A nomogram for predicting the risk of neck node metastasis in pathologically node-negative oral cavity carcinoma.

OBJECTIVE: To generate a nomogram for predicting the risk of neck node metastasis in pathologically node-negative patients using a combination of variables comprising of protein expression, ultrastructural alterations and clinicopathological parameters. MATERIALS AND METHODS: Surgically removed oral tumours (n = 103) were analysed for the expression of desmosomal and hemidesmosomal assembly proteins by immunohistochemistry and ultrastructural alterations by transmission electron microscopy (TEM). Protein expression, ultrastructural alterations and clinicopathological variables were used to construct nomogram from the training set in 75 patients. Clinical utility of the nomogram was validated in a discrete set of 28 patients. RESULTS: Univariate and multivariate analyses were performed on the training set, and obtained significant variables comprising of integrin ß4 expression (p = .027), number of hemidesmosomes (p = .027)/desmosomes (p = .046), tumour differentiation grade (p = .033) and tumour thickness (p = .024) were used for construction of the nomogram. The area under the curve was calculated for both training 0.821 (95% CI 0.725-0.918) and validation sets 0.880 (95% CI 0.743-1.000). The nomogram demonstrated a predictive accuracy of 73.3% and 78.6% with the sensitivity of 81.4% and 83.3% in the training and validation sets, respectively. CONCLUSIONS: The nomogram constructed on postsurgical tumour samples will be a value addition to histopathology for the detection of neck node metastasis in pathologically node-negative patients.

Synthesis of ceria based superhydrophobic coating on Ni20Cr substrate via cathodic electrodeposition.

In this work, superhydrophobic cerium oxide coating surface (111) with dual scale texture on Ni20Cr substrate is obtained by combination of electropolishing the substrate and subsequent cathodic electrodeposition and long-term UVH surface relaxation. To form hierarchical structures of CeO2 is controllable by varying the substrate roughness, and electropolishing period. The results indicated that at the optimal condition, the surface of the cerium oxide coating showed a superhydrophobicity with a great water contact angle (151.0 ± 1.4°) with Gecko state. An interface model for electropolishing of substrate surface in cerium nitrate medium is proposed. We expect that this facile process can be readily and widely adopted for the design of superhydrophobic coating on engineering materials.

Role of RT-PCR and FISH in diagnosis and monitoring of acute promyelocytic leukemia.

BACKGROUND: Patients with a presence of Promyelocytic Leukemia-Retinoic Acid Receptor Alpha (PML-RARA) genes rearrangement predict a favorable response to all-trans retinoic acid (ATRA), and a significant improvement in survival. Therefore, establishing the presence of PML-RARA rearrangement is important for optimal patient management. AIM: The objective of this study is to compare and assess the role of fluorescent in situ hybridization (FISH) and reverse transcriptase polymerase chain reaction (RT-PCR) in the diagnosis and long-term monitoring of Acute Promyelocytic Leukemia (APL). MATERIALS AND METHODS: We compared 145 samples received at different interval of times to analyze the sensitivity of RT-PCR and FISH. RESULTS: The failure rate for RT-PCR was 4% at baseline, 13% at induction, and 0% at the end of consolidation. And for FISH it was 8% at baseline, 38% at induction, and 66% at the end of consolidation. The predictive values of relapse in the patients who were positive and negative by RT-PCR, at the end of induction, were 60% and 3%, respectively, and at end of consolidation it was 67% and 4%, respectively. On the other hand the predictive values of relapse in patients who were positive and negative by FISH at end of induction were 57% and 6%, respectively; while at end of consolidation it was 14% who were negative by FISH. CONCLUSION: Both RT-PCR and FISH are important for the diagnosis of APL cases, as both techniques complement each other in the absence or failure of any one of them. However, RT-PCR is more sensitive than FISH for the detection of minimal residual disease in the long-term monitoring of these patients. The present study shows that the predictive value of relapse is more associated with minimal residual disease (MRD) results by RT-PCR than that by FISH.

Immunophenotypic profile of acute leukemia: critical analysis and insights gained at a tertiary care center in India.

