Cautious optimism-the current role of immunotherapy in gastrointestinal cancers.

Immunotherapy has been described as the "fourth pillar" of oncology treatment, in conjunction with surgery, chemotherapy, and radiotherapy. However, the role of immunotherapy in gastrointestinal tumours is still evolving. Data for checkpoint inhibition in esophagogastric, hepatocellular, colorectal, and anal squamous cell carcinomas are expanding. In phase iii trials in the second-line setting, PD-1 inhibitors have demonstrated positive results for the subset of esophageal cancers that are positive for PD-L1 at a combined positive score of 10 or more. Based on results of phase ii trials, PD-1 inhibitors were approved in North America for use in PD-L1-positive chemorefractory gastric cancers, in hepatocellular carcinoma after sorafenib exposure, and in treatment-refractory deficient mismatch repair (dmmr) or high microsatellite instability (msi-h) tumours, regardless of tissue site. Combination use of PD-1 and ctla-4 inhibitors has been approved by the U.S. Food and Drug Administration for chemorefractory dmmr or msi-h colorectal cancer. Responses to checkpoint inhibition are durable, particularly in the dmmr or msi-h colorectal cancer cohort. As trials of combination immunotherapy, immunotherapy in combination with other systemic therapies, and immunotherapy in combination with other treatment modalities move forward in multiple tumour sites, cautious optimism is called for. The treatment landscape is continually changing, and expanded indications are likely to be just around the corner.

Magnetic resonance imaging of Ménière's disease: early clinical experience in a UK centre.

BACKGROUND: Recent developments in magnetic resonance imaging have enabled demonstration of endolymphatic hydrops, and the clinical application of these imaging studies in Ménière's disease is being explored. OBJECTIVE: To evaluate our centre's experience to date of hydrops magnetic resonance imaging in patients with episodic vertigo. METHODS: Magnetic resonance imaging was performed using a high-resolution three-dimensional fluid-attenuated inversion recovery sequence on a 3 Tesla scanner at 4 hours following double-dose gadolinium administration. RESULTS: The study included 31 patients, 28 of whom had a clinical diagnosis of Ménière's disease. In unilateral Ménière's disease, magnetic resonance imaging was able to lateralise endolymphatic hydrops to the clinically symptomatic ear in all cases. Mild hydrops was often seen in clinically asymptomatic ears. CONCLUSION: There is a good correlation between the clinical symptoms and lateralisation of hydropic changes on magnetic resonance imaging. Further refinements of imaging techniques and grading system will likely improve the diagnostic accuracy and clinical utilisation of hydrops magnetic resonance imaging.

A case report of melioidosis complicated by infective sacroiliitis in Sri Lanka.

BACKGROUND: Melioidosis is an infection caused by a facultative intracellular Gram-negative bacterium, Burkholderia pseudomallei. It can present as septicemia, localized infection with/without septicemia, asymptomatic infections, ulcers, pneumonia, visceral abscesses, neurological infection, musculoskeletal infections and can involve any organ. CASE PRESENTATION: A 56 year old Sri Lankan diabetic female presented with fever, chills and rigors for 2 weeks. She also had malaise and loss of appetite, but no other features. On examination, she was febrile (temperature was 101.4 0 F) and rest of the examination was unremarkable. Her blood culture was positive for Burkholderia pseudomallei and she was started on IV antibiotics, on day 3. During her 2nd week of hospital stay, she developed right sided low back pain with buttock pain, right hip joint pain and restricted hip joint movements suggestive of right sacroiliitis. CE CT and MRI scans confirmed the diagnosis of right iliopsoas abscesses and right sacroiliitis.Incision and drainage was performed and a pigtail catheter was left in place for continuous drainage of abscesses. Her intensive phase was initiated with IV ceftazidime 2 g every 6 h for 12 days, then changed over to IV meropenem 2 g every 8 h together with oral co-trimoxazole. 2 weeks later, oral co-trimoxazole was replaced by oral doxycycline for another 6 weeks (due to transient pancytopaenia). She made a complete and uneventful recovery with oral co-trimoxazole for another 6 months, in her eradication phase.We report this case to show the importance in early diagnosis of melioidosis, and to consider it in the differential diagnosis of multiple abscesses and to emphasize the importance in suspecting melioidosis as a causative agent in infective sacroiliitis. DISCUSSION: Melioidosis can have 2 major presentations; acute infection (symptoms lasting less than 2 months) and chronic infection (symptoms lasting more than 2 months). Musculoskeletal melioidosis is a well-recognized manifestation of the disease, which can manifest as soft tissue abscesses, septic arthritis, spondylitis, sacroiliitis and osteomyelitis.Management of melioidosis consists of 2 phases. The intensive phase and the eradication phase. These are aimed at the importance of rapidly treating the septicemia, the need of eradication of the persistent disease and the prevention of recurrent infections or relapses. The intensive phase consists of minimum 10-14 days of IV antibiotics: IV ceftazidime or IV carbapenem (meropenem/ imipenem). Eradication phase should be followed by 3-6 months of oral co-trimoxazole alone or in combination with oral doxycycline/ oral amoxiciliin-clavulanic acid.

