Comparison of high and low dose of cyclophosphamide in lupus nephritis patients: a long-term randomized controlled trial

To evaluate the outcome of low doses of cyclophosphamide (Cyclo) therapy in lupus nephritis (LN) patients, we studied 117 biopsy-proven, de novo LN WHO class IV patients double-blinded and randomized in December 1997 to receive Cyclo in different doses; Group I (n=73) received Cyclo 10 mg/kg monthly for six months then every two months for 12 months. Group II (n=44) received Cyclo 5 mg/kg monthly for six months then every two months for 36 months. The patients were followed-up till January 2007. Six months post-induction values for creatinine clearance were significantly higher in Group I (67.7 ± 28.6 mL/min) compared with Group II (55.1 ± 30.1 mL/min), P = 0.026. Serum C4 and ANA were not significantly different between the groups (P > 0.05). At the mean follow-up of 6.77 ± 3.3 years, the mean creatinine clearance was 44.74 ± 31.7 mL/min in Group I vs. 49.3 ± 38.8 in Group II. Urinary protein was 1.65 ± 1.8 g/dL in Group I vs. 1.02 ± 1.01 in Group II (P = 0.03). The survival curve showed that kidney survival overtime was comparable in both groups (P = 0.2). Complete remission was observed in 25 (34.2%) patients in Group I vs. 11 (25%) in Group II (P = 0.288), while partial remission was similar in both groups; 43 (58.9%) patients in Group I vs. 26 (59%) patients in Group II. End-stage renal disease was observed in 10 (13.7%) patients in Group I vs. 9 (20.4%) patients in Group II (P = 0.359). Side-effects were more frequent in Group I patients than in Group II patients; gonadal toxicity and malignancy were lower in Group II patients (P = 0.0000). Moreover, different infections occurred in 23 (31.3%) patients vs. six (13.6%), digital infarcts occurred in 1.35% vs. 0%, diabetes in 4.1% vs. 2.27%, and vasculitis in 4.1% vs. 2.27% in Group I vs. Group II, respectively. Sustained amenorrhea without pregnancy was observed in both groups; however, significantly more in Group I patients, P ≤ 0.05. We conclude that low-dose Cyclo therapy is sufficiently effective for WHO class IV LN patients with lower side-effects compared with standard dose.     

Comparative analysis of the effects of hubble-bubble (Sheesha) and cigarette smoking on respiratory and metabolic parameters in hubble-bubble and cigarette smokers

OBJECTIVES AND BACKGROUND: Hazard of smoking tobacco is believed to be minimized by smoking hubble-bubble (HB) instead of cigarettes. Our aims were to (i) develop an assay for estimating nicotine and cotinine; and (ii) evaluate the effect of smoking on respiratory and metabolic parameters in cigarette and HB smokers. METHODS: Urine samples were collected from 152 volunteer smokers (75 cigarette and 77 HB) as well as from 16 healthy controls. We optimized an HPLC method for the determination of nicotine and cotinine. Subjects were asked to complete a chronic respiratory symptoms questionnaire and to undergo spirometry. Fasting blood samples were collected for the determination of their lipid profile. RESULTS: The intra-assay coefficients of variation for nicotine and cotinine were 16.6% and 6.6%, respectively. The mean of cotinine in cigarette smokers (1321.4 ng/mL) was significantly (P = 0.008) higher than the mean cotinine (677.6 ng/mL) in HB smokers. The mean nicotine level in cigarette smokers (1487.3 ng/mL) was significantly (P < 0.0001) higher than the mean nicotine (440.5 ng/mL) in HB smoker. The urinary cotinine and nicotine levels of the control subjects were lower than the detection levels of the assay. The mean high-density lipoprotein cholesterol was lower in cigarette smokers (0.99 mmol/L) compared with HB smoker smokers (1.02 mmol/L) but this was not significant (P = 0.28). Spirometric values were comparable among the three groups but the chronic respiratory symptoms in the smoking groups appeared at an earlier age in the HB smokers compared with the cigarettes smokers (P < 0.05). CONCLUSION: Smoking HB does not reduce the risk of tobacco exposure and it's potentially harmful metabolites on health.     

A thermally targeted elastin-like polypeptide-doxorubicin conjugate overcomes drug resistance

The ability of cancer cells to become simultaneously resistant to different drugs, a trait known as multidrug resistance, remains a major obstacle for successful anticancer therapy. One major mechanism of resistance involves cellular drug efflux by expression of P-glycoprotein (P-gp), a membrane transporter with a wide variety of substrates. Anthracyclines are especially prone to induction of resistance by the P-gp mechanism. P-gp mediated resistance is often confronted by use of P-gp inhibitors, synthesis of novel analogs, or conjugating drugs to macromolecular carriers in order to circumvent the efflux mechanism. In this report, the effect of free and Elastin-like polypeptide (ELP) bound doxorubicin (Dox) on the viability of sensitive (MES-SA and MCF-7) and multidrug resistant (MES-SA/Dx5 and NCI/ADR-RES) human carcinoma cells was studied in vitro. The resistant MES-SA/Dx5 cells demonstrated about 70 times higher resistance to free Dox than the sensitive MES-SA cells, and the NCI/ADR-RES cells were about 30 fold more resistant than the MCF-7 cells. However, the ELP-bound Dox was equally cytotoxic in both sensitive and resistant cell lines. The ELP-bound Dox was shown to accumulate in MES-SA/Dx5 cells, as opposed to free Dox, which was rapidly pumped out by the P-gp transporter. Since ELP is a thermally responsive carrier, the effect of hyperthermia on the cytotoxicity of the ELP-Dox conjugate was investigated. Both cytotoxicity and apoptosis were enhanced by hyperthermia in the Dox resistant cells. The results suggest that ELP-Dox conjugates may provide a means to thermally target solid tumors and to overcome drug resistance in cancer cells.     

