Circulating galectin-3 in infections and non-infectious inflammatory diseases

Recent studies point to a dual role for galectin-3 as both a circulating damage-associated molecular pattern and a cell membrane-associated pattern recognition receptor. The aim of this study was to assess the potential of circulating galectin-3 for discriminating between infections and non-infectious inflammatory disorders on the one hand, and between fungal and bacterial infections on the other. Galectin-3 and C-reactive protein (CRP) were measured in the plasma of 127 patients with either non-infectious inflammatory disorders (gout, autoinflammatory syndrome or pancreatitis) or an infection (viral lower respiratory tract infection, bacterial sepsis or candidaemia). Circulating galectin-3 concentrations were increased in patients with infections when compared with healthy volunteers or patients with non-infectious inflammatory diseases. At cut-off values with a specificity of 95 %, the sensitivity of galectin-3 (>20.6 ng/ml) to discriminate between an infection and non-infectious inflammation was higher than that of CRP (>156 mg/l): 43 % [95 % confidence interval (CI) 33–53 %] versus 27 % (95 % CI 19–37 %), p?=?0.03. After exclusion of patients with CRP <156 mg/l, galectin-3 concentration >20.6 ng/ml could identify 41 % (95 % CI 29–53 %) of the patients with an infection at the cost of one false-positive with non-infectious inflammation. Using this sequential approach, 57 % of the patients with an infection could be selected. Galectin-3 concentrations were similar in patients with bacterial and Candida sepsis, while being lower in viral respiratory infections. Although galectin-3 does not discriminate between bacterial and Candida sepsis, the sequential use of CRP and galectin-3 in distinguishing infectious diseases from non-infectious inflammation may be superior to CRP alone.     

Considerable variation of trough β-lactam concentrations in older adults hospitalized with infection—a prospective observational study

In older adults, few studies confirm that adequate concentrations of antibiotics are achieved using current dosage regimens of intravenous β-lactam antibiotics. Our objective was to investigate trough concentrations of cefotaxime, meropenem, and piperacillin in older adults hospitalized with infection. We included 102 patients above 70 years of age. Total trough antibiotic concentrations were measured and related to suggested target intervals. Information on antibiotic dose, patient characteristics, and 28-day outcomes were collected from medical records and regression models were fitted. Trough concentrations for all three antibiotics exhibited considerable variation. Mean total trough concentrations for cefotaxime, meropenem, and piperacillin were 6.5 mg/L (range 0–44), 3.4 mg/L (range 0–11), and 30.2 mg/L (range 1.2–131), respectively. When a target range of non-species-related breakpoint ? 5× non-species-related breakpoint was applied, only 36% of patients had both values within the target range. Regression models revealed that severe sepsis was associated with varying concentration levels and increasing age and diminishing kidney function with high concentration levels. The study was not powered to demonstrate consequences in clinical outcomes. Conclusively, in older adults treated with cefotaxime, meropenem, or piperacillin-tazobactam, trough antibiotic concentrations varied considerably. Better predictors to guide dosing regimens of β-lactam antibiotics or increased use of therapeutic drug monitoring are potential ways to address such variations.     

Quantitative Evidence of Wear-Off Effect at the End of the Intravenous IgG (IVIG) Dosing Cycle in Primary Immunodeficiency

Purpose

Intravenous IgG (IVIG) treatment wear-off is commonly experienced by patients, who report increased susceptibility to infection, and decreased quality of life towards the end of their 3- or 4-week dosing cycle, when serum IgG levels approach their trough. We quantified IVIG wear-off in terms of treatment efficacy and patient well-being.

Methods

Data were collected from patients enrolled in three Phase III trials of Sandoglobulin® NF Liquid or Privigen®, treated every 3- or 4- weeks. Pooled analyses of raw patient data compared the rate of infection and other clinical outcomes during the course of the dosing cycle. Subjective symptoms of wear-off were quantified by comparing patient-reported overall well-being scores.

Results

The probability of a first infection in the final week of the IVIG cycle was 1.26 (95 % confidence intervals [CI]: 0.76–2.11; p = 0.3621) and 1.55 (95 % CI: 1.04–2.32; p = 0.0314) times higher than in the first week, for patients on a 3-week cycle and 4-week dosing cycles, respectively. Wear-off, as manifested by a decrease in overall well-being, was experienced in 10 % of all cycles and reported at least once by 61 % of the patients on a 3-week cycle, and 43 % of those on a 4-week cycle.

