Patients and

Methods: After initially performing

Patients and

Methods: After initially performing Raf inhibitor >50 cases of robot-assisted laparoscopic radical prostatectomies (RALRP), between December 2009 and April 2010, we performed 12 RALRC procedures with BELND. Bilateral (n = 10) and unilateral (n = 1) intrafascial NVB preservation was performed in 11 patients; nonnerve-sparing RALRC was performed in 1 patient.

Results: Patient characteristics and surgical and postoperative parameters were mean patient age (y): 60 (43-80); American Society of Anesthesiologists score: 2 (1-3); body mass index (kg/m(2)): 24.5 (19.3-31.2); preoperative International

Index of Erectile Function (IIEF) score: 25 (5-65); operative time (h): 10 (8.1-11.5); intraoperative blood loss (mL): 455 (100-700); lymph node (LN) yield: 21.3 (8-38); hospital stay (d): 10.7 (9-16); lodge drain removal (d): 10 (9-15). Five patients received neoadjuvant chemotherapy. Surgical margins were negative in all patients. Postoperative pathologic stages were: pT(0) (n = 2), pT(1) (n = 1), pT(2a) (n = 2), pT(2b) (n = 2), pT(3a) (n = 4), and pT(4a) (n = 1). Positive LNs and BIBF1120 incidental prostate cancer were detected in five and three patients, respectively. Perioperative death rate was zero. Right external iliac vein

injury occurred in one patient during the performance of BELND; surgery was converted to an open procedure and the injury was repaired. Colonic fistula

developed in one patient at postoperative day 40; the patient died from cardiac disease at day 60. At a mean follow-up of 7.1 +/- 2.3 months, three patients died from metastatic disease. Of the available seven patients, six were fully continent and one had mild daytime incontinence.

Conclusions: Although RALRC with bilateral intrafascial NVB preservation, BELND, and intracorporeal Studer pouch formation is a complex procedure, it can be performed with excellent short-term surgical and pathological outcomes and satisfactory functional results after considerable experience www.selleckchem.com/products/blebbistatin.html gained with RALRP procedures.”
“Rice consumption has increased worldwide over recent decades, as it has become one of the most common foods. Although the analysis of environmental samples coming from rice areas has been well documented, there is less information regarding the analysis of pesticide residues in rice-grain samples.

Rice (paddy, brown and white) can be considered a complex matrix, leading to difficulties in the application of the different multiresidue methods described in the literature. This review addresses and compares the principal extraction and clean-up methodologies [e.g.

This was

better than using the ion-exchange modality at b

This was

better than using the ion-exchange modality at below 10 mS cm1. CONCLUSIONS: Dual salt precipitation followed by chromatographic capture using this resin were found to be complementary to one another since the removal of protein impurities by dual salt precipitation resulted in a two-fold improvement in terms of binding capacity. (c) 2012 Society of Chemical Industry”
“Tryptophan (Trp) is an essential amino acid required not only for protein synthesis but also for the production of many plant metabolites, including the hormone auxin. Mutations that disrupt Trp biosynthesis result in various developmental defects in plant organs, but how Trp affects organ growth and development remains unclear. Here, we identify an Arabidopsis mutant, small VX-770 in vivo organ1 (smo1/trp2-301),

which exhibits a reduction in the size of its aerial organs as a result of JNK signaling inhibitors the retardation of growth by cell expansion, rather than by the retardation of growth by cell proliferation. smo1/trp2-301 contains a lesion in TSB1 that encodes a predominantly expressed Trp synthase beta-subunit, and is allelic with trp2 mutants. Further analyses show that in trp2 leaf cells, the nuclear endoreduplication is impaired and chloroplast development is delayed. Furthermore, cell expansion and leaf growth in trp2 can be restored by the exogenous application of Trp, but not by auxin, and the general protein synthesis is not apparently affected in trp2 mutants. Our findings suggest that the deficiency in Trp or its derivatives is a growth-limiting

factor for cell expansion during plant organogenesis.”
“Background: Myelodysplastic syndromes (MDS) comprise Selleck DMXAA a heterogeneous group of hematologic malignancies, with an incidence rate of 3.4 cases per 100,000 in the United States. MDS affects patients predominantly over 60 years of age. As these syndromes are not well understood by many medical practitioner, patients with MDS may be underrecognized or underdiagnosed. The availability of new MDS treatment options further establishes the need to more closely assess gaps in clinical practice and underscores the necessity to develop educational activities to address those gaps.

