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Introduction: A resurgence of pertussis has been reported in numerous countries. This study aimed to determine the incidence, clinical characteristics, and outcome of pertussis among infants in Sarawak, Malaysia., Methodology: We conducted a descriptive retrospective study of infants aged < 12 months with laboratory-confirmed pertussis admitted to Bintulu Hospital in Sarawak, Malaysian Borneo, from 2015 until 2021. Pertussis was confirmed in all patients using a polymerase chain reaction of nasopharyngeal aspirates., Results: Of 588 infants who had a nasopharyngeal aspirate, 108 (18%) had laboratory-confirmed pertussis. The average annual incidence was 482 per 100,000 infants aged < 12 months between 2015 and 2019, with a marked decline in 2020 and 2021. Eighty-two (76%) were < 3 months of age. Seventy-eight (72%) were unvaccinated for pertussis, including 75 (96%) who were too young to receive the first dose. A third of the cases had atypical presentations. Severe disease characterized by hypoxemia, pulmonary hypertension, recurrent apnea, encephalopathy, or cardiovascular dysfunction occurred in 32%. Forty-eight percent required humidified high-flow nasal cannula oxygen therapy and 22% required invasive ventilation. Twenty-four percent overall needed intensive care. One (1%) infant had a fatal outcome. Nearly all cases of severe disease or those that required invasive ventilation or intensive care had received ≤ 1 dose of pertussis vaccination., Conclusions: A high incidence of pertussis with a high rate of severe disease was observed in Sarawak, Malaysia, predominantly among infants too young to be vaccinated. Additional vaccination strategies such as maternal vaccination or cocooning should be considered., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2024 Anand Mohan, Yee-Yen Tan, Rohaidah Hashim, David Chun-Ern Ng, Veronica Huey-Shin Wong, Da-Wei Liew, Su-Lin Chien, Lee-See Tan, Peter Sie-Teck Lau, Thilagam Rajandran, Yuwana Podin, Mong-How Ooi.)

Background: Melioidosis, the infection caused by Burkholderia pseudomallei, is associated with a high case fatality rate, due in part to difficulties in clinical recognition and diagnostic confirmation of the disease. Although head and neck involvement is common in children, specific disease manifestations differ between geographic regions. The aim of this study was to provide a detailed description of melioidosis of the head and neck among children in Sarawak, Malaysia, and determine if fine-needle aspiration of suspected head or neck lesions could improve melioidosis diagnosis., Methods: We conducted a retrospective descriptive study of all children aged < 12 years with culture-confirmed melioidosis presenting with head and neck manifestations and admitted to Bintulu Hospital in Sarawak, Malaysia, from January 2011 until December 2020. Fine-needle aspiration of head and neck lesions suspected to be due to melioidosis with inoculation in blood culture bottles (FNA + BCB) was used from the beginning of 2016., Results: Of 34 children with culture-confirmed melioidosis, 20 (59%) had an infection involving one or more sites in the head and neck. Of these, 17 (85%) were diagnosed in or after 2016. Cervical lymph nodes were the most common organ or site affected, involved in 19 (95%) children. Clinical presentations of B. pseudomallei lymph node infections were highly variable. Five (25%) children had salivary gland involvement. Lacrimal gland involvement (dacryocystitis) and skin or soft tissue infection (scalp abscess) were less frequent. B. pseudomallei was isolated from the head or neck using FNA + BCB in 15 (75%) children and by standard culture methods of direct plating of pus on agar following incision and drainage in only 2 (10%) children. B. pseudomallei was isolated from non-head or neck specimens or blood in 3 (15%) children., Conclusions: Manifestations of pediatric head and neck melioidosis in Sarawak, Malaysia, differ from those of other regions. Fine-needle aspiration, mainly of affected cervical lymph nodes, facilitates B. pseudomallei detection and enables confirmation of melioidosis infections., (© 2021. The Author(s).)