BACKGROUND: To analyze the spectrum of various types and subtypes of acute leukemia. METHODS: Two thousand five hundred and eleven consecutive new referral cases of acute leukemia (AL) were evaluated based on WHO classification. RESULTS: It included 1,471 cases (58%) of acute lymphoblastic leukemia (ALL), 964 cases (38%) of acute myeloid leukemia (AML), 45 cases (1.8%) of chronic myelogenous leukemia in blast crisis (CMLBC), 37 cases (1.5%) of biphenotypic acute leukemia (BAL), 1 case of Triphenotypic AL, and 2 cases of acute undifferentiated leukemia (AUL). Common subtypes of ALL were B-cell ALL (76%), which comprised of intermediate stage/CALLA positive (73%), early precursor/proBALL (3%). T-cell ALL constituted 24% (351 cases) of ALL. Common subtypes of AML included AMLM2 (27%), AMLM5 (15%), AMLM0 (12%), AMLM1 (12%), APML (11%), and AML t(8;21) (9%). CMLBC was commonly of myeloid blast crisis subtype (40 cases). CONCLUSION: B-cell ALL was the commonest subtype in children and AML in adults. Overall incidence of AML in adults was low (53% only). CD13 was most sensitive and CD117 most specific for determining myeloid lineage. A minimal primary panel of nine antibodies consisting of three myeloid markers (CD13, CD33, and CD117), B-cell lymphoid marker (CD19), T-cell marker (CD7), with CD45, CD10, CD34, and HLADR could assign lineage to 92% of AL. Cytogenetics findings lead to a change in the diagnostic subtype of myeloid malignancy in 38 (1.5%) cases.

Negative effects of chronic oral chlorpromazine and olanzapine treatment on the performance of tasks designed to assess spatial learning and working memory in rats.

Learning potential and memory capacity are factors that strongly predict the level of rehabilitation and the long-term functional outcome in patients with schizophrenia. Unfortunately, however, the effects of antipsychotic drugs (i.e. the primary treatments for schizophrenia) on these components of cognition are unclear, particularly when they are administered chronically (i.e. a standard clinical practice). In this rodent study we evaluated the effects of different time periods (ranging from 2 weeks to 6 months) of oral treatment with the first generation antipsychotic chlorpromazine (10.0 mg/kg/day), or the second generation antipsychotic olanzapine (10.0 mg/kg/day) on the repeated acquisition of a water maze task (i.e. a method of assessing spatial learning potential in a repeated testing format). We assessed locomotor function (in an open field) and employed a radial arm maze (RAM) task to assess antipsychotic effects (5.0 and 10.0 mg/kg/day doses) on spatial working memory during the treatment period between 15 days and 2 months. Finally, we conducted experiments using liquid chromatography/tandem mass spectrometry (LC-MS/MS) to evaluate the therapeutic relevance of our method of drug delivery (oral administration in drinking water). In the water maze experiments, both antipsychotics were associated with impairments in acquisition in the earlier test sessions that could eventually be overcome with repeated testing while olanzapine also impaired retention in probe trials. Both antipsychotics were also associated with impairments in delayed non-match-to-position trials in the RAM and some impairments of motor function (especially in the case of olanzapine) as indicated by slightly reduced swim speeds in the water maze and decreased activity in some components of the open field assessment. Finally, LC-MS/MS studies indicated that the method of antipsychotic administration generated clinically relevant plasma levels in the rat. These animal data indicate that chronic oral treatment with chlorpromazine or olanzapine can impair the performance of tasks designed to assess specific components of cognition that are affected in schizophrenia.

Insulin sensitivity as a risk factor for common carotid intima media thickness (IMT): its relation to atherosclerosis.

