Global maps of travel time to healthcare facilities.

Access to healthcare is a requirement for human well-being that is constrained, in part, by the allocation of healthcare resources relative to the geographically dispersed human population1-3. Quantifying access to care globally is challenging due to the absence of a comprehensive database of healthcare facilities. We harness major data collection efforts underway by OpenStreetMap, Google Maps and academic researchers to compile the most complete collection of facility locations to date. Leveraging the geographically variable strengths of our facility datasets, we use an established methodology4 to characterize travel time to healthcare facilities in unprecedented detail. We produce maps of travel time with and without access to motorized transport, thus characterizing travel time to healthcare for populations distributed across the wealth spectrum. We find that just 8.9% of the global population (646 million people) cannot reach healthcare within one hour if they have access to motorized transport, and that 43.3% (3.16 billion people) cannot reach a healthcare facility by foot within one hour. Our maps highlight an additional vulnerability faced by poorer individuals in remote areas and can help to estimate whether individuals will seek healthcare when it is needed, as well as providing an evidence base for efficiently distributing limited healthcare and transportation resources to underserved populations both now and in the future.

Managing thymic enlargement in Graves' disease.

Thymic enlargement (TE) in Graves' disease (GD) is often diagnosed incidentally when chest imaging is done for unrelated reasons. This is becoming more common as the frequency of chest imaging increases. There are currently no clear guidelines for managing TE in GD. Subject 1 is a 36-year-old female who presented with weight loss, increased thirst and passage of urine and postural symptoms. Investigations confirmed GD, non-PTH-dependent hypercalcaemia and Addison's disease (AD). CT scans to exclude underlying malignancy showed TE but normal viscera. A diagnosis of hypercalcaemia due to GD and AD was made. Subject 2, a 52-year-old female, was investigated for recurrent chest infections, haemoptysis and weight loss. CT thorax to exclude chest malignancy, showed TE. Planned thoracotomy was postponed when investigations confirmed GD. Subject 3 is a 47-year-old female who presented with breathlessness, chest pain and shakiness. Investigations confirmed T3 toxicosis due to GD. A CT pulmonary angiogram to exclude pulmonary embolism showed TE. The CT appearances in all three subjects were consistent with benign TE. These subjects were given appropriate endocrine treatment only (without biopsy or thymectomy) as CT appearances showed the following appearances of benign TE - arrowhead shape, straight regular margins, absence of calcification and cyst formation and radiodensity equal to surrounding muscle. Furthermore, interval scans confirmed thymic regression of over 60% in 6 months after endocrine control. In subjects with CT appearances consistent with benign TE, a conservative policy with interval CT scans at 6 months after endocrine control will prevent inappropriate surgical intervention. Learning points: Chest imaging is common in modern clinical practice and incidental anterior mediastinal abnormalities are therefore diagnosed frequently. Thymic enlargement (TE) associated with Graves' disease (GD) is occasionally seen in view of the above. There is no validated strategy to manage TE in GD at present. However, CT (or MRI) scan features of the thymus may help characterise benign TE, and such subjects do not require thymic biopsy or surgery at presentation. In them, an expectant 'wait and see' policy is recommended with GD treatment only, as the thymus will show significant regression 6 months after endocrine control.

Combination of Anti-Diabetic Drug Metformin and Boswellic Acid Nanoparticles: A Novel Strategy for Pancreatic Cancer Therapy.