Methods: A multidisciplinary panel was convened to examine current educational needs and gaps. A group consensus approach incorporating a modified nominal group technique was utilized to prioritize and review needs identified in the pre-meeting survey and to evaluate data provided by panelists prior to the meeting.

Results: The panel identified and prioritized seven educational areas of need: (1) MDS disease awareness, (2) diagnosis, (3) classification and risk stratification, (4) treatment issues, (5) referral to stem cell transplantation or new treatment protocols, (6) clinical monitoring and toxicity management, and (7) translation of new data into patient care.

The extract promoted GLUT4 translocation in skeletal muscle of ra

The extract promoted GLUT4 translocation in skeletal muscle of rats and mice, but did not inhibit -glucosidase activity in the small intestine under our experimental conditions. It was confirmed that propolis extract promoted phosphorylation of both PI3K and AMPK in rat skeletal muscle. In conclusion, we show that Brazilian propolis has the potential to prevent hyperglycemia through the promotion of GLUT4 translocation

in skeletal muscle and that kaempferide is one of the candidates for active compound in propolis. (c) 2013 BioFactors, 39(4):457-466, 2013″
“Excessive deposition of extracellular matrix (ECM) proteins, a condition known as fibrosis, is a hallmark of Duchenne muscular dystrophy. Among the factors that trigger muscle fibrosis are GANT61 concentration transforming growth factor beta (TGF-) and angiotensin II (Ang-II). Ang-II belongs to the renin-angiotensin system, and its biological effects are exerted by Ang-II receptors type 1 and type 2 (AT-1 and AT-2, respectively).

This study aims to determine the effect of TGF-1 on the expression of AT-1 and AT-2 receptor in skeletal muscle. C2C12 myoblasts exposed to TGF-1 showed a dose-dependent increase in AT-2 expression but with no effect on AT-1 levels. Injection of TGF-1 in the skeletal muscle of mice increased the levels of AT-2 and ECM protein but unchanged AT-1 levels. We also detected higher expression levels selleck inhibitor of AT-2 receptor in dystrophic skeletal muscle of mdx mice than in normal mice. The induction of AT-2 was mediated by the canonical TGF- pathway because under the inhibitory conditions of the kinase activity of TGF receptor I or the knockdown of Smad2/3 levels, TGF–induced AT-2 receptor increase was strongly inhibited. Furthermore,

we demonstrated that p38MAPK activity in response to TGF- is also required for AT-2 increase as evaluated by a p38MAPK inhibitor. Our results show that the levels of AT-2 but not AT-1 receptor are modulated by the pro-fibrotic factor TGF-1 in myoblasts and mouse skeletal muscle. This finding suggests that AT-2 might be involved in the physiopathology of fibrosis in dystrophic skeletal muscle. (c) 2013 BioFactors, 39(4):467-475, 2013″
“Iron, either in its chelated form or as holotransferrin (hTf), prevents selleck compound the dedifferentiation of Schwann cells (SC), cells responsible for the myelination of the peripheral nervous system (PNS). This dedifferentiation is promoted by serum deprivation through cAMP release, PKA activation, and CREB phosphorylation. Since iron elicits its effect in a transferrin (Tf)-free environment, in this work we postulate that non-transferrin-bound iron (NTBI) uptake must be involved. Divalent metal transporter 1(DMT1) has been widely described in literature as a key player in iron metabolism, but never before in the PNS context.

Levels of serum IL-1 were measured with a specific enzyme-linked

Levels of serum IL-1 were measured with a specific enzyme-linked immunoassay kit. Mean serum levels were significantly higher in SSc patients than in those healthy control subjects.

