Patient characteristics driving clinical utility in psychiatric pharmacogenetics: a reanalysis from the AB-GEN multicentric trial.

Clinical utility of commercial multi-gene pharmacogenetic tests in depression is starting to be studied with some promising results on efficacy and tolerability. Among the next steps is the definition of the patient profile that is most likely to benefit from testing. Here we present a reanalysis of data from the AB-GEN randomized clinical trial showing that clinical utility of pharmacogenetic testing can be markedly influenced by patient characteristics such as age, baseline severity and duration of current depressive episode.Trial registration ClinicalTrials.gov NCT02529462.

Is it possible to prevent recurrent vulvovaginitis? The role of Lactobacillus plantarum I1001 (CECT7504).

The purpose of this study was to prospectively evaluate the impact of the use of L. plantarum I1001 applied vaginally on Vulvovaginal Candidiasis (VVC) time-until-recurrence after treatment with single-dose vaginal clotrimazole. This was a clinical open-label, prospective study of two non-randomized parallel cohorts with symptomatic acute VVC: (1) 33 sexually active women 18-50 years old, prescribed a standard single-dose 500 mg vaginal tablet of clotrimazole followed by vaginal tablets with L. plantarum I1001 as adjuvant therapy, and (2) 22 women of similar characteristics but prescribed single-dose clotrimazole only. Use of the probiotic and factors that might influence recurrence risk (age, recurrent VVC within previous year, antibiotic prior to study enrolment, diaphragm or IUD contraception, among others) were included in a multivariate Cox regression model to adjust for potential between-cohort differences. Probiotic use was associated with a three-fold reduction in the adjusted risk of recurrence (HR [95 %CI]: 0.30 [0.10-0.91]; P = 0.033). Adjusted free-survival recurrence was 72.83 % and 34.88 % for the probiotic and control groups, respectively. A higher cumulative recurrence was also observed in cases with use of antibiotics prior to enrolment (HR [95 %CI]: 10.46 [2.18-50.12]; P = 0.003). Similar findings were found at six months after azole treatment in women with RVVC. Overall, good compliance with the probiotic was reported for 91.3 % of women. The study suggests that follow-up therapy with vaginal tablets with L. plantarum I1001 could increase the effectiveness of single-dose 500 mg clotrimazole at preventing recurrence of VVC, an effect that was also observed in women with recurrent vulvovaginal candidiasis (RVVC) after six months of azole treatment.

A mixture of Lactobacillus plantarum CECT 7315 and CECT 7316 enhances systemic immunity in elderly subjects. A dose-response, double-blind, placebo-controlled, randomized pilot trial.

BACKGROUND & AIM: Immunosenescence can increase morbi-mortality. Lactic acid producing bacteria may improve immunity and reduce morbidity and mortality in the elderly. We aimed to investigate the effects of a mixture of two new probiotic strains of Lactobacillus plantarum--CECT 7315 and 7316--on systemic immunity in elderly. METHODS: 50 institutionalized elderly subjects were randomized, in a double-blind fashion, to receive for 12 weeks 1) 5·10(8) cfu/day of L. plantarum CECT7315/7316 ("low probiotic dose") (n = 13), 2) 5·10(9) cfu/day of the probiotic mixture ("high probiotic dose") (n = 19), or 3) placebo (n = 15). Leukocyte subpopulations, and cytokine levels (IL-1 , IL-10, TGF-ß1) were measured in venous blood at baseline, end of treatment (week 12), and end of follow-up (week 24). Infection and survival rates were recorded. RESULTS: After treatment, high probiotic dose resulted in significant increases in the percentages of activated potentially T-suppressor (CD8+CD25+) and NK (CD56+ CD16+) cells, while low probiotic dose increased activated T-helper lymphocytes (CD4+CD25+), B lymphocytes (CD19+), and antigen presenting cells (HLA-DR+). Also, plasma TGF-ß1 concentration significantly decreased after treatment with both probiotic doses. Most of these changes remained 12 weeks after probiotic discontinuation. Incidence of infections during treatment showed a significant trend to be lower in the high probiotic dose group. In addition, there was a significant trend for mortality to be greater in the placebo group vs. both probiotic groups. CONCLUSIONS: Depending on the dose, L. plantarum CECT7315/7316 have different immune-enhancing effects in elderly subjects. These effects might result in a better clinical outcome.