Maternal mortality in Syria: causes, contributing factors and preventability

Objectives  To describe the biomedical and other causes of maternal death in Syria and to assess their preventability.
Methods  A reproductive age mortality study (RAMOS) design was used to identify pregnancy related deaths. All deaths among women aged 15–49 reported to the national civil register for 2003 were investigated through home interviews. Verbal autopsies were used to ascertain the cause of death among pregnancy related maternal deaths, and causes and preventability of deaths were assessed by a panel of doctors.
Results  A total of 129 maternal deaths were identified and reviewed. Direct medical causes accounted for 88%, and haemorrhage was the main cause of death (65%). Sixty nine deaths (54%) occurred during labour or delivery. Poor clinical skills and lack of clinical competency were behind 54% of maternal deaths. Ninety one percent of maternal deaths were preventable.
Conclusions  The causes of maternal death in Syria and their contributing factors reflect serious defects in the quality of maternal care that need to be urgently rectified.     

Efficacy of monotherapies and artesunate-based combination therapies in children with uncomplicated malaria in Somalia

In order to guide the antimalarial treatment policy of Somalia, we conducted therapeutic efficacy studies of routinely used antimalarial monotherapies as well as artemisinin-based combination therapies (ACTs) for uncomplicated malaria in three sentinel sites during 2003-2006. Therapeutic efficacy of chloroquine (CQ), amodiaquine (AQ) and sulfadoxine/pyrimetahmine (SP) monotherapies, and artesunate plus SP (AS + SP) or AQ (AS + AQ) were evaluated in children 6 months to 10 years old with uncomplicated malaria. For the assessment of the monotherapies, 2003 WHO protocol with 14-day follow-up was used while the 2005 WHO protocol with 28-day follow-up was used for testing the ACTs. Of the monotherapies, CQ performed very poorly with treatment failures varying from 76.5% to 88% between the sites. AQ treatment failure was low except for Janale site with treatment failure of 23.4% compared to 2.8% and 8% in Jamame and Jowhar, respectively. For SP, treatment failures from 7.8% to 12.2% were observed. A 28-day test of artemisinin-based combinations, AS + SP and AS + AQ, proved to be highly efficacious with cure rates of 98-100% supporting the choice of AS + SP combination as first line treatment for uncomplicated malaria for Somalia.     

High prevalence of vitamin D deficiency in type 1 diabetes mellitus and healthy children

Epidemiological studies suggest a link between vitamin D deficiency in early life and the later onset of type 1 diabetes. The aim of this matched case-control study was to find the association between vitamin D and T1DM then to study the difference in the level of vitamin D in T1DM and healthy subjects, and to determine the associated environmental risk factors in young Qatari population. The study was carried out among T1DM children and healthy subjects below 16 years at the pediatric endocrinology outpatient clinics of the Hamad General Hospital and the Primary Health care Clinics (PHCs). The survey was conducted over a period from 6 August to 25 December 2007. The subjects were Qatari nationals male and female aged below 16 years. The study is based on matching by age, gender and ethnicity of 170 cases with those of 170 controls. Face-to-face interviews were based on a questionnaire that included variables such as socio-demographic information, assessment of non-dietary covariates, assessment of dietary intake, vitamin D intake, type of feeding, clinical manifestations and laboratory investigations. Their health status was assessed by medical conditions, family history, BMI, past or present clinical manifestations, 25 (OH)D, Calcium, alkaline phosphatase, phosphorus, HbA1C, PTH, Mg and creatinine analysis. The study revealed that vitamin D deficiency was considerably higher in T1DM children (90.6%) compared to non-diabetic children (85.3%). There was a significant difference found in the mean value of vitamin D between T1DM and non-diabetic children (P = 0.009). There were statistically significant differences between type 1 diabetic and healthy subjects with respect to the occupation of parents (P < 0.001) and consanguinity rate (P < 0.047). Family history of vitamin D deficiency was considerably higher among T1DM children (35.3%) with a significant difference between diabetic and non-diabetic children (22.9) (P < 0.012). Vitamin D supplement with breast milk was very poor in diabetic children (37.4%) compared to non-diabetic children (47.7%). Majority of the studied subjects were breast-fed children (95.1% of diabetic children and 97.2% of healthy children). Multivariate logistic regression analysis revealed that fathers and mothers occupation, family history of DM, physical activity, low duration of time under sun light, breast feeding less than 6 months and low vitamin D level were considered as the main factors associated with the T1DM. In conclusion, the present study revealed that vitamin D deficiency was higher in T1DM children compared to non-diabetic. Moreover, vitamin D deficiency was common in Qatari young population. Vitamin D intake was very poor in children and it shows that supplementing infants with vitamin D might be a safe and effective strategy for reducing the risk of T1DM.     

