Underestimated olfactory domains in Huntington's disease: odour discrimination and threshold.

BACKGROUND: Olfaction has recently found clinical value in prediction, discrimination and prognosis of some neurodegenerative disorders. However, data originating from standard tests on olfactory dysfunction in Huntington's disease are limited to odour identification, which is only one domain of olfactory perceptual space. METHOD: Twenty-five patients and 25 age- and gender-matched controls were evaluated by the Sniffin' Sticks test in three domains of odour threshold, odour discrimination, odour identification and the sum score of them. Patients' motor function was assessed based on the Unified Huntington's Disease Rating Scale. RESULTS: Compared with controls, patients' scores of all olfactory domains and their sum were significantly lower. Besides, our patients' odour threshold and odour discrimination impairments were more frequently impaired than odour identification impairment (86 per cent and 81 per cent vs 34 per cent, respectively). CONCLUSION: Olfactory impairment is a common finding in patients with Huntington's disease; it is not limited to odour identification but is more pronounced in odour discrimination and odour threshold.

The potential role of Bifidobacterium spp. as a preventive and therapeutic agent in controlling inflammation via affecting inflammatory signalling pathways.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease with relapses and periods of remission. Forasmuch as, dysregulation of the immune system is one of the triggers of IBD, taking probiotics as one of the immunomodulators in the gut, could help to control inflammation and IBD via influencing signalling pathways. Here, we aimed to investigate the efficacy of five selected Bifidobacterium strains in modulating JAK/STAT and NF-kB inflammatory signalling pathways via using the in vitro assay. A quantitative real-time polymerase chain reaction assay was used to analyse the expression of JAK/STAT and inflammatory genes followed by potential probiotic treatments before, after and simultaneously with the inflammation induction (sonicated pathogen). The production of IL-6 and IL-1ß after probiotic treatment was evaluated. Probiotic treatment resulted in the downregulation of TIRAP, IRAK4, NEMO and RIP genes in the NF-kB pathway, as well as JAK genes compared to sonicate-treated cells. The expression of STAT genes was different after our selected Bifidobacterium strains treatment. The production of IL-6 and IL-1ß decreased after probiotic treatment. These strains of Bifidobacterium spp. showed anti-inflammatory effects on HT-29 cells via modulation of JAK/STAT and NF-kB signalling pathways. The use of Bifidobacterium spp. could be considered as a suitable preventive and complementary treatment for patients with inflammatory bowel disease.

Hydrazone analogues with promising antibacterial profiles: Synthesis, morphology, in vitro and in silico approaches.

The emergence of resistance to antibacterial drugs remains an important global threat that necessitates an urgent need for the discovery of alternative drugs. This study was undertaken to synthesize some novel nitroaryl/heteroaryl hydrazone derivatives as potential antibacterial agents. After synthesizing by a simple reaction between quinoline/quinazoline hydrazine and nitroaryl/heteroaryl aldehydes, all the compounds were screened for their antibacterial activities, cytotoxicity and in silico investigations. The compound, 2-(4-nitrobenzylidene)-1-(quinazolin-4-yl)hydrazine (1b), displayed significant antimicrobial activity against several susceptible and resistant bacteria without any cytotoxicity. Moreover, scanning electron microscopy (SEM) revealed the complete destruction of Staphylococcus aureus and Escherichia coli following exposure to this compound after 2 h exposure. The in silico studies confirmed the better binding energy of these compounds in comparison with the reference drugs in complex with topoisomerase IV and bacterial ribosomal receptor. Compound 1b can be considered a promising lead compound for the development of broad-spectrum antibacterial medications after further studies.

Radionuclide gastric emptying scintigraphy in patients with suspected gastroparesis in Hospital Kuala Lumpur: A preliminary experience.

