Understanding the role of cerebellum in early Parkinson's disease: a structural and functional MRI study.

Increasing evidence suggests that the cerebellum may have a role in the pathophysiology of Parkinson's disease (PD). Hence, the scope of this study was to investigate whether there are structural and functional alterations of the cerebellum and whether they correlate with motor and non-motor symptoms in early PD patients. Seventy-six patients with early PD and thirty-one age and sex-matched healthy subjects (HS) were enrolled and underwent a 3 T magnetic resonance imaging (MRI) protocol. The following MRI analyses were performed: (1) volumes of 5 cerebellar regions of interest (sensorimotor and cognitive cerebellum, dentate, interposed, and fastigial nuclei); (2) microstructural integrity of the cerebellar white matter connections (inferior, middle, and superior cerebellar peduncles); (3) functional connectivity at rest of the 5 regions of interest already described in point 1 with the rest of brain. Compared to controls, early PD patients showed a significant decrease in gray matter volume of the dentate, interposed and fastigial nuclei, bilaterally. They also showed abnormal, bilateral white matter microstructural integrity in all 3 cerebellar peduncles. Functional connectivity of the 5 cerebellar regions of interest with several areas in the midbrain, basal ganglia and cerebral cortex was altered. Finally, there was a positive correlation between abnormal functional connectivity of the fastigial nucleus with the volume of the nucleus itself and a negative correlation with axial symptoms severity. Our results showed that structural and functional alterations of the cerebellum are present in PD patients and these changes contribute to the pathophysiology of PD in the early phase.

The first probe of a FLASH proton beam by PET.

The recently observed FLASH effect related to high doses delivered with high rates has the potential to revolutionize radiation cancer therapy if promising results are confirmed and an underlying mechanism understood. Comprehensive measurements are essential to elucidate the phenomenon. We report the first-ever demonstration of measurements of successive in-spill and post-spill emissions of gammas arising from irradiations by a FLASH proton beam. A small positron emission tomography (PET) system was exposed in an ocular beam of the Proton Therapy Center at MD Anderson Cancer Center to view phantoms irradiated by 3.5 × 1010protons with a kinetic energy of 75.8 MeV delivered in 101.5 ms-long spills yielding a dose rate of 164 Gy s-1. Most in-spill events were due to prompt gammas. Reconstructed post-spill tomographic events, recorded for up to 20 min, yielded quantitative imaging and dosimetric information. These findings open a new and novel modality for imaging and monitoring of FLASH proton therapy exploiting in-spill prompt gamma imaging followed by post-spill PET imaging.

The first PET glimpse of a proton FLASH beam.

We demonstrate the first ever recorded positron-emission tomography (PET) imaging and dosimetry of a FLASH proton beam at the Proton Center of the MD Anderson Cancer Center. Two scintillating LYSO crystal arrays, read out by silicon photomultipliers, were configured with a partial field of view of a cylindrical poly-methyl methacrylate (PMMA) phantom irradiated by a FLASH proton beam. The proton beam had a kinetic energy of 75.8 MeV and an intensity of about 3.5 × 1010protons that were extracted over 101.5 ms-long spills. The radiation environment was characterized by cadmium-zinc-telluride and plastic scintillator counters. Preliminary results indicate that the PET technology used in our tests can efficiently record FLASH beam events. The instrument yielded informative and quantitative imaging and dosimetry of beam-activated isotopes in a PMMA phantom, as supported by Monte Carlo simulations. These studies open a new PET modality that can lead to improved imaging and monitoring of FLASH proton therapy.

Study of commonly used organophosphate pesticides that induced oxidative stress and apoptosis in peripheral blood lymphocytes of rats.

In a previous study, we have found that organophosphate (OP) pesticides such as chlorpyrifos (CPF), methyl parathion (MPT), and malathion (MLT) significantly induced genotoxicity in peripheral blood lymphocytes of rats. To explore the mechanism of OP-induced genotoxicity, we measured the formation of DNA interstrand cross-links (DICs) and apoptosis in peripheral blood lymphocytes of rats. Peripheral blood lymphocytes of rats were treated with CPF, MPT, and MLT individually and in combination at concentrations of 0.1 and 0.25 LC50 for 2, 4, 8, and 12 h at 37°C. Lipid peroxidation (LPO) was measured as a biomarker of oxidative stress. Apoptosis induced by CPF, MPT, and MLT individually and in combination was determined by measuring the intracellular level of active caspase-3 and caspase-9 by spectrofluorimetry. We found significant dose- and time-dependent increases in LPO, DICs formation and increase of intracellular active caspase-3 and caspase-9 in exposed peripheral blood lymphocytes of rats. These findings suggest that the studied pesticides have potential to induce oxidative stress, cause DNA adduct formation, and cause failure of adduct repair, which leads to apoptosis that is partially mediated by activation of intracellular caspase-3 and caspase-9.