A mixture of Lactobacillus plantarum CECT 7315 and CECT 7316 enhances systemic immunity in elderly subjects. A dose-response,double-blind, placebo-controlled, randomized pilot trial / Una mezcla de Lactobacillus plantarum CECT 7315 y CECT 7316 mejora la inmunidad sistémica en ancianos. Un ensayo aleatorio piloto, de dosis-respuesta, doble ciego y controlado con placebo

Background & aim: Immunosenescence can increase morbi-mortality. Lactic acid producing bacteria may improve immunity and reduce morbidity and mortality in the elderly. We aimed to investigate the effects of a mixture of two new probiotic strains of Lactobacillus plantarum-CECT 7315 and 7316- on systemic immunity in elderly. Methods: 50 institutionalized elderly subjects were randomized, in a double-blind fashion, to receive for 12 weeks 1) 5·108 cfu/day of L. plantarum CECT7315/7316 ("low probiotic dose") (n = 13), 2) 5·109 cfu/day of the probiotic mixture ("high probiotic dose") (n = 19), or 3) placebo (n = 15). Leukocyte subpopulations, and cytokine levels (IL-1 , IL-10, TGF-β1) were measured in venous blood at baseline, end of treatment (week 12), and end of follow-up (week 24). Infection and survival rates were recorded. Results: After treatment, high probiotic dose resulted in significant increases in the percentages of activated potentially T-suppressor (CD8+CD25+) and NK (CD56+ CD16+) cells, while low probiotic dose increased activated T-helper lymphocytes (CD4+CD25+), B lymphocytes (CD19+), and antigen presenting cells (HLA-DR+). Also, plasma TGF-β1 concentration significantly decreased after treatment with both probiotic doses. Most of these changes remained 12 weeks after probiotic discontinuation. Incidence of infections during treatment showed a significant trend to be lower in the high probiotic dose group. In addition, there was a significant trend for mortality to be greater in the placebo group vs. both probiotic groups. Conclusions: Depending on the dose, L. plantarum CECT7315/7316 have different immune-enhancing effects in elderly subjects. These effects might result in a better clinical outcome (AU)

Introducción y objetivos: La inmunosenescencia puede aumentar la morbi-mortalidad. Las bacterias productoras de ácido láctico pueden mejorar la inmunidad y disminuir la morbilidad y mortalidad en los ancianos. Nuestro objetivo fue investigar los efectos de una mezcla de dos nuevas cepas probióticas de Lactobacillus plantarum -CECT 7315 y 7316- sobre la inmunidad sistémica en ancianos. Métodos: 50 ancianos institucionalizados se aleatorizaron, en un diseño a doble-ciego, para recibir durante 12 semanas 1) 5·108 ufc/día de L. plantarum CECT7315/ 7316 ("dosis baja de probiótico") (n = 13), 2) 5·109 ufc/día de la mezcla probiótica ("dosis alta de probiótico") (n = 19), o 3) placebo (n = 15). Se determinaron las subpoblaciones leucocitarias y los niveles de citokinas (IL-1 , IL-10, TGF-β1) en sangre venosa periférica basalmente, al final del tratamiento (sem. 12) y al final del seguimiento (sem. 24). Se registró la tasa de infecciones y la mortalidad. Resultados: Tras el tratamiento, la dosis alta de probiótico indujo aumentos significativos en los porcentajes de células potencialmente T-supresoras (CD8+CD25+) y NK (CD56+CD16+) activadas, en tanto que la dosis baja aumento los linfocitos T-colaboradores activados (CD4+CD25+), los linfocitos B (CD19+), y las células presentadoras de antígeno (HLA-DR+). Asimismo, la concentración plasmática de TGF-β1 disminuyó tras el tratamiento con ambas dosis de probiótico. La mayor parte de estos cambios se mantuvieron 12 semanas después de suspender el tratamiento. La incidencia de infecciones durante el tratamiento mostró una tendencia significativa a ser menor con la dosis alta de probiótico, mientras que se observó una tendencia significativa a que la mortalidad fuera mayor el grupo placebo vs. ambos grupos tratados con probiótico. Conclusiones: Dependiendo de la dosis, L. plantarum CECT7315/7316 tiene distintos efectos inmunoestimulantes en ancianos. Dichos efectos podrían contribuir a una mejor evolución clínica (AU)

