Effect of diarrhoea on Tacrolimus trough level in a post liver transplant patient.

Tacrolimus, which bonds to an immunophilin, FK506 binding protein (FKBP) has emerged as one of the most widely used immunosuppressant post solid organ transplantation. It offers excellent patient survival rates post-transplantation and a lesser number of acute rejections as compared to cyclosporine. Tacrolimus has a narrow therapeutic window with overexposure leading to acute and chronic forms of nephrotoxicity. Remarkably few data have been published on the overexposure to tacrolimus following mild diarrhoea in post-transplant patients who received treatment with tacrolimus. We observed a post-liver transplant patient with increased trough level of tacrolimus during severe diarrhoea with no complications following a timely adjustment on the dose of tacrolimus.

Development of an international core outcome set for peripheral vascular malformations: the OVAMA project.

BACKGROUND: An important limitation in vascular malformation research is the heterogeneity in outcome measures used for the evaluation of treatment outcome. OBJECTIVES: To reach international consensus on a core outcome set (COS) for clinical research on peripheral vascular malformations: lymphatic (LM), venous (VM) and arteriovenous malformations (AVM). In this consensus study, we determined what domains should constitute the COS. METHODS: Thirty-six possibly relevant outcome domains were proposed to an international group of physicians, patients and the parents of patients. In a three-round e-Delphi process using online surveys, participants repeatedly rated the importance of these domains on a five-point Likert scale. Participants could also propose other relevant domains. This process was performed for LM, VM and AVM separately. Consensus was predefined as 80% agreement on the importance of a domain among both the physician group and the patient/parent group. Outcomes were then re-evaluated in an online consensus meeting. RESULTS: 167 physicians and 134 patients and parents of patients with LM (n = 50), VM (n = 71) and AVM (n = 29) participated in the study. After three rounds and a consensus meeting, consensus was reached for all three types of vascular malformations on the core domains of radiological assessment, physician-reported location-specific signs, patient-reported severity of symptoms, pain, quality of life, satisfaction and adverse events. Vascular malformation type-specific signs and symptoms were included for LM, VM and AVM, separately. CONCLUSIONS: Our recommendation is that therapeutic-efficacy studies on peripheral vascular malformations should measure at least these core outcome domains.

Prevalence and predictors of suicidality among medical students in a public university.

BACKGROUND: Undergraduate medical students have been the most distressed group among the student population. Depression and anxiety have been found to be more prevalent in this group of students compared to others. OBJECTIVE: This study was conducted to determine the prevalence and predictors of suicidality among undergraduate medical students in a public university. METHODS: This was an analytical cross-sectional study, conducted in a public university in Selangor, Malaysia. Data were collected using self-administered questionnaires from January to February 2013, and analysed using the Statistical Package for Social Sciences Software (version 21). RESULTS: Out of 625 undergraduate medical students, 537 (85.9%) participated in the study. The prevalence of the suicidality among undergraduate medical students was 7.0%. The significant predictors of suicidality based on multiple logistic regression were the respondent's lifetime suicide attempts (Adjusted Odds Ratio, AOR 10.4, 95% CI 2.7 to 40.9); depression (AOR 5.9, 95% CI 1.5 to 23.0); breaking off a steady love relationship (AOR 5.4, 95% CI 1.3 to 22.4); hopelessness (AOR 4.9, 95% CI 1.1 to 21.6); and something valued being lost or stolen (AOR 4.4, 95% CI 1.2 to 15.9). CONCLUSION: These findings indicate that mental health care services should be strengthened at university level. The results show a need for an intervention programme to reduce suicidality among the undergraduate medical students.

Moderate-to-severe food insecurity is positively correlated with the risk of eating disorders in the aftermath of the COVID-19 pandemic.