Moreover, contracture of phalanges was found at a significantly lower prevalence in SSc patients with elevated serum IL-1 levels than those with normal levels. These results suggest that IL-1 may play a role in the pathogenesis of SSc.”
“Alterations of cell walls of Acremonium chrysogenum occurring at intensive synthesis Apoptosis Compound Library in vitro of cephalosporin C has been studied. It is shown, using electron microscopy, that the cell wall of the cells of ATCC 11550 strain (“”wild”" type) became looser and thicker during growth. The cell wall of the cells of strain 26/8 (hyperautotroph of cephalosporin C) considerably degraded by the end of the stationary phase. Biochemical analysis has shown that these alterations entailed decrease of the proteins’ content covalently or noncovalently linked with the polysaccharides of cell walls of both strains. An increase of sensitivity of cell walls of the strain-hyperautotroph to an activity of lytic enzymes of chitinase, laminarinase, proteinase K, and lyticase preparation has been observed during the growth, but this increase has not been found in the case of “”wild”" type strain. The obtained results evidence

to the structure failure of the cell wall of A. chrysogenum entailing the intensive creation of antibiotic.”
“Pattern hair loss (PHL) is the most common form of baldness in

both sexes. The NorwoodHamilton classification is the most commonly SB273005 cost used classification worldwide, but it has many limitations. The basic and specific (BASP) classification Epigenetics inhibitor was introduced as an improvement over the NorwoodHamilton classification. Previous research was done to estimate the reliability of the NorwoodHamilton classification and the result was unsatisfactory. However, the reliability of the BASP and NorwoodHamilton classifications has not yet been compared. Eight dermatological specialists, 17 dermatological residents and 15 general physicians classified PHL in 100 sets of photographs using both the BASP and NorwoodHamilton classifications. Intergroup reproducibility was evaluated by examining the match rate of the individual data in each group and the match rate between hair specialist and the other examiners. Intragroup repeatability was determined by calculating the match rate between the first and second studies. In terms of intergroup reproducibility of the match rate for individual data in each group, the basic type had the best agreement, the specific type had the second best, and the NorwoodHamilton classification had the lowest match rate. In comparison, hair specialist and intragroup repeatability showed the same patterns.

There is ample evidence that treatments that typically produce am

There is ample evidence that treatments that typically produce amnesia become innocuous when animals are submitted to a procedure of enhanced training. We now report that extinction of inhibitory avoidance (IA), trained with relatively low foot-shock

intensities, induces pruning of dendritic spines along the length of the apical dendrites of hippocampal CA1 neurons. When animals are trained with a relatively high foot-shock there is a high resistance to extinction, and pruning in NU7441 manufacturer the proximal and medial segments of the apical dendrite are seen, while spine count in the distal dendrite remains normal. These results indicate that pruning is involved in behavioral extinction, while maintenance of spines is a probable mechanism that mediates the protecting effect against amnesic treatments produced by enhanced training.”
“Purpose: see more To investigate the electro-reduction behaviour and determination of ciprofloxacin using a hanging mercury drop electrode.

Methods: Cyclic voltammograms of ciprofloxacin recorded in Britton -Robinson buffers pH 2 – 5 exhibit a single irreversible cathodic peak. The dependence of the peak current and peak potential values on buffer (nature, pH and concentration) and

accumulation conditions (time and potential) were examined and used for the quantitative analysis of ciprofloxacin in dosage forms and urine. Acetate buffer (0.08 M, pH 3.6) was selected as a supporting electrolyte for quantitative purposes by differential pulse and square wave adsorptive cathodic stripping voltammetry.

Results:

A reduction wave was seen in the range of -1.3 to -1.5 V. These techniques were successfully validated as per ICH guidelines and comparable to US Pharmacopoeia HPLC method. The techniques was applied to the determination of ciprofloxacin in pharmaceutical formulations (i. e. precision (RSD < 1%) and accuracy (99 -101%)), and was further extended to determine ciprofloxacin in spiked human urine with no matrix effect (i. e. LLOQ 0.01 mu g/ml, precision (RSD < 15%) and accuracy (85 -115%)).

Conclusion: Validated adsorptive cathodic stripping voltammetric technique can be recommended selleck chemicals llc for use in quality control and pharmacokinetics studies.”
“Stiff-person syndrome is a rare disorder characterized by rigidity of axial or limb muscles with episodes of co-contraction of agonist and antagonist muscles during the spasms. In some patients axial or limb involvement may predominate and may have unusual manifestations.

Case report.

Tertiary care teaching hospital.

A 42-year-old farmer presented with seasonal occurrence of hiccup and vomiting during summer months for the last 3 years. He had painful lower limb spasms lasting for 2-3 minutes every 10-15 minutes for the past 20 days.

