Efficacy and safety of adjunctive treatment with perampanel in epilepsy patients.

INTRODUCTION: Epilepsy is a neurological disease with high global prevalence. Almost one-third of epilepsy patients continue having seizures despite adequate treatment. Perampanel has been widely used in the Western countries as an adjunctive therapy for both generalized and focal seizures. Owing to its high cost, the use of perampanel is limited in our country. MATERIALS AND METHODS: We conducted a descriptive, retrospective study among epilepsy patients treated with perampanel. We aimed to assess the efficacy and safety of perampanel as an adjunctive in our hospital. RESULTS AND CONCLUSIONS: From our cohort of 25 patients, most of the patients were either on one or three anti-seizure medications (ASMs) prior to initiation of perampanel. Perampanel was added in 88% of them due to persistent seizures. Twenty-two (88%) patients experienced reduction in seizure frequency. 12% experienced mild side effects, which were leg cramps, hyponatremia and drowsiness. Only 1 patient stopped perampanel due to its side effects. CONCLUSION: Perampanel is a well-tolerated ASM that should be widely used as an adjunctive. More studies with regards to its efficacy and safety involving more centres are encouraged in Malaysia.

Health-related quality of life of Malaysian patients with chronic non-malignant pain and its associated factors: a cross-sectional study.

BACKGROUND: Chronic pain has a major impact on a patient's quality of life, affecting physical and psychological functioning. It has debilitating consequences on social and economic aspects too. This study aimed to explore the status of health-related quality of life (HRQoL) of Malaysian patients suffering from chronic non-malignant pain. METHODS: Four hospitals offering pain clinic services were involved in this multicentre cross-sectional study conducted between June and September 2020. Adult patients who had been diagnosed with non-malignant chronic pain lasting for at least three months and able to communicate in English or Malay language were recruited in this study. Participants were informed about the study and were made aware that their participation was entirely voluntary. A battery of questionnaires consists of the EuroQol-5 dimensions-5 levels questionnaire (EQ-5D-5L) and the EuroQol visual analogue scale (EQ VAS), the Pain Self-Efficacy questionnaire (PSEQ) and the Pain Catastrophizing Scale (PCS) were self-administered by the patients. Besides, a structured questionnaire was used to collect their socio-demographic information, pain condition, sleep quality and working status. Participants' usage of pain medications was quantified using the Quantitative Analgesic Questionnaire (QAQ). RESULTS: A total of 255 patients participated in this study. A median EQ-5D index value of 0.669 (IQR: 0.475, 0.799) and a median EQ VAS score of 60.0 (IQR: 50.0, 80.0) were recorded. Malay ethnicity (Adj. B: 0.77; 95% CI: 0.029, 0.126; p = 0.002) and a higher level of self-efficacy (Adj. B: 0.008; 95% CI: 0.006, 0.011; p < 0.001) were predictors of a better HRQoL, while suffering from pain in the back and lower limb region (Adj. B: -0.089; 95% CI: - 0.142, - 0.036; p = 0.001), the use of a larger amount of pain medications (Adj. B: -0.013; 95% CI: - 0.019, - 0.006; p < 0.001), and a higher degree of pain magnification (Adj. B: -0.015; 95% CI: - 0.023, - 0.008; p < 0.001) were associated with a poorer HRQoL. CONCLUSIONS: These findings suggested that Malay ethnicity and a higher level of self-efficacy were predictors of a better HRQoL in patients with chronic pain, whereas pain-related factors such as higher usage of medication, specific pain site and pain magnification style were predictors of poorer HRQoL.

High intensity non-invasive positive pressure ventilation for refractory decompensated acute hypercapnic respiratory failure in advanced chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a debilitating progressive lung disease characterised by irreversible airflow obstruction. In addition to an increase in morbidity and mortality, exacerbation also results in frequent hospital visits, which place a burden on healthcare systems. Non-invasive positive pressure ventilation (NPPV) with conventional inspiratory pressures is the standard ventilatory support for patients in exacerbation. At present, the use of higher inspiratory pressures through high intensity noninvasive positive pressure ventilation (Hi-NPPV) during an exacerbation remains unknown. We describe a novel application of Hi-NPPV in a patient with acute exacerbation who was refractory to conventional NPPV.

