Efficacy and safety of antidepressant augmentation of continued antipsychotic treatment in patients with schizophrenia.

OBJECTIVE: To evaluate the efficacy and safety of antidepressant augmentation of antipsychotics in schizophrenia. METHODS: Systematic literature search (PubMed/MEDLINE/PsycINFO/Cochrane Library) from database inception until 10/10/2017 for randomized, double-blind, efficacy-focused trials comparing adjunctive antidepressants vs. placebo in schizophrenia. RESULTS: In a random-effects meta-analysis (studies = 42, n = 1934, duration = 10.1 ± 8.1 weeks), antidepressant augmentation outperformed placebo regarding total symptom reduction [standardized mean difference (SMD) = -0.37, 95% confidence interval (CI) = -0.57 to -0.17, P < 0.001], driven by negative (SMD = -0.25, 95% CI = -0.44-0.06, P = 0.010), but not positive (P = 0.190) or general (P = 0.089) symptom reduction. Superiority regarding negative symptoms was confirmed in studies augmenting first-generation antipsychotics (FGAs) (SMD = -0.42, 95% CI = -0.77, -0.07, P = 0.019), but not second-generation antipsychotics (P = 0.144). Uniquely, superiority in total symptom reduction by NaSSAs (SMD = -0.71, 95% CI = -1.21, -0.20, P = 0.006) was not driven by negative (P = 0.438), but by positive symptom reduction (SMD = -0.43, 95% CI = -0.77, -0.09, P = 0.012). Antidepressants did not improve depressive symptoms more than placebo (P = 0.185). Except for more dry mouth [risk ratio (RR) = 1.57, 95% CI = 1.04-2.36, P = 0.03], antidepressant augmentation was not associated with more adverse events or all-cause/specific-cause discontinuation. CONCLUSIONS: For schizophrenia patients on stable antipsychotic treatment, adjunctive antidepressants are effective for total and particularly negative symptom reduction. However, effects are small-to-medium, differ across antidepressants, and negative symptom improvement seems restricted to the augmentation of FGAs.

High risk of post-infectious irritable bowel syndrome in patients with Clostridium difficile infection.

BACKGROUND: Infectious enteritis is a commonly identified risk factor for irritable bowel syndrome (IBS). The incidence of Clostridium difficile infection (CDI) is on the rise. However, there is limited information on post-infectious IBS (PI-IBS) development following CDI and the host- and infection-related risk factors are not known. AIM: To determine the incidence and risk factors for PI-IBS following CDI. METHODS: A total of 684 cases of CDI identified from September 2012 to November 2013 were surveyed. Participants completed the Rome III IBS questionnaire and details on the CDI episode. Predictive modelling was done using logistic regression to evaluate risk factors for PI-IBS development. RESULTS: A total of 315 CDI cases responded (46% response rate) and 205 were at-risk (no pre-CDI IBS) for PI-IBS development. A total of 52/205 (25%) met the Rome III criteria for IBS ≥6 months following CDI. IBS-mixed was most common followed by IBS-diarrhoea. In comparison to those without subsequent PI-IBS, greater percentage of PI-IBS patients had CDI symptoms >7 days, nausea, vomiting, abdominal pain during CDI, anxiety and a higher BMI. Using logistic regression, CDI symptoms >7 days [Odds ratio (OR): 2.96, P = 0.01], current anxiety (OR: 1.33, P < 0.0001) and a higher BMI (OR: 1.08, P = 0.004) were independently associated with PI-IBS development; blood in the stool during CDI was protective (OR: 0.44, P = 0.06). CONCLUSIONS: In this cohort study, new-onset IBS is common after CDI. Longer CDI duration, current anxiety and higher BMI are associated with the diagnosis of C. difficile PI-IBS. This chronic sequela should be considered during active management and follow-up of patients with CDI.

(13) C mannitol as a novel biomarker for measurement of intestinal permeability.