Quality of care in patients with diabetic kidney disease in Asia: The Joint Asia Diabetes Evaluation (JADE) Registry.

AIMS: Diabetic kidney disease independently predicts cardiovascular disease and premature death. We examined the burden of chronic kidney disease (CKD, defined as an estimated GFR < 60 ml/min/1.73 m(2) ) and quality of care in a cross-sectional survey of adults (age ≥ 18 years) with Type 2 diabetes across Asia. METHODS: The Joint Asia Diabetes Evaluation programme is a disease-management programme implemented using an electronic portal that systematically captures clinical characteristics of all patients enrolled. Between July 2007 and December 2012, data on 28 110 consecutively enrolled patients (China: 3415, Hong Kong: 15 196, India: 3714, Korea: 1651, Philippines: 3364, Vietnam: 692, Taiwan: 78) were analysed. RESULTS: In this survey, 15.9% of patients had CKD, 25.0% had microalbuminuria and 12.5% had macroalbuminuria. Patients with CKD were less likely to achieve HbA1c < 53 mmol/mol (7.0%) (36.0% vs. 42.3%) and blood pressure < 130/80 mmHg (20.8% vs. 35.3%), and were more likely to have retinopathy (26.2% vs. 8.7%), sensory neuropathy (29.0% vs. 7.7%), cardiovascular disease (26.6% vs. 8.7%) and self-reported hypoglycaemia (18.9% vs. 8.2%). Despite high frequencies of albuminuria (74.8%) and dyslipidaemia (93.0%) among CKD patients, only 49.0% were using renin-angiotensin system inhibitors and 53.6% were on statins. On logistic regression, old age, male gender, tobacco use, long disease duration, high HbA1c , blood pressure and BMI, and low LDL cholesterol were independently associated with CKD (all P < 0.05). CONCLUSIONS: The poor control of risk factors, suboptimal use of organ-protective drugs and high frequencies of hypoglycaemia highlight major treatment gaps in patients with diabetic kidney disease in Asia.

Diseases in Disaster: Post-Earthquake Dermatoses, Nepal 2015.

Nepal experienced a devastating earthquake measuring 7.8 Richter scale on 25th April 2015. Although the heightened effects were secondary to trauma, the indirect effects were also of prime importance. We came across different dermatoses, directly or indirectly secondary to earthquake. We here present an audit of the cutaneous effects following four months of the major shock presenting to a tertiary care center of central Nepal. A total of 7326 patients presented to the dermatology department over a period of four months following the major shock. Among them a total of 3833 patients (52.32%) had direct or indirect dermatoses following earthquake.

Evaluation of genotoxic potential of commonly used organophosphate pesticides in peripheral blood lymphocytes of rats.

Chlorpyrifos (CPF), methyl parathion (MPT), and malathion (MLT) are among the most extensively used organophosphate (OP) pesticides in India. DNA protein cross-links (DPC) and DNA strand breaks are toxic lesions associated with the mechanism(s) of toxicity of carcinogenic compounds. In the present study, we examined the hypothesis that individual and interactive genotoxic effects of CPF, MPT, and MLT are involved in the formation of DPC and DNA strand break. The DNA strand break was measured by comet assay and expressed as DNA damage index, while DPC estimation was carried out by fluorescence emission assay. The results showed that exposure of rat lymphocytes with CPF, MPT, and MLT caused significantly marked increase in DNA damage and DPC formation in time-dependent manner. MPT caused the highest damage, and these pesticides do not potentiate the toxicity of each other.

In vitro studies on organophosphate pesticides induced oxidative DNA damage in rat lymphocytes.