Background: Burkholderia pseudomallei , the causative agent of melioidosis, is intrinsically resistant to a broad range of antibiotics, including aminoglycosides. In Sarawak, Malaysia, a high proportion of melioidosis cases are caused by gentamicin-susceptible isolates. There are limited epidemiological and clinical data on these infections., Methods: We conducted a retrospective study of culture-confirmed melioidosis among adults admitted to Bintulu Hospital in Sarawak, Malaysia, from January 2011 until December 2016., Results: One hundred forty-eight adults with culture-confirmed melioidosis were identified. Of 129 (87%) tested, 84 (65%) had gentamicin-susceptible B pseudomallei . The average annual incidence of melioidosis was 12.3 per 100 000 population, with marked variation between districts ranging from 5.8 to 29.3 per 100 000 population. Rural districts had higher incidences of melioidosis and overwhelmingly larger proportions of gentamicin-susceptible B pseudomallei infection. Significantly more patients with gentamicin-susceptible infection had no identified risk factors, with diabetes less frequently present in this group. Ninety-eight percent had acute presentations. Pneumonia, reported in 71%, was the most common presentation. Splenic abscesses were found in 54% of those imaged. Bacteremia was present in 88%; septic shock occurred in 47%. Forty-five (35%) patients died. No differences in clinical, laboratory, or outcome characteristics were noted between gentamicin-susceptible and gentamicin-resistant infections., Conclusions: Gentamicin-susceptible B pseudomallei infections are common in Sarawak and dominate in the high-incidence rural interior regions. Clinical manifestations and outcomes are the same as for gentamicin-resistant B pseudomallei infections. Further studies are required to determine if all gentamicin-susceptible B pseudomallei infections in Sarawak are clonal and to ascertain their environmental drivers and niches., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives: Melioidosis is associated with extremely high case fatality ratios. The aim of this study was to determine whether detection of abdominal visceral abscesses can facilitate diagnosis of melioidosis in children., Methods: We conducted a retrospective analysis of all children who had liver and/or spleen abscesses on abdominal ultrasonography admitted to Bintulu Hospital in Sarawak, Malaysia, from January 2014 until December 2018., Results: Fifty-three children had liver and/or spleen abscesses. Spleen abscesses were present in 48 (91%) cases; liver abscesses in 15 (28%). Melioidosis was confirmed by culture in 9 (17%) children; small occult splenic abscesses were present in all cases. In 78% of these cases, the lesions were detected before any positive culture (or serology) results were available. Four (8%) children had bacteriologically-confirmed tuberculosis. Two (4%) had Staphylococcus aureus infection. Of the remaining 38 (72%) culture-negative cases, 36 (95%) had clinical and imaging characteristics similar to that of children with culture-confirmed melioidosis and improved with empirical melioidosis antibiotic therapy., Conclusions: A large number of children in Bintulu Hospital in Sarawak, Malaysia, were found to have spleen abscesses. Melioidosis was the most common etiology identified in these children. Abdominal ultrasonography is extremely useful in facilitating the diagnosis of pediatric melioidosis., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Invasive Salmonella infections result in significant morbidity and mortality in developing countries. In Asia, typhoid and paratyphoid fever are reported to be the major invasive Salmonella infections, while invasive non-typhoidal Salmonella (iNTS) infections are believed to be uncommon. Data from Sarawak, in Malaysian Borneo, are limited., Methods: A retrospective study identifying all children aged < 15 years with invasive Salmonella infections from 2011 to 2016 was conducted in Bintulu Hospital in Sarawak. Population incidences, clinical and bacterial characteristics were examined., Results: Forty-four patients were identified during the 6-year study period: 43 had iNTS infection and 1 had typhoid fever. The average annual iNTS incidence was 32.4 per 100,000 children aged < 5 years. None of the children had malaria or HIV infection, and only 7% were severely malnourished. Salmonella Enteritidis and Salmonella Java were the commonest NTS serovars identified. Pneumonia was the most common manifestation of iNTS disease, present in 20 (47%) children. Other manifestations included gastroenteritis, fever without a source, septic arthritis and meningitis. Salmonella Enteritidis was identified in 76% of those with pneumonia, significantly more frequently than in children with other manifestations. Over 25% of children with iNTS developed severe disease and nearly 10% suffered long term morbidity or mortality. While 78% of Salmonella Java isolates were multi-drug resistant, nearly all other isolates were susceptible to most antimicrobials, including ampicillin., Conclusions: Bintulu Division in Sarawak observed a very high incidence of childhood iNTS infections. Enteric fever was uncommon. The epidemiology of invasive Salmonella infections in Malaysian Borneo differs considerably from that of neighbouring countries in Asia.