Splenic Syndrome in a Young Man at High Altitude with Undetected Sickle Cell Trait.

INTRODUCTION: Splenic syndrome is a rare presentation of sickle cell disease. It is important to rule out this possibility when an ethnically vulnerable patient presents with an acute abdominal symptoms in a background of precipitating events. CASE REPORT: A 26-year-old man who developed a severe abdominal pain at high altitude, found to have a tender splenomegaly. However, further inquiry revealed he is from an area where sickle cell disease is prevalent. Screening for sickle cell disease was positive. Radiological investigations confirmed a massive splenic infarction keeping with a diagnosis of splenic syndrome. Patient was managed conservatively. CONCLUSION: Sickle cell trait is considered a benign carrier state. However, rarely they can present with life-threatening conditions. Therefore, a high degree of clinical suspicion is required for early diagnosis of these specific entities to avoid increased morbidity and mortality of these patients.

Cardiac rehabilitation delivery model for low-resource settings

"OBJECTIVE: Cardiovascular disease is a global epidemic, which is largely preventable. Cardiac rehabilitation (CR) is demonstrated to be cost-effective and efficacious in high-income countries. CR could represent an important approach to mitigate the epidemic of cardiovascular disease in lower-resource settings. The purpose of this consensus statement was to review low-cost approaches to delivering the core components of CR, to propose a testable model of CR which could feasibly be delivered in middle-income countries. METHODS: A literature review regarding delivery of each core CR component, namely: (1) lifestyle risk factor management (ie, physical activity, diet, tobacco and mental health), (2) medical risk factor management (eg, lipid control, blood pressure control), (3) education for self-management and (4) return to work, in low-resource settings was undertaken. Recommendations were developed based on identified articles, using a modified GRADE approach where evidence in a low-resource setting was available, or consensus where evidence was not. RESULTS: Available data on cost of CR delivery in low-resource settings suggests it is not feasible to deliver CR in low-resource settings as is delivered in high-resource ones. Strategies which can be implemented to deliver all of the core CR components in low-resource settings were summarised in practice recommendations, and approaches to patient assessment proffered. It is suggested that CR be adapted by delivery by non-physician healthcare workers, in non-clinical settings. CONCLUSIONS: Advocacy to achieve political commitment for broad delivery of adapted CR services in low-resource settings is needed."

Cardiovascular risk factors in middle-aged and elderly residents in South-East Nigeria: the influence of urbanization.

Cardiovascular diseases (CVD) were previously considered a problem of the developed nations only. Emerging facts show that CVD and their risk factors are now prevalent in developing countries. We carried out a cross-sectional, population-based survey to determine the relation between place residence (rural or urban) and the burden of CVD risk factors in South East Nigeria. Hypercholesterolaemia, hypertension, abnormal blood glucose and obesity were assessed for, in middle-aged and elderly residents of two communities in Enugu, South East Nigeria. A total of 543 adults (308 at Ogwofia Owa and 235 at Emene) participated in the study. The mean and 95% CI for mean of the characteristics of subjects showed that they were in the middle-age group with apparently normal mean cardiovascular risk indices except for systolic and diastolic blood pressure indices which suggested pre-hypertension. The subjects residing in the rural area were older than those residing in the urban area but cardiovascular risk factors had higher mean values in urban residents except systolic blood pressure (SBP). The most prevalent cardiovascular risk factors in the study group were hypertension and obesity. Urban residence was found to influence the prevalence of risk factors, specifically obesity and diastolic hypertension.