Organophosphate (OP) pesticides are widely used for agricultural and household pest control. We studied the genotoxicity of the commonly used OP pesticides chlorpyrifos (CPF), methyl parathion (MPT), and malathion (MLT), individually and in combination, in Wistar rat peripheral blood lymphocytes in vitro. DNA single-strand and double-strand breaks were measured by single cell gel electrophoresis (SCGE; comet assay). To test whether the DNA lesions were caused by oxidative stress, the DNA repair enzymes formamidoaminopyrimidineglycosylase (Fpg) and endonuclease (Endo III), which convert base damages to strand breaks, were used. Significant increases in strand breaks and in levels of the reactive oxygen species (ROS) superoxide anion and hydrogen peroxide were observed in lymphocytes treated with pesticides. MPT exposure caused the greatest DNA damage and ROS production, followed by CPF and ML. Our results demonstrate genotoxic potential of these OP pesticides.

A comparative study on use of 3% saline versus 0.9% saline nebulization in children with bronchiolitis.

BACKGROUND: Bronchiolitis is a common clinical problem in children below 2 years presenting with respiratory symptoms. As there is necrosis and sloughing of epithelial cells, edema, increased secretion of mucus causing obstruction of large and small airways we aim to see the clinical profile and the effect of use of hypertonic (3%) saline nebulization in these children. METHODS: A double blind randomized controlled trial was conducted at department of Pediatrics, in a hospital from July 2012 to August 2013. The computer generated random number was used to select the case and control group. All eligible patients were randomly assigned to one of two groups: receiving inhalation of 4 ml normal (0.9%) saline or hypertonic (3%) saline. Treating physicians, researchers and nurses were all blinded of the solution. Both saline were kept in two identical containers and labeled as solution A and solution B. Patients in each group will receive three treatments on each day of hospitalization and clinical score were obtained 30 minutes before each inhalation session. RESULTS: Bronchiolitis accounted 11.26% of total admissions. Their mean age (±SD) was 8.56 (±5.013) months with range from 45 days to 24 months. A total of 53 (74%) male were enrolled in the study. Fifty-seven (79%) children were less than 12 months and 15 (21%) were 12 months - 24 months. The mean (±SD) for duration of hospital stay was 44.82 (±23.15) and 43.60 (±28.25) for 3% and 0.9% group respectively (p=0.86). Likewise, mean (SD) duration of oxygen supplementation was 32.50 (±20.44) and 34.50 (±26.03) for 3% and 0.9% group respectively (p=0.85). Moreover, time required for normalization of clinical score was 36.79 (±19.53) and 38.34 (±26.67) for 3% and 0.9% group respectively (p=0.80). CONCLUSIONS: There is no advantage of hypertonic saline over normal saline nebulization in the management bronchiolitis.

Profile of children with urinary tract infection and the utility of urine dipstick as a diagnostic tool.

BACKGROUND: Urinary tract infection is a common problem in children and its early diagnosis and treatment is important to prevent long-term complications. Urine dipstick can be an important tool in this respect. The aim of this study is to look at the utility of urine dipstick as a diagnostic tool for UTI and will also see the clinical profile of children with UTI and sensitivity pattern of antibiotics among the isolates of urine culture. METHODS: Urine samples of all children below 14 years of age who were suspected of urinary tract infection were sent for routine microscopic examination and dipstick testing. Urine culture and sensitivity were sent for those samples that were tested positive for nitrite, leucocyte esterase activity or both. For every fifth sample, which is dipstick negative, a culture and sensitivity testing was done. RESULTS: Among 110 children enrolled, 32(29%) cases had significant bacteriuria. Out of 32 culture positive cases 18(56%) were female. Fever was the main complaint (62.5%)). Escherichia Coli was isolated in 81.25% of cases. Amikacin was sensitive in 93% and amoxicillinwas resistant in 82%. The sensitivity, specificity, positive predictive value, negative predictive value of nitrite test was 65%, 80%, 58%, 85% respectively; those of leucocyte esterase are 84%, 55%, 43%, 89% respectively; those for significant microscopic pyuria >10/hpf were 65%, 74%, 51%, 84% respectively. CONCLUSIONS: E. Coli is the commonest uropathogen in children with UTI. Amikacin is the most sensitive antibiotic against all the isolates. A positive dipstick both for nitrite and leucocyte esterase is associated with high sensitivity and specificity for urinary tract infection as compared to either of them positive alone. In addition, urine WBC ≥10/hpf is associated with high probability of UTI.

Causes of stillbirths and neonatal deaths in Dhanusha district, Nepal: a verbal autopsy study.