INTRODUCTION: The relationship between insulin resistance and atherosclerosis (ATH) in non-diabetic hypertensive patients from the Asian Indian population remains poorly understood. To resolve this issue, the present study was designed to analyze whether insulin sensitivity in a non-diabetic individual is related to the development of ATH.(by using IMT as an index) and whether this relationship is dependent on the presence of other cardiovascular disease (CVD) risk factors such as dyslipidemia and hypertension. METHODOLOGY: This study included 68 healthy controls with no diabetes and hypertension and 41 hypertensive patients who underwent four-point oral glucose tolerance test (OGTT) and intravenous glucose tolerance test (IVGTT). A biochemical profile, beta mode ultrasonography for intima media thickness of carotid artery, and ECG determination was carried out. RESULTS: Hypertensive patients in our study exhibited significantly increased abdominal obesity. Blood pressure, fasting and 2 hr plasma glucose (4.62 +/- 0.08 and 5.55 +/- 0.17 mmol/l), and triglyceride (1.47 +/- 0.067 mmol/l) levels were compared to those of control subjects (p < 0.05). The fasting insulin levels and HOMA-IR were also significantly increased and Composite Insulin Sensitivity Index (CISI) reduced compared to controls with p < 0.01. Intima media thickness of the left (0.08 +/- 0.01) and right (0.069 +/- 0.008) CA were both significantly increased in hypertensives (p < 0.01). Correlation analysis showed that IMT of the left carotid artery was significantly associated with triglyceride levels (r = 0.813, p < 0.05) but not with insulin measures such as HOMA-IR and CISI. CONCLUSION: Hyperinsulinemia was observed in our non-diabetic hypertensive patients, but no association was found between IMT and insulin resistance. That IMT of hypertensives was associated with triglyceride levels suggests that high levels of insulin may be related to the development of ATH indirectly through its effects on lipid metabolism in our population.

Protracted effects of chronic oral haloperidol and risperidone on nerve growth factor, cholinergic neurons, and spatial reference learning in rats.

The primary therapeutic agents used for schizophrenia, antipsychotic drugs, ameliorate psychotic symptoms; however, their chronic effects on cognition (or the physiologic processes of the brain that support cognition) are largely unknown. The purpose of this rodent study was to extend our previous work on this subject by investigating persistent effects (i.e. during a 14 day drug-free washout period) of chronic treatment (i.e. ranging from 45 days to 6 months) with a representative first and second generation antipsychotic. Drug effects on learning and memory and important neurobiological substrates of memory, the neurotrophin, nerve growth factor (NGF) and its receptors, and certain components of the basal forebrain cholinergic system were investigated. Behavioral effects of oral haloperidol (2.0 mg/kg/day), or risperidone (2.5 mg/kg/day) were assessed in an open field, a water maze task, and a radial arm maze procedure and neurochemical effects in brain tissue were subsequently measured by enzyme-linked immunosorbent assays (ELISAs). The results indicated that both antipsychotics produced time-dependent and protracted deficits in the performance of a water maze procedure when compared with vehicle-treated controls, while neither drug was associated with significant alterations in radial arm maze performance. Interestingly, haloperidol, but not risperidone, was detectible in the rodent brain in appreciable levels for up to 2 weeks after drug discontinuation. Both antipsychotics were also associated with reduced levels of NGF protein in the basal forebrain and prefrontal cortex and significant (or nearly significant) decreases in phosphorylated tropomyosin-receptor kinase A (TrkA) protein and the vesicular acetylcholine transporter (depending on the brain region analyzed). Neither antipsychotic markedly affected TrkA or p75 neurotrophin receptor levels. These data in rats indicate that chronic treatment with either haloperidol or risperidone may be associated with protracted negative effects on cognitive function as well as important neurotrophin and neurotransmitter pathways that support cognition.

Oral haloperidol or risperidone treatment in rats: temporal effects on nerve growth factor receptors, cholinergic neurons, and memory performance.

First and second generation antipsychotics (FGAs and SGAs) ameliorate psychotic symptoms of schizophrenia, however, their chronic effects on information processing and memory function (i.e. key determinants of long term functional outcome) are largely unknown. In this rodent study the effects of different time periods (ranging from 2 weeks to 6 months) of oral treatment with the FGA, haloperidol (2.0 mg/kg/day), or the SGA, risperidone (2.5 mg/kg/day) on a water maze repeated acquisition procedure, the levels of nerve growth factor receptors, and two important cholinergic proteins, the vesicular acetylcholine transporter and the high affinity choline transporter were evaluated. The effects of the antipsychotics on a spontaneous novel object recognition procedure were also assessed during days 8-14 and 31-38 of treatment. Haloperidol (but not risperidone) was associated with impairments in water maze hidden platform trial performance at each of the time periods evaluated up to 45 days, but not when tested during days 83-90. In contrast, risperidone did not impair water maze task performance at the early time periods and it was actually associated with improved performance during the 83-90 day period. Both antipsychotics, however, were associated with significant water maze impairments during the 174-180 day period. Further, haloperidol was associated with decrements in short delay performance in the spontaneous novel object recognition task during both the 8-14 and 31-38 day periods of treatment, while risperidone was associated with short delay impairment during the 31-38 day time period. Both antipsychotics were also associated with time dependent alterations in the vesicular acetylcholine transporter, the high affinity choline transporter, as well as tyrosine kinase A, and p75 neurotrophin receptors in specific brain regions. These data from rats support the notion that while risperidone may hold some advantages over haloperidol, both antipsychotics can produce time-dependent alterations in neurotrophin receptors and cholinergic proteins as well as impairments in the performance of tasks designed to assess spatial learning and episodic memory.