Gaps in capacity in primary care in low-resource settings for implementation of essential noncommunicable disease interventions.

Objective. The objective was to evaluate the capacity of primary care (PC) facilities to implement basic interventions for prevention and management of major noncommunicable diseases (NCDs), including cardiovascular diseases and diabetes. Methods. A cross-sectional survey was done in eight low- and middle-income countries (Benin, Bhutan, Eritrea, Sri Lanka, Sudan, Suriname, Syria, and Vietnam) in 90 PC facilities randomly selected. The survey included questions on the availability of human resources, equipment, infrastructure, medicines, utilization of services, financing, medical information, and referral systems. Results and Conclusions. Major deficits were identified in health financing, access to basic technologies and medicines, medical information systems, and the health workforce. The study has provided the foundation for strengthening PC to address noncommunicable diseases. There are important implications of the findings of this study for all low- and middle-income countries as capacity of PC is fundamental for equitable prevention and control of NCDs.

Activins and inhibins in mammalian testis development: new models, new insights.

The discovery of activin and inhibins as modulators of the hypothalamic-pituitary-gonadal axis has set the foundation for understanding their central importance to many facets of development and disease. This review contains an overview of the processes and cell types that are central to testis development and spermatogenesis and then provides an update focussed on information gathered over the past five years to address new concepts about how these proteins function to control testis development in fetal and juvenile life. Current knowledge about the interactive nature of the transforming growth factor-ß (TGFß) superfamily signalling network is applied to recent findings about activins and inhibins in the testis. Information about the regulated synthesis of signalling components and signalling regulators in the testis is integrated with new concepts that demonstrate their functional significance. The importance of activin bioactivity levels or dosage in controlling balanced growth of spermatogonial cells and their niche at different stages of testis development is highlighted.

Pattern of Blood Pressure Indices among the Residents of a Rural Community in South East Nigeria.

Cardiovascular diseases (CVDs) are the main causes of death in industrialized countries, and are significant causes of morbidity and mortality in sub-Saharan Africa. Hypertension is the most common cardiovascular disease in Nigerians, and the risk of CVD associated with hypertension is independent of other risk factors. Despite the high level of awareness of its presence in the developed countries, the level of control is still poor. CVDs tend to be commoner in urban settlements, and it has been hypothesized that rural sub-Saharan Africa is at an early stage of epidemiological transition from communicable to non-communicable diseases (NCD) because of the gradual adoption of unhealthy lifestyles. This study aimed at describing the pattern of blood pressure indices among the hypertensive residents of a rural community in South East Nigeria. A total of 858 individuals comprising 247 males and 611 females took part in the study. 46.4% of the subjects had hypertension. Hypertension was commoner in the males (50.2% vs. 44.8%) (χ(2)(1) = 1.484; P = 0.223). The males were significantly older and heavier than the females while the females had higher mean values of BMI and WC. The prevalence of hypertension is becoming alarmingly high in the rural communities of sub-Saharan Africa.

Prevention and care of stroke in low- and middle-income countries; the need for a public health perspective.

Stroke is a leading public health problem, causing significant disability and premature mortality, particularly in low- and middle-income countries (LMIC). A public health strategy is required for the prevention and care of stroke in LMIC. Although specific estimates are difficult to calculate, increasing cost-effective interventions that reduce cardiovascular risk in the population can have a substantial impact on stroke burden. Public health interventions that address tobacco use, unhealthy diet (salt and transfat), and physical inactivity of the population need to be complemented with equitable stroke services. The main components of an equitable stroke service include: * assessment and management of cardiovascular risk in primary care, * assessment and follow-up of transient ischaemic attack (TIA) patients, * provision of secondary prevention through a primary health care approach, * education of the public, health care staff and patients with stroke, * equitable access to acute stroke care and stroke rehabilitation and * community and family engagement for support to care givers and stroke patients. Unless services for stroke care are complemented with prevention programmes to reduce stroke risk in the population, health care costs will continue to escalate due to increasing rates of stroke.

Body mass index, waist circumference and waist:hip ratio as predictors of cardiovascular risk--a review of the literature.