INTRODUCTION: Gastroparesis is a medical condition that can cause significant morbidity. Its prevalence in Malaysia is not known and is often under diagnosed. The gold standard in the assessment of gastroparesis is radionuclide gastric emptying scintigraphy (GES). The aim of this study was to evaluate the added benefit of performing GES in patients with suspected gastroparesis in Hospital Kuala Lumpur (HKL). METHODS: The clinical data and scintigraphic findings of consecutive patients referred to the Department of Nuclear Medicine, HKL for GES from July 2020 to December 2020 were retrospectively reviewed. RESULTS: Thirteen patients underwent the study (6 males and 7 females) with a mean age of 47.9 years (age range of 25 to 72 years). The majority of patients (n=11) were diagnosed with either type I or type II diabetes mellitus. Ten patients reported abnormal scan findings with only 3 patients had normal GES findings. Scintigraphic findings from our patients, association of symptoms with abnormal GES as well as the challenges in implementing GES in Malaysia is discussed. CONCLUSION: GES provides valuable information to the referring physician in the diagnosis and management of patients with gastric motility disorders. However, its use is limited because of limited availability, cost restriction, lack of familiarity among clinicians, and lack of understanding of the test. Further effort is thus needed to enhance the availability and usage of GES in Malaysia.

Combined Techniques of Non-invasive 99mTc-Besilesomab/99mTc-Sulfur Colloid with Hybrid SPECT/CT Imaging in Characterising Cellulitis from Symptomatic Perimegaprosthetic Infection: A Case Report.

Megaprosthesis is used to restore the form and function of massive skeletal defects, but it is accompanied by risks of failure, mainly due to perimegaprosthetic infection (PMI). In practice, the diagnosis of infected megaprosthesis among patients with a high index of clinical suspicion, elevated serological markers, and multiple negative or inconclusive imaging can be very challenging and poses a diagnostic conundrum to many orthopaedic surgeons. We present the case of a symptomatic 26-year-old female with large B-cell lymphoma who developed cellulitis with suspected complication of PMI 15 months post-implantation. The combination of advanced nuclear medicine imaging strategies, i.e., 99mTc-besilesomab/99mTc-sulfur colloid scintigraphy with hybrid single-photon emission computed tomography/computed tomography (SPECT/CT) scanning helps to characterise and delineate both infections. Invasive procedures such as joint aspiration and biopsy were avoided, and the patient was successfully treated with antibiotics. Hence, we report a case where advanced imaging modalities were decisive in the investigation of PMI.

Referral patterns of special needs patients at the Royal Dental Hospital of Melbourne, Victoria, Australia.

BACKGROUND: Special Needs Dentistry (SND) has been recognized as a dental specialty in Australia since 2003 but there have been no studies addressing the profile of patients for specialist care. The purpose of this study is to identify, via referrals received, the profile of patients and quality of referrals at the largest public SND unit in Victoria, Australia. METHODS: All referrals received over a 6-month period (1 January-30 June 2013) by the integrated SND unit (ISNU) were reviewed prior to allocation to the outpatient clinic (OP), domiciliary (DOM) or general anaesthetic (GA) services. RESULTS: Six-hundred and eighty-eight referrals were received with the majority for the OP clinic (68.3%), followed by DOM (22.4%) and GA services (9.3%) (χ2  = 360.2, P < 0.001). A referral may have specified more than one special needs condition with the most common category being those who were medically compromised (81.7%). The reasons for referral included lack of compliance (27.2%), further management due to multiple medical conditions or GA services required (9.9%), or for multiple other reasons (62.9%). CONCLUSIONS: A diverse pattern of SND patients was referred to the ISNU with a majority of referrals having no specific referral reason cited, suggesting poor quality of referrals.

Evaluation of potential probiotic characteristics and antibacterial effects of strains of Pediococcus species isolated from broiler chickens.

Pediococcus spp. were isolated from poultry rectum, faeces and food as good probiotic candidates in order to select strains to be used as probiotic in poultry feed. A total of 168 lactic acid bacteria were isolated and 51 isolates including 31 Lactobacillus spp. and 20 Pediococcus spp. were able to survive in low pH and bile salt concentration. The Pediococcus spp. were identified and their ability to form biofilm, adhesion to Caco-2 cells and antimicrobial activities against enteric pathogenic bacteria were determined. The results showed the presence of two strains, Pediococcus acidilactici P17 and P19 in rectal swab samples from 21-d old chickens with significant antibacterial activities against Salmonella enteritidis and Escherichia coli. The results suggest that only a few isolates of Pediococcus with potential probiotic activities are present in the poultry industry.

Spread of carbapenem-resistant Acinetobacter baumannii global clone 2 in Asia and AbaR-type resistance islands.

