Search

Recent studies delineate substantial genetic components in Parkinson's disease (PD). However, very few studies were performed in Sub-Saharan African populations. Here, we explore the contribution of known PD-causing genes in patients of indigenous Zambian ancestry. We studied thirty-nine Zambian patients, thirty-eight with PD and one with parkinsonian-pyramidal syndrome (18% familial; average onset age 54.9 ± 12.2 years). In the whole group, all SNCA exons and LRRK2 exons 29 to 48 (encoding for important functional domains) were sequenced. In the familial patients and those with onset <55 years (n = 22) the whole LRRK2 coding region was sequenced (51 exons). In the patients with onset <50 years (n = 12), all parkin, PINK1, and DJ-1 exons were sequenced, and dosage analysis of parkin, PINK1, DJ-1, LRRK2, and SNCA was performed. Dosage analysis was also performed in the majority of the late-onset patients. The LRRK2 p.Gly2019Ser mutation was not detected. A novel LRRK2 missense variant (p.Ala1464Gly) of possible pathogenic role was found in one case. Two heterozygous, likely disease-causing deletions of parkin (exon 2 and exon 4) were detected in an early-onset case. Pathogenic mutations were not detected in SNCA, PINK1, or DJ-1. We also report variability at several single nucleotide polymorphisms in the above-mentioned genes. This is the first molecular genetic study in Zambian PD patients, and the first comprehensive analysis of the LRRK2 and SNCA genes in a Sub-Saharan population. Common disease-causing mutations were not detected, suggesting that further investigations in PD patients from these populations might unravel the role of additional, still unknown genes., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Manganese is essential for several metabolic pathways but becomes toxic in excessive amounts. Manganese levels in the body are therefore tightly regulated, but the responsible protein(s) remain incompletely known. We studied two consanguineous families with neurologic disorders including juvenile-onset dystonia, adult-onset parkinsonism, severe hypermanganesemia, polycythemia, and chronic hepatic disease, including steatosis and cirrhosis. We localized the genetic defect by homozygosity mapping and then identified two different homozygous frameshift SLC30A10 mutations, segregating with disease. SLC30A10 is highly expressed in the liver and brain, including in the basal ganglia. Its encoded protein belongs to a large family of membrane transporters, mediating the efflux of divalent cations from the cytosol. We show the localization of SLC30A10 in normal human liver and nervous system, and its depletion in liver from one affected individual. Our in silico analyses suggest that SLC30A10 possesses substrate specificity different from its closest (zinc-transporting) homologs. We also show that the expression of SLC30A10 and the levels of the encoded protein are markedly induced by manganese in vitro. The phenotype associated with SLC30A10 mutations is broad, including neurologic, hepatic, and hematologic disturbances. Intrafamilial phenotypic variability is also present. Chelation therapy can normalize the manganesemia, leading to marked clinical improvements. In conclusion, we show that SLC30A10 mutations cause a treatable recessive disease with pleomorphic phenotype, and provide compelling evidence that SLC30A10 plays a pivotal role in manganese transport. This work has broad implications for understanding of the manganese biology and pathophysiology in multiple human organs., (Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the clinical diagnostic reasoning process as a tool to decrease the number of unnecessary endoscopies for diagnosing peptic ulcer disease. tudy, Design: Cross-sectional KAP study., Place and Duration of Study: Shifa College of Medicine, Islamabad, from April to August 2010., Methodology: Two hundred doctors were assessed with three common clinical scenarios of low, intermediate and high pre-test probability for peptic ulcer disease using a questionnaire. The differences between the reference estimates and the respondents' estimates of pre-test and post test probability were used for assessing the ability of estimating the pretest probability and the post test probability of the disease. Doctors were also enquired about the cost-effectiveness and safety of endoscopy. Consecutive sampling technique was used and the data was analyzed using SPSS version 16., Results: In the low pre-test probability settings, overestimation of the disease probability suggested the doctors' inability to rule out the disease. The post test probabilities were similarly overestimated. In intermediate pre-test probability settings, both over and under estimation of probabilities were noticed. In high pre-test probability setting, there was no significant difference in the reference and the responders' intuitive estimates of post test probability. Doctors were more likely to consider ordering the test as the disease probability increased. Most respondents were of the opinion that endoscopy is not a cost-effective procedure and may be associated with a potential harm., Conclusion: Improvement is needed in doctors' diagnostic ability by more emphasis on clinical decision-making and application of bayesian probabilistic thinking to real clinical situations.