Here, we review the theoretical models that examine how these fee

Here, we review the theoretical models that examine how these feedbacks influence the nature and extent of the defence that will evolve. We begin by briefly comparing different evolutionary modelling approaches and discuss in detail the modern game theoretical approach (adaptive dynamics) that allows ecological feedbacks to be taken into account. Next, we discuss a number of models of host defence in detail and, in particular, make a distinction

between ‘resistance’ and ‘tolerance’. Finally, we discuss coevolutionary models and the potential use of models that include genetic and game theoretical approaches. Our aim is to review theoretical approaches that investigate the evolution of defence and to explain how the type NSC23766 cost of defence and the costs associated with its acquisition are important in determining the level of defence that evolves.”
“Soybean genotypes MG/BR46 (Conquista) and BR16, drought-tolerant and -sensitive, respectively, were compared in terms of morphophysiological check details and gene-expression responses to water stress during two stages of development. Gene-expression analysis showed differential responses in Gmdreb1a and Gmpip1b mRNA expression within 30 days of water-deficit initiation in MG/BR46 (Conquista) plants. Within 45 days of initiating stress, Gmp5cs

and Gmpip1b had relatively higher expression. Initially, BR16 showed increased expression only for Gmdreb1a, and later (45 days) for Gmp5cs, Ricolinostat purchase Gmdefensin and Gmpip1b. Only BR16 presented down-regulated expression of genes, such as Gmp5cs

and Gmpip1b, 30 days after the onset of moisture stress, and Gmgols after 45 days of stress. The faster perception of water stress in MG/BR46 (Conquista) and the better maintenance of up-regulated gene expression than in the sensitive BR16 genotype imply mechanisms by which the former is better adapted to tolerate moisture deficiency.”
“Background The treatment of breast cancer tends to result in physical side effects (e.g., vaginal dryness, stomatitis, and atrophy) that can cause sexual problems. Although studies of early-stage breast cancer have demonstrated that sexual problems are associated with increased depressive symptoms for both patients and their partners, comparatively little is known about these associations in metastatic breast cancer (MBC) and how patients and partners cope together with sexual problems. We examined the links between sexual problems, depressive symptoms, and two types of spousal communication patterns (mutual constructive and demandwithdraw) in 191 couples in which the patient was initiating treatment for MBC. Methods Patients and partners separately completed paper-and-pencil surveys.

There were differences in the target populations between the two

There were differences in the target populations between the two studies; for example, the

ToGA study limited patients to those with HER2-positive tumors; therefore, efficacy was evaluated separately.

Ninety-four Japanese patients in the AVAGAST study and 50 in the ToGA study received XP alone. Median overall and progression-free survivals were 14.2 and 5.7 months, respectively, in the AVAGAST study, and 17.7 and 5.6 months, respectively, in the ToGA study. Overall response rates were 49.2 % in the AVAGAST and 58.5 % in the ToGA study. Adverse events were TPX-0005 nmr generally mild; the most common grade 3/4 events were neutropenia, anemia, anorexia, and nausea.

XP is effective and well tolerated in Japanese patients with mGC, and could be one of the standard regimens for the first-line treatment in this cohort.”
“Contents The aim of this study was to assess whether refractoriness to long photoperiod (LP) could be reversed by subjecting tomcats to a period of short days. Our hypothesis was that photoperiod changes can avoid refractoriness and restore sperm quality and production to that before refractoriness. Tomcats (n=6) were

housed in a conditioned room with LP (12L: 12D) for 45days of acclimation and then maintained under HSP inhibitor LP for 18month. Then, tomcats were changed to a period of decreasing light at a rate of 8min/day for 1month. Tomcats stayed for 1month with short photoperiod (SP; 8L: 16D) and then were switched back to a period of increasing light at a rate of 8min/day for 1month. The experiment HSP990 inhibitor was completed after tomcats remained in LP for 2months. Toms were anaesthetized and semen samples were collected

