24 months of followup. These differences were statistically significant (The mean number of IVB injections per eye was 4.1 ± 2.1 (range: 1 to 8 injections) at a mean interval of 14.8 ± 10.4 wks. Twenty-one eyes (47.7%) needed a second injection due to recurrence of RN at a mean of 12.4 weeks (range from 4 to 34 weeks), and seven eyes (15.9%) needed a third injection due to recurrence of neovascularization at a mean of 17.3 weeks (range from 11 to 22 weeks). Three patients without previous PRP (“naive”) and with vitreous hemorrhage have avoided vitreoretinal surgery. There were no episodes of inflammation or severe loss of vision immediately after an injection. Regarding adverse events at 24 months, two thromboembolic events were reported, a cerebrovascular accident in 1 patient (2.6%) and a myocardial infarction in 1 patient (2.6%). One TRD was reported (2.3%), and one eye (2.3%) developed a vitreous hemorrhage. To determine the effect of an intravitreal injection of bevacizumab on actively growing new vessels, we chose the variation in vitreous leakage from RN as our primary outcome. The detection of NVD and NVE on FA allowed the use of a systematic anatomical approach to monitor the area of leaking new vessels over time. Finally, to determine the effect of an intravitreal injection of bevacizumab on macular edema, we measured the variation on retinal thickness with OCT. Our studies have demonstrated that intravitreal bevacizumab resulted in marked regression of RN on fundus examination and FA in patients with PDR and previous PRP, specially in the first six months . FurtherThere was a tendency towards a decrease in response to IVB overtime with 60.5% of eyes at 24 months requiring additional PRP or vitrectomy, which raises the question of tachyphylaxis. However, further analysis of our data seems to rule out this possibility.Intravitreal bevacizumab seems to be a useful treatment for PDR, minimizing the risk for exudative complications, progression of retinal neovascularization, vitreous hemorrhage, and decreased vision caused by macular edema. Intravitreal bevacizumab may potentially be used as an adjuvant agent to PRP for PDR.In our updated retrospective review, we have identified 25 eyes (patients) out of 698 IVT injections that developed or had progression of TRD with decrease of BCVA after intravitreal bevacizumab prior to vitrectomy for the management of PDR for an incidence of 3.5%. All patients had had a PRP at least 2 months before intravitreal bevacizumab. All eyes had PDR refractory to PRP. The mean age of the study group was 61 ± 8.5 years (range from 24 to 76 years), and 52% were female. Eighteen (72%) patients had DM type 2 with a mean of 14 ± 5.9 years from diagnosis (range: 1–25 years) and seven (28%) patients had DM type 1 with a mean of 16.3 ± 8 years from diagnosis (range: 7 to 30 years). In the current study, eleven (44%) patients used insulin administration as sole treatment for glycemic control, seven (28%) diabetic patients controlled glycemic levels with oral therapy, and the remainder seven (28%) patients used combination therapy with insulin and oral hypoglycemic agents for glycemic control. However, all patients had uncontrolled diabetes associated with elevated glycosylated hemoglobin (HbA1c mean = 9.2%). Eleven (44%) eyes had local TRD on indirect ophthalmoscopy, ultrasound, or biomicroscopic noncontact fundus examination with a 66- or a 78-diopter lens before intravitreal bevacizumab.Twenty-five (3.2%) eyes (patients) out of 698 IVT injections developed or had progression of TRD, . NineteeP ≤ .0001). One patient developed a retinal break as a result of the increased traction, and a combined total tractional-rhegmatogenous retinal detachment was apparent 3 weeks after intravitreal bevacizumab. The mean baseline  BCVA was log MAR = 1.4 ± 0.7 (range from 0.2 to 2.9) . At TRD development or progression, the mean BCVA was log MAR = 1.9 ± 0.6 (range: 0.3 to 2.9) , this difference was statistically significant compared to baseline BCVA (P = .012). Subgroup analysis of final BCVA after vitrectomy demonstrated that 12 (54.5%) out of 22 eyes improved two or more ETDRS lines of BCVA when compared to TRD BCVA. However, when compared to baseline BCVA, final BCVA after vitrectomy demonstrated that 8 (36.4%) eyes improved, 5 (22.7%) eyes remained stable, and 9 (40.9%) eyes lost two or more ETDRS lines of BCVA.Twenty-two eyes underwent vitrectomy, two patients refused or were unable to undergo surgery, and in one patient surgery was not recommended. Vitrectomy was performed in a mean of 18.8 ± 11.5 days (range from 5 to 37 days) after intravitreal injection of bevacizumab. Tractional retinal