BACKGROUND: Gastrointestinal (GI) and non-GI disorders are associated with altered intestinal permeability, which can be measured in vivo by urinary excretion after oral lactulose and mannitol ingestion. Inadvertent dietary consumption of (12) Carbon ((12) C, regular) mannitol in food or from other sources may interfere with the test's interpretation. (13) Carbon ((13) C) constitutes 1% of carbon in nature and (13) C mannitol is a stable isotope. Our aim was to determine the performance of (13) C mannitol for measurement of intestinal permeability. METHODS: Ten healthy volunteers underwent intestinal permeability assay using coadministered (12) C mannitol, (13) C mannitol and lactulose, followed by timed urine collections. Urinary sugar concentrations were measured using tandem high performance liquid chromatography-mass spectrometry. KEY RESULTS: We found that (13) C mannitol can be distinguishable from (12) C mannitol on tandem mass spectrometry. In addition, (13) C mannitol had ~20-fold lower baseline contamination compared to (12) C mannitol. We describe here the (13) C mannitol assay method for the measurement of intestinal permeability. CONCLUSIONS & INFERENCES: In conclusion, (13) C mannitol is superior to (12) C mannitol for measurement of intestinal permeability. It avoids issues with baseline contamination and erratic excretions during the testing period.

To study the prevalence and profile of metabolic syndrome, levels of hs-CRP, Lp(a) and serum ferritin in young Indian patients (< or = 45 years) with acute myocardial infarction.

OBJECTIVE: To study the prevalence and profile of metabolic syndrome, levels of hs-CRP, Lp(a) and serum ferritin in young Indian patients (< or = 45 years) with acute MI. METHODS: A total of 80 subjects in two groups (40 cases and 40 controls) of age < or = 45 years were studied. Diagnosis of MI was made using the American College of Cardiology and European Society of Cardiology guidelines for acute MI. Patients were assessed for presence of MetS, diagnosed as per modified ATP III criteria. The anthropometric measurements (including height, weight, waist circumference) and sample collection for lipid profile, fasting blood sugar, hs-CRP, Lp(a) and serum ferritin were done after seventy two hours of admission. RESULTS: The mean age for cases was 39.23 +/- 4.80 years and for controls it was 38.9 +/- 4.23 years. 19 (47.5%) patients out of 40 in group 1 fulfilled > or = 3/5 criteria for MetS while only 8 (20%) subjects in control group had MetS. Among five components of metabolic syndrome, increased waist circumference was most predominant factor followed by decreased HDL, increased TG, increased blood pressure and impaired fasting glucose. The mean value of serum ferritin was 279.33 +/- 46.69 mg in case group as compared to 245.15 +/- 56.94 in control group. hs-CRP (16.048 +/- 10.27 mg/l vs 1.8 +/- 1.6 mg/l) and Lp(a) (38.74 +/- 26.15 mg/dl vs 20.54 +/- 16.27 mg/dl) levels were significantly raised in cases as compared to control subjects. CONCLUSION: The present study revealed high prevalence of metabolic syndrome (47.5%) in young patients with acute MI. Serum hsCRP, a diagnostic and prognostic novel marker of inflammation was also significantly elevated in cases. Its relationship with metabolic syndrome is also well established. Lp(a) and serum ferritin were also raised in cases.

An unusual phaeoid fungi: Ulocladium, as a cause of chronic allergic fungal sinusitis.

Allergic fungal sinusitis (AFS) has been recognized as an important cause of chronic sinusitis commonly caused by Aspergillus spp. and various dematiaceous fungi like Bipolaris, Alternaria, Curvalaria, and etc. Ulocladium botrytis is a non pathogenic environmental dematiaceous fungi, which has been recently described as a human pathogen. Ulocladium has never been associated with allergic fungal sinusitis but it was identified as an etiological agent of AFS in a 35 year old immunocompetent female patient presenting with chronic nasal obstruction of several months duration to our hospital. The patient underwent FESS and the excised polyps revealed Ulocladium as the causative fungal agent.

Motor unit firing variability and synchronization during short-term light-load training in older adults.