Conclusions

These findings confirm the existence of decreased efficacy (treatment wear-off) towards the end of a 3–4 week IVIG dosing cycle, and provide a quantifiable evaluation to a phenomenon typically reported anecdotally. For patients experiencing wear-off, increasing the IgG dose or shortening the dosing interval and/or a switch to SCIG may be beneficial.

     

Comparative serum biochemical profiles of three types of donkeys in Ethiopia

A cross-sectional study was conducted on the three types of working donkeys in Ethiopia (Abyssinian, Ogaden, and Sennar) while they are in their ecological adaptation sites to evaluate and compare the reference values of serum biochemical profiles. Blood samples were collected from a total of 229 apparently healthy adult working donkeys (134 Abyssinian, 55 Ogaden, 40 Sennar types), and ten serum biochemical analytes (total serum protein, glucose, creatinine, gamma glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), sodium, chloride, and potassium) were analyzed using a commercial kit (Centronic GmbH, Wartenberg, Germany) for the target groups. A comparison based on the serum biochemical profile of the three donkey types irrespective of sex has shown significantly lower serum activities of ALT (19.20?±?3.55 IU/l; CI, 18.06–20.34) and AST (178.13?±?55.70; confidence interval (CI), 160.31–195.94) for Sennar donkeys compared to the activities of ALT (23.65?±?7.73; CI, 21.56–25.75) and AST (240.60?±?110.20; CI, 210.81–270.39) (P?<?0.05) for Ogaden-type adult donkeys. A significantly lower serum activity of GGT (36.36?±?14.70 IU/l; CI, 33.85–38.87) was observed for Abyssinian donkeys than for Ogaden donkeys (48.24?±?16.59 IU/l; CI, 43.75–52.72) (P?<?0.001). The serum sodium (147.55?±?21.81 mmol/l; CI, 141.65–153.44) and chloride (116.67?±?16.23 mmol/l; CI, 112.28–121.06) concentrations of Ogaden donkeys were found to be significantly higher than the sodium (132.68?±?14.16 mmol/l; CI, 128.15–137.20) and chloride (104.50?±?6.45 mmol/l; CI, 102.44–106.56) (P?<?0.001) concentrations of Sennar donkeys. A significantly higher serum potassium concentration (4.84?±?0.63 mmol/l; CI, 4.73–4.94) of Abyssinian donkeys was found compared to those of Sennar (4.38?±?0.49 mmol/l; CI, 4.22–4.54) and Ogaden donkeys (4.31?±?0.78 mmol/l; CI, 4.10–4.52) (P?<?0.05). There was no significant variation in the serum concentration of total protein, glucose, creatinine, and ALP activity among the three types of donkeys. A comparison of the serum biochemical profile of adult jacks has shown a significantly different result for the serum activities of GGT, ALT, and AST and the concentrations of serum chloride and sodium among the three donkey types. Abyssinian jennies in Afar had significantly higher serum activities of AST (248.92?±?120.05 IU/l; CI, 202.78–295.07) (P?<?0.05) and ALT (29.04?±?8.34 IU/l; CI, 25.83–32.24) (P?<?0.001) than the AST (192.57?±?66.60 IU/l; CI, 176.97–208.17) and ALT (20.76?±?6.61 IU/l; CI, 19.21–22.31) activities for jennies in Sebeta but had lower serum glucose and chloride concentrations. In conclusion, the findings of the present study could be used as reference values for the serum biochemical parameters of the three types of donkeys in Ethiopia, and clinical interpretation of the biochemical parameter based on the standard reference values should consider the types of donkeys.     