Overweight and obesity have become a major public health problem in both developing and developed countries as they are causally related to a wide spectrum of chronic diseases including type II diabetes, cardiovascular diseases and cancer. However, uncertainty regarding the most appropriate means by which to define excess body weight remains. Traditionally, body mass index (BMI) has been the most widely used method by which to determine the prevalence of overweight in, and across, populations as well as an individual's level of risk. However, in recent years, measures of central obesity, principally waist circumference and the waist:hip ratio and to a lesser extent the waist:height ratio, which more accurately describe the distribution of body fat compared with BMI, have been suggested to be more closely associated with subsequent morbidity and mortality. There is also uncertainty about how these measures perform across diverse ethnic groups; earlier, most of the evidence regarding the relationships between excess weight and risk has been derived chiefly from Caucasian populations, and hence, it remains unclear whether the relationships are consistent in non-Caucasian populations. The purpose of this review, therefore, is to provide an overview of the current evidence-base focusing predominantly on three main questions: (1) Which, if any, of the commonly used anthropometric measures to define excess weight is more strongly associated with cardiovascular risk? (2) Which of the anthropometric measures is a better discriminator of risk? and (3) Are there any notable differences in the strength and nature of these associations across diverse ethnic groups?

The metabolic syndrome: useful concept or clinical tool? Report of a WHO Expert Consultation.

This article presents the conclusions of a WHO Expert Consultation that evaluated the utility of the 'metabolic syndrome' concept in relation to four key areas: pathophysiology, epidemiology, clinical work and public health. The metabolic syndrome is a concept that focuses attention on complex multifactorial health problems. While it may be considered useful as an educational concept, it has limited practical utility as a diagnostic or management tool. Further efforts to redefine it are inappropriate in the light of current knowledge and understanding, and there is limited utility in epidemiological studies in which different definitions of the metabolic syndrome are compared. Metabolic syndrome is a pre-morbid condition rather than a clinical diagnosis, and should thus exclude individuals with established diabetes or known cardiovascular disease (CVD). Future research should focus on: (1) further elucidation of common metabolic pathways underlying the development of diabetes and CVD, including those clustering within the metabolic syndrome; (2) early-life determinants of metabolic risk; (3) developing and evaluating context-specific strategies for identifying and reducing CVD and diabetes risk, based on available resources; and (4) developing and evaluating population-based prevention strategies.

Acute ischemic strokes due to bites by Daboia russelii in Sri Lanka - first authenticated case series.

UNLABELLED: Bites due to Russell's Viper (Daboia russelii) are common in Sri Lanka. Commonest haematological manifestation is consumptive coagulopathy and bleeding. Commonest neurological manifestations are ptosis, ophthalmoplegia and rarely respiratory failure which are due to presynaptic inhibition of neuromuscular transmission. There are no authenticated reports of acute ischemic strokes following bites by D. russelii. We report the first authenticated case series of ischemic strokes following bites by D. russelii in Sri Lanka. METHODS: This was a prospective observational study of all atypical neurological manifestations following bites by D. russelii admitted to a hospital in Sri Lanka. We documented clinical features of all atypical neurological manifestations of D. russelii bites and recorded the findings of brain imaging. RESULTS: During a period of 18 months, at one centre, 9 patients out of an estimated 500 victims of D. russelii bites were found to have Computerized Tomographic evidence of single or multiple ischemic (non-haemorrhagic) strokes of medium to large vessel territories of the brain. These patients had either low Glasgow coma scale or hemiparesis within minutes to 4 days following bites. One patient died and another had gross neurological deficit, while others had mild or no neurological deficit at three months. DISCUSSION: This report confirms that ischemic strokes can occur following envenoming by D. russelii. Involvement of multiple medium to large vessel territories and absence of watershed infarctions points to prothrombotic properties of the venom as the putative mechanism.