BACKGROUND: Perinatal (stillbirths and first week neonatal deaths) and neonatal (deaths in the first 4 weeks) mortality rates remain high in developing countries like Nepal. As most births and deaths occur in the community, an option to ascertain causes of death is to conduct verbal autopsy. OBJECTIVE: The objective of this study was to classify and review the causes of stillbirths and neonatal deaths in Dhanusha district, Nepal. MATERIALS AND METHODS: Births and neonatal deaths were identified prospectively in 60 village development committees of Dhanusha district. Families were interviewed at six weeks after delivery, using a structured questionnaire. Cause of death was assigned independently by two pediatricians according to a predefined algorithm; disagreement was resolved in discussion with a consultant neonatologist. RESULTS: There were 25,982 deliveries in the 2 years from September 2006 to August 2008. Verbal autopsies were available for 601/813 stillbirths and 671/954 neonatal deaths. The perinatal mortality rate was 60 per 1000 births and the neonatal mortality rate 38 per 1000 live births. 84% of stillbirths were fresh and obstetric complications were the leading cause (67%). The three leading causes of neonatal death were birth asphyxia (37%), severe infection (30%) and prematurity or low birth weight (15%). Most infants were delivered at home (65%), 28% by relatives. Half of women received an injection (presumably an oxytocic) during home delivery to augment labour. Description of symptoms commensurate with birth asphyxia was commoner in the group of infants who died (41%) than in the surviving group (14%). CONCLUSION: The current high rates of stillbirth and neonatal death in Dhanusha suggest that the quality of care provided during pregnancy and delivery remains sub-optimal. The high rates of stillbirth and asphyxial mortality imply that, while efforts to improve hygiene need to continue, intrapartum care is a priority. A second area for consideration is the need to reduce the uncontrolled use of oxytocic for augmentation of labour.

Ambient air quality monitoring during the H1N1 influence period in Pune (India).

Ambient air quality in an urban area is directly linked with activity level in the city including transport, business and industrial activities. Maharashtra Pollution Control Board (MPCB) has established an ambient air quality network in the city including state-of-the-art continuous air quality monitoring stations which indicate short duration air quality variations for criteria and non-criteria pollutants. The influence of H1N1 outbreak in Pune hitting its worst pandemic condition, led the civic authorities to implement stringent isolation measures including closure of schools, colleges, business malls, cinema halls, etc. Additionally, the fear of such a pandemic brought the city to a stand still. It was therefore necessary to assess the impacts of such activity level on ambient air quality in the city. It has been observed that such events have positive impacts on air quality of the city. There was a decrease in PM concentration almost to the tune of 30 to 40% if the impacts of precipitation, i.e. seasonal variations, are taken into account. Similarly, the non criteria pollutants too showed a marked but unusual decrease in their concentrations in this ever growing city. The influence of these in turn led to lowered concentrations of secondary pollutants, i.e. O3. Overall, the ambient air quality of Pune was found to be improved during the study period.

Pentoxifylline in perforated peritonitis: results of a randomised, placebo controlled trial.

OBJECTIVES: To evaluate the role of pentoxifylline as an adjuvant to operation and routine antibiotic treatment for perforated peritonitis. DESIGN: Randomised controlled clinical trial. SETTINGS: University hospital, India. SUBJECTS: 36 patients with clinically diagnosed and radiologically confirmed perforated peritonitis. 22 (61%) had typhoid enteric perforations, 11 (31%) had duodenal ulcer perforations while 3 (8%) had perforated gastric ulcers. INTERVENTION: Laparotomy with closure of perforation and lavage together with routine antibiotic treatment (ciprofloxacin and metronidazole), and random allocation to pentoxifylline 200 mg/day for 3 days in 500 ml of saline over 3-4 hours or saline alone (n = 18 in each group). MAIN OUTCOME MEASURES: Hospital stay, APACHE II scores, and the condition of the wound during the postoperative period. RESULTS: The baseline characteristics of the two groups were essentially similar. However, their preoperative APACHE II scores differed significantly (mean (SD) 12 (3) in the pentoxifylline group compared with 10 (2) in the saline group; p <0.01). The outcome was better in the pentoxifylline group in terms of significantly reduced hospital stay (median 8, range 6-17, compared with 11, 7-27, p=0.02) improved postoperative APACHE II scores (mean (SD) 8 (2) compared with 9 (2), p=0.02), and reduced incidence of wound infection (6/18 compared with 12/18, p=0.02). CONCLUSION: The addition of pentoxifylline to our standard management protocol for patients with perforated peritonitis helped to improve their outcome significantly compared with a placebo-treated group.