Once- versus twice-daily dosing of eliglustat in adults with Gaucher disease type 1: The Phase 3, randomized,double-blind EDGE trial

Eliglustat is a first-line oral therapy for adults with Gaucher disease type 1 (GD1) with compatible CYP2D6-metabolizer phenotypes (> 90% of patients). The randomized, double-blind EDGE trial (NCT01074944, Sanofi Genzyme) evaluated once-daily eliglustat dosing compared with the approved twice-daily regimen at the same total daily dose in adults with GD1. Subjects received twice-daily dosing during a 6- to 18-month lead-in period. Only subjects who attained prespecified treatment goals for hemoglobin, platelet count, spleen and liver volumes, and bone symptoms during the lead-in period were randomized to once- or twice-daily dosing. Of 170 enrolled patients, 156 completed the lead-in period and 131 met all requirements to enter the double-blind treatment period. To achieve the composite primary endpoint in the double-blind period, patients had to maintain clinical stability relative to baseline on all five endpoints (hemoglobin, platelet count, spleen and liver volumes, and bone symptoms) and meet pharmacokinetic and other tolerability requirements as determined by the investigator after 1 year of eliglustat treatment. After 1 year, 80.4% (95% CI: 67.6, 89.8) of once-daily patients were stable compared with 83.1% (95% CI: 71.0, 91.6) of twice-daily patients. The 95% CI for the mean difference of ? 2.7% between groups was ? 17.7, 11.9. Because the lower bound of the CI exceeded the pre-defined non-inferiority margin of ? 15%, once-daily dosing could not be declared non-inferior to twice-daily dosing. Both once-daily and twice-daily patients maintained mean values for hematologic and visceral measures within established therapeutic goals during the double-blind treatment and long-term extension periods. Eliglustat was generally well-tolerated during this long-term trial (mean treatment duration: 3.3 years), with just four withdrawals (2%) for related adverse events (AE), and similar AE profiles for both dosing regimens. Patients on twice-daily eliglustat showed more stability overall, and this dose regimen was better tolerated, confirming the dosing regimen for most patients specified in the drug label.     

Cadmium accumulation and biochemical parameters in juvenile Persian sturgeon, Acipenser persicus, upon sublethal cadmium exposure

The purpose of the present study was to evaluate the effects of exposure to waterborne sublethal cadmium (Cd) concentration on juvenile Persian sturgeon, Acipenser persicus. Fish were exposed to 0.68 mg/l of Cd for 1, 7, and 14 days, and metal bioaccumulations, biochemical responses, and gill ions were investigated. There were significant differences (p?<?0.05) in the kidney (1, 7, and 14) and gills (7 and 14) for Cd concentrations between the control and treatment groups. Also, kidney Cd concentrations were significantly higher (p?<?0.05) at metal treatments on day 14 in comparison to day 1. Results showed that there were significant differences (p?<?0.05) in plasma glucose and cortisol concentrations between the experimental and control groups on day 1 only, and at metal treatments, a significant decrease (p?<?0.05) was observed on days 7 and 14 compared to day 1. No significant alterations were observed in plasma and liver protein contents during the course of the study. Neither triiodothyronine or thyroxine levels nor liver catalase or glutathione-S-transferase activities changed significantly with sublethal dose and with the time. In contrast, liver superoxide dismutase activities were significantly decreased (p?<?0.05) at Cd treatments both over the control group and during Cd exposure on days 7 and 14. Finally, a comparison between the groups revealed no differences in gill ion levels for 2 weeks. This study demonstrated that sublethal dose of Cd was stressful for Persian sturgeon and resulted in rapid changes in some of the biochemical parameters.     

Developmental dynamics of the bronchial (airway) and air sac systems of the avian respiratory system from day 3 to day 26 of life: a scanning electron microscopic study of the domestic fowl,<Emphasis Type="Italic"> Gallus gallus</Emphasis> variant<Emphasis Type="Italic"> domesticus</Emphasis>

The lung buds were first conspicuous on day 3 of embryogenesis. They fused on day 4 and the common growth divided into left and right primordial lungs on day 5. Progressively, the lungs elongated, diverged, and advanced towards the respective dorsolateral aspects of the body wall, reaching their definitive topographical locations in the coelomic cavity on day 6. On day 7, they rotated, attached onto the ribs, gradually started to slide into them, and were deeply inserted by day 8. The primary bronchus (PB) first appeared as a solid cord of epithelial cells (day 4) that successively canalized as it invaded the surrounding mesenchyme, extending along the proximal-distal axis of the lung. From day 8, the secondary bronchi (SB) begun to sprout from the PB in a craniocaudal sequence. On day 9, the parabronchi (PR) started to bud from the SB, projecting into the adjacent mesenchyme. They commenced to canalize on day 10 and greatly increased in length, number, and diameter. By day 13, the PR had anastomosed profusely and totally masked the SB. The luminal surface of the PR was lined by a columnar epithelium from which the atria (day 15), infundibulae (day 16), and air capillaries (ACs) (day 18) developed. At hatching (day 21), the ACs were well developed and had anastomosed profusely with the blood capillaries. Of the air sacs (ASs), the abdominal ones appeared earliest (day 5) followed by the cervical ones on day 6. In quick succession, the other ASs were well formed by day 10. After hatching, no further consequential structures formed: only shifts in topographical locations and an increase in size and number occurred. Morphogenetically, the avian respiratory system differs from the mammalian one in certain key aspects: besides the ASs that are unique to it, the lung is exceptionally complex in structure and is essentially mature at the end of the embryonic life.     

