The peptide antibiotics from the polymyxin–colistin–circulin family (Vogler & Studer, 1966) are active against Gram-negative bacteria; other peptides, such as polypeptins (Sogn, 1976), jolipeptin (Ito & Koyama, 1972), gavaserin and saltavalin

(Pichard et al., 1995), are active against both Gram-negative and Gram-positive bacteria. The second group includes antibiotics such as gatavalin (Nakajima et al., 1972), fusaricidins (Kajimura & Kaneda, 1996, 1997; Beatty & Jensen, 2002) and LI-F complex (Kurusu et al., 1987), which are active against fungi, actinomycetes and Gram-positive bacteria. Bacteriophage infection of starter cultures remains a significant problem in fermentation BTK inhibitor industries. Many bacteriophages are active against strains of the genus Paenibacillus. Most frequently reported are the bacteriophages infecting P. polymyxa and Paenibacillus larvae, and only a few bacteriophages from P. Torin 1 ic50 polymyxa strains have been described in detail thus far. Francis & Rippon (1949) were first to report isolation of four bacteriophages infecting the members of this species. They characterized the host specificity, particle

size, heat resistance, citrate sensitivity and serological reactions of these phages. Other bacteriophages active against P. polymyxa strains were isolated later (Seldin et al., 1984; Starosciak et al., 1985; Matseliukh & Burova, 2004). They were examined by electron microscopy and their lytic spectrum was specified. These double stranded DNA phages are members of the

Siphoviridae and Myoviridae families and, similar to the phages described by Francis & Rippon (1949), they were specific only to the strains of P. polymyxa. One of the bacteriophages – designated IPy1 (Seldin et al., 1984) – was recently used for evaluation of the genetic diversity within the species P. polymyxa (dos Santos et al., 2002). Phage IPy1 DNA served as a probe in hybridization studies. In this study, the bacteriophage ΦBP active against P. polymyxa CCM 7400 is described. We characterized its host spectrum, morphology, structural protein profile, genome size and Immune system presence of the phage sequences on the bacterial host genome, and identified a cassette of lytic genes in its genome. Bacteriophage ΦBP appears to be a virulent mutant of the temperate phage and is the first such phage of P. polymyxa described in detail. Paenibacillus polymyxa CCM 7400 (Czech Collection of Microorganisms, Brno, Czech Republic) was used as the primary host for the isolation, propagation and characterization of the bacteriophage ΦBP. The isolates of P. polymyxa CCM 7400 represented clones of the same strain picked from agar plates. The following strains of the genus Paenibacillus were tested for ΦBP sensitivity: P. polymyxa S292 and P. polymyxa N36 (both from DSMZ, Germany), P. polymyxa CCM 1460, P. polymyxa CCM 1465, P. polymyxa CCM 2000, P. polymyxa CCM 2001 (all from Czech Collection of Microorganisms, Brno, Czech Republic).

NNH was calculated as the reciprocal of the difference between the underlying risks of MI with and without abacavir use. A parametric statistical model was used to calculate the underlying risk of MI over 5 years. The relationship between NNH and Veliparib cost underlying risk of MI is reciprocal, resulting in wide variation in the NNH with small changes in underlying risk of MI. The smallest changes in NNH are in the medium- and high-risk groups of MI. The NNH changes as risk components are modified;

for example, for a patient who smokes and has a systolic blood pressure (sBP) of 160 mmHg and a 5-year risk of MI of 1.3% the NNH is 85, but the NNH increases to 277 if the patient is a nonsmoker and to 370 if sBP is within the normal range (120 mmHg). We have illustrated that the impact of abacavir use on risk of MI varies according to the underlying risk and it may be possible to