Increased prevalence of metabolic syndrome in non-obese asian Indian-an urban-rural comparison.

BACKGROUND: In the present study we evaluated the association of insulin resistance (IR) with different components of Metabolic Syndrome (MS) in an Asian Indian population, and performed a comparative study between urban and rural populations of India. METHODS: A Total of 267 urban men and women aged 25-70 years participated in this study. RESULTS were compared with rural data from a previously published study. Fasting serum insulin, uric acid, and lipid profile were measured along with fasting and 2 hour plasma glucose. Association of MS and IR was studied by using univariate regression analysis. RESULTS: Prevalence of MS was significantly higher in the urban population compared to that of the rural population (35.2% vs 20.6%, chi(2) = 23.2, p < 0.001). Calculated insulin resistence (HOMA-IR) was common in MS group of both populations. Percentage prevalence of IR was high and almost the same in both population (42%). Percentage prevalence of abdominal obesity and hypertriglyceridemia was significantly higher in the urban population compared to the rural population. Linear regression analysis of IR significantly correlated with different components of MS of both the population. CONCLUSIONS: The significant finding of the present study was that the rural population exhibited a high prevalence of MS and IR, though nonobese. IR correlated with components of MS not only in the urban but also in the rural population. To reduce the incidence of Type 2 Diabetes (T2DM) and cardiovascular disease (CVD) in our populations, early identification of populations at risk based on prevalence of MS and IR will become of prime importance.

Chronic treatment with first or second generation antipsychotics in rodents: effects on high affinity nicotinic and muscarinic acetylcholine receptors in the brain.

Several postmortem and neuroimaging studies suggest that central nicotinic and muscarinic acetylcholine receptors are important in both the pathophysiology and pharmacotherapy of schizophrenia. However, while antipsychotic drugs are routinely used in the therapeutics of schizophrenia, little is known about their effects on the densities of these receptors when they are administered for extended periods of time (a common practice in the clinical setting). In the present study in rats, the residual effects of prior chronic exposure to representative first generation antipsychotics and second generation antipsychotics on the densities of high affinity nicotinic acetylcholine receptors and muscarinic acetylcholine receptor in the brain were investigated. Test subjects were treated with the first generation antipsychotics, haloperidol (2.0 mg/kg/day) or chlorpromazine (10.0 mg/kg/day) or the second generation antipsychotics, risperidone (2.5 mg/kg/day) or olanzapine (10.0 mg/kg/day) in drinking water for periods of 90 or 180 days, given a drug-free washout period (i.e. returned to normal drinking water) for two weeks and then killed. Quantitative receptor autoradiography was subsequently performed using 16 mum sagittal slices of whole brain incubated with [3H]-epibatidine, [3H]-pirenzepine or [3H]-AFDX-384 to measure high affinity nicotinic acetylcholine receptors, M1 and M2 muscarinic acetylcholine receptors, respectively. The most notable experimental result was a moderate, but significant (P<0.01) increase in [3H]-AFDX-384 binding sites in a number of brain regions (including cortex, hippocampus, subiculum, substantia innominata, and thalamus) associated with prior exposure to olanzapine for 90, but not 180 days. Olanzapine was also associated with a significantly higher density of [3H]-pirenzepine binding sites in cortex lamina I after 90 days of prior drug exposure. These data indicate that chronic treatment with a commonly used second generation antipsychotic, olanzapine is associated with modest increases in M2 muscarinic acetylcholine receptors in memory-related brain regions that may eventually abate with longer periods of chronic drug exposure.