Treatment outcomes for Mycobacterium avium complex: a systematic review and meta-analysis

To evaluate the existing evidence regarding treatment regimens for Mycobacterium avium complex (MAC), a systematic review of the available therapeutic studies was conducted to assess treatment outcomes. A random-effects meta-analysis was used to assess treatment outcomes. Subgroup analyses were also conducted by separating studies based on each characteristic independently. Twenty-eight trials met the inclusion criteria. Our meta-analysis showed that the estimated pooled treatment success rate for patients with MAC disease was 39 % [95 % confidence interval (CI) 38–41 %]. The rates of failure, relapse, death, and default were 27 % (95 % CI 25–29 %), 6 % (95 % CI 5–7 %), 17 % (95 % CI 15–18 %), and 12 % (95 % CI 11–13 %), respectively. The proportion of patients treated successfully did not differ significantly on the basis of the study characteristics. However, studies with treatment regimens containing macrolides had significantly higher pooled success proportions (42 %, 95 % CI 40–44 %) than that of other studies (28 %, 95 % CI 24–32 %). Substantial heterogeneity in the study characteristics prevented more conclusive determination of what factors had the greatest effect on the proportion of patients that achieve treatment success and limited the validity of this analysis. This review underscored the importance of strong patient support and treatment follow-up systems to develop successful MAC treatment programs.     

Pharmacokinetic and Pharmacodynamic Properties of a New Long-Acting Granulocyte Colony-Stimulating Factor (HM10460A) in Healthy Volunteers

Background

HM10460A is a newly developed recombinant human granulocyte colony-stimulating factor with long-lasting characteristics. This factor is expected to be used for chemotherapy-related neutropenic conditions.

Objective

The aim of the present study was to evaluate the pharmacokinetics and pharmacodynamics of HM10460A following subcutaneous administration to healthy Korean subjects.

Methods

A randomized, double-blind, placebo-controlled, escalating single-dose study was conducted in 40 healthy Korean subjects. The subjects were allocated to single-dose groups of 5, 15, 45, 135 or 350 μg/kg, or placebo. Serial blood samples for pharmacokinetic/pharmacodynamic analyses were collected up to 22 days, and urine samples for pharmacokinetic analysis were collected up to 3 days after subcutaneous administration of HM10460A. The serum and urine concentrations were analyzed by enzyme-linked immunosorbent assay.

Results

Most of the serum concentrations in the 5 and 15 μg/kg dosing groups were below the lower limit of quantification (LLOQ). The median times to the peak concentration (T_max) of HM10460A in the 45, 135, and 350 μg/kg dosing groups were 8.0, 14.0, and 24.0 h, respectively. The mean ± standard deviation values of the dose-normalized maximum concentration (C_max) and dose-normalized area under the concentration-time curve (AUC_last) for the 45, 135, and 350 μg/kg dosing groups were 14.13 ± 6.37, 66.19 ± 38.71, and 34.65 ± 19.69 μg/L/mg, respectively, and 265.0 ± 124.1, 2144 ± 1232, and 1386 ± 701.2 μg h/L/mg, respectively. The concentrations of HM10460A in the urine were below the LLOQ in all of the subjects. In all of the dosing groups, the area under the effect-time curve (AUEC_last) of both the absolute neutrophil count (ANC) and the CD34⁺ cell count increased as the dose increased.

Conclusion

HM10460A showed dose-dependent pharmacokinetic characteristics, and the systemic exposure of HM10460A was positively correlated with the ANC and CD34⁺ cell counts.     