increase considerably the NNH by decreasing the underlying risk of MI using standard of care interventions, such as smoking cessation or control of hypertension. Abacavir is a common antiretroviral used in the treatment of HIV-1 infection and is currently recommended as one of the possible components of initial combination antiretroviral treatment [1–3]. The D:A:D study group recently reported an increased risk of myocardial infarction (MI) related to current or recent use of abacavir [4,5]. Some of the HIV-1 treatment guidelines have already taken into account the Dactolisib in vitro clinical implications of the D:A:D findings by emphasizing that clinicians should consider Dichloromethane dehalogenase careful assessment of patients who are on abacavir and at high risk of MI [2,6,7]. It is therefore of great importance

to ensure that the risk of MI attributed to abacavir use, together with the underlying risk of MI, is correctly interpreted and understood. Presenting results as relative risks (RRs) is standard in observational studies [8], but may be difficult to translate into clinical practice. The number needed to treat (NNT) and absolute risk reduction may be more clinically relevant, when assessing the beneficial effect of treatment [9–11], and the number needed to harm (NNH), together with absolute risk increase (ARI), will better reflect any adverse effect of treatment than RR in clinical terms [12]. Both NNH and RR are measures that attempt to summarize two numbers (the risks of MI with and without abacavir). RR summarizes the relative increase in the underlying risk of an event according to whether the patient receives a given treatment or not and the NNH indicates the number of patients that need to be treated to observe the adverse effect of a treatment in one additional patient. This approach was first proposed in 1988 [13], but it is still infrequently used to describe risk of adverse events of medicines [14–17]. NNH is a tool that can be used in different settings [18].

Executive functioning involves the complex cognitive abilities to plan and execute multi-step tasks and process new information and is thought to be impaired

in chronic HIV infection as a result of widespread synaptodendritic injury to frontal-striato-thalamo-cortical brain circuits [17]. Such repair of this synaptodendritic injury may not occur immediately after controlling HIV viraemia with cART, and may explain the observation we have made in our study that executive function improvements occurred later than improvements in the other cognitive domains assessed. Cysique and colleagues have recently described changes in NC function over a 1-year period in 37 HIV-infected selleck subjects commencing cART, and, similar to our study findings, they observed peak improvements in NC function to occur after 24–36 weeks of therapy [15] with prolonged improvements observed over a 1-year period. However, allocation of cART within this cohort was based on clinician choice, restricting the interpretation of such observations to discern differences between different cART regimens. Also, not all subjects were naïve to cART and all subjects had documented

NC function impairment at baseline. Unlike our study, these Z-VAD-FMK datasheet factors limited the relevance of these observations to HIV-infected neuro-asymptomatic subjects, who represent the majority of HIV-infected subjects commencing cART for the first time. While we have attributed improvements in NC function to the effects of commencing cART, we cannot fully account for confounding factors which may also have resulted in improvements in NC function over the study period. A control arm

within our study allocating subjects not to receive antiretroviral therapy would have strengthened our observations if no improvements Evodiamine in NC function were observed in subjects allocated to this arm. However, such an approach would not be ethical or feasible as individuals selected to enter the study clinically required to commence antiretroviral therapy. Furthermore, cognitive function is likely to decline over time, rather than improve, and this decline has been reported to be greater in HIV-infected subjects [18], strengthening the argument that the improvements in NC function observed are secondary to commencing cART. Lastly, a learning effect may account for improvements in NC performance. However, all subjects undertook a practice NC test during the study screening period prior to the study baseline test used in our analysis in order to minimize effects of learning on the study results [10], and such effects would not explain the differences in improvements we observed between the study treatment arms.