In this surveillance study, we identified the genotypes, carbapenem resistance determinants, and structural variations of AbaR-type resistance islands among carbapenem-resistant Acinetobacter baumannii (CRAB) isolates from nine Asian locales. Clonal complex 92 (CC92), corresponding to global clone 2 (GC2), was the most prevalent in most Asian locales (83/108 isolates; 76.9%). CC108, or GC1, was a predominant clone in India. OXA-23 oxacillinase was detected in CRAB isolates from most Asian locales except Taiwan. blaOXA-24 was found in CRAB isolates from Taiwan. AbaR4-type resistance islands, which were divided into six subtypes, were identified in most CRAB isolates investigated. Five isolates from India, Malaysia, Singapore, and Hong Kong contained AbaR3-type resistance islands. Of these, three isolates harbored both AbaR3- and AbaR4-type resistance islands simultaneously. In this study, GC2 was revealed as a prevalent clone in most Asian locales, with the AbaR4-type resistance island predominant, with diverse variants. The significance of this study lies in identifying the spread of global clones of carbapenem-resistant A. baumannii in Asia.

Changing trends in antimicrobial resistance and serotypes of Streptococcus pneumoniae isolates in Asian countries: an Asian Network for Surveillance of Resistant Pathogens (ANSORP) study.

Antimicrobial resistance in Streptococcus pneumoniae remains a serious concern worldwide, particularly in Asian countries, despite the introduction of heptavalent pneumococcal conjugate vaccine (PCV7). The Asian Network for Surveillance of Resistant Pathogens (ANSORP) performed a prospective surveillance study of 2,184 S. pneumoniae isolates collected from patients with pneumococcal infections from 60 hospitals in 11 Asian countries from 2008 to 2009. Among nonmeningeal isolates, the prevalence rate of penicillin-nonsusceptible pneumococci (MIC, ≥ 4 µg/ml) was 4.6% and penicillin resistance (MIC, ≥ 8 µg/ml) was extremely rare (0.7%). Resistance to erythromycin was very prevalent in the region (72.7%); the highest rates were in China (96.4%), Taiwan (84.9%), and Vietnam (80.7%). Multidrug resistance (MDR) was observed in 59.3% of isolates from Asian countries. Major serotypes were 19F (23.5%), 23F (10.0%), 19A (8.2%), 14 (7.3%), and 6B (7.3%). Overall, 52.5% of isolates showed PCV7 serotypes, ranging from 16.1% in Philippines to 75.1% in Vietnam. Serotypes 19A (8.2%), 3 (6.2%), and 6A (4.2%) were the most prominent non-PCV7 serotypes in the Asian region. Among isolates with serotype 19A, 86.0% and 79.8% showed erythromycin resistance and MDR, respectively. The most remarkable findings about the epidemiology of S. pneumoniae in Asian countries after the introduction of PCV7 were the high prevalence of macrolide resistance and MDR and distinctive increases in serotype 19A.

High prevalence of multidrug-resistant nonfermenters in hospital-acquired pneumonia in Asia.

RATIONALE: Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) remain important causes of morbidity and mortality. Increasing antimicrobial resistance has aroused the concern of the failure of antibiotic treatment. OBJECTIVES: To determine the distribution of the bacterial isolates of HAP and VAP, their antimicrobial resistance patterns, and impact of discordant antibiotic therapy on clinical outcome in Asian countries METHODS: A prospective surveillance study was conducted in 73 hospitals in 10 Asian countries from 2008-2009. A total of 2,554 cases with HAP or VAP in adults were enrolled and 2,445 bacterial isolates were collected from 1,897 cases. Clinical characteristics and antimicrobial resistance profiles were analyzed. MEASUREMENT AND MAIN RESULTS: Major bacterial isolates from HAP and VAP cases in Asian countries were Acinetobacter spp., Pseudomonas aeruginosa, Staphylococcus aureus, and Klebsiella pneumoniae. Imipenem resistance rates of Acinetobacter and P. aeruginosa were 67.3% and 27.2%, respectively. Multidrug-resistant rates were 82% and 42.8%, and extensively drug-resistant rates were 51.1% and 4.9%. Multidrug-resistant rate of K. pneumoniae was 44.7%. Oxacillin resistance rate of S. aureus was 82.1%. All-cause mortality rate was 38.9%. Discordant initial empirical antimicrobial therapy increased the likelihood of pneumonia-related mortality (odds ratio, 1.542; 95% confidence interval, 1.127-2.110). CONCLUSIONS: Acinetobacter spp., P. aeruginosa, S. aureus, and K. pneumoniae are the most frequent isolates from adults with HAP or VAP in Asian countries. These isolates are highly resistant to major antimicrobial agents, which could limit the therapeutic options in the clinical practice. Discordant initial empirical antimicrobial therapy significantly increases the likelihood of pneumonia-related mortality.

