Lithium treatment alleviates impaired cognition in a mouse model of fragile X syndrome.

Fragile X syndrome (FXS) is caused by suppressed expression of fragile X mental retardation protein (FMRP), which results in intellectual disability accompanied by many variably manifested characteristics, such as hyperactivity, seizures and autistic-like behaviors. Treatment of mice that lack FMRP, Fmr1 knockout (KO) mice, with lithium has been reported to ameliorate locomotor hyperactivity, prevent hypersensitivity to audiogenic seizures, improve passive avoidance behavior and attenuate sociability deficits. To focus on the defining characteristic of FXS, which is cognitive impairment, we tested if lithium treatment ameliorated impairments in four cognitive tasks in Fmr1 KO mice, tested if the response to lithium differed in adolescent and adult mice and tested if therapeutic effects persisted after discontinuation of lithium administration. Fmr1 KO mice displayed impaired cognition in the novel object detection task, temporal ordering for objects task and coordinate and categorical spatial processing tasks. Chronic lithium treatment of adolescent (from 4 to 8 weeks of age) and adult (from 8 to 12 weeks of age) mice abolished cognitive impairments in all four cognitive tasks. Cognitive deficits returned after lithium treatment was discontinued for 4 weeks. These results show that Fmr1 KO mice exhibit severe impairments in these cognitive tasks, that lithium is equally effective in normalizing cognition in these tasks whether it is administered to young or adult mice and that lithium administration must be continued for the cognitive improvements to be sustained. These findings provide further evidence that lithium administration may be beneficial for individuals with FXS.

Clinical and laboratory assessment of distal peripheral nerves in Gulf War veterans and spouses.

BACKGROUND: The prevalence of symptoms suggesting distal symmetric polyneuropathy (DSP) was reported to be higher among deployed veterans (DV) to the Persian Gulf in 1990-1991 than to control non-deployed veterans (NDV). The authors therefore compared the prevalence of DSP by direct examination of DV and their spouses to control NDV and spouses. METHODS: The authors performed standardized neurologic examinations on 1,061 DV and 1,128 NDV selected from a cohort of veterans who previously participated in a national mail and telephone survey. Presence of DSP was evaluated by history, physical examination, and standardized electrophysiologic assessment of motor and sensory nerves. Similar examinations were performed without electrophysiologic tests in 484 DV spouses and 533 NDV spouses. Statistical analyses were performed with appropriate adjustments for the stratified sampling scheme. RESULTS: No differences between adjusted population prevalence of DSP in DV and NDV were found by electrophysiology (3.7% vs 6.3%, p = 0.07), by neurologic examination (3.1% vs 2.6%, p = 0.60), or by the methods combined (6.3% vs 7.3%, p = 0.47). Excluding veterans with non-military service related diseases that may cause DSP did not alter outcomes. DV potentially exposed to neurotoxins from the Khamisiyah ammunition depot explosion did not significantly differ in DSP prevalence compared to non-exposed DV. The prevalence of DSP in DV spouses did not differ from NDV spouses (2.7% vs 3.2%, p = 0.64). CONCLUSIONS: Neither veterans deployed during the Gulf War era nor their spouses had a higher prevalence of DSP compared to NDV and spouses.

Oculopharyngeal muscular dystrophy in Hispanic New Mexicans.

CONTEXT: Oculopharyngeal muscular dystrophy (OPMD) is a rare myopathy caused by polyalanine triplet repeat expansion in the gene for poly(A) binding protein 2 (PABP2) and is found in isolated cohorts throughout the world. We have observed numerous cases of OPMD in New Mexico. OBJECTIVE: To characterize the clinical, genetic, and demographic features of the OPMD population in New Mexico. DESIGN, SETTING, AND PARTICIPANTS: Cohort study with analysis of outpatient clinic medical records from 1965 to 2001 at the University of New Mexico Hospital and the New Mexico VA Health Care System in Albuquerque, which serve the entire state. MAIN OUTCOME MEASURES: Clinical phenotype, supplemented with genetic confirmation (n = 10 patients) and in-depth clinical evaluations (n = 49 patients). RESULTS: We identified 216 cases of OPMD (99 women and 117 men) from 39 kindreds of New Mexicans spanning up to 4 generations. All patients were Hispanic, and the majority of probands came from northern New Mexico. In patients who had both ocular and pharyngeal muscle weakness, ptosis was just as likely to occur before or concurrent with dysphagia. Proximal limb muscle weakness and gait abnormalities were common and occurred later than ocular or pharyngeal weakness. The clinical expression of OPMD caused marked debility, although life-table analysis showed no decrease in life expectancy compared with unaffected family members (P =.81). Ten individuals from different kindreds were found to have an identical polyalanine triplet repeat expansion ([GCG](9)) in the PABP2 gene. CONCLUSIONS: Individuals in this cohort had clinical and genetic characteristics of classic OPMD. Longevity was not affected, but patients experienced considerable morbidity. The origin of the PABP2 mutation in New Mexican OPMD patients is unclear, although the geographic and genetic isolation of northern New Mexicans with a long ancestry in this region may have contributed to the development of this cohort. This disease cohort represents a large and previously unrecognized health care issue in the state of New Mexico and should serve to raise the awareness of this disorder among clinicians who treat Hispanics in the Southwest and throughout the United States.