We compared motor unit synchronization and firing rate variability within and across synergistic hand muscles during a pinching task following short-term light-load training to improve force steadiness in older adults. A total of 183 motor unit pairs before training and 158 motor unit pairs after training were recorded with intramuscular fine-wire electrodes within and across the first dorsal interosseous (FDI) and adductor pollicis (AdP) muscles during a pinch task performed by ten older adults before and after a 4-week short-term light-load training program. Nine younger adults performed the same experimental sessions 4 weeks apart with no training intervention. Two-minute sustained contractions of 2, 4, 8, and 12% maximal voluntary contraction (MVC) were performed with the non-dominant hand. The coefficient of variation (CV) of force was greater in older than in younger adults and was lower at the 2 and 4% MVC levels in both the finger (0.12 +/- 0.01 vs. 0.08 +/- 0.01, and 0.08 +/- 0.01 vs. 0.05 +/- 0.01, respectively) and thumb (0.11 +/- 0.01 vs. 0.08 +/- 0.01, and 0.09 +/- 0.01 vs. 0.05 +/- 0.01, respectively) compared to higher force levels following training in the older adults. There were no changes in CIS or k'-1 values following training. Motor unit firing rate variability significantly decreased at low force levels in the FDI muscle and also tended to decrease with training in the AdP muscle (p = 0.06). No changes occurred in the younger control group. These findings are the first to show that motor unit synchronization does not change during light-load training. Thus, it is likely that force steadiness in older adults improves by reducing motor unit firing variability rather than by changing motor unit synchronization.

Ultrasound quantification of anterior soft tissue thickness fails to predict difficult laryngoscopy in obese patients.

Morbid obesity is associated with difficult laryngoscopy and intubation. In the general population, bedside indices for predicting difficult intubation (i.e. Mallampati classification, thyromental distance, sternomental distance, mouth-opening and Wilson risk score) have poor-to-moderate sensitivity (20-62%) and moderate-to-fair specificity (82-97%). In the obese population, although the risk of difficult intubation after a positive Mallampati test is 34%, it is still not sufficient to be used as a single predictive test. An abundance of pretracheal soft tissue anterior to the vocal cords, as quantified by ultrasound, was a better predictor of difficult laryngoscopy than body mass index (BMI) in Israeli patients. Obesity is a growing problem in the United States: therefore we sought to confirm this finding in the obese population in the United States. We used ultrasound to quantify the neck soft tissue, from the skin to the anterior aspect of the trachea at the vocal cords, in 64 obese patients (BMI > 35). We assessed thyromental distance, mouth-opening, jaw movement, limited neck mobility, modified Mallampati score, abnormal upper teeth, neck circumference, confirmed obstructive sleep apnoea, BMI, age, race and gender as predictors. Twenty patients were classified as difficult laryngoscopy; they were older (47 +/- 9 vs 42 +/- 1 years; P = 0.048; mean +/- SD) and had less soft pretracheal tissue (20.4 +/- 3.0 vs 22.3 +/- 3.8 mm; P = 0.049) than did easy laryngoscopy patients. Multivariate regression indicated that none of the factors was an independent predictor of difficult laryngoscopy. We conclude that the thickness of pretracheal soft tissue at the level of the vocal cords is not a good predictor of difficult laryngoscopy in obese patients in the United States.

Candidemia--an under-recognized nosocomial infection in Indian hospitals.

OBJECTIVE: To study the occurrence of candidemia as a nosocomial infection in a large Indian teaching hospital and to evaluate the predisposing factors for development of such infections. METHODS: One hundred and one hospitalized patients that developed signs and symptoms of nosocomial bloodstream infections were screened for candidemia and were analyzed for the various predisposing factors like the age of the patient, the duration of hospitalization before the development of fever, neutropenia, use of chemotherapeutic agents, central venous catheters, broad spectrum antibiotics, infection with HIV, diabetes mellitus, use of corticosteroids, administration of total parenteral nutrition, haemodialysis, use of mechanical ventilation, hematological or other malignancies, underlying disease, and any surgical procedure performed on the patient. Candidemic patients were followed up for outcome and the effect of nosocomial candidemia on mortality was assessed and analyzed statistically. RESULTS: Out of the 101 patients, seven patients had candidemia, an incidence in study population of 6.9%. Three (42.8%) were infected with albicans and the rest with non-albicans candidemia. All the patients with candidemia were admitted in the Intensive Care Units. Amongst the risk factors, the length of hospitalization (p = 0.018), broad-spectrum antibiotics (p = 0.045), central venous catheters (p = 0.005), mechanical ventilation (p = 0.0139) and total parenteral nutrition (p = 0.001) were found to be significantly related to acquisition of nosocomial candidemia. Mortality in the candidemic patients was influenced only by the age of the patients (p = 0.001). Although the mortality amongst the candidemic patients was twice as much as that of the patients not having this infection, still the difference did not reach significance (p = 0.117). CONCLUSION: Candidemia is an important problem in Indian hospitals. Diagnostic delays could be shortened by more active screening for candidemia especially in the intensive care settings. The rising incidence of non-albicans candidemia in the United States probably is true here as well. There should be a concerted effort to control known risk factors especially in intensive care units.

