A postpartum haemorrhage package with condom uterine balloon tamponade: a prospective multi-centre case series in Kenya, Sierra Leone, Senegal, and Nepal.

OBJECTIVE: To evaluate the effectiveness and safety of an ultra-low-cost uterine balloon tamponade package (ESM-UBT™) for facility-based management of uncontrolled postpartum haemorrhage (PPH) in Kenya, Sierra Leone, Senegal, and Nepal. DESIGN: Prospective multi-centre case series. SETTING: Facilities in resource-scarce areas of Kenya, Sierra Leone, Nepal, and Senegal. POPULATION: Women with uncontrolled postpartum haemorrhage in 307 facilities across the four countries. METHODS: A standardised ESM-UBT package was implemented in 307 facilities over 29 months (1 September 2012 to 1 February 2015). Data were collected via a multi-pronged approach including data card completion, chart reviews, and provider interviews. Beginning in August 2014, women who had previously undergone UBT placement were sought and queried regarding potential complications associated with UBT use. MAIN OUTCOME MEASURES: All-cause survival, survival from PPH, and post-UBT use complications (surgery, hospitalisation, antibiotics for pelvic infection) associated with UBT use. RESULTS: 201 UBTs were placed for uncontrolled vaginal haemorrhage refractory to all other interventions. In all, 38% (71/188) of women were either unconscious or confused at the time of UBT insertion. All-cause survival was 95% (190/201). However, 98% (160/163) of women survived uncontrolled PPH if delivery occurred at an ESM-UBT online facility. One (1/151) potential UBT-associated complication (postpartum endometritis) was identified and two improvised UBTs were placed in women with a ruptured uterus. CONCLUSIONS: These pilot data suggest that the ESM-UBT package is a clinically promising and safe method to arrest uncontrolled postpartum haemorrhage and save women's lives. The UBT was successfully placed by all levels of facility-based providers. Future studies are needed to further evaluate the effectiveness of ESM-UBT in low-resource settings. TWEETABLE ABSTRACT: Evidence for ESM-UBT as a clinically promising and safe method to arrest uncontrolled PPH and save women's lives.

Buspirone treatment of alcoholism: age of onset, and cerebrospinal fluid 5-hydroxyindolacetic acid and homovanillic acid concentrations, but not medication treatment, predict return to drinking.

Disturbances in central nervous system serotonin (5-HT) have been implicated in the pathophysiology of alcoholism. To test the hypothesis that increasing 5-HT function could promote treatment compliance, we randomized patients who had completed a 5-week inpatient treatment program for alcoholism to receive either buspirone or placebo for 1 year. Ten of the 49 patients remained in the study for the entire year. The days to relapse did not differ significantly between patients receiving buspirone or placebo. Regardless of the medication, late-onset alcoholics had a longer time to relapse than early-onset alcoholics. Cerebrospinal fluid showed that patients with high concentrations of both the 5-HT metabolite, 5-hydroxyindoleacetic acid, and the dopamine metabolite, homovanillic acid, were more likely to relapse, compared with patients with low concentrations of cerebrospinal fluid 5-hydroxyindoleacetic acid and homovanillic acid.

Effects of moderate alcohol consumption on the central nervous system.

