Assessment of the Relationship between Non-motor features and Severity of Parkinson's Disease Patients in Bangladesh.

Parkinson's disease (PD) is second most common neurodegenerative disorder after Alzheimer's disease that may present with both motor and non-motor symptoms (NMSs). Many of the ignored NMSs may potentiate further deterioration of the patient's quality of life (QoL). But there is scarcity of data regarding NMSs of PD patients and their relationship with the disease severity in Bangladesh. This study was aimed to investigate the frequency of NMSs and assess their debatable impact on the severity of PD patients in Bangladesh. This cross-sectional type of observational study was conducted in neurology department of Dhaka Medical College Hospital, Bangladesh from January 2012 to June 2013 which recruited 60 eligible PD patients. The PD patients and disease severity was demonstrated by UK Parkinson's Disease Society Brain Bank criteria for idiopathic PD and the Hoehn and Yahr scale respectively. Whereas, NMSs were demonstrated by the self-structured questionnaire which had encountered 30 common symptoms of PD. The mean age of our study cohort was found 57.88±10.56 years with male female ration 2:1. According to the Hoehn and Yahr (H & Y) severity scale 38.3%, 38.3%, 20.1% and 3.3% patients had been suffering from stage ?, stage II, stage III and stage ?V Parkinson's disease respectively. Irrespective of the severity of the PD the frequency of NMSs was nocturia (66.7%), sadness or blues (65.0%), memory disturbance (61.7%), anxiety (58.3%), insomnia (56.7%), orthostatic hypotension (55.0%), erectile dysfunction (50.0%), urinary urgency (46.7%), anhedonia (45.0%), olfactory disturbance (38.3%), constipation (38.3%), hyper or hypo sexuality (31.7%) and restless leg syndrome (31.7%). However, after head-to-head NMSs analysis, daytime dribbling of saliva (p=0.024), urinary urgency (p=0.036), nocturia (p=0.001), weight loss (p=0.001), anhedonia (p=0.027), excessive daytime sleepiness (p=0.024), insomnia (p=0.007), vivid dream (p=0.024), REM behavior disorder (p=0.010), restless leg syndrome/ periodic leg movements (p=0.043) had significantly been reported higher among the stage II PD patients than that of stage I patients. Whereas fall (p=0.001), dysphagia or choking (p=0.002), constipation (p=0.003), fecal incontinence (p=0.033), excessive daytime sleepiness (p=0.033), anxiety (p=0.036) and anhedonia (p=0.044) were significantly more prevalent among the advanced stage (III) than stage (II) PD patients. Mean total NMS increased significantly with PD severity based on H and Y staging with a mean NMSQ-T (Non-Motor Symptoms Questionnaire Test) of 5.43 in stage 1, 9.22 in stage 2, 13.75 in stage 3 and 17.0 in stage 4 (p=0.0001). This study revealed that there was high frequency of NMSs among the PD patients and most common symptoms were nocturia, sadness, memory impairment, anxiety, insomnia, orthostatic hypotension, erectile dysfunction, anhedonia, urinary urgency and constipation. Finally, the more advanced disease as indicated by a higher H&Y stage was associated with significantly higher number of reported NMSs.

Carvacrol hinders the progression of hepatic fibrosis via targeting autotaxin and thioredoxin in thioacetamide-induced liver fibrosis in rat.