Intermittent versus continuous energy restriction on weight loss and cardiometabolic outcomes: a systematic review and meta-analysis of randomized controlled trials

Background

This systematic review and meta-analysis summarized the most recent evidence on the efficacy of intermittent energy restriction (IER) versus continuous energy restriction on weight-loss, body composition, blood pressure and other cardiometabolic risk factors.

Methods

Randomized controlled trials were systematically searched from MEDLINE, Cochrane Library, TRIP databases, EMBASE and CINAHL until May 2018. Effect sizes were expressed as weighted mean difference (WMD) and 95% confidence intervals (CI).

Results

Eleven trials were included (duration range 8–24 weeks). All selected intermittent regimens provided?≤?25% of daily energy needs on “fast” days but differed for type of regimen (5:2 or other regimens) and/or dietary instructions given on the “feed” days (ad libitum energy versus balanced energy consumption). The intermittent approach determined a comparable weight-loss (WMD: ? 0.61 kg; 95% CI ? 1.70 to 0.47; p?=?0.87) or percent weight loss (WMD: ? 0.38%, ? 1.16 to 0.40; p?=?0.34) when compared to the continuous approach. A slight reduction in fasting insulin concentrations was evident with IER regimens (WMD?=?? 0.89 µU/mL; ? 1.56 to ? 0.22; p?=?0.009), but the clinical relevance of this result is uncertain. No between-arms differences in the other variables were found.

Conclusions

Both intermittent and continuous energy restriction achieved a comparable effect in promoting weight-loss and metabolic improvements. Long-term trials are needed to draw definitive conclusions.

     

Evidence for a true post-β-lactamase-inhibitor effect of clavulanic acid against Klebsiella pneumoniae and Haemophilus influenzae

Objective   The purpose of this study was to investigate and characterize in vitro the post- β -lactamase inhibitor effect (PLIE) of clavulanic acid against two β -lactamase-producing species of bacteria.
Methods   The PLIE was investigated against one strain of Klebsiella pneumoniae and one strain of Haemophilus influenzae . A stationary-phase inoculum of about 10⁷ colony-forming units per mL of each bacterium was pre-exposed for 2 h to clavulanic acid, either alone or in combination with amoxicillin at various concentrations. After pre-exposure, the dilution required to remove the β -lactamase inhibitor was 1:100 or 1:1000 according to the bacterial species and their susceptibilities to clavulanic acid. Bacteria were counted hourly after drug removal, on solid agar medium.
Results   Control cultures exposed to amoxicillin alone after dilution, showed a delay in growth, which may be inherent to the time required to synthesize sufficient β -lactamase after the dilution steps. Control experiments clearly distinguished the post-antibiotic effect and the growth delay from the PLIE.
Conclusion   The PLIE could be one of several factors explaining why β -lactam/ β -lactamase inhibitor combinations remain effective throughout the dosing interval, even if a few hours after in vivo administration, serum concentrations of β -lactamase inhibitor fall below levels that are active in vitro.     

Effect of polyethylene glycol on single and combined topical application of diminazene aceturate (Berenil®) and metronidazole (Metrodine®) in Trypanosoma brucei- and T. congolense-infected mice

The effect of polyethylene glycol on single and combined topical applications of Berenil® and Metrodine® in Trypanosoma brucei- and Trypanosoma congolense-infected mice was evaluated. Parasitaemia in T. brucei group A was cleared by day 24 post-infection (p.i.) following topical application of Berenil® (3.5 mg/kg) in polythene glycol. In group B, Berenil® given intraperitoneally caused parasite clearance by day 12 (p.i.). Topical application of 16 mg/kg of Metrodine® in polyethylene glycol (group C) or orally (group D) caused a decline in parasitaemia by day 36 (p.i.). The combinations of both drugs in polythene glycol topically (group E) and intraperitoneally/orally (group F) cleared parasitaemia within 24 h. In their infected control (group G), parasitaemia disappeared by day 20 and reappeared by day 32 (p.i.). For T. brucei groups A, C, E and F, packed cell volume (PCV) declined by day 8 and appreciated by day 36 (p.i.). In group B, it did so by day 4 and appreciated by day 36 (p.i.). In group D, it did so by day 36 (p.i.) and appreciated slightly. In group G, it declined by day 32 (p.i.). For T. congolense groups A and B, parasite clearance was achieved by day 24 (p.i.). In groups C and D, it was by days 40 and 52 (p.i.), respectively. In groups E and F, it was by day 20 (p.i.). In group G, it increased by day 40 (p.i). In T. congolense groups A and B, PCV declined by day 20 and in group C by day 24. In group D, it did so by day 36 (p.i). The pre-infection PCV values for groups A–D were attained by day 52 (p.i.). In groups E and F, it did so by day 16, but appreciated by day 32 (p.i.). In group G, it did so by day 40 (p.i.). The vital organs of the infected controls showed degenerative changes. In conclusion, polyethylene glycol caused topical absorption of the drugs which were more effective in combinations.     