The concept of moderate consumption of ethanol (beverage alcohol) has evolved over time from considering this level of intake to be nonintoxicating and noninjurious, to encompassing levels defined as "statistically" normal in particular populations, and the public health-driven concepts that define moderate drinking as the level corresponding to the lowest overall rate of morbidity or mortality in a population. The various approaches to defining moderate consumption of ethanol provide for a range of intakes that can result in blood ethanol concentrations ranging from 5 to 6 mg/dl, to levels of over 90 mg/dl (i.e., approximately 20 mM). This review summarizes available information regarding the effects of moderate consumption of ethanol on the adult and the developing nervous systems. The metabolism of ethanol in the human is reviewed to allow for proper appreciation of the important variables that interact to influence the level of exposure of the brain to ethanol once ethanol is orally consumed. At the neurochemical level, the moderate consumption of ethanol selectively affects the function of GABA, glutamatergic, serotonergic, dopaminergic, cholinergic, and opioid neuronal systems. Ethanol can affect these systems directly, and/or the interactions between and among these systems become important in the expression of ethanol's actions. The behavioral consequences of ethanol's actions on brain neurochemistry, and the neurochemical effects themselves, are very much dose- and time-related, and the collage of ethanol's actions can change significantly even on the rising and falling phases of the blood ethanol curve. The behavioral effects of moderate ethanol intake can encompass events that the human or other animal can perceive as reinforcing through either positive (e.g., pleasurable, activating) or negative (e.g., anxiolysis, stress reduction) reinforcement mechanisms. Genetic factors and gender play an important role in the metabolism and behavioral actions of ethanol, and doses of ethanol producing pleasurable feelings, activation, and reduction of anxiety in some humans/animals can have aversive, sedative, or no effect in others. Research on the cognitive effects of acute and chronic moderate intake of ethanol is reviewed, and although a number of studies have noted a measurable diminution in neuropsychologic parameters in habitual consumers of moderate amounts of ethanol, others have not found such changes. Recent studies have also noted some positive effects of moderate ethanol consumption on cognitive performance in the aging human. The moderate consumption of ethanol by pregnant women can have significant consequences on the developing nervous system of the fetus. Consumption of ethanol during pregnancy at levels considered to be in the moderate range can generate fetal alcohol effects (behavioral, cognitive anomalies) in the offspring. A number of factors--including gestational period, the periodicity of the mother's drinking, genetic factors, etc.--play important roles in determining the effect of ethanol on the developing central nervous system. A series of recommendations for future research endeavors, at all levels, is included with this review as part of the assessment of the effects of moderate ethanol consumption on the central nervous system.

Effect of alcoholism on the incidence of lactate-induced panic attacks.

BACKGROUND: Chronic alcohol use is associated with higher than expected rates of panic disorder. METHODS: To study the relationship between alcoholism and panic disorder, we administered the panicogenic agent, sodium lactate, to 26 alcoholics with either panic disorder or frequent panic attacks (ALCPAN), 20 nonalcoholics with panic disorder (PAN), 14 alcoholics without a history of panic attacks, and 14 healthy volunteers. RESULTS: PAN were significantly more likely to have a lactate-induced panic attack (65%) than ALCPAN (23%). ALCPAN who had the onset of panic attacks prior to alcoholism also had a reduced frequency of lactate-induced panic attacks (26.7%) compared to PAN. CONCLUSIONS: There is a reduced incidence of lactate-induced panic attacks in ALCPAN. This reduction does not appear to be explained by the relative onset of panic attacks to alcoholism. The role of excessive alcohol consumption in the decreased frequency of lactate-induced panic attacks seen in ALCPAN needs further study.

Fine motor speed deficits in alcoholic Korsakoff's syndrome.

Forty-two alcoholic Korsakoff's syndrome (KS) patients (12 in study 1, 30 in study II) averaged slower tapping speeds than 35 alcoholic controls on the Halstead-Reitan manual finger tapping task. KS subjects also tapped slower than 26 normal volunteers in study II. Inverse relationships were found between finger-tapping speed dominant hand and verbal word fluency in one sample, and tapping speed and time to completion on Trail Making Part B and Tactual Performance Test in the other. The most powerful demographic predictors of tapping speed among age, education, length of abstinence, and affective state were age and education. Tapping speed was associated with cognitive tasks measuring frontal systems function (i.e., verbal fluency and Trail Making Part B) in KS subjects. There was no relationship between fine motor performance and general memory scores in the KS subjects. Decreased tapping speed for KS patients was postulated to result from compromised fine motor task initiation and persistence rather than mere slowing, as in Parkinson's disease. These findings suggest disruption of frontocerebellar systems that influence motor generation and set maintenance not previously explored in KS.