Magnesium sulphate only slightly reduces the shivering threshold in humans.

BACKGROUND: Hypothermia may be an effective treatment for stroke or acute myocardial infarction; however, it provokes vigorous shivering, which causes potentially dangerous haemodynamic responses and prevents further hypothermia. Magnesium is an attractive anti-shivering agent because it is used for treatment of postoperative shivering and provides protection against ischaemic injury in animal models. We tested the hypothesis that magnesium reduces the threshold (triggering core temperature) and gain of shivering without substantial sedation or muscle weakness. METHODS: We studied nine healthy male volunteers (18-40 yr) on two randomly assigned treatment days: (1) control and (2) magnesium (80 mg kg(-1) followed by infusion at 2 g h(-1)). Lactated Ringer's solution (4 degrees C) was infused via a central venous catheter over a period of approximately 2 h to decrease tympanic membrane temperature by approximately 1.5 degrees C h(-1). A significant and persistent increase in oxygen consumption identified the threshold. The gain of shivering was determined by the slope of oxygen consumption vs core temperature regression. Sedation was evaluated using a verbal rating score (VRS) from 0 to 10 and bispectral index (BIS) of the EEG. Peripheral muscle strength was evaluated using dynamometry and spirometry. Data were analysed using repeated measures anova; P<0.05 was statistically significant. RESULTS: Magnesium reduced the shivering threshold (36.3 [SD 0.4] degrees C vs 36.6 [0.3] degrees C, P = 0.040). It did not affect the gain of shivering (control, 437 [289] ml min(-1) degrees C(-1); magnesium, 573 [370] ml min(-1) degrees C(-1); P=0.344). The magnesium bolus did not produce significant sedation or appreciably reduce muscle strength. CONCLUSIONS: Magnesium significantly reduced the shivering threshold. However, in view of the modest absolute reduction, this finding is considered to be clinically unimportant for induction of therapeutic hypothermia.

Successful pregnancy in untreated limited Wegener's granulomatosis.

A thirty four year old female presented with upper and lower respiratory symptoms in the third trimester of pregnancy. After the delivery of a healthy baby, the symptoms progressed to involve multiple organ systems and eventually a diagnosis of limited Wegener's Granulomatosis (Carrington-Liebow syndrome) was made. The extremely rare combination of WG and pregnancy, especially the onset of disease in late pregnancy is discussed. The successful outcome of pregnancy even without treatment of WG is the highlight of the case.

Block-dependent sedation during epidural anaesthesia is associated with delayed brainstem conduction.