A systematic review of the prevalence of limited health literacy in Southeast Asian countries.

OBJECTIVES: Health literacy is increasingly recognized as a public health concern. Most of the literature on health literacy concentrate in the Western countries. Therefore, this study aimed to systematically review and examine the available studies on health literacy in Southeast Asian countries and estimate its prevalence in this region. STUDY DESIGN: Systematic review. METHODS: A search for relevant articles was carried out using Cumulative Index to Nursing and Allied Health Literature (CINAHL) and MEDLINE (via EBSCOhost), Scopus, Science Direct, PubMed and Google Scholar with multiple search terms. Inclusion criteria comprised articles published in English language and assessing general health literacy. Risk of bias reduced with the involvement of two independent reviewers in the screening of the literature and the quality assessment process. RESULTS: A total of 11 studies were included, which only consist of studies from five countries out of 11 making up the Southeast Asian region. The overall prevalence of limited health literacy varied considerably, 1.6%-99.5% with a mean of 55.3% (95% confidence interval [CI]: 35.1%-75.6%). A much higher prevalence was noted in studies conducted in healthcare settings, 67.5% (95% CI: 48.6%-86.3%). The most common factors associated with limited health literacy were education attainment, age, income and socio-economic background. Other factors identified were gender and health behaviours. CONCLUSIONS: In summary, despite the little evidence available and existences of high heterogeneity among studies, limited health literacy is still prevalent in Southeast Asian countries. Urgent strategies to improve and promote health literacy in the region are highly warranted. Besides, more studies on health literacy with better quality on the methodology aspect are needed.

7S nerve growth factor is an insulin-like growth factor-binding protein protease.

Insulin-like growth factor (IGF)-binding protein (IGFBP) proteases modulate IGF action by cleaving IGFBPs into fragments with lower affinity to IGFs, thereby increasing the levels of free IGFs. We have previously documented that prostate-specific antigen (PSA), a serine protease of the kallikrein family, is an IGFBP-3 protease. In this study, we characterized the potential IGFBP proteolytic activity of nerve growth factor (NGF gamma-subunit), which shares high sequence homology with PSA. [125I]IGFBP-3 was cleaved by NGF (but not other kallikreins) at a 3-fold lower concentration than that of PSA, thus proving NGF to be a more potent IGFBP protease than PSA. NGF-generated, lower mol wt IGFBP-3 fragments, detected by immunoblotting and cross-linking to IGFs, had a lower affinity to IGFs than intact IGFBP-3. Unlike PSA, which cleaves primarily IGFBP-3 and -5, NGF also displayed potent proteolytic activity against IGFBP-4 and -6. These data suggest that NGF may be involved in the growth of cells by more than one mechanism. In addition to binding to its receptors, NGF is capable of cleaving IGFBPs and, thus, enhancing IGF action. This synergistic action between NGF and IGF may have important implications on cell growth, development, and repair in the brain and other tissues.

Decreased expression of Wilms' tumor gene WT-1 and elevated expression of insulin growth factor-II (IGF-II) and type 1 IGF receptor genes in prostatic stromal cells from patients with benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a common proliferative disorder of unknown etiology. We have previously documented that the insulin-like growth factor (IGF) axis is critical for prostate cell growth and is abnormal in BPH. The type 1 IGF receptor (IGF-1R) is constitutively expressed by most body tissues and plays a significant role in regulating cell proliferation, consistent with the role of its ligands (IGF-I and IGF-II) as important mitogenic factors. The Wilms' tumor gene product (WT-1) is a tumor suppressor that has been shown to be altered in rare kidney tumors and is known to regulate IGF-II and IGF-1R. We investigated the possibility that the expression of prostatic WT-1, IGF-1R, and IGF-II genes is altered in patients with BPH. We utilized primary cultures of prostatic stromal cells grown from normal (n = 9) and hyperplastic (n = 9) surgical specimens and analyzed WT-1, IGF-1R, and IGF-II messenger RNA levels. In all of the BPH cell strains, WT-1 expression (measured by RT-PCR and RNase protection assays) was strikingly lower than that found in normal strains (0-20% of normal, mean 14% of normal, P < 0.01). The expression of both the IGF-1R (300% of normal, P < 0.05) and IGF-II (1000% of normal, P < 0.01) messenger RNAs was higher in BPH strains as compared with normal strains. No changes were seen in stromal cell strains derived from prostatic adenocarcinoma. Thus, in cultured human prostatic stromal cell strains from patients with BPH, decreased WT-1 gene expression is associated with increases in the expression of the IGF-1R and IGF-II genes that are known transcriptional targets of WT-1. These findings indicate that reduced expression of the WT-1 tumor suppressor gene and elevated IGF-1R and IGF-II gene expression may be involved in the pathophysiology of prostatic hyperplasia, implying a new role for the Wilms' tumor gene in nonmalignant states.