Behavioral and neuroendocrine responses to m-chlorophenylpiperazine in subtypes of alcoholics and in healthy comparison subjects.

OBJECTIVE: The purpose of this study was to explore central serotonergic functions in subgroups of alcoholics and in healthy comparison subjects. METHOD: The mixed serotonin (5-HT) agonist/antagonist m-chlorophenylpiperazine (m-CPP) was administered to male alcoholic patients who were classified according to the criteria of von Knorring et al. as type I alcoholics (late onset) (N = 16) or type II alcoholics (early onset with antisocial traits) (N = 24) and to 22 healthy comparison subjects. Psychological, physiological, and neuroendocrine measures were obtained before and after the m-CPP infusion. RESULTS: m-CPP elicited subtype-related differential effects among the alcoholics; the type I alcoholics reported more anger and anxiety, and the type II alcoholics reported increased euphoria and a greater likelihood of drinking. The healthy comparison subjects exhibited a greater increase in plasma ACTH response to the m-CPP infusion than the alcoholics regardless of subtype. CONCLUSIONS: Differences in certain 5-HT receptor functions may explain some of the clinical characteristics that differentiate the type II and type I subgroups of alcoholic patients. Furthermore, alcoholics may have reduced sensitivity of 5-HT2C receptors in comparison with healthy subjects.

Statistical methods in the Fourier domain to enhance and classify images.

A mathematical model, for which rigorous methods of statistical inference are available, is described and techniques for image enhancement and linear discriminant analysis of groups are developed. Since the gray values of neighboring pixels in tomographically produced medical images are spatially correlated, the calculations are carried out in the Fourier domain to insure statistical independence of the variables. Furthermore, to increase the power of statistical tests the known spatial covariance was used to specify constraints in the spectral domain. These methods were compared to statistical procedures carried out in the spatial domain. Positron emission tomography (PET) images of alcoholics with organic brain disorders were compared by these techniques to age-matched normal volunteers. Although these techniques are employed to analyze group characteristics of functional images, they provide a comprehensive set of mathematical and statistical procedures in the spectral domain that can also be applied to images of other modalities, such as computed tomography (CT) or magnetic resonance imaging (MRI).

Monitoring the source of memory in detoxified alcoholics.

The ability to monitor the source of remembered information and related reflective cognitive processes was examined in normal volunteers and detoxified alcoholics. Normal volunteers were very accurate judges of whether remembered events were presented as stimuli or were self-generated, even when memory was tested 2 days later. In contrast, a subgroup of otherwise cognitively unimpaired alcoholics demonstrated impairments in the ability to track the source of remembered knowledge and were also less able to inhibit intrusion errors in recalling information from memory. These findings provide preliminary evidence of an impairment in cognitive control functions in certain alcoholics. This conclusion is supported by associated findings indicating that, among alcoholics, performance on explicit memory tasks that required reflective cognitive operations were positively correlated with glucose utilization rates in left prefrontal, temporal, and posterior orbital frontal cortical regions.

Early-onset alcoholics have lower cerebrospinal fluid 5-hydroxyindoleacetic acid levels than late-onset alcoholics.