Background: Melioidosis is a serious, and potentially fatal community-acquired infection endemic to northern Australia and Southeast Asia, including Sarawak, Malaysia. The disease, caused by the usually intrinsically aminoglycoside-resistant Burkholderia pseudomallei, most commonly affects adults with predisposing risk factors. There are limited data on pediatric melioidosis in Sarawak., Methods: A part prospective, part retrospective study of children aged <15 years with culture-confirmed melioidosis was conducted in the 3 major public hospitals in Central Sarawak between 2009 and 2014. We examined epidemiological, clinical and microbiological characteristics., Findings: Forty-two patients were recruited during the 6-year study period. The overall annual incidence was estimated to be 4.1 per 100,000 children <15 years, with marked variation between districts. No children had pre-existing medical conditions. Twenty-three (55%) had disseminated disease, 10 (43%) of whom died. The commonest site of infection was the lungs, which occurred in 21 (50%) children. Other important sites of infection included lymph nodes, spleen, joints and lacrimal glands. Seven (17%) children had bacteremia with no overt focus of infection. Delays in diagnosis and in melioidosis-appropriate antibiotic treatment were observed in nearly 90% of children. Of the clinical isolates tested, 35/36 (97%) were susceptible to gentamicin. Of these, all 11 isolates that were genotyped were of a single multi-locus sequence type, ST881, and possessed the putative B. pseudomallei virulence determinants bimABp, fhaB3, and the YLF gene cluster., Conclusions: Central Sarawak has a very high incidence of pediatric melioidosis, caused predominantly by gentamicin-susceptible B. pseudomallei strains. Children frequently presented with disseminated disease and had an alarmingly high death rate, despite the absence of any apparent predisposing risk factor.

The aim of this study was to assess whether the GAITRite gait analysis system an effective tool in evaluating parkinsonian bradykinesia. In their best ON and worst OFF states, 13 parkinsonian patients were asked to perform walking trail at their fastest velocity, and to submit to traditional timed tests. Significant correlations existed between OFF-ON improvement in gait parameters and in UPDRS III score (r(2)=0.59-0.78) except cadence. Among the gait parameters, stride length is the most effective indicator of timed test and UPDRS III score improvements. The GAITRite system is an efficient, yet effective device in evaluating parkinsonian bradykinesia and can be used as a substitute for the traditional timed test.

Elevated inflammatory markers and muscle wasting were common in chronic obstructive pulmonary disease (COPD) patients. The purpose of this study was to investigate the effect of 7-day beta-hydroxy-beta-methylbutyrate (HMB) supplementation on inflammation, protein metabolism, and pulmonary function in COPD patients in an intensive care unit. Thirty-four COPD patients who required mechanical ventilators were randomly assigned to HMB (n=18) or control (n=16) groups. The HMB group received HMB 3 g/d for 7 days. White blood cell count, C-reactive protein, and creatinine were significantly lower, while cholesterol and total protein were significantly higher after HMB supplementation. The body weight remained unchanged in both groups. Ten subjects (55.6%) in the HMB group and 4 subjects (25.0%) in the control group had improved pulmonary function, indicated by their ventilator modes. This short-term study suggests that HMB supplementation may have anti-inflammatory and anticatabolic effect and improve pulmonary function in COPD patients in an intensive care unit setting.