detachments were managed with vitrectomy, membranectomy, photocoagulation, and extended intraocular tamponade with gas in all patients that underwent surgery. Final mean BCVA after surgery was log MAR = 1.4 (range: 0.2 to 2.9) , this difference was statistically significant compared to TRD BCVA  diagnosis, glycemic control, cholesterol levels, triglycerides levels, hemoglobin A1c (HbA1C), dose of bevacizumab, and time from injection to vitrectomy. Twenty-Five eyes (patients) (3.5%) out of 698 intravitreal injections developed or had progression to a TRD after intravitreal bevacizumab. Patients with TDR were followed for an average of 48.9 weeks (range: 0 to 190 weeks), and had a mean age of 54.4 ± 11.5 years. Twelve were male (47.8%) and thirteen were females (52.2%). Thirteen patients (52%) were Hispanic, 6 (24%) were Caucasian, and 6 (24%) were African-American. Seventeen (68%) had diabetes type 2 and 8 (32%) had diabetes type 1. In the current study, twenty (80%) patients with TRD had a previous PRP and had an average HbA1c before treatment of 9.85 ± 2.6%. Seventeen (68%) had less than 15 years diagnosed with DM and 8 (32%) had more than 15 years with a diagnosis of DM. Patients without TRD were followed for an average of 33.1 weeks (range: 0 to 170 weeks) and had a mean age of 53.94 ± 12.61 years. Four hundred and one were male (59.6%) and 272 were female (40.4%). Four hundred and fifty (66.9%) were Hispanic, 122 (18.1%) were Caucasian, and 101 (15%) were African-American. One hundred ninety patients (28.4%) had diabetes type 1 and 482 (71.6%) had diabetes type 2. Four hundred seventy-two (70.15%) patients without TRD had a previous PRP and had an average HbA1c before treatment of 9.08 ± 2.11%. In addition, 242 (36.6%) had less than 15 years of diagnosis with DM and 426 (63.3%) had more than 15 years with a diagnosis of DM.Of these 698 intravitreal injections, 626 applications were with 1.25 mg of bevacizumab  and 72 injections with 2.5 mg of bevacizumab . No systemic adverse events such as thromboembolic events  were reported. All eyes had TRD diagnosed by indirect ophthalmoscopy, fundus biomicroscopy, FA, and OCT at baseline. P = .009), (OR = 0.30), (95CI = 0.10–0.83), (RR = 0.35), more than 13 days from injection to vitrectomy (P = .0001), (OR = 9.9), (95CI = 3.4–29), (RR = 6.9) and the use of a higher dose (2.5 mg) of bevacizumab (P = .022), (OR = 2.7), (95CI = 1.05–7.18), (RR = 2.38). Risk factors for TRD after IVB identified in our study included, more than 15 years from the diagnosis of diabetes mellitus (DM) (P = .123), neovascular membrane (P = .145), or previous use of bevacizumab (P = .653). Fibrovascular proliferation was present in most patients with TRD (95% CI = 73.9–99.8). However, no significant correlation was found between TRD and fibrovascular proliferation despite that 94.7% of the patients had this factor present (P = .260)  .Diabetic macular edema is a manifestation of diabetic retinopathy that produces loss of central vision, and is the most frequent cause of visual impairment in patients with nonproliferative diabetic retinopathy. However, the breakdown of endothelial tight junctions and loss of the blood retinal barrier that lead to DME can be associated with both nonproliferative diabetic retinopathy and PDR. Although several treatment modalities are currently under investigation, the only demonstrated means to reduce the risk of vision loss from DME are laser photocoagulation, as demonstrated by the ETDRS,  intensivThe results of our retrospective study demonstrated the efficacy of 1.25 mg or 2.5 mg of intravitreal bevacizumab as primary treatment of DME as 51.8% of eyes showed anatomical as well as functional improvement. In addition, our results suggest a reduced risk of VA loss in eyes with DME treated with intravitreal bevacizumab (97.1% of eyes). All eyes received an intravitreal injection at the initial visit; however, recurrences were retreated at the discretion of the treating physician. There were a total of 807 IVB injections performed. At 24 months, the mean number of IVB injections per eye was 5.8 (range: 1 to 15 injections) at a mean interval of 12.2 ± 10.4 weeks. Seventy-four (53.2%) cases were treated with an intravitreal injection of 1.25 mg of bevacizumab and sixty-five (46.8%) cases with at a dose of 2.5 mg of IVB. The optimum dosing and sequence for intravitreal bevacizumab in DME is still undetermined. We elected to defer reinjections until there was a recurrence. Our results indicate that intravitreal bevacizumab injections may have a beneficial effect on macular thickness and VA for DDME. Therefore, in the future this new treatment modality could complement