Background: The COVID-19 pandemic may have worsened food insecurity and altered the eating behaviour of young adults. Therefore, this cross-sectional study aims to investigate the correlation between moderate-to-severe food insecurity and the risk of eating disorders among young urbanists in Malaysia after the pandemic-led lockdown. Methods: The food security status and the risk of eating disorders were assessed using the validated Food Insecurity Experience Scale (FIES) and Eating Attitude Test (EAT-26), respectively. Results: Among the 208 young urbanists, approximately one-third (30.8%) were moderate-to-severe food insecure and about one-fifth (18.8%) were at risk of eating disorders after the nationwide lockdown. With the adjustment of gender, the binary logistic regression analysis revealed that moderate-to-severe food insecure individuals were 2.279 times (P = 0.030, 95% CI = 1.084-4.791) more likely to engage in disordered eating in the aftermath of the COVID-19 pandemic. The findings of partial correlation further indicated that moderate-to-severe food insecurity was positively correlated (rpartial = 0.156, P = 0.024) with bulimia and food preoccupation after the outbreak. Conclusions: Governments and non-governmental organizations must work closely to develop effective policies to address food insecurity and disordered eating behaviour among young urbanists - after the pandemic.

Treatment of infantile haemangioma with captopril.

BACKGROUND: Infantile haemangioma (IH) has recently been reported as an aberrant proliferation and differentiation of a primitive mesoderm-derived haemogenic endothelium regulated by the renin-angiotensin system (RAS), leading us to propose angiotensin converting enzyme (ACE) as a potential therapeutic target. OBJECTIVES: To present initial results of our open-labelled observational clinical trial using captopril, an ACE inhibitor (ACEi), in the treatment of problematic proliferating IH. METHODS: After initial screening investigations, infants with problematic IH were admitted for initiation of captopril with a 0·1 mg kg(-1) test dose orally, followed by 0·15 8-hourly over 24 h. This was then followed by dose escalation to 0·3 mg kg(-1) 8-hourly for another 24 hours. The dosage was increased to 0·5 mg kg(-1) 8-hourly 1 week later, if a noticeable involution had not already occurred. The response of IH to captopril was documented clinically and photographically before and after treatment and any side-effect was recorded. RESULTS: Two boys and six girls aged 5-22 weeks (mean 12·9) with problematic IH were recruited with the lesions located in nasal tip (n = 1), cervicofacial (n = 3), periorbital (n = 1) and perineal (n = 2) areas, and shoulder (n = 1). Transient mild renal impairment occurred in one subject but resolved spontaneously. No other complication was observed. The IHs in all patients responded to captopril at a dosage of 1·5 mg kg(-1) daily which led to a dramatic response in three, moderate response in two, and slow response in three patients. Continued involution of IHs was observed during the follow-up period of 8-19 months (mean 15·8) in all subjects. Treatment was ceased at 14 months of age in seven patients with no rebound growth. In the remaining patient, rapid healing occurred with ongoing gradual reduction in the size and colour of a large ulcerated retroauricular lesion following 5·5 months of treatment. The lesion was excised to address its persistent distortion of the ear. CONCLUSIONS: The response of IH to an ACEi supports a critical role for the RAS in IH and represents a paradigm shift in the understanding and treatment of this enigmatic condition.

Extranodal NK/T-cell lymphoma: a case report of renal insufficiency during PD1 inhibitor treatment.

BACKGROUND: Extranodal NK/T-cell lymphoma (ENKTL) is a subtype of non-Hodgkin's lymphoma that accounts for approximately 3-8% of all malignant lymphomas. So far, ENKTL has no standard treatment guidelines, and the current treatment methods pose adverse effects. The combination of programmed death receptors (PD-1) and programmed death receptors' ligands (PD-L1) downregulates effector T cells; hence, it may be an effective treatment for NK/T-cell lymphoma. Here, we report a patient diagnosed with ENKTL whose health was significantly improved after PD-1 immunotherapy. At the same time, the patient suffered from related renal toxic side effects. Immunotherapy is an emerging treatment method for tumors, and the early diagnosis and identification of its side effects are vital for the diagnosis and treatment of tumors. CASE REPORT: Laboratory tests, pathological examinations, and the patient's history were performed to estimate the severity and the cause of renal insufficiency. The patient with ENKTL developed transient renal damage during immunotherapy. During the next treatment and examination, renal insufficiency was irrelevant to PD-1 inhibitors and avoided unnecessary drug withdrawal. CONCLUSIONS: In the present case report, we discuss a patient who developed a severe transient renal impairment during immunotherapy and review published studies regarding immunotherapy and its renal-related side effects. We also outline how to critically distinguish whether a patient's kidney injury is anti-PD-1 treatment. We also provide insights to oncologists to develop an effective follow-up treatment plan for early detection and management of any anti-PD-1 treatment side effects.