A series of 2-substituted methyl 2,3-dihydroimidazo[1, 2-c]quinazolin-5(6H)-ones (4), 3-substituted methyl 2, 3-dihydroimidazo[1,2-c]quinazolin-5(6H)-ones (5), 3-substituted methyl 2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-ones (15a,b), 3-substituted methyl 2,3-dihydroimidazo[2,1-b]quinazolin-5(1H)-ones (16a,b), 3-substituted methyl 2,3-dihydro-1H-imidazo[1,2-b][1,2, 4]benzothiadiazine 5,5-dioxides (33a,b), 2-substituted methyl imidazo[1,2-c]quinazolin-5(6H)-ones (42-45a,b), 3-substituted methyl imidazo[1,2-c]quinazolin-5(6H)-ones (50-53a,b), 3-substituted methyl 5H-thiazolo[2,3-b]quinazolin-5-ones (55-56a,b), and 3-substituted methyl 5-(methylthio)-2,3-dihydroimidazo[1,2-c]quinazoline (57) were synthesized as compound 1conformational rigid congeners for pharmacological evaluation as potential alpha1-adrenoceptor antagonists. Compounds 4, 5, 33a,b, 44a,b, 45a,b, 52a,b, 53a,b, and 57 were found to possess high affinity for the alpha1-adrenoceptor. Compounds 5 and 57 were the most highly selective and potent alpha1 antagonists with Ki = 0.21 +/- 0.02 and 0.90 +/- 0.08 nM, respectively. The S-enantiomers of these two compounds (Ki = 0.13 +/- 0.01 nM for (S)-(-)-5; Ki = 1.0 +/- 0.2 nM for (S)-(+)-57) were 144-200-fold more potent than the R-enantiomers (Ki = 26 +/- 8 nM for (R)-(+)-5; Ki = 144 +/- 23 nM for (R)-(-)-57). Compound 4 showed 8-fold higher affinity to alpha1A-AR better than alpha1B-AR. These compounds possessed weak to no activity against the 5-HT1A receptor.

CD34 is widely used as a marker in the identification and purification of human hematopoietic stem and progenitor cells; however, its function within hematopoiesis is largely unknown. We have investigated the contribution of cytoplasmic domain of CD34 in cytoadhesion signaling and proliferation signaling in hematopoietic cells. Engagement of particular determinants of CD34 by monoclonal antibodies leads to homotypic adhesiveness of the full-length CD34-transfected BaF3 cells. However, this homotypic adhesiveness is abrogated in BaF3 cells transfected with the truncated CD34 lacking the cytoplasmic domain. Cytoadhesion signaling through the cytoplasmic domain of CD34 cannot be restored through that of erythropoietin receptor (EPOR) or granulocyte colony-stimulating factor receptor (G-CSFR), suggesting that the cytoplasmic domain of CD34 is required for its signal transduction of cellular adhesion. In constrast, we show that replacing the cytoplasmic domain of EPOR or G-CSFR with that of CD34 abolished growth signal transduction in response to EPO or G-CSF in the chimeric receptor-transfected BaF3, 32D, and FDCP1 cells, whereas the wild-type EPOR- or G-CSFR-transfected cells responded to EPO or G-CSF growth signaling well. These results suggest that the cytoplasmic portion of CD34 may not contain the elements necessary to transduce a proliferative signal in hematopoietic cells. Thus, the function of CD34 in hematopoiesis is primarily on hematopoietic cell adhesion.

Enzyme replacement is a potential therapy for mucopolysaccharidosis I (MPS I), a lysosomal storage disorder caused by alpha-L-iduronidase deficiency. Previous work showed improvement in the tissues of MPS I dogs treated intravenously for 3 months with recombinant human alpha-L-iduronidase (25,000 units or approximately 0.1 mg/kg/week). We have now treated an MPS I-affected dog for 13 months to assess the clinical effects of enzyme replacement. The treated dog gained more weight, was more active, and had less joint stiffness than the untreated littermate. Biochemical and histologic studies demonstrated uptake of alpha-L-iduronidase and decreased lysosomal storage in the liver, kidney, spleen, lymph nodes, synovium, adrenals, and lungs. The brain had detectable enzyme activity and decreased glycosaminoglycan storage although histologic improvement was not evident. Cartilage and heart valve did not show any detectable improvement. A fivefold higher dose (approximately 0.5 mg/kg) administered five times over 10 days to two other dogs resulted in higher tissue enzyme activity and similarly decreased glycosaminoglycan storage and excretion. Antibodies to human alpha-L-iduronidase were induced in all treated dogs and may be associated with immune complex deposition and proteinuria. Recombinant canine alpha-L-iduronidase also induced antibody formation to a similar degree. The results support the conclusion that enzyme replacement is a promising therapy for MPS I though immunologic complications may occur.