Antibiotics were used as follows: erythromycin (1 μg mL−1), chloramphenicol (10 μg mL−1), and streptomycin (200 μg mL−1). Overnight cultures grown in brain heart infusion broth (BHI) were added at a 1 : 250 (v/v) dilution to fresh BHI and incubated at 37 °C with Selumetinib cell line aeration. CFU mL−1 were determined

by plating dilutions of culture aliquots on BHI agar. Competitive indices of mixed bacterial cultures during stationary phase were performed as previously described (Zambrano et al., 1993; Finkel et al., 2000; Bruno & Freitag, 2010) (Fig. 1a). Aliquots of 12-day-old cultures were stored at −80 °C. For each experiment, an aliquot of frozen cells was thawed and 50 μL was added to 12.5 mL of BHI and grown overnight at 37 °C. One hundred and twenty-five microliters of the overnight 12-day-old culture was added to 12.5 mL of a 1-day-old culture at a ratio of 1 : 100 and incubated at 37 °C for 10 days. Twelve-day-old and 1-day-old cultures were distinguished based on chloramphenicol

resistance of the 1-day-old cultures containing the site-specific integration vector pPL2 that conferred chloramphenicol resistance without influencing bacterial growth (Lauer et al., 2002). this website Every 24 h, an aliquot of the mixed culture was removed, diluted, and plated onto BHI agar to enumerate bacterial CFUs. One hundred and fifty of the resulting colonies were then patched onto BHI agar containing chloramphenicol, selecting for the original 1-day-old chloramphenicol resistant bacteria; this was found to be the most reliable method for clearly distinguishing drug-resistant colonies. The competitive index (CI) value was determined as follows: CI = (test strain CFU)/(reference strain CFU). Mid-log L. monocytogenes were washed and diluted in PBS to a final concentration of 1 × 105 CFU mL−1. Seven- to 8-week-old ND4 Swiss Webster mice (Harlan Laboratories, Inc., Madison, WI) were Enzalutamide cost infected via tail vein with

2 × 104 CFU. Forty-eight hours post infection homogenized tissue dilutions were plated on BHI agar to determine CFU per organ. For CI experiments, mice were infected via tail vein with a 1 : 1 mixture of a reference and test strains. The reference strain was DP-L3903, a wild type strain with a Tn917-LTV3 insertion that confers erythromycin resistance and has been confirmed to have no effect on L. monocytogenes virulence [(Auerbuch et al., 2001) and Fig. 5b]. Strains were grown to mid-log phase and mixed together in PBS. Two hundred microliters of 2 × 104 CFU mixed bacterial suspension were used for infection. After 48 h, livers and spleens were harvested and homogenized. The CI value for each organ was determined as previously described (Auerbuch et al., 2001). Statistical analysis was performed using Prism software (graphpad v.2.0). Where appropriate, a Student’s t-test was used to identify statistically significant differences. In all cases, a P-value <0.05 was considered significant.

The CS54 island is a 25 kb region found between xseA and yfgJ at centisome 54 in S. Typhimurium (Kingsley et al., 2003) and S. Typhi (Fig. S1r). Five genes are found within this island, which are shdA, ratB, ratA, sinI and sinH (sivH). In S. Typhimurium, ShdA was shown to be an outer membrane protein of the autotransporter family that binds fibronectin, RatB is a predicted secreted protein of

unknown function and SinH is a putative outer membrane protein (Kingsley & Bäumler, 2002; Kingsley et al., 2003; Abd El Ghany et al., 2007). shdA, ratB and sinH (sivH) are all implicated in intestinal colonization of BALB/c mice by S. Typhimurium, but are all pseudogenes in S. Typhi (Kingsley et al., 2003). Fimbriae or pili are proteinous structures Selleckchem ABT 888 found on bacteria that can mediate interaction with cells. Fimbriae are normally specific to a receptor and can