BACKGROUND: Neuraxial anaesthesia produces a sedative and anaesthetic-sparing effect. Recent evidence suggests that spinal cord anaesthesia modifies reticulo-thalamo-cortical arousal by decreasing afferent sensory transmission. We hypothesized that epidural anaesthesia produces sensory deafferentation-dependent sedation that is associated with impairment of brainstem transmission. We used brainstem auditory evoked potentials (BAEP) to evaluate reticular function in 11 volunteers. METHODS: Epidural anaesthesia was induced with 2-chloroprocaine 2%. Haemodynamic and respiratory responses, sensory block level, sedation depth and BAEP were assessed throughout induction and resolution of epidural anaesthesia. Sedation was evaluated using verbal rating score (VRS), observer's assessment alertness/sedation (OAA/S) score, and bispectral index score (BIS). Prediction probability (PK) was used to associate sensory block with sedation, as well as BIS with other sedation measures. Spearman's rank order correlation was used to associate block level and sedation with the absolute and interpeak BAEP latencies. RESULTS: Sensory block level significantly predicted VRS (PK=0.747), OAA/S score (PK=0.748) and BIS. BIS predicted VRS and OAA/S score (PK=0.728). The latency of wave III of BAEP significantly correlated with sedation level (rho=0.335, P<0.01) and sensory block (rho=0.394, P<0.01). The other BAEP parameters did not change during epidural anaesthesia. Haemodynamic and respiratory responses remained stable throughout the study. CONCLUSIONS: Sedation during epidural anaesthesia depends on sensory block level and is associated with detectable block-dependent alterations in the brainstem auditory evoked responses. Sensory deafferentation may reduce CNS alertness through mechanisms related to brainstem neural activity.

Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis.

Patients with familial Mediterranean fever suffer sporadic inflammatory attacks characterized by fever and intense pain (in joints, abdomen, or chest). Pyrin, the product of the MEFV locus, is a cytosolic protein whose function is unknown. Using pyrin as a "bait" to probe a yeast two-hybrid library made from neutrophil cDNA, we isolated apoptotic speck protein containing a caspase recruitment domain (CARD) (ASC), a proapoptotic protein that induces the formation of large cytosolic "specks" in transfected cells. We found that when HeLa cells are transfected with ASC, specks are formed. After co-transfection of cells with ASC plus wild type pyrin, an increase in speck-positive cells is found, and speck-positive cells show increased survival. Immunofluorescence studies show that pyrin co-localizes with ASC in specks. Speck localization requires exon 1 of pyrin, but exon 1 alone of pyrin does not result in an increase in the number of specks. Exon 1 of pyrin and exon 1 of ASC show 42% sequence similarity and resemble death domain-related structures in modeling studies. These findings link pyrin to apoptosis pathways and suggest that the modulation of cell survival may be a component of the pathophysiology of familial Mediterranean fever.

Episodic evolution of pyrin in primates: human mutations recapitulate ancestral amino acid states.

Familial Mediterranean fever (FMF; MIM 249100) is an autosomal recessive disease characterized by recurrent attacks of fever with synovial, pleural or peritoneal inflammation. The disease is caused by mutations in the gene encoding the pyrin protein. Human population studies have revealed extremely high allele frequencies for several different pyrin mutations, leading to the conclusion that the mutant alleles confer a selective advantage. Here we examine the ret finger protein (rfp) domain (which contains most of the disease-causing mutations) of pyrin during primate evolution. Amino acids that cause human disease are often present as wild type in other species. This is true at positions 653 (a novel mutation), 680, 681, 726, 744 and 761. For several of these human mutations, the mutant represents the reappearance of an ancestral amino acid state. Examination of lineage-specific dN/dS ratios revealed a pattern consistent with the signature of episodic positive selection. Our data, together with previous human population studies, indicate that selective pressures may have caused functional evolution of pyrin in humans and other primates.

Large-dose oral dextromethorphan as an adjunct to patient-controlled analgesia with morphine after knee surgery.

Dextromethorphan is a weak N-methyl-d-aspartate (NMDA) receptor antagonist that inhibits spinal cord sensitization in animal models of pain and also inhibits the development of cutaneous secondary hyperalgesia after tissue trauma. Perhaps coadministration of an NMDA antagonist with an opioid would lead to better pain relief, particularly with movement and an opioid-sparing effect. This has been shown for ketamine, but previous studies with dextromethorphan that have used small doses have shown only a modest reduction in morphine requirements with no or minimal changes in the postoperative pain experience. We sought to determine whether a large dose of this drug, just below the maximum tolerated dose, could potentiate morphine analgesia while simultaneously causing a significant improvement in the management of the postoperative pain experience. Sixty-six patients undergoing knee surgery were enrolled in the study. The study design was a prospective, randomized double-blinded comparison with placebo of 200 mg of dextromethorphan given eight hourly. Postoperative pain experiences were assessed by postoperative morphine usage. Visual analog and verbal rating scales were used to assess pain with movement as well as side effects. Dextromethorphan treatment led to a significant but modest reduction in morphine requirements (29.3% P < 0.05) but no reduction in postoperative pain levels. We conclude that increasing orally administered dextromethorphan to near maximum tolerated doses does not provide greater morphine sparing than 20-40 mg given 6-8 hourly as in previous studies. Furthermore we conclude that dextromethorphan does not improve pain scores in a manner expected of a drug with NMDA antagonist properties.