Electrically induced blink reflex and facial motor nerve stimulation in beagles.

Electrophysiologic assessment of the blink reflex test and the muscle-evoked potentials evoked by stimulation of the facial nerve were performed in 15 healthy adult Beagles before and after supraorbital (trigeminal) and facial anesthetic nerve blocks performed by lidocaine injections. Unilateral electrical stimulation of the supraorbital nerve elicited 2 ipsilateral (R1 and R2) and a contralateral (Rc) reflex muscle potential in orbicularis oculi muscles. Electrical stimulation of the facial nerve elicited 2 muscle potentials (a direct response [D] and a reflex faciofacial response [RF]) in the ipsilateral orbicularis oculi muscle. Anesthetic block of the left supraorbital nerve resulted in bilateral lack of responses upon left supraorbital nerve stimulation, but normal responses in right and left orbicularis oculi muscles upon right supraorbital stimulation. Right facial anesthetic block produced lack of responses in the right orbicularis oculi muscle regardless the side of supraorbital nerve stimulation. Results of this study demonstrate that the blink reflex can be electrically elicited and assessed in dogs. Reference values for the blink reflex responses and for the muscle potentials evoked by direct facial nerve stimulation in dogs are provided. The potential usefulness of the electrically elicited blink reflex test in the diagnosis of peripheral facial and trigeminal dysfunction in dogs was demonstrated.

[Chronic demyelinating auto-immune acquired neuropathy: Lewis-Sumner syndrome]. / Neuropatías adquiridas autoinmunes desmielinizantes crónicas: síndrome de Lewis-Sumner.

INTRODUCTION: Knowledge of the chronic auto-immune acquired neuropathies has progressed rapidly since the recent description of the Lewis-Sumner syndrome and multifocal motor neuropathy. Some of the most interesting aspects of these conditions are the presence of persistent conduction blocks and the challenge of understanding the mechanisms involved. These blocks are difficult to identify. CLINICAL CASE: We describe the case of a female patient with Lewis-Sumner syndrome, with persistent sensory and motor blocks. The electrophysiological characteristics and differential diagnosis of the two conditions are reviewed.

Neuropatías adquiridas autoinmunes desmielinizantes crónicas: síndrome de Lewis-Sumner / Chronic demyelinating auto-immune acquired neuropathy: Lewis-Sumner syndrome

Introducción. El conocimiento de las neuropatías adquiridas autoinmunes crónicas evoluciona rápidamente con la reciente descripción del síndrome de Lewis-Sumner y la neuropatía motora multifocal. Algunos de los puntos que mayor interés han despertado ambas entidades son la presencia de bloqueos de conducción persistentes y el reto de entender su mecanismo. Los bloqueos son difíciles de objetivar. Caso clínico. Presentamos el caso de una paciente con síndrome de Lewis-Sumner con bloqueos persistentes sensitivos y motores. Revisamos sus características clínico-electrofisiológicas y el diagnóstico diferencial de las dos entidades (AU)

[Macro-electromyography findings in neuropathies and myopathies]. / Hallazgos de la macroelectromiografía en neuropatías y miopatías.