Mandibular growth during adolescence

OBJECTIVE: To evaluate the mandibular growth of whites according to Fishman's method. MATERIALS AND METHODS: Eighty-five subjects, 9 to 18 years of age, were selected from the files of the Department of Orthodontics, Pontificia Universidade Catolica do Rio Grande do Sul, Porto Alegre, Brazil. Patients were evaluated at two time points. At T1, they had a lateral head film and a hand-wrist radiograph and at T2, a lateral head film. The interval between T1 and T2 was 5 to 24 months. Subjects presented a Class I or II skeletal pattern and were divided into three groups according to Fishman's method: group I, in an accelerating growth velocity phase; group II, in peak of growth velocity phase; and group III, in decelerating growth velocity phase. The cephalograms were manually traced and cephalometric points digitalized into DentoFacial Planner Plus 2.0. The absolute growth amount was adjusted to obtain an annual growth rate (mm/y). The annual growth rate was compared between sexes, between individuals with Class I or II skeletal patterns, and among the three groups. RESULTS: Mandibular annual growth rate in puberty was 2.16 mm for the mandibular body length, 3.16 mm for the ramus height, and 4.31 mm for the mandibular length. The results did not show significant differences between sexes, skeletal patterns, and groups, although there was a tendency for growth acceleration in group II. CONCLUSIONS: There is great individual variation in mandibular linear growth.     

R1615P: a novel mutation in ABCA1 associated with low levels of HDL and type II diabetes mellitus

Endomyocardial fibrosis is a restrictive cardiomyopathy, of unknown etiology, which occurs most commonly in tropical and subtropical areas. Typical clinical aspect of the disease shows striking ascites, regardless of which ventricle is involved, contrasting with little or no peripheral edema.     

Multiple Lymphomatous Polyposis Form of Blastoid Variant of Mantle Cell Lymphoma in Colon: a Case Report and Review of Literature

Background

Squamous cell carcinoma (SCC) of the esophagus is one of the most common malignancies of the gastrointestinal tract and carries poor prognosis. The role of mast cell density (MCD) in the prognosis of most human tumors is partly known, and there is a growing body of studies addressing it. However, the prognostic value of MCD has not been investigated in esophageal SCC, and thus, it was the subject during this study.

Methods

In this study, 78 patients with esophageal SCC in pT = 3 were selected, their MCD was evaluated with toluidine blue staining, and the relationship with survival rate was analyzed. Patients were compared in identical groups of lymph node involvement and post-surgery complementary therapy.

Results

Survival rate was significantly decreased in patients with high MCD based on Kaplan–Meier analysis (P?<?0.001). This relationship was also found in groups with similar lymph node involvement and post-surgery therapies.

Conclusions

The results of the current study showed that high MCD in the invasive edge of tumor is related to tumor progression and decreased survival rate following surgery.     

Regorafenib treatment for advanced,refractory gastrointestinal stromal tumor: a report of the UK managed access program

Background

Tyrosine kinase inhibitors (TKI) have revolutionized the treatment of gastrointestinalstromal tumors (GIST) although most patients develop resistance to first and second-line therapies.Regorafenib, an oral multi-targeted TKI, has demonstrated benefit in previously treated GIST patients.

Methods

We assessed safety and activity of regorafenib in patients treated within the Managed Access Program (MAP). All consecutive patients with advanced GIST who had progressed on or were intolerant to imatinib and sunitinib were recruited from the Royal Marsden and University College Hospitals. We retrospectively reviewed the data for response, toxicity, treatment duration and survival. Response was assessed by RECIST and Choi criteria. Toxicity was graded according to CTCAE v4.0 criteria.

Results

20 patients were included in the MAP in the UK between 3/2013 and 9/2013. Median age was 68 (range 45–87), 65% of patients were male. Performance Status was 0–1 for 18 patients (90%), 2 for 2 patients (10%). The median treatment duration was 9.25 months (range 0.1-15.33). 18 patients were assessable for response and all patients attained a best response of at least stable disease. At a median follow-up of 12.6 months, there were 2 partial responses (11%) by RECIST and 7 partial responses (39%) according to Choi criteria. 7 patients remain on regorafenib. 3 patients discontinued treatment due to unacceptable adverse events; fistulation, myalgia and fatigue. 10 (50%) patients had grade 3 toxicities and 11 (55%) patients required a dose reduction. Median PFS was 9.4 months (95% Cl: 6.2-not calculable) and median OS was 12.2 months (95% Cl: 10.5-not calculable). Notably, prolonged stable disease was seen in 1 patient with exon 9 mutation and 1 patient with PDGFR D842V mutation.

Conclusions

These data demonstrate encouraging activity and tolerability of regorafenib in routine clinical practice. The documented adverse events are in line with previous trial data.