Cross-cultural adaptation and psychometric evaluation of the Malay version of the Neck Disability Index.

PURPOSE: Translating the Neck Disability Index (NDI) into the Malay language (NDI-M); evaluation of psychometric properties in patients with neck pain. METHODS: The NDI-M was translated according to established guidelines. In the first visit, 120 participants completed the NDI-M, visual analogue scale (VAS) for pain and demographic details. 98 participants returned to complete similar questionnaires and the Global Rating of Change (GRoC) scale. The NDI-M was evaluated for internal consistency, test-retest reliability, content validity, construct validity and responsiveness. RESULTS: The NDI-M demonstrated excellent internal consistency (Cronbach's α = 0.84) and good test-retest reliability (ICC2,1 = 0.79). Content validity was confirmed with no floor or ceiling effects. Construct validity was established revealing three-factor subscales explaining 68% of the total variance. The NDI-M showed a moderate correlation with VAS (Rp = 0.49, p < 0.001). Regarding responsiveness, a moderate correlation between NDI-M change scores and VAS change scores was found (Rp = 0.40, p < 0.001). However, there was no significant correlation between NDI-M with GRoC (Rs = 0.11, p = 0.27). CONCLUSIONS: The NDI-M is a reliable and valid tool to measure functional outcomes in patients with neck pain. It is responsive in detecting changes in pain intensity during a patient's rehabilitation journey.Implications for rehabilitationThe NDI was translated into the Malay language and culturally adapted for Malay-speaking patients with neck pain.The NDI-M demonstrated an excellent level of internal consistency and good test-retest reliability. It demonstrated content and construct validity, with three-factor subscales, and moderate responsiveness for pain intensity.The NDI-M is a reliable, valid and responsive instrument to measure functional limitations in patients with neck pain for rehabilitation.

Primitive erythropoiesis in infantile haemangioma.

UNLABELLED: BACKGROUND; Infantile haemangioma (IH) is a tumour of the microvasculature composed predominantly of proliferating endothelial cells. It expresses markers associated with endothelial, haematopoietic and mesenchymal lineages. We have previously shown that the cells forming the capillary endothelium of proliferating IH express cell surface markers and transcriptions factors consistent with it being a haemogenic endothelium. OBJECTIVES: We wished to determine whether the expression of transcription factors associated with the erythroid lineage was of physiological relevance and sufficient for IH tissue cultured in vitro to undergo erythropoiesis. METHODS: Immunohistochemical staining of paraffin-embedded sections of proliferating IHs was undertaken and expression of the embryonically associated haemoglobin ζ (HBZ) chain and the erythropoietin receptor (EPO-R) was determined. Relative expression of mRNA encoding these proteins was determined by quantitative reverse transcription-polymerase chain reaction using snap-frozen biopsy samples. Differentiation towards erythrocytes was investigated using freshly resected tissue cultured as explants in Matrigel. RESULTS: The endothelium of the microvessels, but not the pericyte layer, was strongly immunoreactive for the EPO-R and the embryonically associated HBZ chain. Abundant expression of transcripts encoding these proteins was also detected, corroborating the immunohistochemical staining. When tissue was grown in culture the cells emanating from IH explants were able to generate enucleated erythrocytes in vitro. The erythrocytes were immunoreactive for the erythrocyte-specific marker glycophorin A. CONCLUSIONS: The microvessels in IH are a functional haemogenic endothelium that expresses the embryonically associated HBZ chain and is able to form erythrocytes in vitro. IH thus represents a possible extramedullary site for tumour-associated primitive erythropoiesis.

Pretibial injury: key factors and their use in developing laboratory test methods.