Mutations in the TARDBP gene are a cause of autosomal dominant amyotrophic lateral sclerosis (ALS) and of frontotemporal lobar degeneration (FTLD), but they have not been found so far in patients with Parkinson's disease (PD). A founder TARDBP mutation (p.Ala382Thr) was recently identified as the cause of ~30% of ALS cases in Sardinia, a Mediterranean genetic isolate. We studied 327 consecutive Sardinian patients with clinically diagnosed PD (88 familial, 239 sporadic) and 578 Sardinian controls. One family with FTLD and parkinsonism was also included. The p.Ala382Thr heterozygous mutation was detected in eight unrelated PD patients (2.5%). The three patients from the FTLD/parkinsonism family also carried this mutation. Within the control group, there were three heterozygous mutation carriers. During follow-up, one of these individuals developed motoneuron disease and another, a rapidly progressive dementia; the third remains healthy at the age of 79 but two close relatives developed motoneuron disease and dementia. The eight PD patients carrying the p.Ala382Thr mutation had all sporadic disease presentation. Their average onset age was 70.0 years (SD 9.4, range 51-79), which is later but not significantly different from that of the patients who did not carry this mutation. In conclusion, we expand the clinical spectrum associated with TARDBP mutations to FTLD with parkinsonism without motoneuron disease and to clinically definite PD. The TDP-43 protein might be directly involved in a broader neurodegenerative spectrum, including not only motoneuron disease and FTLD but also PD.

Introduction: Breast cancer is the most common malignancy affecting females worldwide but conventional risk factors are able to explain only a small proportion of these cases. A possible viral etiology for breast cancer has been proposed and Epstein-Barr Virus (EBV) is a widely researched candidate virus. The aim of the present study, first one of its kind from India, was to determine if there is a greater association of EBV infection with breast cancer patients as compared to patients with benign breast diseases., Methods: We looked for expression of Epstein-Barr Virus Nuclear Antigen-1 (EBNA-1) in breast cancer tissue specimens by employing immunohistochemistry (IHC). We also measured levels of anti-EBNA-1 Immunoglobulin (IgG) antibodies in stored sera of these patients using commercial Enzyme linked Immunosorbent Assay (ELISA) kit. Patients with benign breast diseases were used as a comparison group for both immunohistochemical and serological analysis., Results: 58 cases of malignant breast disease and 63 of benign breast disease (controls) were included in the study. Using manufacturer determined cut-off of 3 IU/ml, 50/55 tested (90.9%) cases and 27/33 tested (81.8%) controls were seropositive for anti-EBNA-1 IgG. Mean antibody levels were significantly higher for cases (54.22 IU/ml) as compared to controls (18.68 IU/ml). IHC for EBNA-1 was positive in 28/51 cases (54.9%). No IHC positivity was noted in the tested 30 controls. Our results show that EBNA-1 expression is seen in a significant proportion of breast cancer tissue specimens from rural India and as compared to patients with benign breast diseases these patients also have a higher immunological response against EBNA-1.

Hairy cell leukaemia variant is a very rare chronic lymphoproliferative disorder and is closely related to hairy cell leukemia. We hereby describe a case of hairy cell leukaemia variant for the first time in Saudi Arabia. An elderly Saudi man presented with pallor, massive splenomegaly, and moderate hepatomegaly. Hemoglobin was 7.7 g/dl, Platelets were 134 x109/l and white blood count was 140x10 9/l with 97% being abnormal lymphoid cells with cytoplasmic projections. The morphology, cytochemistry, and immunophenotype of the lymphoid cells were classical of hairy cell leukaemia variant. The bone marrow was easily aspirated and findings were consistent with hairy cell leukaemia variant.

Background: AA+/--thalassemia is known to be prevalent in the Eastern region of Saudi Arabia. There are no large scale reports regarding the effect of alpha-thalassemia on red cell indices of cord blood from Saudi Arabia. Similarly, there are no reports regarding the interaction of AA+/--thalassemia and the sickle cell gene in relation to red cell indices in cord blood. To address these issues, we undertook a study on neonatal cord blood samples., Materials and Methods: In a prospective study, cord blood samples from 504 neonates from the Qatif area of the Eastern Province of Saudi Arabia were analyzed for complete blood counts (CBC) and cellulose acetate Hb electrophoresis. Hb S was confirmed by citrate agar Hb electrophoresis., Results: There were 243 case samples with normal Hb electrophoresis (Hb A 27.2+/-7% and Hb F 72.6+/-7.7%). Their mean Hb (g/dL), RBC (x10(12) /L), Hct (%), MCV (fl), MCH (pg), MCHC (g/dL), RDW-SD (fl) and RDWCV (%) were 15.05+/-1.6, 4.5+/-0.5, 47.4+/-5.3, 106+/-8, 33.6+/-2.3, 31.8+/-1.7, 69.2+/-9.5 and 17.9+/-1.7, respectively. There were 136 cases with alpha-thalassemia trait (alphaTT), 57 cases with sickle cell trait (SCT) and 50 cases of sickle cell trait with alpha-thalassemia trait (SCT/alphaTT). There were 10 cases of Hb H disease (6 definite), including one with sickle cell disease (SCD) and two with SCT, Hb Bart's 23.9%-43.6%; four probable with Hb Bart's 10.9%-16.1%, and one with SCT. The effect on red cell parameters in Hb H disease were most pronounced. In addition, there were seven cases of SCD, four of whom had coexistent AA+/--thalassemia trait (SCD/alphaTT)., Conclusion: The prevalence of alpha-thalassemia in this cohort of Saudi population was 39.99%. Hb H disease appeared as common as SCD. Sickle cell gene was seen in 23.4% of neonatal samples. alpha-Thalassemia gene significantly reduces MCH, MCV, RDW-SD, Hct, Hb, and increases RBC count in both normal or sickle cell trait neonates. Generally, the variation of red cell parameters is directly proportional to the amount of Hb Bart's in the cord blood. Sickle cell gene in itself produces low MCV, RDW-SD and MCH in cord blood. Further, normal reference values for red cell parameters of cord blood are established.