Fibrosis is a common outcome of nearly all chronic diseases of liver that results in changes of its functions which requires medical attention. The current research aims to investigate the potential anti-fibrotic efficacy of Carvacrol against thioacetamide (TAA)-induced liver fibrosis in male rats using Ursodeoxycholic acid (UDCA) as a reference anti-fibrotic product. Carvacrol (25 and 50 mg/kg) markedly declined TAA-increased serum liver enzymes; alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) as well as total bilirubin (TB) and direct bilirubin (DB) levels as well as increased levels of total protein (TP) and albumin. Carvacrol significantly reduced glutathione depletion (GSH), Nitric oxide (NOX) and malondialdehyde (MDA) accumulation in liver tissue. Additionally, its anti-oxidant effect brightened up via affecting markers of stress found in the cell as nuclear factor erythroid 2-related factor 2 (Nrf-2) where it still had high content and decreased Thioredoxin (Trx) level. The anti-inflammatory effect of Carvacrol was confirmed by decreasing nuclear factor kappa B (NF-κB), interleukin-1beta (IL-1ß) and inducible nitric oxide synthase (iNOS) contents. Carvacrol showed anti-fibrotic effect clarified by turning down fibrosis-related markers; TGF-ß1, matrix metalloproteinase-3 and 9 (MMP-3 and 9) and Autotaxin (ATX) contents. Furthermore, it decreased alpha smooth muscle actin (α-SMA) and caspase-3 immune-expression. The overall outcome of aforementioned markers results showed that Carvacrol suppresses the progression of liver fibrosis via its anti-oxidant, anti-inflammatory, anti-apoptotic effect and its ability in lowering Thioredoxin and Autotaxin; hence it can be categorized as a hepatoprotective natural substance.

Increases in bispectral index lead to interventions that prevent possible intraoperative awareness.

In this case a woman underwent a cervical laminectomy with a total i.v. anaesthesia technique and during her care two problems occurred with propofol delivery. In both cases, bispectral index increases alerted caregivers to the decreased propofol delivery and allowed them to make corrections in a manner timely enough to prevent the occurrence of awareness during anaesthesia. The case illustrates how intraoperative processed electroencephalographic monitoring may decrease the incidence of recall of awareness following surgery.

In situ hybridization and monoclonal antibody analysis of plasma membrane Ca-pump mRNA and protein in submandibular glands of rabbit, rat and man.

The degree of supersaturation of saliva with calcium (Ca) is related to the mineral phase of enamel in erupted teeth, the incidence of caries, and the formation of calculus. The mechanisms for regulating salivary Ca concentration are therefore of relevance to dentistry. Sections of rabbit, rat and human submandibular gland (SMG) were processed for immuno-histochemistry with a specific anti-plasma membrane Ca-pump antibody, 5F10. Western blots confirm that the molecular weight of the proteins identified by our antibody (135 kDa) is consistent with an appropriate molecular weight for PMCA antigen (135-150 kDa). Tissue sections were also processed for in situ hybridization to study the distribution of the PMCA mRNA isoforms. In mammals, the PMCA1 gene is reported to code for a PMCA protein with a role in maintaining the intracellular Ca levels in both epithelial and non-epithelial cells. Other genes including the PMCA2 and PMCA4 genes may code for PMCA proteins specific to Ca transporting tissues. Our studies demonstrate cytoplasmic labeling of PMCA mRNA with hPMCA-1 and hPMCA-4 specific cDNA probes in humans, and rPMCA-1 and rPMCA-2 specific oligonucleotide probes in rats. Labeling of PMCA protein and all mRNA isoforms was found in the cytoplasm of the interlobular and intralobular ducts (except for intercalated ducts). The demonstrated presence of PMCA in SMGs of rabbit, rat, and man, may suggest a role for PMCA in the regulation of intracellular Ca and in a mechanism for regulating and maintaining the high concentration of Ca in salvia.

Synthesis of novel N-phosphonoalkyl dipeptide inhibitors of human collagenase.

The synthesis of a series of N-phosphonalkyl dipeptides 6 is described. Syntheses were devised that allowed the preparation of single diastereoisomers and the assignment of stereochemistry. The compounds were evaluated in vitro for their ability to inhibit the degradation of radiolabeled collagen by purified human lung fibroblast collagenase. Several of the compounds were potent collagenase inhibitors and were at least 10-fold more potent than their corresponding N-carboxyalkyl analogues. Activity was lost when the phosphonic acid group P(O)(OH)2 was replaced by the phosphinic acid groups P(O)(H)(OH) and P(O)(Me)(OH). At the P1 position, (R)- or (S)-alkyl groups, especially ethyl and methyl (e.g., 12a,b, 52a,b, and 53a,b), or an (R)-phenethyl moiety (55a) conferred high potency (IC50 values in the range 0.23-0.47 microM). (S)-Stereochemistry was preferred for the P1' isobutyl side chain. Structure-activity relationships were also investigated at the P2' site, and interestingly, compounds with basic side chains, such as the guanidine 57a, were equipotent with more lipophilic compounds, such as 52a. As with other series of collagenase inhibitors, potency was enhanced by introducing bicyclic aromatic P2' substituents. The most potent phosphonic acid of the series was the bicyclic aromatic P2' tryptophan analogue 59a (IC50 0.05 microM).