Aims were to 1 characterize pretibial injuries and evaluate protection offered by garments/fabrics; and 2 develop a laboratory test to determine the potential protection provided by such fabrics. Most (>85%) of 75 patients treated for pretibial injury at Hutt Hospital, New Zealand sustained injury to one site and required surgery. Injuries were typically grade 3 or 4, 10-250 mm wide 30-350 mm long, and at the mid- to lower third of the tibia. The severity grade was lower when at least one fabric layer covered the site, slightly lower again with more than one layer, and when a knitted fabric/garment was worn, and a trouser type garment. Laboratory test methods and their application reflected these known variables. The force transmitted through multiple fabric layers was less then through one layer: thick pantyhouse and either denim or fabrics used in 'sweat pants' would minimize transmitted force and maximize impulse.

Cerebral oximetry in cardiac surgery.

There is a need for monitoring of cerebral perfusion during cardiac surgery to reduce neurological complications. Cerebral perfusion is a major factor for regional and global imbalance in oxygen supply-demand, which may result in brain injury following cardiac surgery. Cerebral oximetry (near infrared spectroscopy) is a means to monitor regional cerebral perfusion. It was developed as a non-invasive technology, similar to pulse oximetry, for the continuous assessment of cerebral blood flow. Published studies have demonstrated that the use of cerebral oximetry reduces both postoperative cognitive impairment and the length of hospital stay.

Serum levels of renin, angiotensin-converting enzyme and angiotensin II in patients treated by surgical excision, propranolol and captopril for problematic proliferating infantile haemangioma.

The role of the renin-angiotensin system (RAS) in the biology of infantile haemangioma (IH) and its accelerated involution induced by ß-blockers was first proposed in 2010. This led to the first clinical trial in 2012 using low-dose captopril, an angiotensin-converting enzyme (ACE) inhibitor, demonstrating a similar response in these tumours. This study aimed to compare serial serum levels of the components of the RAS in patients before and after surgical excision, propranolol or captopril treatment for problematic proliferating IH. Patients with problematic proliferating IH underwent measurements of serum levels of plasma renin activity (PRA), ACE and angiotensin II (ATII) before, and 1-2 and 6 months following surgical excision, propranolol or captopril treatment. This study included 27 patients undergoing surgical excision (n = 8), propranolol (n = 11) and captopril (n = 8) treatment. Treatment with either surgical excision or propranolol resulted in significant decrease in the mean levels of PRA. Surgical excision or captopril treatment led to significant decline in the mean levels of ATII. All three treatment modalities had no significant effect on the mean levels of ACE. This study demonstrates the effect of surgical excision, propranolol and captopril treatment in lowering the levels of PRA and ATII, but not ACE, supporting a mechanistic role for the RAS in the biology of IH.

Changing prevalence and treatment outcomes of patients with p16 human papillomavirus related oropharyngeal squamous cell carcinoma in New Zealand.

There has, to our knowledge, been no previous report of changes in the prevalence and outcomes of treatment of HPV-positive (+) oropharyngeal squamous cell carcinoma (SCC) in New Zealand. We identified all affected patients in the greater Wellington region between 1 January 1994 and 30 November 2014 from the New Zealand Cancer Registry. Their personal details, characteristics of their tumours, treatment, complications, and outcomes were collected retrospectively from their casenotes and the New Zealand Death Registry, followed by p16 immunohistochemical staining. Of the 161 patients included, 131 (81%) were men. p16 immunohistochemical staining was done routinely in 13 patients during investigations, and retrospectively for 135 patients. The proportion of p16+ oropharyngeal SCC increased from 24% during 1994-1999, to 76% during 2009-2014 (p<0.001). Oropharyngeal SCC among Europeans was more likely to be p16+ than in non-Europeans (67% compared with 44%, p=0.036). Patients with p16+ disease were younger (mean (SD) 56 (10) compared with 66 (9) years, p<0.01) with fewer coexisting conditions (mean (SD) Charlson Comorbidity Index: 2.45 (0.82) compared with 2.92 (1.16), p=0.01), and less likely to have smoked (57/81(70%) compared with 38/42 (91%) p=0.035), or misused alcohol (12/81 (15%) compared with 14/42 (31%), p=0.042), or both. They were also more likely to have poorly differentiated tumours (30/52 (58%) compared with 9/34 (26%), p=0.019) with nodal metastases (74/85 (87%) compared with 17/30 (57%), p=0.001). Overall 5-year all-cause survival was more favourable for patients with p16+ disease (65/86 (76%) compared with 15/49 (31%), p=0.000). Interestingly, all-cause age at death was younger in p16+ patients (62 (11.1) compared with 71 (11.2) years, p=0.001). The prevalence of p16+ oropharyngeal SCC had tripled in this population between 1994 and 2014, and affected patients have distinct characteristics and outcomes of treatment.