Pancreatic cancer has an infaust prognosis and is the fourth common cause of cancer related death in India. It is highly resistant to conventional treatment modalities such as chemotherapy, radiation therapy and surgery. The association of pancreatic cancer and diabetes mellitus is explored in our study. Pancreatic cancer is more likely to occur in people who have diabetes than people devoid of it, which is supported by the observation that hyperglycaemia occurs at an early stage of pancreatic cancer and is indeed a risk factor. In the present study, we have demonstrated a synergistic relationship between metformin and boswellic acid nanoparticles with varying doses of boswellic acid nanoparticles and constant metformin (20 mM). The effect revealed increased synergism between metformin and boswellic acid nanoparticles through the inhibition of cell proliferation with an effect of 80% for the combination with 0.3 mg/mL and 0.4 mg/mL and a constant concentration of metformin. We examined the effect of combination on cell migration which revealed time dependent inhibitory effect on pancreatic cell line (MiaPaCa-2). Also, we found that the combinatorial approach significantly decreased colony formation and exhibited high rate of induction of apoptosis through DNA fragmentation in pancreatic cancer cells. In-vitro hemolysis confirmed the hemocompatibility of the combination therapy with metformin and boswellic acid nanoparticles. Flow cytometry based apoptosis assay and Caspase mediated apoptosis proved apoptosis mediated cell death. Further, the cells were analysed with mitochondrial membrane potential kit which revealed depolarization of mitochondrial membrane potential due to apoptosis after treatment with drug combination. Hence, the combination approach proved to be a promising therapy towards pancreatic cancer.

Effect of Baliospermum montanum nanomedicine apoptosis induction and anti-migration of prostate cancer cells.

Prostate cancer has been diagnosed as the second most frequent and the sixth among the cancer causing deaths among men worldwide. There is a limited scope for the prevalent therapies as prostate cancer advances and they present adverse aftermaths that have put way for us to delve into naturally available anticancer agents. The main objective of the present work is to compile the advantages of ayurvedic herbal formulations with modern technology. Baliospermum montanum is a plant that is used in ayurveda for the treatment of cancer and the plant is studied to possess various constituents in it that are responsible for its anticancer activity. Stable nanoparticles of B. montanum were prepared from both the aqueous and ethanolic extracts of the plant and its cytotoxic effects were studied on prostate cancer and normal cell lines. Size analysis by DLS and SEM revealed the average size of nanoparticles prepared was 100±50 nm and 150±50 nm for the nanoparticles prepared from aqueous and ethanolic extract respectively. In vitro cytotoxicity showed a concentration and time dependent toxicity on prostate cancer cells with cell viability of 22% and 6% with maximum concentration of aqueous and ethanolic nanoparticles respectively, in 48 h. In vitro hemolysis assay confirmed that the prepared nanoparticles were compatible with blood with no occurrence of hemolysis. The nanoparticles showed a significant reduction in the colony forming ability and wound healing capacity of the prostate cancer cells. These studies hold the anti cancer potential of the B. montanum nanoparticles making it an important candidate for prostate cancer therapy.

Nephrogenic diabetes insipidus partially responsive to oral desmopressin in a subject with lithium-induced multiple endocrinopathy.

Lithium (Li) may cause multiple endocrinopathies, including hypercalcaemia, thyroid dysfunction and nephrogenic diabetes insipidus (NDI), but rarely in the same patient. The management of NDI remains a challenge. We report on a patient on long-term Li who had simultaneous NDI (paired serum and urine samples had abnormal osmolalities, typical of NDI, and treatment with parenteral desmopressin failed to affect urinary volume and serum osmolality), 'destructive' thyroiditis (hyperthyroidism, absent radioiodine uptake and absent thyrotrophin receptor antibodies) and primary hyperparathyroidism (compatible biochemistry, urine calcium excluding 'set point' anomalies and hypocalciuric hypercalcaemia, and normal parathyroid imaging). The thyroiditis resolved spontaneously and hypercalcaemia responded to reduction of Li dose. The NDI was unresponsive to amiloride, thiazides and ibuprofen in combination. However, urine output was reduced by 50% when a high dose of oral desmopressin was given. We conclude that Li-induced multiple endocrinopathy remains rare and, although NDI is difficult to manage, high dose oral desmopressin should be tried when other medications fail.

Thyrotrophin receptor antibody characteristics in a woman with long-standing Hashimoto's who developed Graves' disease and pretibial myxoedema.

