Combined effect of genetic variants in the GluN2B coding gene (GRIN2B) on prefrontal function during working memory performance.

BACKGROUND: The GluN2B subunit of N-methyl-d-aspartate receptors is crucially involved in the physiology of the prefrontal cortex during working memory (WM). Consistently, genetic variants in the GluN2B coding gene (GRIN2B) have been associated with cognitive phenotypes. However, it is unclear how GRIN2B genetic variation affects gene expression and prefrontal cognitive processing. Using a composite score, we tested the combined effect of GRIN2B variants on prefrontal activity during WM performance in healthy subjects. METHOD: We computed a composite score to combine the effects of single nucleotide polymorphisms on post-mortem prefrontal GRIN2B mRNA expression. We then computed the composite score in independent samples of healthy participants in a peripheral blood expression study (n = 46), in a WM behavioural study (n = 116) and in a WM functional magnetic resonance imaging study (n = 122). RESULTS: Five polymorphisms were associated with GRIN2B expression: rs2160517, rs219931, rs11055792, rs17833967 and rs12814951 (all corrected p < 0.05). The score computed to account for their combined effect reliably indexed gene expression. GRIN2B composite score correlated negatively with intelligence quotient, WM behavioural efficiency and dorsolateral prefrontal cortex activity. Moreover, there was a non-linear association between GRIN2B genetic score and prefrontal activity, i.e. both high and low putative genetic score levels were associated with high blood oxygen level-dependent signals in the prefrontal cortex. CONCLUSIONS: Multiple genetic variants in GRIN2B are jointly associated with gene expression, prefrontal function and behaviour during WM. These results support the role of GRIN2B genetic variants in WM prefrontal activity in human adults.

Fourth case of louse-borne relapsing fever in Young Migrant, Sicily, Italy, December 2015. Mini Review Article.

OBJECTIVES: Currently louse-borne relapsing fever (LBRF) is primarily found in limited endemic foci in Ethiopia, Somalia and Sudan; no case of imported LBRF has been reported in Europe in the 9 years prior to 2015. The aim of our paper is to describe a new case of imported LBRF detected in Sicily, Italy, and to review all cases reported in migrants arrived in Europe in the last 10 years. STUDY DESIGN: Mini review of all published cases of louse-borne relapsing fever in Europe in the last 10 years. METHODS: A computerized search without language restriction was conducted using PubMed combining the terms '(louse-borne relapsing fever or LBRF or recurrentis) and (refugee or Europe or migrant)' without limits. Furthermore, the 'Ahead-of-Print Articles' of the top 10 journals (ranked by Impact factor - Web of Science) of Infectious diseases and of Epidemiology were checked. RESULTS: Our search identified 26 cases of LBRF between July and October 2015 in migrants recently arrived in Europe: 8 had been described in Italy; 1 in Switzerland; 2 in the Netherlands; 15 in Germany. We describe data regarding the clinical characteristics, diagnostic methods, therapy and outcome of these patients and of the new case. CONCLUSIONS: LBRF by Borrelia recurrentis should be considered among the clinical hypotheses in migrants presenting with fever, headache, chills, sweating, arthralgia, myalgia, dizziness, nausea and vomiting.

Instrumental monitoring of the birth and development of truffles in a Tuber melanosporum orchard.

Mycorrhizal symbiotic plants, soil suitability, temperature, and humidity are, by general consensus, considered decisive factors in truffle production. However, experimental approaches to define the environmental conditions that stimulate formation of truffle primordia and promote their growth to maturity have been lacking. By analysis of data of many atmospheric and soil parameters collected since 2009 within a Tuber melanosporum orchard, the trends of metabolic activity, detected as CO2 production in the soil, have been identified as the most reliable parameter to indicate the 'birth' of the truffle primordia. They seem to be produced when mycelial activity is intense and undergoes water stress, after which it resumes. About 6-18 days after recovery of metabolic activity, we could collect primordia of T. melanosporum. Many die or develop too early and consequently rot or are eaten by insect larvae. These events occur several times during summer and autumn, those that 'sprout' in late summer or later grow steadily and reach maturity. Using a particular ground-penetrating radar (GPR) setup to discriminate truffles, we could identify individual truffles in the soil after they have enlarged to at least 6 mm in diameter and follow their growth in volume and diameter over time. These two instrumental methods (CO2 sensor and GPR), although yet to be improved, open new important perspectives to better understand truffle biology and manage truffle orchards to support the newly acquired demonstration of the fundamental role of host plants for the nutrient transfer to the ectomycorrhiza-mycelium-fruiting body complex of T. melanosporum.