Introduction of the injectable contraceptive NET-EN into family planning clinics in Bangladesh.

PIP: In preparation for introducing the injectable contraceptive norethisterone enanthate (NET-EN) into the national family planning program, a field study was conducted in 6 family planning clinics in Bangladesh. 3 of the clinics were located in Dhaka, the capital city, 1 was located in a town approximately 15 kilometers from Dhaka, and the other 2 clinics were located several hundred kilometers from Dhaka. A total of 913 women were chosen to receive injections of NET-EN every 8 weeks for 6 months and every 12 weeks thereafter. The mean age of the subjects was 26.8 years, and the mean number of live births was 3.4. The overall cumulative discontinuation rates were 26.3/100 women at 6 months, 37.3/100 at 12 months, and 42.9/100 at 18 months. The most common reason for discontinuing was a disturbance in bleeding. Heavy and/or prolonged bleeding was the single most frequent reason (6.3/100 women at 12 months), but amenorrhea was not uncommon (5.1/100 women at 12 months), while irregular bleeding or spotting was given as a reason somewhat less frequently (3.9/100 women). 3 women became pregnant during the study, giving a cumulative pregnancy rate of 0.4/100 women at 18 months. A variety of complaints fell within the category of "other medical reasons," the most common being fatigue, headache, and dizziness. The overall discontinuation rates varied markedly by center, as did the reasons for discontinuation. The lowest discontinuation rate of 14.7/100 women at 12 months was seen in the Mohammedpur Fertility Services and Training Center. This rate was considerably lower than that in any other center. The highest discontinuation rate was found by the Bangladesh Association for Voluntary Sterilization -- 52.0/100 women at 12 months. The variation in rate of discontinuation because of bleeding disturbances was most dramatic, with relatively high rates at the Bangladesh Association for Voluntary Sterilization, markedly low rates in the Mohammedpur Fertility Services and Training Centre, and intermediate rates elsewhere. Neither the overall discontinuation rate, nor the individual reasons for discontinuation varied much by age group. The most notable finding regarding discontinuation of NET-EN was the marked difference between centers. This is particularly notable given the lack of any major differences with respect to age, parity, residence, and history of contraception of the subjects. These findings suggest that the specific approach used in each clinic had a considerable impact on continuation rates and acceptance of NET-EN.^ieng

The metabolic clearance rate and uterine metabolism and retention of progesterone and 20alpha-hydroxypregn-4-en-3-one during the secretion of uteroglobin in ovariectomized, steroid-treated rabbits.

The metabolic clearance rate (MCR) and in vivo uterine metabolism and retention of progesterone (P) and 20 alpha-hydroxypregn-4-en-3-one (20 alpha-OHP) during the uterine synthesis of uteroglobin in the rabbit have been studied. Oophorectomized rabbits with the uteri ligated received daily im injections of oil vehicle (C), 2 mg P/kg BW, or 2 microgram estradiol/kg BW. The MCR of [14C]P and [3H]20 alpha-OHP did not differ among treatment groups and was 260 +/- 30 and 270 +/- 33(SE) liters/day, respectively. Although the uterine tissue to arterial blood ratio of [14C]P differed between groups (E greater than C greater than P), the tissue to blood ratio of 20 alpha-OHP was the same for the three groups and was about 1. The uterine extraction of P was 32 +/- 6.2(SE)% and was the same for the three treatment groups. The uterine extraction of 20 alpha-OHP was significantly increased by estrogen treatment [33.4 +/- 6.0(SE)%] compared to the control [14.8 +/- 3.3(SE%)] or P[16.9 +/- 4.5(SE)%] groups. These studies indicate that the ability of exogenous 20alpha-OHP to stimulate uteroglobin secretion is probably mediated by its peripheral conversion to P. These studies also indicate the value of continuous infusion of radioactive steroids to evaluate tissue retention and metabolism in vivo.