be used at different critical times during the infection. Each serovar harbours a unique combination of fimbrial operons (Fig. 2). Whole-genome sequence analysis revealed eight putative fimbrial operons shared by both S. Typhimurium and S. Typhi [bcf, csg (agf), fim, saf, stb, stc, std, sth] (McClelland et al., 2001; Parkhill et al., 2001). Salmonella enterica serovar Typhimurium possesses five unique fimbrial sequences selleckchem known as lpf, stf, pef, sti and stj (McClelland et al., 2001). These unique fimbriae were not involved in systemic colonization of the spleen, and Lpf was shown to be involved in intestinal colonization of mice (Weening et al., 2005). A type IVB pilus located on SPI-7 is only found within the S. Typhi genome, along with five other unique fimbrial operons (sef, sta, ste, stg and tcf) (Parkhill et al., 2001). For the majority of these fimbriae, little is known about their true function, expression Anidulafungin (LY303366) conditions or their importance for virulence during infection. Type IV pili are used by Typhi for adhesion to human monocytes and epithelial cells by interaction with the cystic fibrosis transmembrane conductance regulator receptor (Pier et

al., 1998; Zhang et al., 2000; Tsui et al., 2003; Pan et al., 2005). Tcf was recognized by human sera from patients with typhoid (Harris et al., 2006) and Stg mediates adherence to epithelial cells and reduces phagocytosis (Forest et al., 2007). All fimbrial operons are intact in S. Typhimurium strain LT2, although pseudogenes are found within six fimbrial operons of S. Typhi strain CT18 (fimI, safE, sefA, sefD, bcfC, steA, stgC, sthC, sthE) (Townsend et al., 2001) (http://www.pseudogene.org/cgi-bin/db-gen.cgi?type=Prokaryote). The unique repertoire of fimbrial adhesin systems may explain in part some differences observed between the host tropism colonization niches of these two serovars. In Salmonella, the major subunit of flagella is usually encoded by fliC or fljB, which correspond to the H1 and H2 variants of the H antigen, respectively (Silverman & Simon, 1980).

The CS54 island is a 25 kb region found between xseA and yfgJ at centisome 54 in S. Typhimurium (Kingsley et al., 2003) and S. Typhi (Fig. S1r). Five genes are found within this island, which are shdA, ratB, ratA, sinI and sinH (sivH). In S. Typhimurium, ShdA was shown to be an outer membrane protein of the autotransporter family that binds fibronectin, RatB is a predicted secreted protein of

unknown function and SinH is a putative outer membrane protein (Kingsley & Bäumler, 2002; Kingsley et al., 2003; Abd El Ghany et al., 2007). shdA, ratB and sinH (sivH) are all implicated in intestinal colonization of BALB/c mice by S. Typhimurium, but are all pseudogenes in S. Typhi (Kingsley et al., 2003). Fimbriae or pili are proteinous structures Ku-0059436 in vitro found on bacteria that can mediate interaction with cells. Fimbriae are normally specific to a receptor and can

be used at different critical times during the infection. Each serovar harbours a unique combination of fimbrial operons (Fig. 2). Whole-genome sequence analysis revealed eight putative fimbrial operons shared by both S. Typhimurium and S. Typhi [bcf, csg (agf), fim, saf, stb, stc, std, sth] (McClelland et al., 2001; Parkhill et al., 2001). Salmonella enterica serovar Typhimurium possesses five unique fimbrial sequences http://www.selleckchem.com/products/BIBF1120.html known as lpf, stf, pef, sti and stj (McClelland et al., 2001). These unique fimbriae were not involved in systemic colonization of the spleen, and Lpf was shown to be involved in intestinal colonization of mice (Weening et al., 2005). A type IVB pilus located on SPI-7 is only found within the S. Typhi genome, along with five other unique fimbrial operons (sef, sta, ste, stg and tcf) (Parkhill et al., 2001). For the majority of these fimbriae, little is known about their true function, expression Masitinib (AB1010) conditions or their importance for virulence during infection. Type IV pili are used by Typhi for adhesion to human monocytes and epithelial cells by interaction with the cystic fibrosis transmembrane conductance regulator receptor (Pier et