In a 7-year retrospective analysis (1991-97) of the records of the Department of Haematology, Regional Laboratory and Blood Bank (Dammam), 54 patients from all parts of Saudi Arabia's Eastern Province were diagnosed with hereditary coagulation factor deficiencies. The largest group of patients, 42 haemophiliacs, included 4 non-Saudi patients. There were 39 haemophilia A or factor VIII deficiency patients, 2 haemophilia B or factor IX deficiency patients and 1 combined factor VIII and V deficiency patient. There were 5 Saudi patients with probable factor XIII deficiency, and 7 patients, all but one who were Saudi, had von Willebrand disease. The distribution of haemophilia patients in Eastern Province showed some differences compared with those reported from Riyadh and from Western countries. Among Saudis in Eastern Province, the number with suspected factor XIII deficiency, although low, was higher than that reported for other regions. The number of patients with haemophilia B and von Willebrand disease was lower than expected, when compared with the number of haemophilia A cases.

Full text is available as a scanned copy of the original print version.

Fifty four female poultry birds of 3, 4 and 5 months age were given nikethamide and diazepam intramuscularly as stimulant and depresent, respectively. The effects of above two drugs on the levels of biogenic amines were measured Fluorometrically in the rostral, middle and caudal portions of poultry brain. Diazepam increased the levels of 5-HT and dopamine in the caudal and middle portion of the brain respectively. The levels of dopamine and non-epinephrine increased with the nikethamide administration and also with increasing age of the birds, but the effect of diazepam was inconsistant. Unlike the levels of dopamine and nor-epinephrine which were maximum in middle protion, the epinephrine concentration was highest in the caudal portion of brain. It was concluded that 5-HT acted as inhibitory particularly in the caudal portion, whereas, catecholamines as excitatory neurotransmitter of the poultry brain. The increased levels of catecholamines in the poultry brain with increasing age speaks of their positive role in sexual maturity and subsequently in reproduction of the birds.

Acute oliguric renal failure (ARF) developed in a patient two weeks after he was started on intermittent anti-tuberculous therapy including rifampicin. The clinical picture was compatible with acute allergic interstitial nephritis. Renal histology revealed mainly acute tubular necrosis with mild tubulo-interstitial mononuclear cellular infiltrate. Intermittent therapy, as in our patient, has been the major factor in the development of rifampicin induced ARF in cases reviewed in the literature.

Twenty-five consecutive patients with multidrug-resistant enteric fever were evaluated and followed for haemostatic abnormalities. Twenty-one (84%) of the patients had evidence of disseminated intravascular coagulation (DIC) and 12 (48%) also had evidence of associated fibrinolysis. Clinical bleeding was observed in 3 (12%) cases, and did not bear any correlation with clotting abnormalities. Protein C activity was found to be decreased in 11 of the 15 cases with DIC, and a block in its activation, as previously postulated, could not be substantiated. DIC was reversed in most cases within 8 days of the institution of specific antibiotic therapy.