The metabolic clearance rate, the brain extraction and distribution and the uterine extraction and retention of progesterone and R 5020 in estrogen-treated ovariectomized rabbits.

The metabolic clearance rate (MCR), uterine extraction, uterine retention and brain distribution of the synthetic progestin R 5020 and progesterone were studied in estrogen-treated ovariectomized rabbits. The MCR of R 5020 was 163+/-15 (SE) 1/day and was lower than that of progesterone. The uterine extraction of R 5020 (51.4+/-3.9 (SE)%) was greater than that of progesterone (33.7+/-7.7%) as was the uterine tissue:arterial blood ratio (28.1+/-4 vs. 7.3). The brain and pituitary retention and distribution of R 5020 and progesterone were the same and provided no evidence for a selective accumulation of a progestin in the pituitary or hypothalamus.

The head extractions, brain and pituitary uptake and metabolism of progesterone and 5alpha-dihydroprogesterone in anesthetized, female rabbits.

Three days after ovariectomy adult female rabbits were injected intramuscularly with either 2 mug estradiol/kg b.w., 0.5 mg progesterone/kg b.w., 2 mug estradiol plus 0.5 mg progesterone/kg b.w., or oil vehicle daily for 5 days. On the sixth day the animals were anesthetized and given a continuous infusion of [14C]progesterone and [3H]5alpha-pregnane-3,20-dione (5alpha-DHP) for 4 h via the femoral vein. Head extractions, calculated from the difference in blood concentrations of radioactive steriods between the femoral artery and jugular vein, were in the range of 60-75% for both progesterone and 5alpha-DHP and were unaffected by the hormone treatments. Nine brain areas and the pituitary were analyzed for [14C]progesterone, [3H]5alpha-DHP and [14C]-5alpha-DHP. Generally, the brain and pituitary retention and distribution of [14C]progesterone and [3H]5alpha-DHP and the brain and pituitary metabolism of [14C]progesterone were unaffected by hormone treatments. In the cerebellum, progesterone treatment increased [14C]progesterone retention as compared to oil treatment. All tissues contained 2-7 times more [14C]progesterone than arterial blood concentrations. [3H]5alpha-DHP tissue: arterial blood concentrations ratios were much lower ranging from 0.9 to 1.78. [14C]progesterone and [3H]5alpha-DHP showed similar brain distribution with highest concentrations in the pons, pons reticulum and midbrain reticulum. All tissues converted progesterone to 5alpha-DHP, but only the cerebellum contained more [14C]5alpha-DHP than [14C]progesterone.

In vivo aspects of progesterone distribution and metabolism.

The end-organ response of any hormone is the result of many factors which precede the event, including biosynthesis, secretion, transport, distribution, and metabolism. These factors vary among different species. The metabolic clearance rate (MCR) of progesterone varies between 40 and 180 L./day/Kg. in man (60 to 70), monkey (40 to 50), rabbit (55 to 60), sheep (110), rat (120), and guinea pig (180). Major sites of clearance include liver, brain, and uterus. Specific metabolites of progesterone include 20 alpha-hydroxypregn-4-en-3-one (20 alphaOHP) and alpha-pregnan-3,20-dione (5 alpha-DPH). Liver, brain, and uterine clearances, extractions, and conversions of progesterone to these metabolites have been studied in various species under apparent steady-state conditions. A specific hormone action of progesterone, the appearance of uteroglobin in the rabbit uterus, has also been studied in varying horomonal states (estrogen, estrogen plus progesterone, and progesterone alone). These have all been used as examples of progesterone distribution and metabolism.