Insulin-like growth factor-binding protein-3 is partially responsible for high-serum-induced apoptosis in PC-3 prostate cancer cells.

Cells are known to undergo apoptosis when cultured in high serum concentrations. However, the serum factors responsible for this induction of apoptosis have not been identified. The IGF-binding protein-3 (IGFBP-3), a negative growth regulator, is found at concentrations of 5 microgram/ml in serum. We have recently demonstrated that IGFBP-3 induces apoptosis in PC-3 cells, a prostate cancer cell line, at a concentration of 500 ng/ml. In this communication, we demonstrate the role of IGFBP-3 as one of the apoptosis-inducing agents in high serum concentrations. Treatment of PC-3 cells with increasing concentrations (40% to 90%) of intact human serum (HS) resulted in a dose-dependent decrease in cell growth. Valinomycin, an ionophore, was used as a positive control to measure the induction of apoptosis by serum treatment in PC-3 cells. Treatment with 90% serum showed significant suppression of growth (P<0.001) compared with the effect of 10% serum. Treatment with increasing concentrations of HS (40% to 90%) resulted in a dose-dependent increase in apoptosis. Treatment with 90% HS showed a 10-fold increase in apoptotic index compared with cells treated with 10% HS. Treatment of PC-3 cells with IGFs and IGFBP-3-depleted 90% human sera (depleted serum=DS) demonstrated significantly lower levels of apoptosis (50% reduction in the effect of 90% HS) suggesting a role of IGFBP-3 in inducing apoptosis in high serum concentration. Furthermore, treatment with DS supplemented with recombinant IGFBP-3 (500 ng/ml) brought the apoptotic index down close to the level of apoptosis induced by 90% intact serum treatment (P<0.001). However, DS supplemented with physiological concentrations of IGFs (500 ng/ml) showed only partial recovery of cell survival demonstrated by 90% DS. This data indicates that IGFBP-3 is one of the factors in serum that is responsible for high-serum-induced apoptosis.

An alga-like organism associated with an outbreak of prolonged diarrhea among foreigners in Nepal.

An unidentified organism was found in the stools of 55 immunocompetent patients who presented to the CIWEC Clinic in Kathmandu, Nepal between June and November 1989. The microscopic features of the organism share characteristics of both coccidia and cyanobacteria species. From June 26, 1989 to November 17, 1989, 55 persons were identified as having the organism in at least one stool sample. The illness was characterized by prolonged watery diarrhea, anorexia, fatigue, and weight loss. The mean +/- SD duration of illness was 43 +/- 24 days (range 4-107). Thirty-four patients received a total of 78 courses of antimicrobial treatment (2.3 courses/patient). The mean +/- SD duration of illness in 34 treated patients was 46 +/- 24 days. In 14 untreated patients, the mean +/- SD duration of illness was 35 +/- 23 days. The organism is 8.0-9.0 microns in diameter, floats in Sheather's solution, and stains red with the modified acid-fast stain. Since the agent was closely associated with a prolonged, self-limited diarrheal illness, it could easily have been misdiagnosed as Cryptosporidium. The organism should be looked for in the stools of patients with persistent diarrhea and a history of foreign travel.

The role of hysterosalpingography in modern gynaecological practice.