BACKGROUND: We investigated the interrelationships of age at onset of excessive alcohol consumption, family history of alcoholism, psychiatric comorbidity, and cerebrospinal fluid monoamine metabolite concentrations in abstinent, treatment-seeking alcoholics. METHODS: We studied 131 recently abstinent alcoholics. Supervised abstinence was maintained on a research ward at the National Institutes of Health Clinical Center for a minimum of 3 weeks. All alcoholics received a low-monoamine diet for a minimum of 3 days before lumbar puncture. Lumbar punctures were performed in the morning after an overnight fast. Monamine metabolites and tryptophan in cerebrospinal fluid were quantified with liquid chromatography by means of electrochemical detection. Psychiatric diagnoses were established from blind-rated Schedule for Affective Disorders and Schizophrenia-Lifetime version interviews administered by a research social worker. Severity and age at onset of excessive alcohol consumption were documented with a structured lifetime drinking history questionnaire and with selected alcoholism screening questionnaires (CAGE and Michigan Alcoholism Screening Test). Family history of alcoholism was obtained from the probands. RESULTS: A majority of the treatment-seeking, primarily white male alcoholics had a lifetime history of psychiatric disorders other than alcoholism. None fulfilled criteria for antisocial personality disorder. Early-onset alcoholics (onset of excessive consumption before 25 years of age) had a more severe course of alcoholism and lower mean cerebrospinal fluid 5-hydroxyindoleacetic acid concentration than late-onset alcoholics. Patients who reported both parents to be alcoholics had particularly low mean cerebrospinal fluid 5-hydroxyindoleacetic acid, homovanillic acid, and tryptophan concentrations. CONCLUSION: Among treatment-seeking alcoholics, early age at onset is generally associated with a more severe course of alcoholism and lower cerebrospinal fluid 5-hydroxyindoleacetic acid concentration.

Relationship of genetically transmitted alpha EEG traits to anxiety disorders and alcoholism.

We tested the hypothesis that a heritable EEG trait, the low voltage alpha (LV), is associated with psychiatric disorders. Modest to moderate evidence for genetic linkage of both panic disorder and the low voltage alpha trait to the same region of chromosome 20q has recently been reported, raising the issue of whether there is a phenotypic correlation between these traits. A total of 124 subjects including 50 unrelated index subjects and 74 relatives were studied. Alpha EEG power was measured and EEG phenotypes were impressionistically classified. Subjects were psychiatrically interviewed using the SADS-L and blind-rated by RDC criteria. Alcoholics were four times more likely to be LV (including so-called borderline low voltage alpha) than were nonalcoholic, nonanxious subjects. Alcoholics with anxiety disorder are 10 times more likely to be LV. However, alcoholics without anxiety disorder were similar to nonalcoholics in alpha power. An anxiety disorder (panic disorder, phobia, or generalized anxiety) was found in 14/17 LV subjects as compared to 34/101 of the rest of the sample (P < 0.01). Support for these observations was found in the unrelated index subjects in whom no traits would be shared by familial clustering. Lower alpha power in anxiety disorders was not state-dependent, as indicated by the Spielberger Anxiety Scale. Familial covariance of alpha power was 0.25 (P < 0.01). These findings indicate there may be a shared factor underlying the transmissible low voltage alpha EEG variant and vulnerability to anxiety disorders with associated alcoholism. This factor is apparently not rare, because LV was found in approximately 10% of unrelated index subjects and 5% of subjects free of alcoholism and anxiety disorders.

Effect of chloride or glucose on the incidence of lactate-induced panic attacks.

OBJECTIVE: This study was designed to test the hypothesis that the addition of chloride to a lactate infusion would reduce the frequency of panic attacks. METHOD: The subjects included 14 healthy volunteers and 20 patients meeting the DSM-IV criteria for panic disorder. All subjects received an infusion of lactate dissolved in 0.9% sodium chloride and an infusion of lactate dissolved in 5% dextrose in water on separate days in a random-order, double-blind procedure. Blood pressure, heart rate, and panic symptoms were measured at 3-minute intervals during the infusions. The occurrence of panic attacks was ascertained through the subjects' reports of losing control, panicking, or "going crazy" and the presence of at least four Research Diagnostic Criteria symptoms of a panic attack. RESULTS: Fifteen (75%) of the patients with panic disorder reported a panic attack during one of the infusions or both; no healthy volunteers had a panic attack. The patients with panic disorder were significantly more likely to have a panic attack during the lactate/sodium chloride infusion than during the infusion of lactate/5% dextrose in water. The number of panic attack symptoms reported at 3-minute intervals did not differ between the two types of infusion. CONCLUSIONS: The coadministration of glucose resulted in a reduced sensitivity to the panicogenic effects of lactate. The hypothesis that adding chloride to the infusion would reduce the frequency of lactate-induced panic attacks was not supported.