al., 1998; Zhang et al., 2000; Tsui et al., 2003; Pan et al., 2005). Tcf was recognized by human sera from patients with typhoid (Harris et al., 2006) and Stg mediates adherence to epithelial cells and reduces phagocytosis (Forest et al., 2007). All fimbrial operons are intact in S. Typhimurium strain LT2, although pseudogenes are found within six fimbrial operons of S. Typhi strain CT18 (fimI, safE, sefA, sefD, bcfC, steA, stgC, sthC, sthE) (Townsend et al., 2001) (http://www.pseudogene.org/cgi-bin/db-gen.cgi?type=Prokaryote). The unique repertoire of fimbrial adhesin systems may explain in part some differences observed between the host tropism colonization niches of these two serovars. In Salmonella, the major subunit of flagella is usually encoded by fliC or fljB, which correspond to the H1 and H2 variants of the H antigen, respectively (Silverman & Simon, 1980).

The activity was measured by decreasing the A340 nm based on the transformation of vanillin to vanillic acid. Influence on latent absorbance by the production of NAD(P)H was adjusted by molar extinction coefficients. Calculations were based on molar extinction coefficients

of vanillin (10.6 × 103; pH 7) and NAD(P)H (6.30 × 103) at 340 nm. The reaction mixture comprised 100 mM KPB, 5 mM NAD(P)+, and 0.25 mM vanillin at the final concentration. The other method investigated the enzyme’s substrate specificity and the effect of pH or temperature on it. IDH activation Enzyme activity was determined by quantification of corresponding oxidized products from aromatic aldehydes by HPLC as described above. The reaction mixture (1.0 mL) comprised 100 mM appropriate buffer, 5 mM NAD(P)+, 2.5 mM substrates, and 0.23 and

0.26 U of purified VDH from Micrococcus sp. TA1 and B. cepacia TM1, respectively. The reaction mixture was incubated for 20 min at an appropriate temperature, after which the reaction was stopped by adding 0.2 mL of Smad inhibitor 0.5 N HCl. The acid produced was quantified by HPLC. One unit of enzyme activity was defined as the amount of enzyme that catalyzes the transformation of 1 μmol of vanillin to vanillic acid. The enzyme from Micrococcus sp. TA1 that catalyzes the dehydrogenation of vanillin was purified from cells as follows: after cultivation on 2 g L−1 vanillin as a carbon source with each liquid medium as described in Materials and methods, cells were harvested by centrifugation (10 000 g, 10 min, 4 °C). The pellet was resuspended in 50 mM KPB (pH 7.5) and the suspension was treated Thiamet G with an ultrasonicator (201 M sonicator; Kubota, Tokyo, Japan) at 9 KHz and 170 W for 15 min; the utmost care was taken to maintain the temperature below 5 °C. The lysate was then centrifuged at 16 000 g for 20 min. The resulting supernatant was used as the cell extract. The cell extract dialyzed against 10 mM Tris-HCl buffer (pH 8.5) was applied to a 100 mL DEAE-Sepharose FF column (GE Healthcare Bio-Science, Buckinghamshire, UK). The enzyme was eluted with a

linear gradient of increasing NaCl concentration (0–0.5 M, total volume 1.5 L). The fractions with VDH activity were pooled. NaCl (2 M) was added with gentle stirring to the pooled fraction, and this solution was applied to a 30-mL butyl-Sepharose column (GE Healthcare Bio-Science). The enzyme was eluted using a gradient of decreasing NaCl concentration (2–0 M, total volume 600 mL). The active fractions were dialyzed against 10 mM Tris-HCl buffer (pH 8.5). The dialyzed enzyme solution was applied to a 1-mL Resource Q column (GE Healthcare Bio-Science). The enzyme was eluted with a linear gradient of increasing NaCl concentration (0–0.5 M, total volume 100 mL). The enzyme from B. cepacia TM1 was purified from the cell extract as follows: the cell extract of B.