A retrospective review of hysterosalpingography (HSG) in a major gynaecological centre was carried out. 324 patients attended (95%) for HSG out of 341 patients referred for this investigation. 189 examinations (58.3%) were abnormal. The requests and radiological findings were reviewed and the results compared with laparoscopy. HSG remains an integral part of gynaecological investigation and its value has not diminished in modern practice.

Effects of Buscopan on gastro-oesophageal reflux and hiatus hernia.

This prospective study was undertaken to establish whether Buscopan (hyosine butyl bromide) interferes with the detection of a hiatus hernia or induces gastro-oesophageal reflux. One hundred and four consecutive patients were included in the study who came for barium meal and swallow examinations over a period of 3 months. Ten patients were excluded from the study. The examinations were performed by the author. The manoeuvres to detect gastro-oesophageal reflux and hiatus hernia were performed before and after intravenous Buscopan. It was found that Buscopan does not induce gastro-oesophageal reflux in the majority of patients, or interfere with detection of a hiatus hernia. The conclusion of this study is that Buscopan can be given early on in the barium meal examination without a significant effect on hiatal function.

Protein distribution and gene expression of collagen type IV in the neonatal rat ovary during follicle formation.

Protein distribution and mRNA expression of basement membrane collagen (type IV) during follicle formation were studied using serial sections from 24, 48 and 72 hrs. old rat ovaries. Collagen type IV, a protein found only in the basal lamina of the basement membrane, was localized under light microscope using a polyclonal antibody. During the first 24 hrs. postpartum, immunostaining was found as thin septa separating the clusters from the stroma. By 72 hrs. postpartum, immunostaining was found around each newly formed primordial follicle. The cell types involved in collagen type IV synthesis were determined by in situ hybridization using a biotinylated riboprobe. Before the follicles had been formed, the stromal cells showed intense staining while the epithelial presumptive granulosa cells showed a pale staining. However, after a follicle had been formed, some of the granulosa cells enclosed within the follicular basement membrane showed strong staining for the message. The presumptive granulosa cells are presumed to be the progenitors of granulosa cells. If so, these observations suggest that the expression of the message coding for collagen type IV by the granulosa cells may be a marker for commitment of the undifferentiated cell to the granulosa cell lineage.

Insulin-like growth factor (IGF)-binding protein-3 induces apoptosis and mediates the effects of transforming growth factor-beta1 on programmed cell death through a p53- and IGF-independent mechanism.

Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) is known to block IGF action and inhibit cell growth. IGFBP-3 is thought to act by sequestering free IGFs or, possibly, act via a novel IGF-independent mechanism. Supporting its role as a primary growth inhibitor, IGFBP-3 production has been shown to be increased by cell growth-inhibitory agents, such as transforming growth factor-beta (TGF-beta), and the tumor suppressor gene p53. In this paper, we demonstrate, for the first time, a novel function of IGFBP-3 as an apoptosis-inducing agent and show that this action is mediated through an IGF.IGF receptor-independent pathway. In the p53 negative prostate cancer cell line, PC-3, the addition of recombinant IGFBP-3 resulted in a dose-dependent induction of apoptosis. 125I-IGFBP-3 bound with high affinity to specific proteins in PC-3 cell lysates and plasma membrane preparations. These membrane-associated molecules may serve as receptors that mediate the direct effect of IGFBP-3 on apoptosis. In addition, in an IGF receptor-negative mouse fibroblast cell line, treatment with recombinant IGFBP-3 as well as transfection of the IGFBP-3 gene induced apoptosis, suggesting that neither IGFs nor IGF receptors are required for this action. Furthermore, treatment with TGF-beta1, a known apoptosis-inducing agent, resulted in the induction of IGFBP-3 expression 6-12 h before the onset of apoptosis. This effect of TGF-beta1 was prevented by co-treatment with IGFBP-3-neutralizing antibodies or IGFBP-3-specific antisense thiolated oligonucleotides. These findings suggest that IGFBP-3 induces apoptosis through a novel pathway independent of either p53 or the IGF.IGF receptor-mediated cell survival pathway and that IGFBP-3 mediates TGF-beta1 induced apoptosis in PC-3 cells.

Fatigue fracture of the sacrum in a child.