CONTEXT: Sequential conversion of Hashimoto's thyroiditis (HT) to Graves' disease (GD) is uncommon. Distinct immune paradigms, paucity of functioning tissue in long-standing HT, and infrequent conversion of blocking (TBAb) to stimulating (TSAb) thyrotrophin receptor antibody (TRAb) may account for this. Molecular and crystal structure analysis helps delineate TSH receptor (TSHR)/TRAb interactions in detail. Such 'fingerprinting' helps determine the behaviour and characteristics of TRAb in longitudinal studies. PATIENT: An 80-year-old woman taking thyroxine for long-standing HT became hyperthyroid. This persisted despite thyroxine withdrawal - free T3 was 7·3 pmol/l (2·6-5·7) and TSH < 0·01 mU/l (0·2-4·5) and TRAb highly positive. She had a goitre (ultrasound - HT), pretibial myxoedema, with mild inactive Graves' orbitopathy. She had RAI treatment and is on thyroxine replacement. MEASUREMENTS AND RESULTS: Blood samples at presentation (A) and 1 year (B) showed high TSAb and TPOAb activity but no TBAb. Experiments involving TSHR mutations confirmed that (i) TRAb had stable characteristics over 1 year; (ii) TSHR mutation R255D caused complete inhibition and (iii) R109A caused marked reduction of cAMP production by M22 (TSHR-stimulating human monoclonal antibody) and A and B; (iv) mutations R80A, E107A and K129A while affecting M22 had little effect on A and B. CONCLUSIONS: The reasons for an immunological paradigm shift in this elderly woman remain speculative. We believe that de-novo TSAb synthesis occurred converting her long-standing HT to GD although the mechanisms responsible remain unexplained. TRAb analysis confirmed stable autoantibody characteristics over 1 year and variable effects of TSHR mutations on TRAb and M22 function.

The role of thyrotrophin receptor antibody assays in graves' disease.

Thyrotrophin receptor antibodies (TRAb) exist as stimulating or blocking antibodies in the serum (neutral TRAb have been identified recently). The clinical features of GD occur when stimulating TRAb predominate. But the relationship of TRAb to clinical phenotype and outcome is not clear when current assay methods are used. Therefore no consensus exists about its utility in diagnosing and predicting outcome in GD. The most commonly used TRAb assays, measure thyroid binding inhibiting immunoglobulins (TBII or "receptor assays") and don't differentiate between stimulating and blocking antibodies. However, the more expensive, technically demanding and less freely available "biological assays" differentiate between them by their ability to stimulate cyclic AMP or failure to do so. Failure to differentiate between TRAb types and its heterogeneous molecular and functional properties has limited TBII use to GD diagnosis and differentiating from other forms of thyrotoxicosis. The current 2nd-3rd generation receptor assays are highly sensitive and specific when used for this purpose. TRAb assays should also be done in appropriate pregnant women. Current data do not support its use in outcome prediction as there is a significant variability of assay methodology, population characteristics and study design in published data, resulting in a lack of consensus.

Can a random serum cortisol reduce the need for short synacthen tests in acute medical admissions?

BACKGROUND: Short synacthen tests (SSTs) are frequently performed in medical inpatients with suspected adrenocortical insufficiency. The utility of a random or baseline serum cortisol in this setting is unclear. We determined random cortisol thresholds that safely preclude SSTs in acute medical admissions. METHODS: We analysed SSTs in acute non-critically ill general medical patients (n = 166, median age 66, range 15-94 y; men 48%, women 52%). The SST was defined according to the 30-min cortisol as 'pass' (>550 nmol/L) or 'fail' (< or =550 nmol/L). Receiver operating characteristics (ROC) curves were generated to determine the predictive value of the basal cortisol for a failed SST. RESULTS: Of 166 SSTs, a pass was seen in 127 (76.5%) tests, while 39 (23.5%) tests failed the SST. ROC curves showed that no single cut-off point of the baseline cortisol was adequately both sensitive and specific for failing the SST despite a good overall predictive value (area under curve 0.94; 95% confidence interval 0.89-0.98). A basal cortisol <420 nmol/L had 100% sensitivity and 54% specificity for failing the SST, while a basal cortisol <142 nmol/L had 100% specificity and 35% sensitivity. Restricting the SST to patients with a basal cortisol <420 nmol/L would have prevented 44% of SSTs while correctly identifying all patients who failed the SST. CONCLUSION: A baseline serum cortisol may prevent unnecessary SSTs in medical inpatients with suspected adrenocortical insufficiency. However, SSTs are still indicated in patients with random cortisol <420 nmol/L, or where the suspicion of adrenal insufficiency is compelling.