Chronic exposure to typical or atypical antipsychotics in rodents: temporal effects on central alpha7 nicotinic acetylcholine receptors.

A decrease in alpha7 nicotinic acetylcholine receptors in the hippocampus has been hypothesized to contribute to alterations in auditory gating and other behavioral impairments in schizophrenia. However, while both typical and atypical neuroleptics are routinely used in the therapeutics of schizophrenia, little is known about their effects on auditory gating or alpha7 nicotinic acetylcholine receptor expression particularly when they are administered for extended periods of time (which is common in the clinical setting). In the present study in normal rats, the residual effects of prior chronic treatment (90 or 180 days) with representative typical and atypical neuroleptics (oral haloperidol, 2.0 mg/kg/day; chlorpromazine, 10.0 mg/kg/day, risperidone, 2.5 mg/kg/day; or olanzapine, 10.0 mg/kg/day) on prepulse inhibition of the auditory gating response were investigated. The densities of alpha7 nicotinic acetylcholine receptors were subsequently measured using [125I]-alpha-bungarotoxin autoradiography. The results indicated that none of the compounds significantly altered the startle amplitude or prepulse inhibition response either during drug treatment (day 60) or after 90 or 180 days of treatment (i.e. during a drug free washout). However, prior exposure to chlorpromazine, risperidone and olanzapine for 90 days resulted in modest but significant (P<0.01) decreases in [125I]-alpha-bungarotoxin binding sites in some brain regions (e.g. posterior cortical amygdala). After 180 days of treatment, decreases in [(125I]-alpha-bungarotoxin binding ranging from approximately 12% (lateral dentate gyrus) up to 24% (e.g. CA1 hippocampal region) were evident in the risperidone group in 13 of the 36 regions analyzed while decreases associated with the other neuroleptics agents were still present, but not statistically significant. These data indicate that the commonly used atypical neuroleptic, risperidone is associated with time dependent and persistent negative effects on an important biological substrate of memory (i.e. the alpha7 nicotinic receptor), but that the magnitude of the deficits was not sufficient to impair auditory gating.

Red blood cell membrane essential fatty acid metabolism in early psychotic patients following antipsychotic drug treatment.

A role of indices of oxidative stress, oxidative injury, and abnormal membrane phospholipid, specifically the phospholipid essential polyunsaturated fatty acids (EPUFAs) metabolism has been suggested based on studies in separate groups of patients with or without medication. The current study investigated the relationship between these biochemical measures in first-episode psychotic patients (N=16) at baseline and after 6 months of antipsychotic treatment (N=5 each with risperidone and olanzapine) and compared them to matched normal subjects. The indices of oxidative stress included: antioxidant enzymes; superoxide dismutase, glutathione peroxidase and catalase; and the oxidative injury as the levels of plasma lipid peroxides. The key membrane EPUFA's been; linolenic acid, arachidonic acid, nervonic acid, docosapentaenoic acid and docosahexaenoic acid. Furthermore, the changes in these biochemical measures were correlated with clinical symptomatology. Data indicated that, at baseline, reduced levels of antioxidant enzymes were associated with increased plasma lipid peroxides and reduced membrane EPUFAs, particularly omega-3 fatty acids. Furthermore, these biochemical measures normalized after 6 months of antipsychotic treatment. Parallel-improved psychopathology indicated that membrane EPUFA status might be partly affected by oxidative damage, which together may contribute to the pathophysiology and thereby, psychopathology of schizophrenia. These data also support the augmentation of antipsychotic treatment by supplementation with a combination of antioxidants and omega-3 fatty acids.

Antipsychotic drugs differentially modulate apolipoprotein D in rat brain.