Nucleotide sequence and expression of the isoamylase gene from an isoamylase-hyperproducing mutant, Pseudomonas amyloderamosa JD210.

The isoamylase gene (ISO) of Pseudomonas amyloderamosa JD210, an isoamylase-hyperproducing mutant, was cloned in an isoamylase-deficient and transformable mutant strain K31. By deletion analysis, the ISO gene was found to be located within a 3.3 kilobases BamHI fragment. Its nucleotide sequence contained an open reading frame of 2328 nucleotides (776 amino acids) encoding a secreted isoamylase precursor. The ISO gene fragment was inserted into plasmids pKT230 and pBR 322 in opposite orientations. The expression of the ISO gene in the constructed plasmids was compared in P. amyloderamosa K31, Pseudomonas aeruginosa PAO1-161, Pseudomonas putida mt-2 and Escherichia coli HB101. In all transformed cells, the majority of the isoamylase produced was secreted and higher isoamylase activities were obtained in transformats with the transcriptional direction of the ISO gene similar to the nearby drug-determinant gene of the vector.

The ionic dependence of cardiac excitability and contractility.

In contrast to the large volume of data supporting the dependence of cardiac excitability and phasic contractility on external Na, Van der Kloot and Rubin (1962) and Singh (1962) have reported the persistence of both electrical and phasic mechanical activity in frog atrial and ventricular preparations soaked in isotonic sucrose solutions. The acute ionic dependence of excitability and contractility in small frog atrial trabeculae has been investigated with the conclusion that excitability and phasic contractions may continue for extended periods of time in sucrose media if the extracellular ionic concentrations remain above 2% of normal. This behavior is attributed to the slow exchange properties of the cell surfaces of the frog cardiac trabeculae and the antagonistic effects of Na, K, and Ca ions on both membrane excitability and fiber contractility.

Orbital immunoglobulin IgG4-related inflammatory fibrosclerosing lesion treated with pentoxifylline and α-tocopherol: case report.

Immunoglobulin G4 (IgG4)-related disease is a distinct group of disorders that are characterised by intense infiltration of an organ with IgG4(+) cells, subsequent inflammation, fibrosis, and masses. We report a new treatment of orbital IgG4-related disease with pentoxyphylline and α-tocopherol, both of which are anti-inflammatory and antifibrotic agents.

Mouth opening and trismus in patients undergoing curative treatment for head and neck cancer.

This study documents mouth opening and the incidence of and factors contributing to trismus (<35 mm mouth opening), as well as the associated impact on quality of life, following curative treatment for head and neck cancer. Patient demographics, cancer type and location, and treatments were documented. Mouth opening was measured at >6 months after treatment completion. Patients rated the impact of mouth opening on quality of life from 0 (no effect) to 10 (greatest effect). The mean mouth opening in 120 patients was 40.1mm (range 11-65 mm), with trismus occurring in 34 (28.3%) patients. Surgery and radiotherapy, surgery and chemoradiotherapy, and resection and reconstruction were associated with reduced mouth opening. The mean effect of mouth opening on quality of life for those with and without trismus was 3.8 and 1.5, respectively. There was a significant difference between the mean effect on quality of life for patients with and without trismus for those patients who underwent chemoradiotherapy or combined surgery and radiotherapy (4.0 vs. 1.0, and 3.6 vs. 1.6 respectively). Trismus impacts negatively on patient quality of life. Multi-modality treatment is associated with decreased mouth opening, an increased incidence of trismus, and reduced quality of life.

Steroid therapy of a proliferating hemangioma: histochemical and molecular changes.