The possibility of overall recording of the electrical activity generated by muscle fibres making up the motor unit in its entire territory, is the characteristic and main objective of macro-EMG studies. This is possible because of the technical characteristics of the electrode and the recording conditions whose methodology is described. We describe how parameters of macro-EMG are obtained in normal healthy people, and define changes in parameters in pathological neurogenic and myogenic disorders and their value in the follow-up of reinnervation processes.

Electrically elicited blink reflex in horses with trigeminal and facial nerve blocks.

OBJECTIVE: To reassess reference values for the components of the electrically induced blink reflex, document reference values for facial motor nerve conduction velocity, and demonstrate usefulness of the blink reflex as a diagnostic tool in peripheral facial and trigeminal nerve dysfunction in horses. ANIMALS: 10 healthy adult horses (8 males, 2 females) without neurologic abnormalities. PROCEDURE: Blink reflex tests were performed by electrical stimulation of the supraorbital nerve and facial (auriculopalpebral) nerve. Reflex and direct muscle-evoked potentials of the orbicularis oculi muscles were recorded from concentric needle electrodes inserted bilaterally in these muscles. Supraorbital and auriculopalpebral nerve blocks were performed by lidocaine hydrochloride injections. RESULTS: Supraorbital nerve stimulation elicited 2 or 3 ipsilateral and 1 contralateral reflex muscle potential in the orbicularis oculi muscles. Auriculopalpebral nerve stimulation elicited a direct and a reflex potential in the ipsilateral orbicularis oculi muscle. After left supraorbital nerve block, no responses could be elicited ipsilaterally or contralaterally upon stimulation of the blocked nerve, but bilateral responses were obtained upon stimulation of the right supraorbital nerve. After right auriculopalpebral nerve block, no responses were recorded from the right orbicularis oculi muscle upon stimulation of left or right supraorbital nerves. CONCLUSIONS AND CLINICAL RELEVANCE: Reference values for the components of the blink reflex and facial motor nerve conduction velocity will allow application of these tests to assist in the diagnosis of equine neurologic disorders involving the trigeminal and facial nerves, the brainstem, and the cranial end of the cervical segment of the spinal cord. This study reveals the usefulness of the blink reflex test in the diagnosis of peripheral trigeminal and facial nerve dysfunction in horses.

Autonomic dysfunction in patients with non-alcoholic chronic liver disease.

AIMS: To assess the presence of autonomic neuropathy in patients with non-alcoholic chronic liver disease and its relationships with the severity of liver damage. METHODS: Thirty non-alcoholic patients with chronic liver disease and 26 healthy control subjects were studied. The silicone imprint technique was used to quantify the number of functioning sweat glands in order to assess peripheral sympathetic dysfunction. Heart rate variations in response to deep breathing at 6 per minute (deltaR6), to a Valsalva maneuver, and with orthostatism (RRmax/RRmin) were determined to assess parasympathetic vagal function. RESULTS: Mean values for autonomic tests were significantly lower in the group of patients with non-alcoholic chronic liver disease than in the control subjects. The number of activated sweat glands in the foot was abnormal in 19 (63%) patients. Among vagal tests, Valsalva ratio was abnormal in 14 (46%) and deltaR6 in 11 (36%) patients with liver disease. Vagal neuropathy (two or more abnormal heart rate tests) was definite in nine patients (30%). CONCLUSIONS: A high prevalence of abnormalities in both sympathetic and parasympathetic function tests, with a poor relationship with liver function parameters, has been found in patients with non-alcoholic chronic liver disease.

Electrically induced blink reflex in horses.

The electrically induced blink reflex was studied electromyographically in 21 healthy adult, detomidine-sedated horses. Using surface electrodes, the supraorbital nerve was electrically stimulated at the supraorbital foramen. The responses were recorded from the ipsilateral and contralateral orbicularis oculi muscles with concentric needle electrodes inserted in the lateral aspect of the ventral eyelids. Ipsilateral and contralateral recordings were made on successive stimulations of the same side of the face, maintaining a constant stimulus intensity. The electromyographically recorded responses consisted of an early R1 response in the orbicularis oculi muscle ipsilateral to the side of stimulation, a bilateral late response (ipsilateral R2 and contralateral Rc) and a third, R3 response, in the ipsilateral orbicularis oculi muscle. All the responses were polyphasic muscle potentials of variable duration and peak to peak amplitudes. The reflex latency of the R1 response was, as in man, fairly stable. The R2 response showed greater variability both within and between individual horses. The Rc response was recorded in only 13 of the 21 horses and showed a slightly longer latency than the corresponding R2. The R3 response, which is significantly related to pain sensation in man, appeared in 19 horses and showed the greatest variability in latency.