A Pilot Study on Wound Healing using an Antibacterial Steroidal Saponin

"Cost effective primary and secondary wound care is needed and have significant importance in current medicine. The steroidal saponin Flabelliferin B with a UV active binder attached (FB); isolated from palmyrah (Borassus flabellifer L.) has a known structure and proven antibacterial activity. The objectives of the study were to (i) study the effects of FB on male Wistar rats in relation to toxicity by wound healing (ii) study the toxicity of FB by the eye tests on rats and rabbits (iii) test the allergenic reactions by topical application of FB on healthy human skin by the ""patch test"" (iv) evaluate the feasibility of full scale clinical trial of the FB on infected wounds of humans. Toxic or other adverse effects on animals were not observed. Allergic reactions were also not observed on normal healthy human skin by the patch test. Having obtained ethical approval a prospective clinical trial was carried out in Colombo South Teaching Hospital. An ointment of 2FB was tested on wounds and ulcers with no subcutaneous tissue involvements. Human volunteers (n = 14) were employed in this study. Wound healing rates after treatment of FB ointment were monitored by measuring the percentage decline in wound area with time using normal standard hospital treatment as control. Microbiological tests by swabbing were carried throughout these experiments. The rate of wound healing was not significantly different from current hospital treatment (p = 0.512) and no allergic or other adverse symptoms were shown. It is concluded that it may be possible to use FB in treatment of wounds and ulcers with no subcutaneous involvement"

Prevalence of hypertension, diabetes and obesity: baseline findings of a population based survey in four provinces in Sri Lanka.

OBJECTIVE: To determine the prevalence of selected cardiovascular risk factors in adult Sri Lankan population in four provinces. DESIGN: Cross-sectional, based on a stratified cluster sampling method. SETTINGS: Four provinces, namely the Western, North Central, Southern and Uva. PATIENTS: Six thousand and forty seven participants (2692 men) between the age of 30 and 65 years were surveyed. MEASUREMENTS: Risk factors measured included height, weight, waist and hip circumference. Waist to hip ratio and body mass index were calculated, and overweight (23 kg/m2) and obesity (> or = 25 kg/m2) determined. Hypertension (systolic blood pressure > or = 140 mmHg or diastolic blood pressure > or = 90 mmHg or use of anti-hypertensive medications), and diabetes mellitus (fasting serum plasma glucose level > or = 7 mmol/L or use of anti-diabetic medications) and impaired fasting glycaemia (> or = 6.1 to < 7 mmol/L) were also determined. RESULTS: The prevalence of hypertension as defined was 18.8% (CI 14.5-23.1) for men and 19.3% (CI 12.2-26.4) for women. The prevalence of diabetes was 14.2% (CI 11.9-16.5) for men and 13.5% (CI 6.9-20.1) for women while impaired fasting glycaemia was 14.2% for men and 14.1% for women. The mean body mass index was 21.5 kg/m2 (SD = 3.7) in men. It was lower than that in women, 23.3 kg/m2 (SD = 4.5). The prevalence of obesity was 20.3% in men and 36.5 % in women. Regional differences were seen in the mean fasting blood glucose and prevalence of diabetes, and mean BMI and prevalence of obesity were highest in Western province. Mean blood pressure and prevalence of hypertension were highest in the Uva Province. Southern Province had the lowest prevalence of hypertension and diabetes, and North Central Province had lowest anthropometric measures of obesity. CONCLUSIONS: The prevalence of the selected cardiovascular risk factors is common in the adult Sri Lankan population surveyed. Regional differences exist in the prevalence of these risk factors. The prevalence of high level of risk factors requires urgent public health action.

Drivers of germ cell maturation.

Spermatogenesis requires progression of germ line stem cells through a precisely ordered differentiation pathway to form spermatozoa. Diverse and dynamic signals from the transforming growth factor-beta (TGF-beta) superfamily influence many stages of germ cell development. For example, interactions between several TGF-beta superfamily ligands (bone morphogenetic proteins, activin, and glial-derived neurotrophic growth factor [GDNF]) appear to govern the onset of spermatogenesis, and we are exploring how germ cells interpret these competing signals. We examined the in vivo impact of activin on testis development using two mouse models, the inhba-/- mouse (which lacks the gene encoding the activin A subunit and dies at birth) and BK mice, with inhbb (encoding the activin betaB subunit) replacing inhba (which survive to adulthood and show delayed fertility onset in males). Distinct effects on Sertoli cell and germ cell populations during fetal and early postnatal development were measured. We recognize that specific proteins, including downstream targets of TGF-beta signals, such as Smads, must move into the nucleus to implement the gene transcription changes required for development. We hypothesized that changes at the level of cellular nuclear transport machinery may be required to mediate this. Examination of proteins involved in classical nuclear import, the importins, revealed that each importin has a developmentally regulated expression pattern in male germ cells. Because each importin binds a selected range of cargo proteins and mediates their nucleocytoplasmic passage, our findings suggest that each importin ferries cargo required for discrete stages of spermatogenesis.