Fluvoxamine treatment of alcoholic amnestic disorder.

The serotonin uptake inhibitor fluvoxamine was assessed in treatment of alcohol-induced Korsakoff's syndrome (KS) using fixed (4 weeks, 200 mg/day) or individualized (6 weeks, plasma concentration > or = 400 ng/ml) dosing in randomized placebo-controlled double-blind crossover studies. Cognitive functions and concentrations of the major cerebrospinal fluid (CSF) metabolites of serotonin (5-HIAA), norepinephrine (MHPG), and dopamine (HVA) were determined in abstinent, nondepressed KS patients (aged 45-75), at baseline and placebo (3-4 weeks), and after 3-4 (n = 10) or 6 (n = 4) weeks of fluvoxamine administration. Fluvoxamine decreased CSF 5-HIAA compared to placebo (P < 0.003) without consistent changes in HVA or MHPG. Reductions in 5-HIAA correlated with improvements on the Wechsler Memory Scale Memory Quotient (P < 0.05), independent of effects on attention/vigilance or Beck Depression Inventory scores. Reductions in 5-HIAA correlated with plasma fluvoxamine (P < 0.03) only for fluvoxamine concentrations below 450 ng/ml. These findings suggest improvement of memory consolidation and/or retrieval in patients with Korsakoff's syndrome by fluvoxamine via serotonergic mechanisms.

Neuropsychological functioning in detoxified alcoholics between 18 and 35 years of age.

OBJECTIVE: The authors determined 1) cognitive functioning in detoxified alcoholics who had alcohol-related problems for a relatively brief time and 2) relationships between neuropsychological test scores and recent and chronic alcohol consumption patterns, childhood symptoms of hyperactivity/minimal brain dysfunction, and extent of familial alcoholism. METHOD: The subjects were 101 detoxified, drug-free alcoholics between 18 and 35 years of age who had consumed excessive amounts of alcohol (average of 114 g four to five times per week) for an average of 6 years. An average of 39 days after the last drink each alcoholic was given an extensive battery of neuropsychological tests assessing language skills, attention, motor skills, intelligence, memory, and cognitive functioning related to the frontal regions of the brain. RESULTS: Only four individuals evidenced mild cognitive dysfunction. Current psychiatric condition, anxiety and depressive states, and liver dysfunction were not related to cognition. Relationships of cognition of lifetime estimates of alcohol consumption (average of 189 kg) and number of days from last drink to testing were determined to be nonlinear and suggested that greater lifetime consumption predicted worse performance and that longer abstinence predicted better performance. Neither extent of familial alcoholism nor number of childhood signs and symptoms of hyperactivity/minimal brain dysfunction was predictive of cognition except that more antisocial behavior predicted poorer cognitive functioning. CONCLUSIONS: Cognition in young alcoholics, averaging 6 years of excessive alcohol consumption, was within normal limits, even though greater lifetime consumption predicted lower test scores and longer abstinence predicted higher scores.

Behavioral and endocrine responses to clomipramine in panic disorder patients with or without alcoholism.

Central nervous system serotonin functions may differ between certain subgroups of alcoholics, patients with panic disorder, and healthy volunteers. To investigate these possibilities we administered the serotonin uptake inhibitor, clomipramine (12.5 mg, i.v.), to patients with alcohol dependence, patients with panic disorder with or without alcohol dependence, and healthy volunteers. Alcoholics did not differ from healthy volunteers in their neuroendocrine or behavioral responses. In contrast, patients with panic disorder exhibited marked dysphoric reactions and/or panic attacks following low-dose i.v. clomipramine, whereas their neuroendocrine responses were similar to the other two groups. Patients with panic disorder may have super-sensitive postsynaptic serotonin receptors in areas of their central nervous system, which are important for mood regulation.