Revisiting the stringent response, ppGpp and starvation signaling.

Microbial adaptation to environmental stress plays an important role in survival. It is necessary to understand the mechanisms underlying the survival of microbes under stress, as they may eventually aid in the successful control of the growth and persistence of these organisms. During nutrient starvation, Escherichia coli elicits a stringent response to conserve energy. The hallmark of the stringent response is the accumulation of guanosine tetra- (ppGpp) and pentaphosphates (pppGpp), which probably bind RNA polymerase to regulate gene expression at certain promoters. Recently, there has been renewed interest in the stringent responses of other microbes, with a view to correlating it with sporulation, virulence and long-term persistence.

High intracellular level of guanosine tetraphosphate in Mycobacterium smegmatis changes the morphology of the bacterium.

Almost one-third of the world population today harbors the tubercle bacillus asymptomatically. It is postulated that the morphology and staining pattern of the long-term persistors are different from those of actively growing culture. Interestingly, it has been found that the morphology and staining pattern of the starved in vitro population of mycobacteria is similar to the persistors obtained from the lung lesions. In order to delineate the biochemical characteristics of starved mycobacteria, Mycobacteria smegmatis was grown in 0.2% glucose as a sole carbon source along with an enriched culture in 2% glucose. Accumulation of the stringent factor guanosine tetraphosphate (ppGpp) with a concomitant change in morphology was observed for M. smegmatis under carbon-deprived conditions. In addition, M. smegmatis assumed a coccoid morphology when ppGpp was ectopically produced by overexpressing Escherichia coli relA, even in an enriched medium. The Mycobacterium tuberculosis relA and spoT homologue, when induced in M. smegmatis, also resulted in the overproduction of ppGpp with a change in the bacterium's growth characteristics.

Primary small bowel malignancies: single-center results of three decades.

We highlight one medical center's experiences with primary malignancies of the small bowel. During a 27-year period, 79 patients were treated for small bowel tumors. Of these, 15 (20%) were lost to follow-up; thus, 64 patients were reviewed retrospectively with emphasis on histological distribution and their topography, perioperative complications, overall survival, and prognostic factors. In our 64-patient series, 33 (51.6%) presented with adenocarcinoma; 10 (15.5%), lymphoma; 8 (12.1%), leiomyosarcoma; 5 (7.6%), neurogenic tumor; 2 (3%), unclassified carcinoma; 5 (7.6%), other types of sarcoma; and 1 patient presented with synchronous adenocarcinoma and lymphoma. Of all patients, 30 (46.9%) were curatively treated, whereas 34 (53.1%) underwent palliative procedures. Hospital lethality was 9.4% and mainly occurred in patients operated on under emergency circumstances. Reoperation rate was 29.7%. The observation period lasted at least five years or until death; three patients were alive less than five years postoperatively. Cumulative five-year survival rate was 22.5% in the adenocarcinoma group, 33.3% in the lymphoma group, 33.3% in the leiomyosarcoma group, and 22.2% in patients with other tumors. The uncharacteristic symptoms presented by patients suffering from small intestinal malignancies make early diagnosis difficult. Therefore, especially in patients with long-standing bowel diseases, malignancy should be considered. Early diagnosis and surgical treatment lead to a good prognosis as shown by our study.

Dracontiasis in Madhya Pradesh II. Statistical analysis on incidence in Arnnhaydhani, a highly endemic village.

1. The village of Arnnhyadhani [District Mandsour] with a total population of 195 was found to be a highly endemic pocket with 40% [78 persons] infection. 2. Statistically, infection rate was found to be maximum at the modal age of 22.91 years after which it decreases. A positive skewness [0.05] supports this finding. 3. A larger percentage of males [48.03%] with the infection taking place late [23.69 years] were found to be infected in comparison to females [31.18%] who get the infection at an earlier [18 years] age. 4. Coefficient of variation [V] test showed that males were nearer to mean [V = = 49.90 than females = 59.83]. 5. The proportion tests Z value was found to be 2.69 [Rewat caste] which was found to be greater than the standard value [1.96] at 5% level; concluded that infection was significant on sex [males]. 6. Infection dependence on caste [Rewat caste] was found out by the chi-square test whose X2 value of 27.654.