Evaluating the efficacy of current treatments for reducing postoperative ileus: a randomized clinical trial in a single center.

AIM: Postoperative ileus has been considered an inevitable consequence of abdominal surgery. The aim of the study was to investigate the efficacy of same treatments in resolving postoperative ileus in various surgical approaches. METHODS: A total of 360 patients underwent abdominal surgery, and was divided into four groups: videolaparoscopic cholecystectomy, laparotomic colo-rectal surgery, laparotomic Hartmann procedure, laparotomic gastric surgery. In each group, patients received different postoperative treatments: chewing gum, olive oil, both, and water. Each group was compared with a control group. RESULTS: In patients who underwent videolaparoscopic cholecystectomy, median postoperative first passage of flatus and stool in the water group was 10 and 34 hours, respectively (P=0.006, P=0.021) and significantly earlier than in the control group (median postoperative 24 and 72 hours). Postoperative stay for the water group was lower (median day 1, 3rd interquartile 2.5) compared with control (median day 3; 3rd interquartile 7.0, P=0.01). In patients who underwent gastric surgery, median postoperative first passage of stool in the olive oil and chewing gum group was 48 hours, significantly earlier than in the control (median postoperative hour 120, P=0.04). Median time to first passage of flatus and stool was also earlier in the other groups compared with the control group, though this difference was not significant. CONCLUSION: Chewing gum, olive oil or both do not induce a relevant reduction of ileus after surgery. Water may be a safe and inexpensive option in reducing ileus. (United States National Institutes of Health, www.clinicaltrial.gov, number NCT01869231).

Ozone effect on the inflammatory and proteomic profile of human macrophages and airway epithelial cells.

Ozone (O3) is one of the most harmful urban pollutants, but its biological mechanisms have not been fully elucidated yet. Human bronchial epithelial cells (HBEpC) and human macrophage cells (differentiated human monocytic cell line) were exposed to O3 at the concentration of 240 µg/m3 (120 ppb), corresponding to the European Union alert threshold. Cell viability, reactive oxygen species (ROS) production, and pro-inflammatory cytokines release (IL-8 and TNF-α) were evaluated. Results indicated that O3 exposure increases ROS production in both cell types and enhances cytokines release in macrophages. O3 stimulated IL-8 and TNF-α in HBEpC when the cells were pretreated with Lipopolysaccharide, used to mimic a pre-existing inflammatory condition. Proteomics analysis revealed that, in HBEpC, O3 caused the up-regulation of aldo-keto reductase family 1 member B10, a recognized critical protein in lung carcinogenesis. In conclusion, our results show that 120 ppb O3 can lead to potential damage to human health suggesting the need for a revision of the actual alert levels.

Nitrogen management is essential to prevent tropical oil palm plantations from causing ground-level ozone pollution.

More than half the world's rainforest has been lost to agriculture since the Industrial Revolution. Among the most widespread tropical crops is oil palm (Elaeis guineensis): global production now exceeds 35 million tonnes per year. In Malaysia, for example, 13% of land area is now oil palm plantation, compared with 1% in 1974. There are enormous pressures to increase palm oil production for food, domestic products, and, especially, biofuels. Greater use of palm oil for biofuel production is predicated on the assumption that palm oil is an "environmentally friendly" fuel feedstock. Here we show, using measurements and models, that oil palm plantations in Malaysia directly emit more oxides of nitrogen and volatile organic compounds than rainforest. These compounds lead to the production of ground-level ozone (O(3)), an air pollutant that damages human health, plants, and materials, reduces crop productivity, and has effects on the Earth's climate. Our measurements show that, at present, O(3) concentrations do not differ significantly over rainforest and adjacent oil palm plantation landscapes. However, our model calculations predict that if concentrations of oxides of nitrogen in Borneo are allowed to reach those currently seen over rural North America and Europe, ground-level O(3) concentrations will reach 100 parts per billion (10(9)) volume (ppbv) and exceed levels known to be harmful to human health. Our study provides an early warning of the urgent need to develop policies that manage nitrogen emissions if the detrimental effects of palm oil production on air quality and climate are to be avoided.