In the hypertrophic stage of rhinoscleroma, both T1- and T2-weighted images show characteristic mild-to-marked high signal intensity.[6] Nasal endoscopy may reveal signs of all three stages of rhinoscleroma and aids accurate diagnosis based on histopathological

http://www.selleckchem.com/products/abt-199.html examination and isolation of K rhinoscleromatis in culture.[7] A positive culture in MacConkey agar is diagnostic of rhinoscleroma, but it is positive in only 50 to 60% of patients. The diagnosis is confirmed by histology. Classic histopathologic findings include plasma cells and large vacuolated Mikulicz cells with clear cytoplasm that contains bacilli and Russell bodies (which are transformed plasma cells). Treatment of rhinoscleroma requires a combination of appropriate antibiotics and surgical debridement if there is significant airway obstruction. The results of current treatment are unsatisfactory and recurrence often occurs.[8] Moreover, no randomized controlled trials exist to compare various antibiotic treatment choices and their efficacy.[8, 9] De Pontual and colleagues in their retrospective series of 11

patients report a treatment duration of 3 to 9 months with ciprofloxacin (7 patients), ceftriaxone (2), tetracycline (2), and clofazimine (2). Relapses occurred in 3 of the 11 patients. They recommend fluoroquinolones as the first drug of choice, because of its good activity against Gram-negative bacilli, intracellular efficacy, and low toxicity profile.[10] Gaafar and colleagues in their

retrospective case series of 56 cases over 10 years report a medical Sunitinib manufacturer treatment duration of 3 months with a combination of co-trimoxazole and rifampicin. Since 2003, this was replaced by ciprofloxacin for 3 months. Results were disappointing, as a high incidence of recurrence was found reaching Baricitinib up to 25% within 10 years.[8] Fawaz and colleagues in their study of 88 cases report a treatment duration of 4 to 20 weeks with rifampicin (63 patients), co-trimoxazole (11), and ciprofloxacin (14). Relapses occurred in 24 out of 88 patients (27%).[11] Recently, Suchanova and colleagues in their study of three cases suggest that management with long-term antibiotics (3–6 months) with the fewest side effects (ciprofloxacin and co-trimoxazole) plus or minus surgical debridement is the mainstay of therapy.[2] Zhong and colleagues in their retrospective case series of 40 patients over 30 years report that 27 patients remained relapse-free 1 to 10 years following treatment with antibiotics supplemented in some cases with surgery or radiotherapy.[12] Tan and colleagues in their study of four cases recommend a treatment regime consisting of a combination of ciprofloxacin and doxycycline for at least 6 months.[13] The cases of recurrences reported in the literature are not associated with any particular treatment regimen.

14 mg mL−1) was dialyzed against Buffer C for 5 h. The UV-visible absorption spectrum, in the presence and absence of sodium PF-01367338 in vivo dithionite (1 mM), was recorded in the range of 200–700 nm (Lambda 35; Perkin-Elmer). The fluorescence emission spectrum of the enzyme (0.14 mg mL−1) was recorded

by exciting it at 450 nm using a fluorescence spectrometer (Jasco V-750). The apoenzyme was prepared using the acid–ammonium sulfate method (Elmorsi & Hopper, 1977). The partially purified enzyme prepared (0.14 mg mL−1) was dialyzed against KPi buffer (50 mM, pH 5.5) containing (NH4)2SO4 (2 M), glycerol (5%) and dithiothreitol (2 mM) for 24 h at 4 °C. Both UV-visible and fluorescence spectral properties were monitored to confirm the apoenzyme preparation. The prosthetic group was extracted by treating the holoenzyme (50 μg mL−1, 1 mL) with perchloric acid (10 μL of 70%) on ice for 5 min, followed by centrifugation at 22 000 g