Effects of subarachnoid lidocaine, meperidine and fentanyl on somatosensory and motor evoked responses in awake humans.

Although the effects of local anaesthetics (LA) on motor and sensory transmission in the spinal cord have been described, the effects of opioids are controversial. Our aim was to evaluate the action of clinically relevant doses of subarachnoid (SA) meperidine (MP) and fentanyl (FN), on somatosensory (SSEP) and cortical motor evoked responses (CMER) in awake subjects. Thirty ASA I-II patients scheduled for infra umbilical surgery received SA (N = 10/group): 1 mg/kg lidocaine (LD), 1 mg/kg MP or 25 mu g FN. SSEP elicited by stimulation of the posterior tibial nerve at the ankle, and cortical motor evoked response at rest (r-CMER) and during facilitation (f-CMER) were obtained prior and 30 min after treatment. Conduction at the proximal segment of the motor nerve (F-wave) was evaluated by stimulation of the posterior tibial nerve at the popliteal fossa. Motor/sensory block and side effects were clinically assessed. LD completely abolished SSEP and CMER. At the same dose, MP abolished SSEP in 40% of the patients, while r-CMER and f-CMER were absent in 70% and 30%, respectively; in addition, the F-wave was absent in 50% of the patients. Fentanyl induced small changes in the latencies of SSEP and F-wave; however, a 28% decrease in the amplitude of the f-CMER (P<0.05) was observed. Pruritus was present in 60% of patients in the FN group (P<0.006). Our results show that while LD and MP block sensory and motor conduction at the spinal roots, FN seems to decrease the excitability of the spinal interneurons in the corticospinal tract.

[Deletion of 17p11.2 chromosome in Spanish families with hereditary neuropathy and abnormal sensitivity to pressure]. / Deleción del cromosoma 17p11.2 en familias españolas con neuropatía hereditaria por vulnerabilidad excesiva a la presión.

Hereditary neuropathy with abnormal liability to pressure palsies (HNPP) is a dominant autosomally transmitted disease that gives rise to foci of peripheral nerve myelination, reducing conduction and leading to episodes of palsy and sensory changes that are all linked to sensitivity to pressure and traction on the affected nerve roots. The molecular basis of HNPP has been identified as a submicroscopic deletion of the 17p11.2 chromosome in exactly the same region that it is duplicated in Charcot-Marie-Tooth disease, type 1A (CMT1A). We report genetic analyses of 13 patients (belonging to 3 families) diagnosed of HNPP by means of physical examination and electrophysiologic and morphologic tests (the last in 3 cases only). Inter- and intrafamilial variation in symptomatology was studied. Some patients presented the usual clinical signs, such as recidivating brachial plexus palsy, permanent sensory polyneuropathy, foot deformities and others that might also be found in patients with CMT1A. All the patients showed electrophysiologic signs of underlying demyelinating polyneuropathy. Genetic study centered on detecting the deletion of 17p11.2 by segregation analysis with the polymorphic markers VAW409R3a (D17S122) and EW401HE (D17S61). Our results confirmed deletion at the CTM1A location of chromosome 17p11.2 in all 13 patients examined. These data suggest that the deletion of 17p11.2 plays a causal role in HNPP and that it is the most prevalent mutation in this disease; our findings constitute new evidence of the importance of the CMT1A/HNPP locus in the formation and control of peripheral myelin and in the ultimate functioning of peripheral nerves.