Anti-inflammatory effects of insulin regular and flunixin meglumine on endotoxemia experimentally induced by Escherichia coli serotype O55:B5 in an ovine model

Background

Endotoxemia is a major cause of mortality in large animals and there are several therapeutic regimens for the treatment of endotoxemia. Recent studies have suggested the anti-inflammatory effects of insulin in endotoxemic human and laboratory animal models but to the best of our knowledge there is no report on the possible therapeutic effect of insulin in large animal endotoxemia.

Objective

This experiment was conducted to evaluate the anti-inflammatory effects of insulin regular compared with flunixin meglumine on the treatment of endotoxemia in sheep.

Methods

Lipopolysaccharide from Escherichia coli was administered intravenously to ewes. Anti-inflammatory effects of flunixin meglumine (at 2.2 mg/kg) and insulin regular (at 1.5 and 3 IU/kg) were evaluated by determination of serum concentrations of acute phase proteins, inflammatory cytokines and oxidative stress biomarkers.

Results

Insulin regular at 3 IU/kg controlled the acute phase response following endotoxemia induction. The anti-inflammatory potency of insulin regular at 3 IU/kg was significantly higher than at 1.5 IU/kg and of flunixin meglumine at 2.2 mg/kg (P < 0.05).

Conclusion

Insulin regular induces its anti-inflammatory effects in a dose-dependent manner. Intravenous use of insulin regular can be a potential new therapeutic regimen for endotoxemia in large animal medicine.     

Postnatal development of the reproductive system in the grey short-tailed opossum,<Emphasis Type="Italic"> Monodelphis domestica</Emphasis>

Postnatal phenotypic sex differentiation has been investigated in a laboratory marsupial, Monodelphis domestica, as part of a larger study to resolve apparent discrepancies between eutherian and marsupial mammals. These include the formation of sex-specific structures in marsupials prior to gonadal differentiation and the retention in both sexes of structures which are sex-specific in eutherians. The time-course and nature of differentiation was investigated in 131 specimens ranging in age from the day of birth to 56 days. Patent wolffian ducts extend to the urogenital sinus in both sexes at birth, while müllerian ducts are identified on day 1 and grow in a cranio-caudal direction to reach the urogenital sinus on day 6. The male müllerian duct shows signs of regression at its cranial end on day 10 and throughout its length on day 12; its lumen has completely disappeared by day 15. By this time the epididymis and vas deferens have developed from the wolffian duct; their histological differentiation occurs between days 26 and 56. Prostatic buds are identifiable in tissue surrounding the male urethra on day 14. In the female, the wolffian duct is larger than the müllerian duct until day 14; thereafter the wolffian duct begins to regress at its cranial end, disappearing by day 17, whereas the müllerian duct begins to enlarge, converging with its fellow at the urogenital sinus by day 19. Lateral vaginae, vaginal culs-de-sac, uteri and oviducts have differentiated from the müllerian ducts by day 25. Gonads of both sexes are elongated in shape at birth, attached along the medial aspect of the large mesonephroi in the abdominal cavity. However, from day 3 onwards the testis becomes more rounded than the ovary. Degeneration of the male mesonephros begins about day 10 and is almost completed by day 19; the female mesonephros is still relatively large at day 14 though it too has almost disappeared by day 19. By postnatal day 13 the abdominal phase of testis descent is underway and the inguinal phase begins at day 15. Testes have reached the scrotal sac by day 24 and achieve their final position at the base of the scrotum by day 28. In summary, postnatal reproductive tract development and gonadal descent has been examined in this important biomedical model, where differentiation of the wolffian and müllerian ducts takes place after gonadal differentiation, according to the normal eutherian pattern.     