Current trend of pneumococcal serotypes distribution and antibiotic susceptibility pattern in Malaysian hospitals.

From January 2008 to December 2009, 433 Streptococcus pneumoniae strains were examined to determine the serotype distribution and susceptibility to selected antibiotics. About 50% of them were invasive isolates. The strains were isolated from patients of all age groups and 33.55% were isolated from children below 5 years. The majority was isolated from blood (48.53%) and other sterile specimens (6.30%). Community acquired pneumonia (41.70%) is the most common diagnosis followed by sepsis (9.54%). Serotyping was done using Pneumotest Plus-Kit and antibiotic susceptibility pattern was determined by modified Kirby-Bauer disk diffusion method and measurement of minimum inhibitory concentration (MIC) using E-test strip. Ten most common serotypes were 19F (15.02%), 6B (10.62%), 19A (6.93%), 14 (6.70%), 1 (5.08%), 6A (5.08%), 23F (4.85%), 18C (3.93%), 3 (2.08%) and 5 (1.85%). Penicillin MIC ranged between ≤ 0.012-4 µg/ml with MIC90 of 1 µg/ml. Penicillin resistant rate is 31.78%. The majority of penicillin less-susceptible strains belonged to serotype 19F followed by 19A and 6B. Based on the serotypes distribution 22 (44.00%), 28 (56.00%) and 39 (78.00%) of the invasive isolates from children ≤ 2 years were belonged to serotypes included in the PCV7, PCV10 and PCV13, respectively.

Epidemiology of cryptococcosis in Malaysia.

This study describes the isolation of Cryptococcus neoformans and Cryptococcus gattii from patients with chronic meningitis who were admitted to 16 Malaysian hospitals, from 2003 to 2004. Of the 96 cryptococcal cases reported over the 2-year period, 74 (77.1%) patients were male and 45 (46.9%) patients were between 30 and 39 years old. Cryptococcosis was uncommon in children. A total of 57 (59.4%) and 23 (24.0%) patients were Malay and Chinese respectively. Human immunodeficiency virus infection was the major underlying disease reported in 36 (37.5%) patients. C. neoformans var. grubii (serotype A and molecular type VNI) was the predominant Cryptococcus species isolated from 88.5% of cryptococcal cases in this country. Cryptococcal cases due to C. neoformans var. grubii were reported from all the five regions in Malaysia, with the most number of cases reported from the central and northern regions. Cryptococcus gattii (all were serotype B and molecular types VGI/II) was isolated from all regions except the southern region. Compared with a study conducted prior to the AIDS era, our findings show substantial changes in the demographical characteristics of patients.

Beijing genotype and other predominant Mycobacterium tuberculosis spoligotypes observed in Mashhad city, Iran.

PURPOSE: The purpose of this study was to understand the molecular epidemiology of tuberculosis in Khorasan province of Iran was studied by spoligotyping 113 Mycobacterium tuberculosis isolates. The spoligotyping results were in comparison to the word Spoligotyping Database of Institute Pasteur de Guadeloupe (SpolDB4). Spoligotyping data from Iran has rarely been described and there is limited information on the major circulating clades of M. tuberculosis in Iran. MATERIALS AND METHODS: Spoligotyping was performed on 113 M. tuberculosis isolates from Mashhad patients between November 2004 and September 2005. RESULTS: The study found 57 spoligopatterns. 17 clusters and 32 true orphan genotype. The biggest cluster with 13 isolates had not been previously reported. The Beijing genotype was seen in eight (7.1%) isolates. CONCLUSIONS: Genotyping and Spoligotyping gives a unifying framework for both epidemiology and evolutionary analysis of M. tuberculosis populations.

Serogroups and antibiotic susceptibility patterns of Neisseria meningitidis isolated from army recruits in a training camp.