Leiomyosarcoma of the larynx: diagnosis aided by advances in immunohistochemical staining.

We present only the 12th reported case of a laryngeal leiomyosarcoma. This tumor was diagnosed with the aid of the newer immunohistochemical stains on archival paraffin-embedded tissue. The diagnosis and management of these tumors is based largely on the patterns seen in the small number of earlier reported cases of head and neck leiomyosarcomas and laryngeal sarcomas.

Nutritional status of the elderly.

Elderly become vulnerable to malnutrition owing to inappropriate dietary intake, poor economic status and social deprivation. Elderly are known to be easily subjected to inanition and avitaminosis resulting in multiple nutritional deficiencies. Urban slum dwellers, rural poor and those living alone appear to be at a higher risk of poor dietary intake. Though food consumption patterns of rural and urban elderly show a distinct difference, these are greatly influenced by regional dietary patterns. The diets of institutionalised and free living elderly reveal adequate nutrient intakes except iron and vitamin A. The nutrients least adequately supplied in the diets of Indian elderly are calcium, Iron, vitamin A, riboflavin and niacin along with energy deficits. Changes in body composition which mark the onset of the ageing process, include decline in lean body mass and increase in adipose tissue. A high prevalence of iron deficiency anaemia has also been reported among Indian elderly.

Apraclonidine and brimonidine effects on anterior ocular and cardiovascular physiology in normal and sympathectomized monkeys.

Apraclonidine and brimonidine administered topically to one eye of ketamine-anesthetized normal cynomolgus monkeys each produced a dose-related bilateral reduction in intraocular pressure which was not dependent on intact sympathetic innervation. Brimonidine was more potent and efficacious (10-12 mmHg maximum intraocular pressure reduction 2 hr after 200 micrograms) but produced a shorter-lasting effect than apraclonidine (4 mmHg maximum intraocular pressure reduction 1-6 hr after 600-1000 micrograms). Apraclonidine had little effect on pupil diameter, but brimonidine produced a dose-related bilateral miosis which was dependent on intact sympathetic innervation. Neither drug significantly affected refractive error. Topical brimonidine, but not apraclonidine, produced a dose-dependent reduction in mean arterial blood pressure, while both drugs lowered heart rate. A dose-dependent bilateral reduction in aqueous humor flow rate calculated over a 6-hr period following drug administration was produced by both topical apraclonidine (maximum 30-35% reduction with 600 micrograms) and brimonidine (maximum 30-45% reduction with 50-250 micrograms), which was not dependent on intact sympathetic innervation. Maintenance of blood pressure by intravenous infusion of angiotensin II had no effect on the aqueous humor flow suppression produced by 100 micrograms of topical brimonidine, but pentobarbital anesthesia abolished it. Intracameral injection of 10 micrograms brimonidine in rhesus monkeys produced an ipsilateral approximately 15% reduction in aqueous humor flow calculated for the 1-3 hr post-injection period. The cardiovascular and contralateral ocular effects observed with both drugs are presumably related to the monkeys' small body weight, and the magnitude of IOP reduction for a given degree of flow suppression would be greater in hypertensive than in normotensive eyes. Caution must therefore be exercised in extrapolating from our data in ocular normotensive monkeys to the glaucomatous human.

Congenital syphilitic hepatitis.

Hepatitis is a known manifestation of congenital syphilis, however hepatitis developing during penicillin therapy is unknown. Ten patients of congenital syphilis were studied and serial liver enzymes were done before and after starting penicillin therapy. Eight of the ten patients developed hepatitis after initiating penicillin therapy. Whether hepatitis in these cases was secondary to toxic reaction to the products of treponemal lysis or an autoimmune reaction needs to be investigated.