Fatigue fractures involving the sacrum are extremely rare, and to our knowledge no occurrence of such a fracture in a child has been reported in the English-language literature. These fractures may mimic primary bone tumours or infection, and it is important to make an accurate diagnosis so that unnecessary biopsy can be avoided. We report a fatigue fracture of the sacrum in an 11-year-old child following prolonged aerobic exercise.

The changing architecture of the neonatal rat ovary during histogenesis.

The purpose of this study was to describe the changing histological organization of the rat ovary during postpartum days one through three (p1-p3). A PC-based image-combining microscope system was used to reconstruct the ovary in three dimensions. On p1, cyclindrical pocket-like structures radiated from the core of the ovary that were open toward the surface epithelium. The walls of the pockets contained connective tissue cells and capillaries (stroma). By p2, these pockets had completely closed; each pocket enclosed a small nest of oocytes and a few presumptive granulosa cells. By p3, the pocket-like organization had disappeared. On p1, only one or two primordial follicle-like structures were observed in the core and toward the periphery of the ovary; most oocytes were not enclosed in follicles. By p3, very few naked oocytes remained; primordial follicles predominated in all the regions of the ovary and some of the follicles had multiple layers of granulosa cells. There were changes in location, area, and volume of the rete tubules during these postnatal days. The extraovarian rete was visible on all 3 days but changed its orientation relative to the ovary. The connecting rete was found beneath the epithelial layer of the ovary on all 3 days and showed dramatic increase in area on p2. The wide lumen of the intraovarian rete was in direct contact with some of the oocytes near by on all 3 days, but these "communication points" were most abundant on p2. Based on our observations of different cell-cell associations during this time period, we hypothesize (1) that the mesenchymal-presumptive granulosa cell association is essential for the completion of folliculogenesis, and (2) the rete ovarii may have an inductive role in follicle assembly. These observations suggest that the first 3 days postpartum are critically important for studying the heterogeneous cell interactions that lead to the assembly of primordial follicles. The regional differences in tissue organization during this formative period may have significant implications on later aspects of follicular development.

IGFBP-3 mediates TGF-beta1-induced cell growth in human airway smooth muscle cells.

Both insulin-like growth factor binding protein-3 (IGFBP-3) and transforming growth factor-beta (TGF-beta) have been separately shown to have cell-specific growth-inhibiting or growth-potentiating effects. TGF-beta stimulates IGFBP-3 mRNA and peptide expression in several cell types, and TGF-beta-induced growth inhibition and apoptosis have been shown to be mediated through the induction of IGFBP-3. However, a link between the growth stimulatory effects of TGF-beta and IGFBP-3-induction has not been shown. In this study, we investigated the role of IGFBP-3 in mediating TGF-beta1-induced cell growth using human airway smooth muscle (ASM) cells as our model. TGF-beta1 (1 ng/ml) treatment induced a 10- to 20-fold increase in the levels of expression of IGFBP-3 mRNA and protein. Addition of either IGFBP-3 or TGF-beta1 to the growth medium resulted in an approximately twofold increase in cell proliferation. Coincubation of ASM cells with IGFBP-3 antisense (but not sense) oligomers as well as with an IGFBP-3 neutralizing antibody (but not with control IgG) blocked the growth induced by TGF-beta1 (P < 0.001). Several IGFBP-3-associated proteins were observed in ASM cell lysates, which may have a role in the cellular responses to IGFBP-3. These findings demonstrate that IGFBP-3 is capable of mediating the growth stimulatory effect of TGF-beta in ASM cells.

Is Blastocystis hominis a cause of diarrhea in travelers? A prospective controlled study in Nepal.