Invasive Neisseria meningitidis infection is rare but carries a high mortality rate. The carriage rate in the normal population is around 10% and can be higher in confined populations. A study on the prevalence of carriage of N. meningitidis was conducted among 3195 army recruits after 2 months of intensive training in an army camp. N. meningitidis was isolated from 37.0% of these recruits. Two hundred and ten of N. meningitidis isolates were subjected to serogrouping and 100 to antibiotic sensitivity testing by the disc diffusion method and E-test for penicillin. Ten (4.8%) of 210 Neisseria meningitidis serogrouped belonged to serogroup W135, 3.33% serogroup A and 81.4% belonged to either serogroup X, Y or Z. With the agar disc diffusion method, all the N. meningitidis showed susceptiblity to chloramphenicol, rifampicin, cefotaxime and levofloxacin; 85% of the strains were resistant to cotrimoxazole and 12.5% resistant to penicillin. However, based on minimum inhibitory concentration, none of the Neisseria meningitidis tested was resistant to penicillin.

Determination of molecular types and genetic heterogeneity of Cryptococcus neoformans and C. gattii in Malaysia.

The molecular types and genetic heterogeneity of Cryptococcus neoformans and C. gattii clinical isolates in Malaysia were determined in this study. Of 44 C. neoformans collected between 1980 and 2003, 42 (95.5%) were molecular type VNI, 2 (4.5%) were molecular type VNII. Of 17 C.gattii isolates, 13 (76.5%) were molecular type VGI, and 4 (23.5%) were molecular type VGII. A difference was noted when comparing the molecular types of cryptococcal isolates in the earlier and recent cases of cryptococcosis. While both molecular types VNI and VGI were equally predominant in the earlier cases of cryptococcosis, VNI was the most predominant molecular type isolated from the recent cases. VNII was a new molecular type, isolated from 5.1% of the recent cases. All the bird dropping isolates were molecular type VNI. The genetic heterogeneity of the two predominant molecular types, i.e., VNI, VGI clinical isolates and bird dropping isolates of C. neoformans were further determined by polymerase chain reaction (PCR) fingerprinting method, using (GTG)5 as single primer. Two clusters of cryptococcal isolates were distinguished at 68.5% of similarity, with cluster I consisting of VNI isolates and cluster II consisting of VGI isolates. Each cluster was further subdivided into three subtypes at >/=80% of similarity. Fourteen bird dropping isolates were grouped into a subtype within VN1, sharing 82.7% of similarity with the clinical isolates. A higher degree of similarities, ranging from 93.4-97.6% was noted between 3 bird dropping isolates with the clinical isolates in another subtype. This study demonstrated the existence of various molecular types of C. neoformans isolates in Malaysia and the genetic heterogeneity within the predominant molecular types. The study also provides evidence for genetic relatedness of clinical isolates with bird dropping isolates in the environment.

In vitro susceptibilities of Malaysian clinical isolates of Cryptococcus neoformans var. grubii and Cryptococcus gattii to five antifungal drugs.

The in vitro susceptibilities of Malaysian clinical isolates of Cryptococcus neoformans var. grubii and C . gattii to five antifungal drugs (amphotericin B, flucytosine, fluconazole, itraconazole and ketoconazole) were determined using the Etest method. None of the Malaysian isolates was resistant to amphotericin B and ketoconazole. Isolates resistant to flucytosine, fluconazole and itraconazole were observed in this study. Minimum inhibition concentrations (MICs) of > or = 32 microg ml(-1) against flucytosine, > or = 64 microg ml(-1) against fluconazole and > or = 1 microg ml(-1) against itraconazole were noted in four (8.3%), two (4.2%) and one (2.1%) isolates respectively. There was no significant difference in the MICs for both Cryptococcus species (P > 0.05), indicating that C. gattii was as susceptible as var. grubii to all the antifungal drugs tested. No significant difference in the MICs for both Cryptococcus species collected from 1980 to 1990 and 2002 to 2004 were observed (P > 0.05).

The isolation, characterization and antifungal susceptibilities of Cryptococcus neoformans from bird excreta in Klang Valley, Malaysia.