at 4 °C. The supernatant (40 μL) was subjected to HPLC (Jasco 1100 series) using an RP-C18 column (250 × 4 mm). A chromatogram was developed using an isocratic solvent system consisting of methanol (40%) and ortho-phosphoric acid (10 mM, 60%; v/v) in water. The eluent was identified by comparing the retention time and UV-visible spectral properties with that of the authentic FAD (retention time, E7080 purchase 3.62 min) and FMN (retention time, 4.85 min) treated under the same conditions. Kinetic constants were determined by measuring the initial reaction velocities with varying concentrations of 1-H2NA (10–800 μM), NAD(P)H (30–800 μM) or FAD (1–200 μM) using Oxygraph. The kinetic constants (Km and Vmax) were determined by plotting the enzyme activities Montelukast Sodium versus substrate concentrations. All kinetic experiments were repeated twice with five different enzyme preparations. SDs observed between different sets of experiments are indicated appropriately. The kinetic data for 1-H2NA and NAD(P)H were fitted with (Vmax[S]n/Kmn+[S]n), while that for FAD were fitted with

(Vmax[S]/Km+[S]). Phenanthrene-grown culture showed a bright orange color in the early-log phase (9 h), which subsided and turned to pale green as it entered the stationary phase (30 h). Metabolites from the early-log (9 h), mid-log (18 h) and stationary (30 h) phase culture were extracted, resolved by TLC and identified by comparing their Rf values and fluorescence properties with those of authentic compounds. Three metabolite spots were detected in the spent medium of the early-log phase culture, which were identified as 1-H2NA, 1,2-DHN and salicylic acid (Rf values 0.95, 0.11 and 0.9, respectively). The spent medium of the late-log phase culture showed two spots corresponding to 1-H2NA and salicylic acid; while a single spot, salicylic acid, was identified in the stationary phase culture. Phenanthrene-grown cells were able to transform salicylaldehyde to salicylic acid and catechol (Rf values 0.9 and 0.37, respectively).

A subset of patients have features of both morphological abnormalities. Patients with lipoatrophy experience a loss of SAT, most noticeably in the limbs and face. Patients with fat accumulation typically

have gains of VAT in the abdomen and may have dorsocervical fat pad enlargement. Thus, we feel that if fat atrophy and fat accumulation co-exist in a patient, they should be addressed independently. Our results suggest that GH axis therapy may not be effective for improving SAT. Thus, for patients with both SAT loss and VAT gains, clinicians could consider combined therapy using GH axis drugs for the management of VAT and agents such as thiazolidinediones LDK378 MK0683 cell line for the treatment of SAT loss. Thiazolidinediones, such as pioglitazone, have been shown to be beneficial in the treatment of SAT loss, but their use remains investigational [25]. Additionally, clinicians might consider

pioglitazone in patients with lipoatrophy who have evidence of insulin resistance. This could reduce SAT loss and improve some metabolic abnormalities. The major side effects of GH axis therapies listed in the studies were oedema, arthralgias, myalgias and, less commonly, carpal tunnel syndrome and diabetes mellitus. Although some studies reported no risk of adverse events with treatment, our meta-analyses showed statistically significant increases in the frequencies of oedema and arthralgias in the treatment groups. However, providers must be careful in considering a summary effect of adverse events with these different drugs grouped together. As seen in Figure 4, when considered by itself, tesamorelin did not produce a significant increase in the frequency of arthralgias or oedema. While these summary effects may raise questions about the pathophysiological mechanisms of GH axis drugs, each drug should be considered individually

in terms of its adverse Cyclic nucleotide phosphodiesterase effects. Until more results from large, randomized, placebo-controlled studies are available, clinicians must weigh the benefits and risks of each GH axis agent and individualize treatment for their patients. The large number of participants across the included studies allows us to form some hypotheses and draw some conclusions regarding GH axis drugs. However, because of the limited number of studies available for each specific drug type, we cannot make any definitive statements about the individual effectiveness of GH, GHRH, IGF-1 or tesamorelin. Furthermore, few studies evaluated whether the benefits of the intervention persisted after discontinuation of treatment, which is an important consideration given the costs and potential long-term side effects of the intervention. Lastly, no long-term studies have examined the benefits and consequences of extended use of these drugs.