focal/grid laser photocoagulation. Furthermore, focal/grid laser photocoagulation could be used to consolidate the results obtained with one or a series of intravitreal bevacizumab injections and decrease the need for reinjections.In addition, we demonstrated that intravitreal bevacizumab resulted in marked regression and then stability of RN on fundus examination and FA in patients with PDR and previous PRP. A rapid resolution of vitreous hemorrhage can also be seen. Furthermore, intravitreal bevacizumab demonstrated a similar beneficial response on macular thickness in eyes with PDR, and probably bevacizumab prevents exacerbation of macular edema in patients with concomitant CSME and PDR. Regression of neovascularization and decrease of retinal thickening occurred in some injected eyes as soon as 7 to 15 days after the intravitreal injection of bevacizumab. Twenty-one eyes (47.7%) needed a second injection due to recurrence of neovascularization at a mean of 12.4 weeks, and seven eyes (15.9%) needed a third injection due to recurrence of neovascularization at a mean of 17.3 weeks. We elected to defer reinjection only when there was a recurrence of RN. Interestingly, we noted that RN responded better to IVB at a dose of 2.5 mg than to a dose of 1.25 mg. Nevertheless, the optimum dose and dosing sequence for IVB is still undetermined. Another interesting finding at 24 months is an increase in the number of eyes that did not respond to IVB with complete RN regression as compared to our previously published 6-month data . It is pWe have identified 25 eyes (patients) out of 698 IVT injections that developed or had progression of TRD with decrease in BCVA after intravitreal bevacizumab prior to vitrectomy for the management of PDR. The natural course of PDR is characterized by a cycle of proliferation and regression typical of new vessels; proliferation of fibrous tissue accompanying new vessels; formation of adhesions between the fibrovascular proliferations and the posterior vitreous surface; contraction of the posterior vitreous surface and associated proliferation. The development or progression of TRD in PDR following intravitreal bevacizumab in our patients could have happened by natural history or rapid neovascular involution with accelerated fibrosis and posterior hyaloidal contraction as a response to decreased levels of VEGF. In the current study, eleven (44%) patients used insulin administration as sole therapy for glycemic control, seven (28%) diabetic patients controlled glycemic levels with oral therapy and the remainder seven (28%) patients used combination therapy with insuline and oral hypoglycemic agents for glycemic control. They all had uncontrolled diabetes associated with elevated glycosylated hemoglobin (HbA1c mean = 9.2%).Results of this study suggest that TRD in PDR may occur or progress after intravitreal bevacizumab used as an adjuvant to vitrectomy. However, in the eyes that underwent vitrectomy, we had the impression that there was a reduced risk of intraoperative bleeding facilitating the removal of fibrovascular membranes. A bloodless field allows for better visibility and the surgeon may be less likely to create an iatrogenic retinal break. In addition, the chances of postoperative complications such as rebleeding or fibrinoid syndrome may be decreased. All these advantages may allow us to save more eyes utilizing preoperative intravitreal bevacizumab regardless of increased traction on some severe PDR cases. Moreover, most patients with development or progression of TRD had poorly controlled diabetes mellitus associated with elevated HbA1c, insulin administration, PDR refractory to panretinal photocoagulation, and longer time between intravitreal bevacizumab and vitrectomy. These factors needed to be studied to determine if they are indeed risk factors for the development or progression of TRD after preoperative IVB in PDR.Finally, we did study the risk factors for the development or progression of TRD after preoperative IVB in PDR. In our retrospective review, we identified 25 eyes (patients) with development or progression of TRD after intravitreal bevacizumab prior to vitrectomy for the management of PDR for an incidence of 3.5%; the risk factors associated with these patients were more than 15 years from the diagnosis of diabetes mellitus, more than 13 days from injection to vitrectomy and the use of a higher dose (2.5 mg) of bevacizumab. Variables such as smoking history, hypertension, myocardial infarction, levels of triglycerides, cholesterol, blood glucose, previous vitreous hemorrhage, and macular thickness were not related to the development or progression of tractional