Although the pathogenicity of Blastocystis hominis has been extensively debated in the medical literature, controlled studies of the association between B. hominis and diarrhea are lacking. We conducted a case-control study among expatriates and tourists in Kathmandu, Nepal, in which we compared the prevalence of the organism among patients with diarrhea to that among a control group without diarrhea. B. hominis was detected in 56 (30%) of 189 patients with diarrhea, compared with 40 (36%) of 112 asymptomatic controls. Patients with diarrhea were significantly more likely to have > or = 10 B. hominis organisms per high-power (400x) field than were controls. However, among the 25 patients with this concentration of organisms, other enteric pathogens were detected in 17 (68%). Only 8 (4%) of 189 patients with diarrhea had > or = 10 B. hominis organisms per high-power field detected in the absence of other pathogens, compared with 5 (5%) of 112 asymptomatic controls. Thus, B. hominis in higher concentrations was not associated with diarrhea. There were no specific symptoms associated with B. hominis infection, and the presence of higher concentrations of the organism in stool was not associated with more-severe symptoms. Despite the high prevalence of the organism among travelers and expatriates in Nepal, the results of this study suggest that B. hominis does not cause diarrhea in this population.

Insulin-like growth factor binding protein (IGFBP) proteases: functional regulators of cell growth.

The IGFBP proteases were first described in pregnancy serum as a proteolytic activity against IGFBP-3. Since then, IGFBP proteases have been described in many other clinical situations, in various body fluids, and have been shown to cleave IGFBP-2 to -6 with varying specificity. The molecular nature of some of these proteases is being unraveled and three classes of IGFBP proteases have been recognized. These include kallikreins, cathepsins and matrix metalloproteinases (MMPs). We utilized two cellular systems to demonstrate the significance of IGFBP proteases in cellular growth regulation. In primary cultures of prostatic cells, we have shown that prostate-specific antigen (PSA) has the ability to enhance IGF mitogenic action by reducing the effects of IGFBPs. Similar kallikreins such as gamma nerve growth factor (NGF) share this activity. Within the prostatic milieu, we have also demonstrated epithelial production of the acid-activated IGFBP protease, cathepsin D, and its secretion into seminal plasma, as well as the serum of patients with prostate malignancy. We have also identified MMPs in prostatic cells and fluids. Using cultured airway smooth muscle (ASM) cells, we have demonstrated the synergism between IGFs and inflammatory agents in mediating ASM cell proliferation. Examination of this phenomenon revealed that these agents (e.g. leukotriene D4 and interleukin1-beta) induce the secretion of an IGFBP protease which cleaves the IGFBPs secreted by ASM cells, allowing IGFs to stimulate proliferation. Using several methods, including immunoblotting and immunodepletion techniques, we have identified this protease as MMP-1. These two pathophysiological systems demonstrate the importance of IGFBP proteases as autocrine paracrine growth regulators. Furthermore, IGFBP proteases may be critical elements in malignant and benign proliferative diseases, including prostate cancer and the ASM hyperplasia of long-standing asthma.

Leukotriene D4 induces MMP-1, which functions as an IGFBP protease in human airway smooth muscle cells.

We have previously demonstrated that the asthma-associated proinflammatory eicosanoid leukotriene D4 (LTD4) is comitogenic with insulin-like growth factors (IGF) in airway smooth muscle (ASM) cells. This synergistic effect of LTD4 and IGF on ASM cell growth involves proteolysis of ASM-produced inhibitory IGF-binding proteins (IGFBP). In this report, we analyzed the conditioned media (CM) from LTD4-treated human ASM cells (ASM-LTD4-CM) by Western ligand blotting and demonstrated a marked LTD4-induced reduction in the levels of the intact IGFBP (predominantly IGFBP-2) secreted by these cells. The IGFBP-2 in the ASM-LTD4-CM was identified as lower-molecular-weight fragments by Western immunoblotting. Incubation with 125I-labeled IGFBP demonstrated that an IGFBP protease was induced in the ASM cells in response to LTD4 treatment. Immunodepletion of ASM-LTD4-CM with anti-matrix metalloproteinase (MMP)-1 antibodies demonstrated a dose-dependent reduction of IGFBP proteolysis. Tissue inhibitor of MMP-1 and Batimastat (synthetic) inhibited proteolysis of IGFBP. Immunoblotting the ASM-LTD4-CM with anti-MMP-1 demonstrated a dose-dependent increase in MMP-1 protein. Similar results were also obtained by immunocytochemistry. Collectively, these observations demonstrate that MMP-1 is an IGFBP protease induced by leukotrienes that plays a significant role in modulating IGF action in ASM cells. A similar mechanism may be applicable in vivo in the airways of patients with asthma.