Apolipoprotein-D (apoD), a member of the lipocalin family of proteins, binds to arachidonic acid and cholesterol among other hydrophobic molecules. Recently, elevated apoD levels have been reported in the post-mortem brains, as well as plasma, of schizophrenic patients and in rodent brains after chronic treatment with clozapine (CLOZ). These findings and the evidence for altered membrane lipid metabolism in schizophrenia suggest that apoD may have a role in the pathophysiology of illness, and also in the differential clinical outcome following treatment with typical and atypical antipsychotic drugs. Here, we compared the effects of these antipsychotics on the expression of apoD in rat brain. Chronic treatment with typical antipsychotic, haloperidol (HAL) reduced apoD expression in hippocampus, piriform cortex and caudate-putamen (p = 0.027-0.002), whereas atypical antipsychotics, risperidone (RISP) and olanzapine (OLZ) increased (p = 0.051 to < 0.001 and p = 0.048 to < 0.001, respectively) apoD expression. In hippocampus, HAL-induced changes were present in CA1, CA3 and dentate gyrus, however, apoD levels in motor cortex were unchanged. There were also very dramatic effects of HAL on the neuronal morphology, particularly, cellular shrinkage and disorganization with the loss of neuropil. Post-treatment, either with RISP or OLZ, was very effective in restoring the HAL-induced reduction of apoD, as well as cellular morphology. Similarly, pre-treatments were also effective, but slightly less than post-treatment, in preventing HAL-induced reduction of apoD. The increased expression of apoD by atypical antipsychotics may reflect a novel molecular mechanism underlying their favorable effects compared with HAL on cognition, negative symptoms and extra-pyramidal symptoms in schizophrenia.

Haematologic and immunophenotypic profile of acute myeloid leukemia: an experience of Tata Memorial Hospital.

OBJECTIVES: To study the hematologic and immunophenotypic profile of 260 cases of acute myeloid leukemia at diagnosis. MATERIAL AND METHODS: This is a retrospective analysis of 260 cases of AML diagnosed at our institution between 1998 and 2000. Diagnosis was based on peripheral blood and bone marrow examination for morphology cytochemistry and immunophenotypic studies. SPSS software package, version 10, was used for statistical analysis. RESULTS: Seventy-six percent of our cases were adults. The age of the patients ranged from one year to 78 years with a median age of 27.2 years. There were 187 males and 73 females. The commonest FAB subtype, in both children and adults, was AML-M2. The highest WBC counts were seen in AML-M1 and the lowest in AML-M3 (10-97 x 10(9)/L, mean 53.8 x 10(9)/L). The mean values and range for hemoglobin was 6.8 gm/l (1.8 gm/l to 9.2 gm/l), platelet count 63.3 x 10(9)/L (32-83 x 10(9)/L), peripheral blood blasts 41.4% (5 to 77%) and bone marrow blasts 57.6% (34-96%). Myeloperoxidase positivity was highest in the M1, M2 and M3 subtypes. CD13 and CD33 were the most useful markers in the diagnosis of AML. CD14 and CD36 were most often seen in monocytic (38%) and myelomonocytic (44%) leukemias. Lymphoid antigen expression was seen in 15% of cases. CD7 expression was the commonest (11%). CONCLUSION: AML accounted for 39.8% of all acute leukemias at this institution. The most common subtype was AML-M2. Myeloperoxidase stain was a useful tool in the diagnosis of myeloid leukemias. CD13 and CD33 were the most diagnostic myeloid markers.

Differential effects of chronic haloperidol and olanzapine exposure on brain cholinergic markers and spatial learning in rats.

RATIONALE: In psychiatric patients, haloperidol (HAL) induces a number of adverse extrapyramidal and cognitive symptoms, which appear to be less problematic with olanzapine (OLZ). In animals, HAL may initiate a number of harmful effects on central nervous system neurons, including damage to cholinergic pathways - an effect that could be especially deleterious to those experiencing memory dysfunction. The identification of the neurobiological substrates of such effects in animal models may help to improve the algorithms used for proper drug selection especially for long-term neuroleptic use. OBJECTIVES: The aim of this study was to compare the effects of chronic (45-day and 90-day), continuous oral exposure to HAL with OLZ for effects on cognitive performance and cholinergic markers in rats. METHODS: After chronic neuroleptic exposure (and a 4-day washout) spatial memory performance was measured in a water maze task, and choline acetyltransferase (ChAT) immunoreactivity was assessed with immunofluorescence staining. RESULTS: In water maze experiments, HAL and OLZ (relative to vehicle) administered for 90 days (but not 45 days) significantly impaired learning performance (i.e., higher mean latencies across several trials to reach a hidden platform). HAL administered for 90 days was associated with impairment across a greater number of trials than OLZ and it also impaired probe trial performance, as indicated by a reduced number of crossings over the previous platform area (when compared with OLZ or vehicle). Both 45 days and 90 days of HAL treatment reduced ChAT staining in the cortex and hippocampus when compared with OLZ or vehicle. CONCLUSIONS: The results in the rat suggest that OLZ (relative to HAL) may be more desirable as an antipsychotic for patients suffering from memory dysfunction especially for those in which cholinergic deficits may already be present.