The occurrence of Cryptococcus neoformans in bird excreta in Klang valley, Malaysia was determined in this study. Of 544 samples of bird excreta collected from a local zoo, pet shops and public areas, 20 strains of C. neoformans were isolated. All C. neoformans strains were serotype A and thus identified as C. neoformans variety grubii. All did not produce color changes on canavanine-glycine-bromothymol blue agar. All were of alpha-mating types, as determined by a pheromone-specific PCR assay. The antifungal susceptibility testing using agar diffusion method Neo-sensitabs showed that all were susceptible to amphotericin B, fluconazole and itraconazole.

In-vitro activity of quinupristin/dalfopristin, levofloxacin and moxifloxacin against fusidic acid and rifampicin-resistant strains of methicillin-resistant Staphylococcus aureus (MRSA) from Malaysian hospitals.

The in-vitro susceptibility of quinupristin/dalfopristin, levofloxacin and moxifloxacin against methicillin-resistant Staphylococcus aureus (MRSA) strains, which are also resistant to fusidic acid and rifampicin were carried out to determine whether these antibiotics can be used as an alternative treatment for multiply resistant MRSA strains. The minimum inhibitory concentrations (MIC) of these antibiotics were determined by E-test. Quinupristin/dalfopristin had good activity (MIC90 = 1 mg/L) against these strains while most of the strains showed intermediate resistance to moxifloxacin with MIC90 = 2 mg/L). However, more than 90% of these strains were resistant to levofloxacin with the MICs that ranged from 8 mg/L to 16 mg/L with the majority inhibited at 8 mg/L.

Renal failure in Yemen.

Renal failure remains a serious cause of mortality in Yemen. Our region has 1.25 million population and our hospital is the central hospital, which has a nephrology department and performs dialysis for the region. Between January 1998 and December 2002, we admitted 547 patients; including children, with acute renal failure (ARF) and chronic renal failure (CRF). CRF was observed in 400 patients, an incidence of 64 per million per year and a prevalence of 320 per million. ARF occurred in 147 persons with an incidence of 23.5 per million per year and a prevalence of 117.5 patients per million. Of all patients, 72% were adults (age range, 20-60 years) with a male preponderance. As a tropical country, malaria (27.9%), diarrhea (13.6%), and other infectious diseases were the main causes. Next most common were obstructive diseases causing CRF and ARF (26.8% and 12.9%, respectively), mainly urolithiasis, Schistosomiasis, and prostatic enlargement. However the cause of CRF in 57.5% of patients was unknown as most persons presented late with end-stage disease (64.7%), requiring immediate intervention. Other causes, such as hepatorenal syndrome, snake bite, diabetes mellitus, and hypertension, showed low occurrence rates. Patients presented to the hospital mostly in severe uremia and without a clear history of prior medications. The major findings were vomiting, acidosis, and hypertension with serum creatinine values ranging between 2.8-45 mg/dL (mean value, 13.4 mg/dL). Anemia was observed in 80.4% of CRF versus 62.6% of ARF patients. Hypertension prevalence was 65.5% among CRF patients, of whom 25% were in hypertensive crisis, whereas among ARF the prevalence was only 26.5%.

Oral snuff impairs endothelial function in healthy snuff users.

AIMS: Oral snuff is a less dangerous drug and therefore a good substitute for cigarette smoking. The aim of this study was to determine whether oral moist snuff induces acute endothelial dysfunction. Previous studies have shown that endothelial dysfunction predicts cardiovascular morbidity. METHODS AND RESULTS: Twenty healthy middle-aged snuff users underwent ultrasound assessment of endothelial-dependent flow-mediated dilatation (FMD) of the brachial artery. FMD measurements were performed in duplicate at baseline and then 20 and 35 min after the administration of 1 g portion-bag-packed moist snuff or placebo. Ten of the subjects were examined twice according to a randomized cross-over procedure, once with snuff and once with placebo. All images were arbitrarily analysed off-line by a single blinded observer. FMD values declined significantly from 3.4 +/- 2.0% to 2.3 +/- 1.3% (P < 0.05) 35 min after the administration of 1 g oral moist snuff. Heart rate, systolic and diastolic blood pressure increased significantly (P < 0.05) after snuff administration. All parameters remained unchanged after placebo. CONCLUSIONS: Oral moist snuff significantly impaired FMD of the brachial artery. As endothelial dysfunction predicts cardiovascular morbidity, use of oral snuff should be discouraged.