Diagnosis of congenital toxoplasmosis: pre- and post-natal evaluation in Sicilian (Italy) epidemiological area. Preliminary data.

To evaluate the usefulness of conventional serological methods with western blot assay (WB) in congenital toxoplasmosis diagnosis, we prospectively enrolled in a clinical and serological follow-up all pregnant women with Toxoplasma gondii infection and their offspring, referred to us from October 2004. Western blot and standard serological test were performed on sera collected from mother during pregnancy and from mother and child at birth, at postpartum month 1-3-6-9 and 12. At this point in time, 22 pregnant women and 14 infants have completed the follow-up. 4 newborns were infected and 2 had specific toxoplasmosis anomalies at the birth. In mothers without seroconversion, the WB performed during pregnancy demonstrates the highest accordance with postnatal follow-up whereas in 1 case the negative result of PCR analysis was not confirmed by postnatal observation. The detection of anti-T gondii IgG against 8 kDa accessory antigenic band and against the accessory band included between 35 and 40 kDa band in immunoblot assay was useful for diagnosis of acute phase but did not improve the evaluation of comparative postnatal profile. Althougth few infants have concluded the postnatal follow-up, the preliminary results showed a greater value of using a IgM and IgA WB test than other standard method for the early diagnosis of toxoplasmosis at birth also in child born to treated mothers. The comparative anti-T gondii IgG immunoblot profile of mother and child permitted us to reduce the time of ruling out infection in newborns born to mothers with probable or possible infection and/or when prenatal diagnosis is negative or not performed.

DRD2 co-expression network and a related polygenic index predict imaging, behavioral and clinical phenotypes linked to schizophrenia.

Genetic risk for schizophrenia (SCZ) is determined by many genetic loci whose compound biological effects are difficult to determine. We hypothesized that co-expression pathways of SCZ risk genes are associated with system-level brain function and clinical phenotypes of SCZ. We examined genetic variants related to the dopamine D2 receptor gene DRD2 co-expression pathway and associated them with working memory (WM) behavior, the related brain activity and treatment response. Using two independent post-mortem prefrontal messenger RNA (mRNA) data sets (total N=249), we identified a DRD2 co-expression pathway enriched for SCZ risk genes. Next, we identified non-coding single-nucleotide polymorphisms (SNPs) associated with co-expression of this pathway. These SNPs were associated with regulatory genetic loci in the dorsolateral prefrontal cortex (P<0.05). We summarized their compound effect on co-expression into a Polygenic Co-expression Index (PCI), which predicted DRD2 pathway co-expression in both mRNA data sets (all P<0.05). We associated the PCI with brain activity during WM performance in two independent samples of healthy individuals (total N=368) and 29 patients with SCZ who performed the n-back task. Greater predicted DRD2 pathway prefrontal co-expression was associated with greater prefrontal activity and longer WM reaction times (all corrected P<0.05), thus indicating inefficient WM processing. Blind prediction of treatment response to antipsychotics in two independent samples of patients with SCZ suggested better clinical course of patientswith greater PCI (total N=87; P<0.05). The findings on this DRD2 co-expression pathway are a proof of concept that gene co-expression can parse SCZ risk genes into biological pathways associated with intermediate phenotypes as well as with clinically meaningful information.

A Case of Epididymo-orchitis after intravesical bacille Calmette-Guérin therapy for superficial bladder carcinoma in a patient with latent tuberculosis infection.

BACKGROUND: Intravesical instillation of bacille Calmette-Guérin (BCG) has been established as efficient therapy for superficial bladder carcinoma. Overall, intravesical BCG is well tolerated and results in complications of less than 5 %. However, adverse effects such as granulomatous prostatitis, pneumonitis, hepatitis, sepsis, and hypersensitivity reactions may occur. The reported rate for tuberculous orchitis after BCG intravesical therapy is 0.4 %. FINDINGS: We report a case of monolateral tuberculous orchitis occurring one month after the second course of intravescical instillation of bacille Calmette-Guérin in a patient with proven superficial bladder carcinoma and latent tuberculosis infection. CONCLUSIONS: In our opinion intravesical instillation of BCG should be considered on an individual patient basis, with full patient disclosure of the potentially significant risks. A screening with an intradermal Mantoux before starting the first cycle of BCG instillation should be recommended and isoniazid would be indicated as the treatment for latent tuberculosis infection.