Oxidative stress and role of antioxidant and omega-3 essential fatty acid supplementation in schizophrenia.

1. Schizophrenia is a major mental disorder that has a lifetime risk of 1% and affects at young age (average age at the onset 24 +/- 4.6 years) in many cultures around the world. The etiology is unknown, the pathophysiology is complex, and most of the patients need treatment and care for the rest of their lives. 2. Cellular oxidative stress is inferred from higher tissue levels of reactive oxygen species (ROS, e.g., O2*-, OH*, OH-, NO* and ONOO--) than its antioxidant defense that cause peroxidative cell injury, i.e., peroxidation of membrane phospholipids, particularly esterified essential polyunsaturated fatty acids (EPUFAS), proteins and DNA. 3. Oxidative stress can lead to global cellular with predominantly neuronal peroxidation, since neurons are enriched in highly susceptible EPUFAs and proteins, and damages DNA is not repaired effectively. 4. Such neuronal peroxidation may affect its function (i.e., membrane transport, loss of mitochondrial energy production, gene expression and therefore receptor-mediated phospholipid-dependent signal transduction) that may explain the altered information processing in schizophrenia. 5. It is possible that the oxidative neuronal injury can be prevented by dietary supplementation of antioxidants (e.g., vitamins E, C and A; beta-carotene, Q-enzyme, flavons, etc.) and that membrane phospholipids can be corrected by dietary supplementation of EPUFAs. 6. It may be that the oxidative stress is lower in populations consuming a low caloric diet rich in antioxidants and EPUFAs, and minimizing smoking and drinking. 7. Oxidative stress exists in schizophrenia based on altered antioxidant enzyme defense, increased lipid peroxidation and reduced levels of EPUFAs. The life style of schizophrenic patients is also prooxidative stress, i.e., heavy smoking, drinking, high caloric intake with no physical activity and treatment with pro-oxidant drugs. 8. The patients in developed countries show higher levels of lipid peroxidation and lower levels of membrane phospholipids as compared to patients in the developing countries. 9. Initial observations on the improved outcome of schizophrenia in patients supplemented with EPUFAs and antioxidants suggest the possible beneficial effects of dietary supplementation. 10. Since the oxidative stress exists at or before the onset of psychosis the use of antioxidants from the very onset of psychosis may reduce the oxidative injury and dramatically improve the outcome of illness.

Is dietary fiber beneficial in chronic ischemic heart disease?

OBJECTIVES: To evaluate the benefit of a dietary fiber preparation (Fibernat) in patients with chronic ischemic heart disease (IHD). METHODS: From January 1997 to March 1998, 114 consecutive patients with chronic IHD were enrolled in this prospective double blind randomized placebo controlled trial. The fiber (F) and placebo (P) groups were comparable at baseline. All patients were given advice regarding dietary and lifestyle modifications. Concomitant drug therapy was not altered. The drug (consisting of soluble and insoluble fibers obtained from fenugreek, guar gum and wheat bran) and placebo were administered for six months (10 grams twice daily). RESULTS: The following parameters improved in both groups: HDL cholesterol (32 to 39 mg/dl, p < 0.0009 in F and 33 to 38, p < 0.007 in P), total: HDL cholesterol ratio (6.7 to 5.6, p < 0.0007 in F and from 7.0 to 6.0, p < 0.01 in P) and weight (64.0 to 63.0 kg, p < 0.002 in F and 60.3 to 59.5, p < 0.002 in P). The Apolipoprotein B increased (101 to 129 mg/dl, p < 0.00001 in F and 98 to 127, p < 0.0008 in P). The following parameters improved only in group F: LDL cholesterol (146 to 134, p < 0.027), Apolipoprotein A-1 (105 to 139, p < 0.001), body mass index (24.9 to 24.5, p < 0.03) and waist circumference (37.2 to 36.7, p < 0.03). Total cholesterol, VLDL cholesterol, triglycerides, hip circumference, W:H ratio, exercise time and blood sugar were unchanged in both groups. CONCLUSIONS: Fibernat is well tolerated, safe and had favorable effects on LDL cholesterol, Apolipoprotein A-1, body mass index and waist circumference.