Acute respiratory distress syndrome with pulmonary calcification in two patients with B cell malignancies.

Two patients, one with B cell lymphoma and hypercalcemia and the other with multiple myeloma and hypercalcemia developed acute progressive respiratory insufficiency characteristic of the adult respiratory distress syndrome (ARDS). Both were intubated and placed on mechanical ventilation. Lung compliance deteriorated and became refractory to mechanical inflation. Examination of the lungs at post mortem examination disclosed widespread calcification within alveolar septa and diffuse alveolar damage with hyaline membrane formation consistent with ARDS. Although ARDS has been described with lymphomatous involvement of the lungs, its development in association with metastatic calcification in B cell malignancy has not been previously reported.

Fibroblast and epidermal cell-type I collagen interactions: cell culture and human studies.

Fibroblast and epidermal cell-type I collagen sponge interactions were studied in cell culture as well as in humans. In cell culture, fibroblasts were observed to migrate and proliferate throughout a type I collagen sponge containing either hyaluronic acid (HA) or fibronectin (FN). Fibroblasts accumulated in the center of the pores in sponges containing HA and appeared to surround themselves with newly synthesized extracellular matrix. In sponges containing FN, fibroblasts attached to and elongated along the collagen fibers of the sponge. In the absence of FN or HA protein synthesis of fibroblasts appeared to be inhibited by the presence of the type I collagen sponge. Epidermal cells grown on plastic or on type I collagen, formed sheets. Epidermal cells grown on a collagen sponge morphologically appeared different than cells grown on plastic. The type I collagen matrix studied in cell culture was applied to dermal wounds of patients with pressure ulcers in order to evaluate its effect on dermal wound healing. The areas of ulcers treated for 6 weeks with a type I collagen sponge decreased by about 40% compared with no change in the areas of untreated controls. Preliminary results suggest that a type I collagen sponge is a biocompatible substrate with fibroblasts and epidermal cells and may be effective in enhancing healing of chronic skin ulcers.

Hemangioma of the uterine cervix and pregnancy. A case report.

A cervical hemangioma was diagnosed in a nullipara and expectantly followed through a subsequent pregnancy.

Role of bone scanning for evaluation of carcinoma of the cervix.

The value of X-ray studies and bone scan studies of cervix cancer patients was evaluated by a review of patient charts and bone scans or X-ray studies. No in situ cancer patients had positive studies. A low frequency of positive X-ray studies was observed ranging from 1% with stage I to 10% with stage IV disease. Recurrent carcinoma had 10% positive studies. Bone scans correlated well with positive X-ray studies but 10% false-positive scans were seen, mostly osteoarthritis. The bone scan was much more sensitive and appeared to detect an earlier stage lesion, usually associated with symptoms which with radiation and other treatments could follow a more indolent course than the patient with a positive X-ray study. The present study evaluates the appearance and value of these studies, the frequency and circumstances under which useful information was obtained, and what type of survival followed the establishment of the diagnosis.

Value of bone scanning in detecting occult skeletal metastases from adenocarcinoma of the endometrium.

Bone scans were obtained in patients with adenocarcinoma of the uterus in order to search for occult skeletal metastases. Radiological studies in 350 patients with adenocarcinoma of the uterus treated at the University of Kentucky Medical Center were reviewed. All patients studied in Stage 1A, Stage 1BG1, and Stage G2 were negative. Bone scans performed since 1973 were reviewed. One out of 11 patients studied with G3 lesions had a positive scan. Four out of 41 patients with Stage 2 lesions had positive scans, seven out of 18 in Stage 3, and two out of nine in Stage 4 disease. Four out of 71 patients with recurrent tumor had positive scans. In general, all positive scans were associated with significant symptoms in the patients studied. The results correlated well with x-ray findings as evaluated by conventional radiologic studies.