by electroejaculation every 2weeks. Sperm parameters were evaluated in all ejaculates, and data were analysed by anova. Motility, velocity, volume, sperm concentration, total sperm count, viability, acrosome integrity, plasma membrane integrity and sperm morphology were higher during LP compared with a refractory LP (p<0.01). Likewise, velocity, viability, acrosome integrity, plasma membrane integrity and sperm morphology were higher in a LP compared with a SP (p<0.05). On the other hand, motility, volume, concentration and total sperm count were similar between LP and SP (p>0.20).Whereas motility, velocity, viability, acrosome integrity and plasma membrane integrity were similar in a refractory LP compared with SP (p>0.05), volume, sperm concentration, total sperm count and sperm morphology were lower in a refractory LP compared with SP (p<0.05). In conclusion, refractoriness and reduced sperm production and quality induced by a prolonged LP of 18month can be restored after placing tomcats to a SP.”
“Vitrification techniques employ a relatively high concentration of cryoprotectant in vitrification solutions. Exposure of oocytes to high concentrations of cryoprotectant is known to damage the oocytes via both cytotoxic and osmotic effects.

More than 90% of the patients achieved stable analgesic dose with

More than 90% of the patients achieved stable analgesic dose within 3 days. After using SR oxycodone tablets for 1 week, sleep quality was significantly (P < 0.01) improved. In week 1, the average dose of SR oxycodone tablets was 16.63 +/- 7.79 mg.

The average daily dose of most patients was about 20 mg after 2 weeks. In all the enrolled patients, 38 (47.5%) had adverse reactions. No serious adverse reactions took place.

Conclusion. The results of this clinical observation further elaborated the efficacy and safety of SR oxycodone tablets in the treatment of moderate to severe painful diabetic peripheral neuropathy in China.”
“Objective-To determine the prevalence of lymphoplasmacytic synovitis (LPS) in dogs with naturally occurring cranial cruciate ligament (CCL) rupture and compare CH5183284 clinical, radiographic, cytologic, and histologic findings in dogs with and without LPS.

Design-Cross-sectional study.

Animals-110 dogs with naturally occurring CCL rupture.

Procedures-Histologic examination of synovial biopsy specimens obtained at the www.selleckchem.com/HIF.html time of surgical treatment was used to identify dogs with LPS. Clinical, radiographic, cytologic, and histologic findings were compared between

dogs with and without LPS.

Results-56 (51%) dogs had histologic evidence of LPS. There were no significant differences in age, body weight, duration of lameness, severity of lameness, severity of radiographic signs of degenerative joint disease, extent of CCL rupture (partial vs complete), or gross appearance of the medial meniscus between dogs with and without LPS. Mean tibial plateau angle was significantly lower in dogs with LPS than in dogs without LPS, and dogs with LPS were significantly more likely to have neutrophils in their synovial fluid. Lymphocytes were seen in synovial fluid from a single dog with LPS.

Conclusions and Clinical Relevance-Results suggested that LPS was common in dogs with naturally occurring CCL rupture. However,

only minor clinical, radiographic, cytologic, and histologic differences were identified between dogs with and without LPS. (J Am Vet Med Assoc 2009;235:386-390)”
“Protein-protein SB525334 cost interaction networks (PPINs) are a powerful tool to study biological processes in living cells. In this review, we present the progress of PPIN studies from abstract to more detailed representations. We will focus on 3D interactome networks, which offer detailed information at the atomic level. This information can be exploited in understanding not only the underlying cellular mechanisms, but also how human variants and disease-causing mutations affect protein functions and complexes’ stability. Recent studies have used structural information on PPINs to also understand the molecular mechanisms of binding partner selection. We will address the challenges in generating 3D PPINs due to the restricted number of solved protein structures.

Moreover, studies have illustrated a tight relationship between o

Moreover, studies have illustrated a tight relationship between obstructive sleep apnea and the development of DN. The purpose of this review is to present the latest advances in identifying promising predictors to DN, which will help guide the future research questions in this field. Aiming at limiting this paramount threat, further efforts are necessary to identify and control independent modifiable

risk factors, while developing an integrative algorithm for utilization in DN future screening programs.”
“Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), which has staphylococcal cassette chromosome mec (SCCmec) type IV or V, has become a major concern worldwide. However, the PKC412 clinical trial involvement of SCCmecIV (or V) in community