Anthropometry, lipid profile and dietary pattern of patients with chronic ischaemic heart disease.

The anthropometry, lipid profile and dietary characteristics of 114 patients with chronic ischaemic heart disease (IHD) were evaluated. There were 91 (80%) men and the mean age was 56 +/- 9 years. The body mass index was near normal (24.4 +/- 3.4), but the waist: hip ratio was high (0.94 +/- 0.06) suggesting central obesity. This was well in accordance of the step II recommendations of the NCEP guidelines as regards their caloric intake and its break-up in terms of carbohydrate, protein and fat (including saturated, mono-unsaturated and poly-unsaturated fatty acids) content. Their daily cholesterol intake (31 +/- 32 mg/day, range 4-180) was very low. The total cholesterol (212 +/- 37 mg%) was marginally elevated, HDL cholesterol (33 +/- 7.5 mg%) was low, LDL cholesterol (148 +/- 39 mg%) was high and the total: HDL ratio (6.8 +/- 2.0) was significantly abnormal. The serum triglyceride level (154 +/- 68 mg%) was on the higher side of normal. These observations give further credence to the recently evolving view that there are different and hitherto unrecognised risk factors of IHD in Indians, who seem to have the highest incidence of IHD amongst all ethnic groups of the world despite consuming a diet low in fat and cholesterol content.

Elevated plasma lipid peroxides at the onset of nonaffective psychosis.

BACKGROUND: Impaired antioxidant defense and increased lipid peroxidation has been reported in chronic schizophrenic patients. Recently, we have reported an impaired antioxidant defense in never medicated first-episode schizophrenic and schizophreniform patients. We report now a concomitant increase in plasma lipid peroxides. METHODS: The plasma lipid peroxides [thiobarbituric acid reactive substances (TBARS)] were analyzed by chemical and high performance liquid chromatography procedures in 26 patients admitted for a first episode of schizophrenic (N = 17) or schizophreniform psychosis (N = 9) and 16 normal control subjects. The patients had a duration of 4.5 days (SD 2.8) of psychosis at the time of the study. RESULTS: Plasma TBARS levels were significantly higher in the patients than in normal controls (P < .002). TBARS levels were above the normal range in 16 of the 26 patients. Higher TBARS levels were associated with a greater severity of negative symptoms and lower red blood cell activity of the glutathione peroxidase. CONCLUSIONS: The findings indicate ongoing oxidative injury at the very onset of psychosis. If valid, this would indicate the need for adjunctive antioxidant treatment from the beginning of the course of nonaffective psychoses. This might prevent a deteriorating course and development of the deficit syndrome.

Cultured skin fibroblasts as a cell model for investigating schizophrenia.

Cultured skin fibroblasts, among other non-neuronal cells (e.g. platelets, lymphocytes, red blood cells), provide an advantageous system for investigating dynamic molecular regulatory processes underlying abnormal cell growth, metabolism, and receptor-mediated signal transduction, without the confounding effects of disease state and its treatment in a variety of brain disorders, including schizophrenia, and are useful for studies of systemic biochemical defects with predominant consequences for brain function. These cells are also useful for studying aspects of neurotransmitter functions because the cells express enzymes involved in their metabolism, as well as their receptors with complete machinery for signal transduction. These processes also function predictably with receptors that are transfected in fibroblasts. This review will focus on the use of cultured skin of which have also been studied in post-mortem brains. These mechanisms might involve DNA processing and mitogenesis, cell-cell adhesion molecules, actions of growth factors, oxidative damage, and membrane phospholipid derived second messengers. This review will further discuss the implications of these processes to clinical and structural brain abnormalities. An understanding of these biochemical processes might help establish therapeutic implications and identify the risk for illness through experimental strategies such as epidemiology, family pedigree and high risk populations. Finally, despite some methodological limitations, skin fibroblasts are relatively easy to grow and maintain as primary cultures or as immortalized cell lines for long periods of time for use in investigating newly identified biochemical abnormalities.