Dolutegravir(DTG,S/GSK1349572) combined with other ARTs is superior to RAL- or EFV-based regimens for treatment of HIV-1 infection: a meta-analysis of randomized controlled trials

Background

The first-generation integrase inhibitors (INIs) raltegravir (RAL) and elvitegravir (EVG) have shown efficacy against HIV infection, but they have the limitations of once-more daily dosing and extensive cross-resistance. Dolutegravir (DTG, S/GSK1349572), a second-generation drug that overcomes such shortcomings, is under spotlight. The purpose of this study is to review the evidence for DTG use in clinical settings, including its efficacy and safety.

Methods

PubMed, EMbase, Ovid, Web of Science, Science Direct, and related websites were screened from establishment until July 2013, and scientific meeting proceedings were manually searched. Two reviewers independently screened 118 citations repeatedly to identify randomized controlled trials comparing the efficacy and safety of DTG-based regimen with those of RAL- or elvitegravir-based regimens. Using the selected studies with comparable outcome measures and indications, we performed a meta-analysis based on modified intention-to-treat (mITT), on-treatment (OT), and as-treated (AT) virological outcome data. Independent data extraction and quality assessment were conducted.

Results

Four unique studies were included with the use of DTG in antiretroviral therapy-naive patients. In therapy-naive patients, DTG combined with abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) resulted in a significantly better virological outcome with a mITT relative risk (RR)of 1.07 (95 % confidence interval (95 % CI 1.03–1.12). Evidence further supported use of DTG had a better virological suppression in the 50 mg once daily group (mITT RR 1.07; 95 % CI 1.03–1.12) as well as in the sub-analysis in dolutegravir/efavirenz(DTG/EFV) and dolutegravir/raltegravir (DTG/RAL) groups (RR 1.09, 95 % CI 1.03–1.15; RR 1.06, 95 % CI 0.98–1.15, respectively). In the matter of safety of DTG-based regimen, the risk of any event was RR 0.98 (95 % CI 0.94–1.01), the risk of serious adverse events (AEs) was RR 0.84 (95 % CI 0.62–1.15), and the risk of drug-related serious AEs was RR 0.33 (95 % CI 0.13–0.79).

Conclusion

In general, DTG 50 mg given once daily combined with an active background drug is a better choice in terms of both efficacy and safety.

     

Serum concentrations of interferon-γ and intercellular adhesion molecule-1 eight years after an early respiratory syncytial virus infection

BACKGROUND: Respiratory syncytial virus (RSV) infection may influence the development of recurrent wheezing and atopy, but the mechanisms are unclear. OBJECTIVE: The purpose was to evaluate serum concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), CD14, IgE, IL-5 and IFN-gamma in children 6-10 years after an RSV infection and their correlation with subsequent asthma and atopy. METHODS: Fifty-one subjects admitted to hospital for RSV infection during the first year of life and controls matched for birth date and sex underwent clinical examinations including lung function, skin prick and blood tests. RESULTS: The RSV subjects had significantly higher serum concentrations of IFN-gamma and sICAM-1 than the controls (for IFN-gamma 224.9 pg/mL (standard deviation (SD) 271.3) vs. 187.1 pg/mL (372.9), difference 37.8 pg/mL, 95% confidence interval (CI) -90.3 to 166.0, P = 0.05; for sICAM-1 170.2 ng/mL (SD 63) vs. 147.8 ng/mL (SD 57), difference 22.4 ng/mL, 95% CI -1.4 to 46.1, P = 0.04). The RSV subjects with asthma had significantly higher concentrations of IFN-gamma than the controls with asthma, and the RSV subjects with wheezing during the previous 12 months had significantly higher concentrations of both IFN-gamma and sICAM-1 than the controls with wheezing. CONCLUSIONS: Children hospitalized for RSV infection in infancy still differ in IFN-gamma and sICAM-1 production 6-10 years after the infection. The data suggest that the pathomechanism of asthma and wheezing after an early RSV infection may be different from that of children without an early RSV infection.     

Epidemiology and antimicrobial susceptibility of non-typeable Haemophilus influenzae in otitis media in Taiwanese children

Background

Concerns about non-typeable Haemophilus influenzae (NTHi) in otitis media (OM) have grown after the introduction of pneumococcal conjugate vaccine (PCV). We aim to better understand the clinical role of NTHi in pediatric OM.