Recombinant human keratinocyte growth factor (rhKGF) is a fairly unstable protein, posing a challenging problem for long-term storage. During storage, the protein unfolds at relatively low temperatures and the unfolded proteins aggregate rapidly, leading to the formation of large visible precipitates. Thermal unfolding of rhKGF displays a similar pattern, i.e., unfolding is followed immediately by aggregation as the temperature is increased. As the unfolding and aggregation (precipitation) of rhKGF limit the storage life of the protein, a search for stabilizers to suppress rhKGF unfolding and aggregation has been done by examining the effects of excipients on thermal melting temperature and on the rate of protein aggregation during storage. Sulfated polysaccharides and citrate are found to be effective in increasing the melting temperature of rhKGF or preventing its aggregation. In particular, 0.5% (w/v) heparin and high molecular weight dextran sulfate, and 0.5 M citrate are highly effective, decreasing the rates of rhKGF aggregation by about 50-fold. Other negatively charged small ions, such as phosphate, also have moderate stabilizing effects on rhKGF. A mechanistic study of the aggregation pathway of rhKGF has led to a better understanding of the stabilizing effects of these molecules. Molecules which enhance rhKGF conformational stability are capable of effectively suppressing rhKGF aggregation.

Arginase has been detected in high levels in gastric cancer tissues. The effect of arginase on the activities of splenic natural killer (NK) cell, phytohemagglutinin activated killer (PAK) cell, and interleukin-2 activated killer (LAK) cell in patients with gastric cancer (N = 12) was evaluated in vitro. These activities in patients (N = 10) with trauma and benign lesions were used as control. The splenic NK and PAK cell activities in patients with gastric cancer were significantly lower than in the controls (P < 0.05), whereas LAK cell activity did not have significant difference. Arginase inhibited all splenic killer cell activities to a similar degree between patients with gastric cancer and the controls. The inhibition was dose-related. These data suggest that arginase may play a positive role in the spread of gastric cancer cells. However, LAK may be a potential approach of immunoadoptive therapy in the future.

A series of 2-[(substituted phenylpiperazin-1-yl)methyl]- and 2-[(substituted phenylpiperidin-1-yl)methyl]-2,3-dihydroimidazo[1,2- c]quinazolin-5(6H)-ones or -5(6H)-thiones, and 3-[(substituted phenylpiperazin-1-yl)methyl]-2,3-dihydroimidazo[1,2-c]quinaz oline derivatives were synthesized, as conformationally restricted analogues of SGB-1534 and ketanserin, for evaluation as alpha-antagonists and antihypertensive agents. Most compounds containing a (substituted phenylipiperazinyl)methyl side chain displayed high binding affinity for alpha 1-adrenoceptor with no significant activity at alpha 2-sites. Compounds having a (substituted phenylpiperazinyl)methyl at the 3-position of 2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one ring system had a better activity than those with the same substituent at the 2-position. Structure-activity relationships for alpha 1-adrenoceptor affinity are presented and indicate that compounds with substitution at the ortho position on the benzene ring of the phenylpiperazine side chain moiety are more potent than those without substitution and/or substitutions at the 3- and 4-positions. Computer-assisted superimposition of SGB-1534 and 20b showed little structural correspondence between the quinazolinone and 2,3-dihydroimidazo[1,2-c]quinazoline nucleus, and specific interactions of these molecular fragments with the receptor protein appear unlikely. Antihypertensive activity was evaluated via intravenous administration of each compound to spontaneously hypertensive rats, and compounds (16a, 16b, 20b, and 28b) illustrated similar efficacy to SGB-1534 when assessed after 6 h. The pA2 value for 16a against phenylephedrine in rat aorta was much higher than that of prazosin. On the basis of alpha 1-adrenoceptor affinity/selectivity in vitro and duration of antihypertensive action in vivo, compounds 20b and 28b warrant further evaluation.

Gastric cancer tissues have high levels of glucocorticoid receptors (GR) and arginase. To investigate the interrelation of glucocorticoid, GR and arginase, three human gastric cancer cell lines (AZ-521, NUGC-3, KATO-III) were treated with hydrocortisone in the presence or absence of a glucocorticoid antagonist RU38486. GR were found to be present in all three lines, and hydrocortisone significantly increased the production of total arginase in all 3 lines. The induction of arginase production by hydrocortisone was inhibited by RU38486. These findings suggest that the regulation of arginase production by hydrocortisone in gastric cancer cells is mediated through GR.