retinal detachment.Based on our data, we now believe that extreme care must be taken in using a dose of 2.5 mg or more of bevacizumab in patients with PDR. In addition, to have over 15 years with a diagnosis of diabetes can increase the risk of TRD and that careful follow-up evaluation following injection is mandatory. The timing of surgery after the injection is also important, as there are concerns that bevacizumab may cause progression of the TRD. It is important that surgery is performed once the antiangiogenic effect of bevacizumab has fully developed, but before there is further fibrous proliferation; physicians must be prepared to perform the vitrectomy preferably before 13 days after the application of bevacizumab and to perform a vitrectomy immediately on those patients in whom a TRD occurs. The results of this study show that intravitreal bevacizumab therapy is a well-tolerated treatment option for PDR for carefully selected patients, but we can safely assume that the application of bevacizumab may lead to tractional retinal detachment in a proportion of 3.58% (CI 95% = 2.13–5.03) of patients.Intravitreal bevacizumab seems to be a promising treatment for PDR, minimizing the risk for exudative complications, progression of retinal neovascularization, vitreous hemorrhage, and decreased vision caused by macular edema. Intravitreal bevacizumab may potentially be used as an adjuvant agent to PRP for PDR. In addition, primary intravitreal bevacizumab at doses of 1.25 mg or 2.5 mg seems to provide stability and improvement in VA, OCT, and FA in diabetic macular edema. Evaluation in a multicenter, randomized, controlled clinical trial with longer followup is needed to evaluate the safety and efficacy of this new treatment. Tractional retinal detachment in PDR may occur or progress after IVB used as an adjuvant to vitrectomy. Surgery should be performed 4 days after IVB. Based on our multivariate and bivariate analysis, risk factors for TRD after IVB in PDR are time from diagnosis of DM of more than 15 years, time interval from IVB to vitrectomy of more than 13 days, and the use of the higher dose of IVB (2.5 mg).The authors have no financial or proprietary interest in any of the products or techniques mentioned in this paper.


To estimate and to compare ten-year survival rates in unselected patients with early-onset breast cancer, with and without a BRCA1 mutation. To identify prognostic factors among unselected BRCA1-positive breast cancer patients.3354 women who were diagnosed with stage I to stage IV breast cancer, at or below 50 years of age, between January 1996 and December 2006 were contributed from 17 clinical centers in Poland. All patients were offered genetic testing for three founder mutations in BRCA1 . Information on tumour characteristics at presentation and on treatments received was retrieved by reviewing the medical records. Mortality and dates of death were obtained by linkage to the vital statistics database of the Polish Ministry of Administration and Internal Affairs. Survival curves for the mutation-positive and mutation-negative sub-cohorts were constructed using Kaplan–Meier statistics and compared. Predictors of survival were determined using the Cox proportional hazards method.3354 patients were enrolled in the study, of whom 234 (7.0%) were found to carry a BRCA1 founder mutation. The average age of diagnosis was 44 years (range 21 to 50 years). The ten-year survival for mutation carriers was 80.9% (95% CI 75.4% to 86.4%) and for non-carriers was 82.1% (95% CI 80.5% to 83.7%). After adjusting for other prognostic variables, the hazard ratio associated with carrying a BRCA1 mutation was 1.40 (95% CI: 0.99 to 1.99). Among BRCA1 mutation carriers, in the multivariable analysis, positive lymph node status was a strong predictor of mortality . Among BRCA1 carriers with a small (< 2 cm) node-negative breast cancer, the ten-year survival rate was 91.7% and tumour size was not predictive of survival (HR = 1.01 for 1-2 cm versus 0-1 cm tumors). Chemotherapy was associated with improved survival in BRCA1 carriers  but not in non-carriers . The interaction between chemotherapy, mutation status and survival was statistically significant (p = 0.009).The survival of women with breast cancer and a BRCA1 mutation is similar to that of patients without a BRCA1 mutation. For women with a small, node-negative breast cancer and a BRCA1 mutation, the ten-year survival rate was 91.7%. Among women with a BRCA1 mutation, survival was better for women who received chemotherapy than for women who did not receive chemotherapy. Future studies should investigate what is the optimum chemotherapy regimen.