[Pulmonary infection caused by Blastoschizomices capitatus]. / Infezione polmonare da Blastoschizomices capitatus.

Geotrichum capitatum, now known as Blastoschizomyces capitatus, can be responsible for several opportunistic infections (systemic infection or localized at lungs, liver, kidney, encephalitis or meningitis) in an immunocompromised host, especially in those patients affected by leukaemia or under immunosuppressive therapies. A 66-year-old woman with polimyosite under steroid and immunosuppressant therapy was hospitalized in ICU for an acute respiratory distress with moderate hypoxaemia and normocapnia. Pulmonary X-ray revealed a bilateral pneumonia. Hypoxaemia became severe 48 hours later and the patient underwent mechanical ventilation and empirical antibiotic therapy. Blood cultures, urine cultures and serological tests were negative, while yeast was identified by Gram's stain of bronchoaspirate. Before identifying the yeasts Fluconazole was added to therapy. At day 5 the clinical conditions remained severe and Candida spp were excluded: so Fluconazole was switched to liposomal Amphotericin B. At day 8 B. capitatus was identified. At day 26 the patient died of refractory respiratory insufficiency. B. capitatus infection is infrequent and its prognosis is severe, with a high mortality rate (>50%). Microbiological diagnosis requires time to characterize the yeast. At present no standard therapy is available although some authors report a good susceptibility to Amphotericin B and Voriconazole (100%), according to NCCLS guidelines.

Monocyte and lymphocyte apoptosis resistance in acute and chronic brucellosis and its possible implications in clinical management.

This study evaluated the level of susceptibility of monocytes and lymphocytes to spontaneously induced and CH11-induced apoptosis in 16 patients with Brucella infection. The expression of some immunological and apoptotic markers was evaluated. Before therapy, monocytes showed a high level of resistance to spontaneously induced or CH11-induced apoptosis in all patients. In patients with acute infection, this resistance persisted for 10-20 days after treatment was initiated, then decreased; in chronically infected patients, it persisted after 45 days of treatment. Lymphocytes were also more resistant to CH11-induced apoptosis. The level of activated CD8(+) T lymphocytes was high in patients with acute infection. The data indicate that the CD95-mediated apoptotic pathway is not involved in CH11 resistance. Lymphocytes are not infected by Brucella, so their resistance to apoptosis may be due to a soluble factor released by infected monocytes. The evaluation of levels of susceptibility to CH11-induced apoptosis in monocytes may be used to test the effectiveness of the therapy.

Serum leptin and interleukin-6 levels in pediatric patients with HIV.

Recent therapeutic approaches have improved the prognosis of children with HIV. Many new efforts could be involved in their quality of life and therefore could need additional diagnostic strategies. Leptin regulates pubertal development; furthermore a continuous immune stimulus, as in chronic infectious diseases, can enhance leptin's secretion by the action of cytokines such as interleukin (IL)-6. To clarify this role in patients infected with HIV, we assayed leptin and IL-6 and evaluated the influence of HIV severity on its secretion. IL-6 (380.5 +/- 257.6 pg/ml; range: 22-900 pg/ml) showed a significant correlation with leptinemia, HIV-1 RNA, and viremia related to the stage of HIV disease. The difference in leptinemia from a control group (3 +/- 3.2 ng/ml; range: 1-12 ng/ml in HIV patients; 6.72 +/- 8 ng/ml in the controls) did not reach statistical significance, nor did it correlate with pubertal stage, BMI, viremia, CD4 or anti-retroviral therapy. There was a statistically significant correlation between leptinemia and the stage of the HIV disease, and with IL-6 level. We want to stress the role of immunological factors in enhancing leptin secretion.

[Respiratory syncytial virus lower respiratory tract infection: our series]. / Le infezioni delle basse vie aeree da virus respiratorio sinciziale: la nostra casistica.

The authors report 57 cases of Respiratory Syncytial Virus (RSV) lower respiratory tract infection. The diagnosis was performed by detection of specific serum antibodies of IgM class or by direct detection of RSV antigens in nasopharyngeal specimens. Most of the patients were younger than one year. No one had risk factors for severe RSV infection form. All patients recovered. The authors emphasize the difficulties to discriminate between bronchiolitis and interstitial pneumonitis on the basis of the clinical and radiological features.