Decreased cingulate and precuneate glucose utilization in alcoholic Korsakoff's syndrome.

Localized cerebral glucose utilization was determined for nine abstinent alcoholic men with Korsakoff's syndrome and 10 age-matched normal men who underwent positron emission tomography with [18F]2-fluoro-2-deoxyglucose (FDG). Patients with Korsakoff's syndrome showed relatively decreased glucose utilization in cingulate and precuneate areas. These decreases persisted even after correction for group differences in ventricular and sulcal cerebrospinal fluid measured on computed tomography. Electroencephalographic recordings at the time of FDG uptake showed no group differences, a finding that demonstrates that the metabolic differences could not be explained by differences in physiological arousal at the time of scanning. It is concluded that the decreased glucose utilization in the patients reflects a disruption of memory circuitry, the Papez circuit, caused by diencephalic lesions induced by thiamine deficiency.

Abstinent alcoholics exhibit an exaggerated stress response to 2-deoxy-D-glucose challenge.

Chronic excessive alcohol consumption can significantly disturb the hypothalamic control of glucose metabolism; however, the mechanism and clinical significance of this disturbance are poorly understood. We used 2-deoxy-D-glucose (2-DG), which produces intracellular glucoprivation, to compare neurochemical, physiological, and behavioral responses to glucoprivic stress between alcoholics abstinent for 3 weeks and healthy volunteers. Twenty-six male alcoholics and 15 male healthy volunteers received intravenous infusions of placebo, 12.5 mg/kg, and 25.0 mg/kg of body weight of 2-DG over 30 min on three separate days, following a random-ordered, double-blind procedure. Minimal effects were observed following administration of the 12.5 mg/kg of body weight dose of 2-DG. Following 25.0 mg/kg, alcoholics showed both exaggerated ACTH and cortisol responses and greater increases in caloric intake when compared with controls. Although anxiety, desire to consume alcohol, plasma progesterone, and sympathetic and adrenal medullary activity all increased following 2-DG, these responses did not differ between alcoholics and controls. The present findings suggest certain specificity for the exaggerated hypothalamic and adrenocortical responses to mild glucoprivic stress in 3-week-abstinent alcoholics.

Impairments in reflective cognitive functions in alcoholics: a neuropharmacological model.

The ability to make use of reflective cognitive operations in monitoring and evaluating remembered events is impaired in subgroups of nominally cognitively unimpaired, detoxified alcoholics. Alcoholics, relative to controls, make more errors in identifying the source of remembered information (i.e. whether a remembered word was self-generated or was a stimulus word presented by the experimenter), and are impaired in their ability to inhibit confabulatory errors (intrusions). The cognitive-memory impairment expressed in benzodiazepine-treated normal volunteers mimics this impairment in alcoholics. Disturbances in prefrontal and frontal lobe functions may be involved in this selective impairment in cognition in many alcoholics and may also contribute to what accounts for the failures in reflective cognitive operations observed in amnestic patients.

Improving spatial and temporal resolution in evoked EEG responses using surface Laplacians.

Spline generated surface Laplacian temporal wave forms are presented as a method to improve both spatial and temporal resolution of evoked EEG responses. Middle latency and the N1 components of the auditory evoked response were used to compare potential-based methods with surface Laplacian methods in the time domain. Results indicate that surface Laplacians provide better estimates of underlying cortical activity than do potential wave forms. Spatial discrimination among electrode sites was markedly better with surface Laplacian than with potential wave forms. Differences in the number and latencies of peaks, and their topographic distributions, were observed for surface Laplacian, particularly during the time period encompassing the middle latency responses. Focal activities were observed in surface Laplacian wave forms and topographic maps which were in agreement with previous findings from auditory evoked response studies. Methodological issues surrounding the application of spline methods to the time domain are also discussed. Surface Laplacian methods in the time domain appear to provide an improved way for studying evoked EEG responses by increasing temporal and spatial resolution of component characteristics.