P > 0.05) between bucks aged <1–1.5 and 2–2.5 years. However, bucks aged 3–3.5 year a had lower (P < 0.05) incidence of pathological conditions than other age groups. Histopathological evidence of inflammation, degeneration, and atrophy was observed in the testes, while inflammatory changes were observed in the prepuce.The study of pathological conditions of the male reproductive system is paramount to understanding reproductive inefficiency in the Sahel goat. In this study, 1048 Sahel bucks presented for slaughter at the Maiduguri metropolitan abattoir were evaluated for the presence of various pathological abnormalities of the reproductive system. A total incidence of 15.08% was recorded for various pathological conditions, with testicular, penile, and scrotal conditions having incidences of 7.82%, 4.80 and 2.50%, respectively. Bilateral testicular hypoplasia and atrophy and unilateral cryptorchidism accounted for incidences of 4.10%, 2.38%, and 1.24%, respectively, while paraphimosis and scrotal laceration had incidences of 1.72% and 1.05%, respectively. Age specific incidence of pathological conditions were not significant ( The male reproductive system is essential for domestic animals' species propagation and survival . The tesZ-test using computer statistical software .One thousand and forty-eight male Sahel goats presented for slaughter at the Maiduguri metropolitan abattoir in March–July, 2010, were used for this study. The age of the bucks was estimated before slaughter by dental examination. The bucks were categorized into three age groups of <1–1.5, 2–2.5, and 3–3.5 years. After slaughter, the whole genitalia consisting of the penis, prepuce, testes, epididymis, and scrotal sac were examined for evidence of gross pathological abnormalities. Testicular conditions such as bilateral testicular hypoplasia and atrophy were identified through gross changes in size, texture, and consistency of the testes. Briefly, hypoplastic testes were identified as small, soft, and flabby, while atrophic testes were small and hard due to regression in size and thickening of the tunica albuginea. Unilateral cryptorchidism was identified on the basis of retention of one testicle (right of left) either in the abdominal or inguinal cavities. Tissue samples were collected and fixed in 10% buffered formalin, processed, sectioned, and stained with hematoxylin and eosin for histopathological examination using light microscopy. Confirmation of testicular hypoplasia and atrophy was done microscopically by examination of the seminiferous tubules from testicular tissue sections for evidence of spermatogenesis, degeneration, inflammation, and fibrosis. Data obtained were summarized and presented as number of occurrences and percent or proportion of total population examined. A statistical comparison among the age groups was made with Evidence of some gross lesions observed in the testes, penis, and scrotum is shown in The age specific incidence of pathological conditions in the male reproductive tract of the Sahel goat is summarized in P > 0.05) between bucks aged <1–1.5 years and 2–2.5 years. Similarly, there was no significant difference (P > 0.05) between all testicular and penile conditions observed in bucks aged <1–1.5 years and 2–2.5 years. However, there was a significant difference (P < 0.05) in the occurrence of scrotal conditions in these two age groups. In bucks aged 3–3.5 years, BTH, UC, and balanoposthitis had a significantly lower (P < 0.05) incidence when compared with incidences in bucks aged <1–1.5 and 2–2.5 years. The incidence of all other conditions did not vary significantly (P > 0.05) among the three age groups.The age specific incidence of all pathological conditions encountered was 18.85% in bucks aged 2–2.5 years, 15.06% in bucks aged <1–1.5 years, and 8.46% in bucks aged 3–3.5 years. These incidences did not vary significantly  reported for the Sahel buck from a previous study –10. All Balanoposthitis had an incidence of 0.86%; this was slightly lower than the prevalence reported for ulcerative balanoposthitis in feral male goats (1.1%) . Other gThe histopathological evaluation of testicular conditions  showed findings that were consistent with what was reported in the literature . Bucks wUC and BTH are congenital conditions that are hereditary and irreversible, while BTA is mostly acquired due to chronic pathologic changes affecting the testes such as degeneration and inflammation –6. In thIt was observed that testicular conditions were more common in occurrence than penile or scrotal conditions in the male Sahel goats. Similarly, it was also noted that bucks aged <1–1.5 and 2–2.5 years had higher incidence of all genital conditions than those aged 3–3.5 years.