Cerebral vascular ischemic strokes are known to precipitate Cheyne-Stokes periodic breathing. Interestingly, Cheyne-Stokes-like breathing during sleep may be associated with obstructive sleep apnea (OSA) in some individuals. Therefore, it was reasoned that stroke patients with periodic breathing in sleep would be susceptible to OSA. Because oscillations in upper airway resistance can occur as a component of sleep-induced periodic breathing, we hypothesized that stroke patients with sleep-induced periodic breathing would have oscillations in upper airway resistance. These oscillations in resistance would be expected to contribute to OSA. We studied stroke patients with sleep-induced periodic breathing and control subjects to evaluate the relationship between upper airway resistance and ventilation in periodic breathing in sleep. Ventilation and upper airway resistance were measured in presleep wakefulness and in stage 2 NREM sleep. Mean tidal volume, minute ventilation, respiratory cycle timing variables, and upper airway resistance were not different between stroke and control subjects, either awake or asleep. Upper airway resistance increased and ventilation volume decreased from wakefulness to sleep in both groups. In an equivalent number of subjects from each group, reciprocal patterned oscillations in tidal volume and upper airway resistance were present at a 5 to 12.5 breath frequency during sleep. As upper airway resistance increased, tidal volume decreased. Stroke patients had wider fluctuations in upper airway resistance than control subjects, likely contributing to the higher number of sleep-disordered breathing events observed in the stroke patients.

The techniques of Western blotting and the monoclonal antibody specific immobilization of platelet antigen (MAIPA) assay were used to detect antibodies to platelet glycoproteins in 43 samples of serum from 23 anti-HIV positive haemophiliacs (8 with severe thrombocytopenia, 6 with moderate thrombocytopenia, and 9 with a normal platelet count), six anti-HIV negative haemophiliacs and ten controls. Antibodies were present in the majority of anti-HIV positive patients' sera even before the onset of thrombocytopenia. Thrombocytopenia was associated with an increase in the incidence of antibodies to GPIIIa and GPIb, whereas the antigen most frequently recognized in patients without thrombocytopenia was GPIIb. Anti-GPIIb and/or GPIIIa reactivity was also seen in three out of the six anti-HIV negative patients. There was no correlation between the absolute platelet count and the detection of antibodies in either assay. Effective therapy for thrombocytopenia with zidovudine, interferon or splenectomy did not influence the presence of antibody. Eight of nine patients with AIDS were negative in the MAIPA assay, consistent with their depressed immune status. It is concluded that the production of antibodies to platelet membrane glycoprotein in anti-HIV positive haemophiliacs is influenced by factors other than HIV. The presence of such antibodies is independent of the platelet count and is therefore unlikely to play a causative role in HIV-related thrombocytopenia.

The synthesis of some 5-hydroxy-4-imino-2,3-dihydrobenzopyran derivatives of GABA and alkylamines is described. The products were tested for their GABA-receptor binding and anticonvulsant activity in mice. Some compounds showed anticonvulsant activity. No binding to GABA receptors was observed.

A series of 4-(alkylimino)-5-hydroxy-7-alkyl-2,3-dihydro-4H-1-benzopyrans and -thiopyrans were synthesized and evaluated for anticonvulsant activity. Preliminary screening of these compounds revealed that 2,2-dimethyl-4-[(2-hydroxyalkyl)imino]-5-hydroxy-7-pentyl-2,3- dihydro-4H-1-benzopyrans 19 and 29, the 7-butyl analogue 34, and the corresponding 7-pentyl-4H-1-benzothiopyrans 38 and 39 had the most promising anticonvulsant activity. Synthesis of both enantiomers of 29 and 39 indicated that the R isomers 30 and 40 were the most active and showed very good protection against MES, pentylenetetrazole, and mercaptopropionic acid induced seizures after oral administration in mice. In the Irwin test these compounds showed a generalized depressant activity but at dosages higher than those showing anticonvulsant activity, whereas acute toxicity after oral administration was low (LD50 higher than 400 mg/kg).

Inorganic phosphorus and alkaline phosphatase activities were measured in serum samples from goats, buffaloes, cows, bullocks and also in amniotic and allantoic fluid of goats using ascorbic acid as reductant for phosphomolybdate. The results were compared with conventional method of FISKE and SUBBAROW (1925). There were no significant differences between the 2 methods. It was possible to measure micro-amounts of inorganic phosphorus and alkaline phosphatase activity with precision even in low cost colorimeters.

Sea-blue histiocytes are described in the bone marrow of a 15-year-old male patient suffering from idiopathic thrombocytopenic purpura. Cytochemically the storage material in these cells appeared to be glycophospholipid. Lipid analysis of blood leucocytes and nucleated cells of bone marrow showed a significant increase in the phospholipids, triglycerides and cholesterol as compared to age-matched controls. Serum lipid analysis showed a mild increase of phospholipids as compared to age-matched controls.

The electrophoretic fractionation of the various compounds of the soluble proteins in the cyst wall (CW), cyst fluid (CF) and zoites (ZT) of the sarcocyst of Sarcocystis fusiformis from buffalo (Bubalus bubalis) was studied by polyacrylamide disc gel electrophoresis. The CW fraction was found to contain at least six components, and ZT and CF contained at least four components with varied Rf values. Each gel was subjected to the gel scanner, and the corresponding areas of the peaks along with the percentage of the proteins in the bands were calculated.