[Tuberculous meningo-encephalitis in pediatrics. Considerations on 71 cases (1968-1993)]. / Meningoencefalite tubercolare in età pediatrica. Considerazioni su 71 casi (1968-1993).

The tuberculous meningitis is an uncommon but severe complication of the tuberculosis mainly in childhood. Neurological sequelae are frequent and high mortality rate, till now, occurs. We reviewed the medical records of 71 cases and we evaluated the most frequent symptoms before the admission and signs and symptoms on the admission according to prognosis. An early diagnosis and specific anti-tuberculous treatment are essential in order to prevent permanent neurological sequelae and fatal outcome

A novel VIM-type metallo-beta-lactamase (VIM-14) in a Pseudomonas aeruginosa clinical isolate from a neonatal intensive care unit.

A Pseudomonas aeruginosa highly resistant to carbapenems was isolated in a neonatal intensive care unit in Palermo, Italy. The strain was found to carry a novel VIM-type enzyme, classified as VIM-14. The novel enzyme differs from VIM-4 in a G31S mutation. VIM-14 was harboured in a class 1 integron with a new organization. The integron carried the genes aac7, blaVIM-14, blaOXA-20 and aac4 in that order.

Diagnostic problems and postnatal follow-up in congenital toxoplasmosis.

AIM: In order to assess the consequences of different clinical approaches in the prenatal management of congenital toxoplasmosis, we retrospectively reviewed 58 pregnant women with Toxoplasma seroconversion and prospectively enrolled their 59 infants, referred to us from 1999 to 2004. METHODS: Data on clinical, laboratory and demographic characteristics of the pregnant women were collected. Their children were entered into a 48-month follow-up programme in which clinical, instrumental, ophthalmologic and serologic evaluations were carried out at birth, at 1, 3, 6, 9, 15, 18, 24, 36 and at 48 months of life. Paediatric treatment with Spiramycin alone or alternated with Pyrimethamine-Sulphadiazine was administered according to the different clinical cases. RESULTS: Time of infection was dated in the first trimester for 24 women (41%), in the second trimester for 18 women (31%) and in the third trimester for 16 (28%). In the first trimester of pregnancy 20 of the 24 infected women had undergone amniocentesis, while the test had not been performed on any of the women infected in the third trimester. Serological follow-up revealed that 11 (19%) of the infants had been infected. An alternating regimen with Pyrimethamine-Sulphadoxine was administered to the infected children. All the infants were clinically asymptomatic, and the instrumental follow-up revealed specific toxoplasmosis anomalies in 4/11 infected children. CONCLUSION: Our results highlight issues and problems concerning current prenatal diagnostic tests and the therapeutic approach based on PCR testing of amniotic fluid alone. The incidence of ocular-cerebral lesions observed in children born to women with seroconversion in the third trimester raises questions about the diagnostic and therapeutic approach for these women and their offspring. Paediatric therapeutic protocol, with alternating Pyrimethamine-Sulphadiazine regimen, applied also to asymptomatic children born to women with inadequate prenatal diagnostic management, could prevent severe sequelae.

Hormonal, auxological and clinical follow-up in children with connatal HIV infection. Personal records.

AIM: HIV infection and antiretroviral drugs have relevant endocrine implications, affecting growth and pubertal development. Moreover stature impairment cannot depend only on decreased hormonal secretion. METHODS: We studied for 7 years growth, puberty, bone maturation, hormonal secretion [Growth Hormone (GH) basal and after stimulation with Clonidin and Insulin, Insulin-like Growth Factor 1 (IGF-1), Insulin-like Growth Factor Binding Protein 3 (IGFBP-3), FSH, LH- gonadic hormones axis, ACTH, Cortisol, TSH, fT4, T4, T3, anti-thyroid antibodies, Leptin] of 10 HIV-infected children. RESULTS: In 3 patients stature was <-2 SDS in the first 2 years and in prepubertal age, with intervals of improved growth. The weight was >2 SDS in 6 children, <-2 SDS in 1 girl, while the other 3 patients had a weight <-2SDS only in the first 2 years of life. Height growth velocity was >10 degrees Centile all over the years of follow-up in 9 patients, while weight growth velocity was pathological in 5. Leptinemia showed higher levels at the beginning of follow up: 0.82-11.68 ng/L (M+/-DS: 3.29+/-4.15) than at the end of the study: 0.2-3 ng/L (M+/-DS: 1.65+/-1.01). Leptin levels showed a statistically significant correlation with CD4/CD8 count (P: 0.010; r: 0.916) and with the CDC stage (P: 0.006; r: 0.937), meaning a strong link to the severity of the disease. CONCLUSIONS: A good clinical control of HIV infection can guarantee growth within physiological centile in most of HIV-infected children. Over all IGFBP-3 and IGF-1 are good markers of growth, more usable than GH.