spread is still not fully understood. In this study, we searched for a possible adhesin gene in SCCmecIV, which could AR-13324 cell line contribute to community colonization and spread. For this, we determined the entire SCCmecIV sequence of CA-MRSA in Japan, which was previously characterized as multilocus sequence type (ST) 8/SCCmecIVx (type IV with unknown subtypes). The SCCmecIV was 25,555 bp in size and flanked by 15-bp att sequences. The 8.2-kb J1 region was unique (through recombination) and contained a 4.8-kb orf (named spj), encoding for a novel 1,604-amino acid cell-wall-anchored surface protein (CWASP/J) with the LPXTG motif. The spj gene had no homology with any sequence submitted to GenBank, indicating a novel gene sequence. The new SCCmec IV was tentatively designated SCCmecIVl. A PCR assay specific to the spj gene was developed. Two steps of PCR for detection of

the spj gene and SCCmecIV showed that ST8/SCCmecIVl MRSA is spreading widely in the community. This study demonstrates a new SCCmecIV encoding a novel CWASP, which could contribute to community spread as a potential colonization factor. Because ST8 CA-MRSA with SCCmecIVl causes skin and soft tissue infections and occasionally invasive infections, surveillance is needed.”
“The effect that gonadotrophin-releasing hormone (GnRH) antagonists exert on endometrial receptivity has not yet been elucidated. GnRH antagonists might directly affect oocytes, the embryo and/or the endometrium. The aim of this study was to investigate the direct effect of GnRH antagonists on the SB273005 endometrium in oocyte donation cycles. In an oocyte donation programme, oocytes from each donor (n = 49), stimulated with gonadotrophins and a GnRH antagonist, were equally shared between two different matched recipients. Recipients were randomly allocated to either receive a GnRH antagonist concomitant to donor during their endometrial priming with oestradiol (group 1, n = 49) or to solely continue with their endometrial preparation (group 11, n = 49). Pregnancy rate was 55.1% in group I and 59.1% in group II. Implantation rate was 26.1% in group I and 24.4% in group II.

Since the illusion was demonstrated at a non-optimal stroking spe

Since the illusion was demonstrated at a non-optimal stroking speed an integrative role for CT afferents within the illusion cannot be fully supported. Pleasant touch, however, does moderate the subjective aspects of the rubber hand illusion, which under certain tactile conditions may interact with proprioceptive information about the body or have a unique influence on subjective body perception.”
“In this study, the application of various concentrations (0.02%, 0.04%, 0.06% and 0.08%) of Satureja khuzestanica essential selleck chemical oil (EO) was examined on the oxidative

stability of sunflower oil and compared to butylated hydroxyanisole (BHA) during storage at 60 degrees C. Gas chromatography (GC) and GC-mass spectrometry analyses of the oils revealed that carvacrol (87.7%) was the major component of EO. Peroxide value and anisidine value measurements in sunflower oil showed that all concentrations of EO had antioxidant effects in comparison

to BHA. Oil samples supplemented with EO concentration of 0.08% were the most stable during storage (p < 0.05). EO also was able to reduce the stable free radical 2, 2-diphenyl-1-picrylhydrazyl with a AG-881 nmr 50% inhibition concentration (IC50) of 31.5 +/- 0.6 mu gmL(-1). Therefore, the results indicate that EO could be used as a natural antioxidant in food lipids.”
“Fear memory enhances connectivity in cortical selleck screening library and limbic circuits but whether treatments disrupting fear reset connectivity to pre-trauma level is unknown.

Here we report that C56BL/6J mice exposed to a tone-shock association in context A (conditioning), and briefly re-exposed to the same tone-shock association in context B (reactivation), exhibit strong freezing to the tone alone delivered 48 h later in context B (long term fear memory). This intense fear response is associated with a massive increase in dendritic spines and phospho-Erk (p-ERK) signaling in basolateral amygdala (BLA) but neurons. We then show that propranolol (a central/peripheral beta-adrenergic receptor blocker) administered before, but not after, the reactivation trial attenuates long term fear memory assessed drug free 48 h later, and completely prevents the increase in spines and p-ERK signaling in BLA neurons. An increase in spines, but not of p-ERK, was also detected in the dorsal hippocampus (DH) of the conditioned mice. DH spines, however, were unaffected by propranolol suggesting their independence from the ERK/beta-ARs cascade. We conclude that propranolol selectively blocks dendritic spines and p-ERK signaling enhancement in the BLA; its effect on fear memory is, however, less pronounced suggesting that the persistence of spines at other brain sites decreases the sensitivity of the fear memory trace to treatments selectively targeting beta ARs in the BLA.