Serum protein electrophoretic pattern in clinically healthy calves and cows determined by agarose gel electrophoresis

The aim of the present study was to determine the physiologic electrophoretic pattern of serum proteins in clinically healthy calves and cows using agarose gel electrophoresis, and to describe the possible influence of age on the concentrations of serum protein fractions in young and adult cattle. Into the evaluation we included 14 clinically healthy calves of a Slovak spotted breed and its crossbreeds at the age of 4–6 months, and 13 clinically healthy cows of the same breed at the age of 3–5 years. Blood serum was analyzed for total serum protein concentrations, and for the absolute and relative values of serum protein fractions using agarose gel electrophoresis. In cows we found significantly higher total serum protein concentrations than in calves (P?<?0.001). Serum protein electrophoresis identified in cows, as well as in calves, six fractions comprising albumin, α₁ and α₂, β₁ and β₂, and γ-globulins. The concentrations of serum protein fractions in cows were 34.8 g/l for albumin, 9.3 g/l for α₁-globulins, 4.9 g/l for α₂-globulins, 6.2 g/l for β₁-globulins, 6.8 g/l for β₂-globulins, and 21.1 g/l for γ-globulins. In calves we observed a marked shift in the concentrations of some protein fractions, with nonsignificantly higher concentrations of α₁-globulins. On the other hand, the values of α₂- and γ-globulins in young animals were significantly lower than those measured in adult ones (P?<?0.01 and P?<?0.001, respectively). Presented results suggest a more marked influence of age on the concentrations of several serum protein fractions in cattle. The relative concentrations of the most of protein fractions showed significant differences between young and adult cattle. Seeing that the analysis of serum proteins and their electrophoretic separation in cattle is less well documented, the study provides important findings for clinicians when evaluating dysproteinemias.     

Prenatal treatment of ornithine transcarbamylase deficiency

Purpose of study

Patients with neonatal urea cycle defects (UCDs) typically experience severe hyperammonemia during the first days of life, which results in serious neurological injury or death. Long-term prognosis despite optimal pharmacological and dietary therapy is still poor. The combination of intravenous sodium phenylacetate and sodium benzoate (Ammonul®) can eliminate nitrogen waste independent of the urea cycle. We report attempts to improve outcomes for males with severe ornithine transcarbamylase deficiency (OTCD), a severe X-linked condition, via prenatal intravenous administration of Ammonul and arginine to heterozygous carrier females of OTCD during labor.

Efficacy and safety of Gammaplex® 5% in children and adolescents with primary immunodeficiency diseases

This open‐label multi‐centre study evaluated Gammaplex^® 5%, a human intravenous immunoglobulin (IVIG) 5% liquid, in 25 children and adolescent patients (aged 3–16 years) with primary immunodeficiency diseases (PIDs). Subjects received Gammaplex 5% (at doses of 300–800 mg/kg/infusion) for 12 months, with a 3‐month follow‐up. The primary efficacy end‐point was the incidence of serious acute bacterial infections (SABIs) during the 12‐month treatment period. Secondary objectives assessed safety and tolerability. Nineteen males and six females were treated using the same infusion schedule as their prior IVIG treatment (14 and 11 subjects on 21‐ and 28‐day dosing schedules, respectively). Two SABIs of pneumonia were reported, resulting in an annual SABI event rate of 0·09 [upper one‐sided 99% confidence interval (CI) = 0·36]. Twenty‐one subjects (84%) experienced ≥ 1 infection during the study, with a median infective episode per subject/year of 3·08 (range = 0–10·4). Sixteen subjects (64%) missed ≥ 1 day of nursery or school because of infection or other illness. All trough immunoglobulin G levels exceeded 7·00 g/l after 15 weeks (mean = 9·69 g/l; range = 7·04–15·35 g/l). Product‐related adverse events occurred in 14 subjects (56%); none were serious. Of 368 total infusions, 97 (26%) were associated temporally with an adverse event (≤ 72 h after infusion), regardless of causality. Laboratory test results and adverse‐reaction data showed no evidence of product‐related haemolysis or thromboembolic events. These data demonstrate that Gammaplex 5% is effective in preventing SABIs and well tolerated in children and adolescents with PID.