[Descriptive analysis of measles epidemic in Palermo, from September 1996 to June 1997. Failure of a vaccination campaign]. / Analisi descrittiva di un'epidemia di morbillo a Palermo dal settembre 1996 al giugno 1997. Insuccesso di una campagna vaccinale.

BACKGROUND: The authors report 1642 measles cases observed from September 1996 to June 1997 at the "G. Di Cristina" Children's Hospital. 34% of patients were hospitalized at the Division of Infectious Diseases. METHODS: The records of children admitted with measles to emergency area were retrospectively collected. The medical records (anamnestic, clinical and laboratory findings) of hospitalized children were obtained from schedules which since 1993 were performed to perspectively collect the exanthematous diseases. International criteria for the definition of measles case were applied. The variables considered were: background, demographic data, seasonal distribution, clinical presentation, complications and days of hospital stay. RESULTS: The results of this research showed that the outbreak involved predominantly infants. The complications accounted for 72% of measles hospitalized cases. Four cases of encephalitis were observed. A total of 1692 days of hospital stay was reported. CONCLUSIONS: These data show the failure in measles control adopted by the Sicilian Region and confirm the difficulties to achieve high percentage of parents participation to the infant recommended vaccination program.

Human cytomegalovirus glycoprotein B genotypes in immunocompetent, immunocompromised, and congenitally infected Italian populations.

Human cytomegalovirus (HCMV) strains, obtained from immunocompetent and immunocompromised Italian hosts, were typed with glycoprotein B (gB) gene restriction analysis. A predominant circulation of HCMV strains with gB type 2 and 3 was detected in both the immunocompetent host with a primary HCMV infection and the immunocompromised host with or without HCMV disease. No association between gB types and subjects with different risks of developing HCMV disease was found. All four gB genotypes were capable of causing congenital infection in Italian babies, with gB type 1 accounting for 50% of the strains examined in symptomatic infants and a remarkable incidence of gB type 4 viruses.

Pulmonary tuberculosis in Italian children by age at presentation.

AIM: To evaluate the clinical characteristics, diagnostic methods and outcome of paediatric pulmonary tuberculosis (PTB) in relation to children's ages when observed. METHODS: Children under 15, who had been admitted to the Children's Hospital with PTB were prospectively evaluated. Our sample included patients with a positive tuberculin skin test and signs or symptoms of tuberculosis (TB), including abnormal chest X-rays which suggested PTB. We collected demographic, clinical, radiographic and microbiological data from the patients, in addition to carrying out contact investigations in order to find a source case. All the patients involved in this study were subjected to anti-tuberculosis treatment. RESULTS: Sixty-two patients (44% under 5) were eligible for inclusion in our study. Children with presenting symptoms were younger than asymptomatic patients (p<0.05). A source case was found in 38 patients out of 62 children (62%) and children under 5 were more likely to have a source case than that found with older children (p<0.05). Ghon complex (infiltrate + adenopathy) tended to occur in young children (median age of 3.25, p<0.05). Fourteen children (23%) had clinical specimens which tested positive for Mycobacterium tuberculosis (MT), and 20 (32%) for MT DNA according to a polymerase chain reaction (PCR). Resistant strains to 1 or more anti-tuberculosis drugs were found in 5 children and in 4 adult sources. The patients with minimal or no radiographic change during therapy displayed symptoms for a longer period of time and were infected by a resistant strain (p<0.05). CONCLUSION: Improvements in case detection, case management and contact investigations are necessary for controlling paediatric TB, especially in young children. Given that any diagnosis of TB in children is supported by epidemiological and clinical evidence rather than isolating MT, detection of the source case is important in selecting appropriate treatment.