Purpose. The use of an S-type oblique excision with a bilateral gluteus maximus advancement flap has recently been described for the surgical treatment of sacrococcygeal pilonidal sinus (SPS). Its use in wide lesions has been limited due to the need for a full-thickness flap. We describe the use of an S-type oblique incision together with the Dufourmentel flap in wide lesions. Method. Twenty-one patients were treated using a technique including an S-shaped oblique excision of the sinus tract and a broad-pedicled full-thickness flap resembling a Dufourmentel flap to close the defect. Results. Of the 21 patients, 19 (90.5%) were male and 2 (9.5%) were female. Their mean age was 24.0 ± 6.1 (range 15–36) years. The mean follow-up period was 14.0 ± 5.8 (range 6–23) months. The postoperative complication rate was 4.8% (one patient), and recurrence was seen in one patient (4.8%). The mean return-to-work time was 13.5 ± 1.9 (range 10–18) days. None of the patients reported dissatisfaction with the cosmetic results. Conclusions. This new technique achieved low morbidity and recurrence rates. We anticipate that this will become an important technique in the surgical treatment of SPS if the observed success is confirmed by randomized prospective trials. A pilonidal sinus is a recurring chronic inflammatory process that is thought to develop in an acquired manner. Hair follicles entering the skin are regarded as the main factor in its pathogenesis , 2. GeneVarious techniques have been described for the surgical treatment of sacrococcygeal pilonidal sinus (SPS). However, there is no consensus regarding the optimal surgical technique. Several authors have maintained that the ideal treatment in pilonidal sinus surgery can be achieved with flattening and lateralization of the natal cleft , 4. The Historically, surgical treatment of pilonidal sinus began with excision and marsupialization or excision and primary closure. Today, these methods have been replaced by excision and closure with advancement flap techniques, which have lower recurrence and complication rates and shorter return-to-work times. Nevertheless, these pilonidal sinus surgery techniques still have room for improvement.Here, we present the results of a novel technique described as a full-thickness rhomboid transpositional flap (modified Dufourmentel flap) with S-type oblique excision designed for the treatment of pilonidal sinus.The study population consisted of 21 patients with SPS treated by using an S-type oblique excision and modified Dufourmentel flap between August 2010 and July 2012. Patients with recurrent disease, massive gluteal involvement , and acute infection were excluded. Each patient was informed about the operation to be performed and gave their written consent. The operations were performed by the first (MY) and second (FC) authors. Age, gender, body mass index (BMI), primary and recurrent disease, duration of the symptoms , and length of hospitalization were recorded. The patient characteristics are summarized in In this surgical procedure, the sinus tract was first excised in the prone position, descending as far as the postsacral fascia with an S-shaped oblique incision facing either right or left . A broadAll operations were performed under spinal anesthesia. An enema was administered preoperatively. A single dose of cefazolin (1 g) was administered 30–60 min before the skin incision for prophylaxis.The patients were mobilized on the first postoperative day and discharged with appropriate instructions for wound care and a 5-day, prescription for oral coamoxicillin (1000 mg) every 12 h. The patients were evaluated on the fifth day, and ultrasonography (USG) was performed to monitor seroma formation. The skin sutures were removed 10–12 days postoperatively. The latest status of patients undergoing surgery was determined by telephone.2. The mean operation time was 40.3 ± 4.4 (range 35–50) min. No flap necrosis or wound site infection was seen in any patient postoperatively. A seroma with negative bacterial culture was seen in one patient, and was aspirated. The total complication rate was 4.8% (1/21). The mean return-to-work time was 13.5 ± 1.9 (range 10–18) days, and the mean follow-up was 14.0 ± 5.8 (range 6–23) months. Recurrence was seen in one (4.8%) patient 7 months postoperatively; this patient was treated with excision plus marsupialization. None of the patients reported dissatisfaction regarding the cosmetic results of the surgery.Of the 21 patients 19 (90.5%) were male and 2 (9.5%) were female. The mean patient age was 24.0 ± 6.1 (range 15–36) years. The mean duration of symptoms was 13.0 ± 10.1 (range 3–42) months. The pilonidal sinus was in the chronic phase in all patients. Apart from two cases in which recurrence was identified 2 and 6 months after excision and primary closure in the midline, none of the patients had previously undergone surgery for this disease. The mean BMI for all cases was 25.1 ± 2.8 (range 19.2–29.7) kg/mPilonidal sinus disease, generally seen in the intergluteal region, was first described by Mayo in 1833 and named by Hodges in 1880 .Techniques such as shaving , phenol Flattening/lateralization of the intergluteal sulcus, prevention of seroma formation, reduction of wound tension, and prevention of wound breakdown and scar formation have been suggested to accelerate wound healing and reduce recurrence . RecurreEfforts to reduce recurrence to minimum, lower complication rates and increase patient satisfaction in the treatment of pilonidal sinus are continuing. Recently, the S-type oblique excision for pilonidal sinus was described, and bilateral advancement of the gluteus maximus fascia in addition to primary repair with this excision has been described as a flap reconstruction technique , 11. KraIn conclusion, S-type oblique excision used together with the modified Dufourmentel flap procedure can be applied to wider lesions. As it resembles the Limberg flap modification described by Mentes et al. , we anti