OBJECTIVES: Hemangioma is a primary tumor of the microvasculature in which angiogenesis is initially excessive, followed by regression of the newly formed vessels. Intervention is necessary in up to 20% of cases, high-dose systemic or intralesional steroids being the first-line treatment. As the mechanism of action of steroids is unknown, we undertook an investigation of the cellular and molecular effects of their action. STUDY DESIGN: A unique opportunity to study the effect of steroid treatment was presented when biopsy material was obtained from an infant with an ulcerated proliferating hemangioma before and after intralesional triamcinolone injection, which resulted in an accelerated regression of the lesion. Histochemical quantitation of mast cells, molecular analysis by reverse transcriptase-polymerase chain reaction (RT-PCR) for 7 growth factor transcripts and differential display RT-PCR (DD RT-PCR) were conducted. RESULTS: After steroid therapy, the mast cell number increased (untreated = 2.22 +/-.27 [standard error of the mean ¿SEM¿]; treated = 8.7 +/-.71 [SEM] mast cells per field, respectively; P <.0001; n = 40 fields for each group), and the transcriptional expression of cytokines: platelet-derived growth factor-A and -B; interleukin-6; transforming growth factor-beta1 and -beta3 decreased, while that of basic fibroblast growth factor (bFGF) and vascular endothelial cell growth factor remained unaltered. Elevated urinary bFGF levels noted in cases of proliferating hemangioma, persisted even after steroid treatment. Using DD RT-PCR an amplicon that shared 100% sequence homology with the human mitochondrial cytochrome b gene was detected in the hemangioma biopsy after steroid treatment. CONCLUSIONS: The regression of this hemangioma subsequent to steroid therapy was accompanied by a significant increase in mast cell density, reduced transcription of several cytokines, and an enhanced expression of the mitochondrial cytochrome b gene.

Clusterin/apoJ expression during the development of hemangioma.

Hemangioma is the most common tumor of infancy. This vascular tumor is characterized by an initial rapid proliferation followed by an inevitable regression. The life cycle of hemangioma is divided into proliferative, involuting, and involuted phases. The cellular and molecular mechanisms responsible for controlling the biological behavior of hemangioma are largely unknown. Differential display analysis using mRNA isolated from biopsy specimens representative of the 3 different phases showed increased expression of clusterin/apoJ (clust/apoJ) in the involuting samples. Clust/apoJ is a multifunctional glycoprotein that has been associated with apoptosis. Reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry showed that both the transcription and protein expression of clust/apoJ were increased in hemangioma as the tumor progressed from the proliferative to the involuting and involuted phases. This suggests that clust/apoJ is involved in regulating apoptosis during the spontaneous regression of hemangioma. It has been suggested that mast cells (MC) play a role in the regression of hemangioma. The increase in the number and proportion of clust/ apoJ-positive MC with progression of hemangioma, along with the localization of clust/apoJ to MC granules, supports this hypothesis. We suggest that MC may be synthesizing/releasing this apoptotic modulator, leading to the regression of the tumor. Better understanding of the pathogenesis of hemangioma by identification of the relevant factors involved in its regression such as clust/apoJ will result in the development of novel therapies for this condition and tumors that do not undergo spontaneous regression.

Mechanism of neurotensin depolarization of rabbit colonic smooth muscle.

The aims of this study were (1) to measure the effect of neurotensin on the membrane potential of circular muscle of the distal colon of the rabbit and (2) to determine the mechanism by which neurotensin affects the membrane potential of this tissue. The membrane potential was measured with microelectrodes placed intracellularly and the double sucrose gap. Neurotensin (10(-11) M to 10(-7) M) dose-dependently decreased the membrane potential. The maximum decrease in membrane potential occurred with 10(-9) M neurotensin. The ED50 of neurotensin depolarization of the membrane potential was 0.87 +/- 0.33 X 10(-10) M. The frequency of the slow waves was unchanged after neurotensin. The voltage response to a constant current pulse decreased as the concentration of neurotensin increased. The amplitude of the voltage response after a 0.6 microA current pulse decreased by 6 +/- 0.5 mV after neurotensin (10(-7) M) compared to the Krebs control (P less than 0.05). Decreasing the [Na+]o to 0-23 mM did not affect the decrease in membrane potential after neurotensin. However, perfusion with a test solution containing no added Ca2+ or verapamil (10(-5) M) inhibited neurotensin depolarization of the tissue. Evidence was found that neurotensin depolarizes colonic circular smooth muscle, and the decrease in membrane potential is associated with an increase in conductance which is dependent on influx of Ca2+.