Autonomic neuropathy in chronic alcoholism: evaluation of cardiovascular, pupillary and sympathetic skin responses.

Autonomic nerve function was evaluated in 30 alcoholics and 30 healthy subjects by means of cardiovascular function tests, pupil cycle time (PCT), and sympathetic skin responses (SSR). Nutritional status was assessed by anthropometric parameters. Autonomic cardiovascular dysfunction was classified as early involvement in 5 patients, definite in 8, severe in 6 and atypical in 3. PCT was abnormal in 17 alcoholics. The duration of PCT became progressively longer as the severity of cardiovascular involvement increased. SSR was absent in 4 alcoholics in the palm and in 16 in the sole. These findings indicate that sympathetic and parasympathetic mediated functions are abnormal in chronic alcoholics with a similar frequency, involving different sites of the autonomic nervous system under variable patterns. Significant correlations between nutritional status and autonomic neuropathy were found.

Comparison of sympathetic sudomotor and skin responses in alcoholic neuropathy.

We evaluated sympathetic sudomotor and parasympathetic vagal function in 30 chronic alcoholic patients and 28 control subjects by means of silicone imprints, sympathetic skin responses (SSR), and cardiorespiratory reflex tests. Mean values from alcoholic patients were significantly lower than those from control subjects for all tests. The number of secreting sweat glands (SGN) was below normal in the foot of 18 patients, and in the hand of 7 patients; 16 patients had absent SSR on the sole, and 4 on the palm. Only two patients had both test results abnormal on the hand and 10 on the foot. The SGN did not correlate with the amplitude of the SSR in the subjects studied. There was no clear correlation of abnormalities found in cardiorespiratory tests and sympathetic tests. Abnormalities in sensory nerve conduction were associated with absent SSR, but not with decreased SGN. The silicone mold technique is a more specific test to detect abnormalities in sympathetic efferent fibers, as SSR may be influenced by sensory afferent fiber involvement.

Diaphragmatic activity induced by cortical stimulation: surface versus esophageal electrodes.

Evoked responses of the diaphragm can be induced by magnetic cortical stimulation and recorded by either surface or esophageal electrodes. The former recording system is tolerated better by the patient but has potential problems with the specificity of the diaphragmatic signal. This study compares the responses of the diaphragm to cortical stimulation that were recorded simultaneously with surface and esophageal electrodes on seven patients (61 +/- 4 yr) with chronic obstructive pulmonary diseases. Stimuli were delivered in three ventilatory conditions: at baseline, during deep breathing, and during voluntary panting. No differences were observed between results recorded by surface and esophageal electrodes [amplitude of the compound motor of the action potential (CMAP), 0.8 +/- 0.1 vs. 0.8 +/- 0.1 mV, NS; latency, 13.1 +/- 0.4 vs. 12.6 +/- 0.5 ms, NS]. In addition, significant correlations were found (CMAP, r = 0.77, P < 0.001; latency, r = 0.71, P = 0.002). The concordance analysis, however, indicated some dissimilarity between the recordings of the electrodes (CMAP, R1 = 0.31; latency, R1 = 0.26). These differences may be due to the area of the muscle mainly recorded by each electrode and/or to the additional activity from other muscles recorded by surface electrodes. On the other hand, the diaphragmatic responses observed in these patients with chronic obstructive pulmonary diseases were similar to those previously reported in healthy subjects.

[Paraneoplastic encephalomyelitis and Lambert-Eaton syndrome]. / Encéphalomyélite et syndrome de Lambert-Eaton paranéoplasiques.

In two men presenting with muscle weakness and disturbances of equilibrium neurophysiological examination by repeated stimulations revealed responses suggestive of Lambert-Eaton syndrome. In the first month of the disease very high levels of anti-Hu antibody were found in the serum and CSF, betraying a malignant lesion. This was confirmed by autopsy 4 months later in one patient and by bronchial biopsy 16 months later in the other patient. Both had small-cell lung carcinoma associated with paraneoplastic encephalomyelitis.