Comparison of amlodipine or nifedipine treatment with developing congestive heart failure: effects on myocyte contractility.

BACKGROUND: Past studies have suggested that amlodipine, a dihydropyridine L-type Ca(2+) channel antagonist, may exert useful effects in congestive heart failure (CHF). The present study examined the effects of amlodipine or nifedipine treatment in a model of developing CHF on left ventricular (LV) pump function and myocyte contractility. METHODS AND RESULTS: Pigs (25 kg) were randomly assigned to 1 of 4 groups: 1) pacing-induced CHF (rapid atrial pacing at 240 bpm) for 3 weeks (n = 9), 2) concomitant Ca(2+) channel blockade with amlodipine (1.5 mg/kg/day) and rapid pacing (n = 7), 3) concomitant Ca(2+) channel blockade with nifedipine (0.7 mg/kg twice daily) and rapid pacing (n = 7), and 4) sham controls (n = 7). LV fractional shortening fell with pacing CHF from baseline values (17% +/- 1% v 42% +/- 1%, P <.05). With rapid pacing and concomitant amlodipine treatment, LV fractional shortening increased from pacing CHF values (24% +/- 1%, P <.05) but was unchanged with concomitant nifedipine treatment (20% +/- 2%, P =.2). LV myocyte velocity of shortening, as measured by high speed videomicroscopy, was reduced with pacing CHF compared with controls (42 +/- 2 microm/s v 87 +/- 9 microm/s, P <.05), and increased from pacing CHF values with amlodipine or nifedipine treatment (62 +/- 8 microm/s, 64 +/- 4 microm/s, respectively; P <.05). Inotropic response to extracellular Ca(2+) (8 mmol/L) was reduced with pacing CHF (94 +/- 5 microm/s v 160 +/- 15 microm/s, P <.05) and increased from CHF values with amlodipine or nifedipine treatment (132 +/- 14 microm/s and 133 +/- 7 microm/s, respectively, P <.05) CONCLUSIONS: These results suggest that the primary mechanism for the effects of amlodipine on myocyte contractility in developing CHF is because of direct Ca(2+) channel blockade.

Expression and activity of pulmonary endothelin converting enzyme in heart failure: relation to endothelin biosynthesis and receptor distribution.

BACKGROUND: Although reduced pulmonary clearance of endothelin-1 (ET-1) has been suggested to contribute to increased circulating levels in congestive heart failure (CHF), the regulation of the pulmonary ET system with CHF remains to be defined. Accordingly, the aim of the present study is to investigate the expression and activity of the ET system with the development of CHF. METHODS AND RESULTS: Pulmonary tissue samples were collected from pigs with pacing CHF (240 bpm, 3 wks, n = 10) and controls (n = 10). The pulmonary messenger RNA (mRNA) and protein levels of endothelin converting enzyme-1 (ECE-1) subisoforms, ET-1, and ET receptor profiles were determined. The gene expression of ET-1 precursor, ECE-1a, and ET(A) was upregulated 4-, 3-, and 2-fold, respectively, with CHF. Pulmonary tissue ET-1 was increased to 13 +/- 2 fmol/mg protein from control values of 5 +/- 1 fmol/mg protein (P <.05), and ECE-1 activity was augmented from 3,264 +/- 665 fmol/mg protein in control animals to 14,073 +/- 654 fmol/mg protein per hour in CHF animals (P <.05). The ET(B) receptor density decreased, whereas ET(A) receptors were increased in CHF, indicating a shift in the ET(A) to ET(B) ratio. CONCLUSIONS: Both the increased synthesis and the decreased clearance of ET-1 via ET(B) receptors may contribute to the increased systemic and pulmonary ET-1 levels in CHF.

Treatment with a growth hormone secretagogue in a model of developing heart failure: effects on ventricular and myocyte function.

BACKGROUND: Exogenous administration of growth hormone (GH) and subsequently increased production of insulin-like growth factor-1 can influence left ventricular (LV) myocardial growth and geometry in the setting of congestive heart failure (CHF). This study determined the effects of an orally active GH secretagogue (GHS) treatment that causes a release of endogenous GH on LV function and myocyte contractility in a model of developing CHF. METHODS AND RESULTS: Pigs were randomly assigned to the following treatment groups: (1) chronic rapid pacing at 240 bpm for 3 weeks (n=11); (2) chronic rapid pacing and GHS (CP-424,391 at 10 mg x kg(-1) x d(-1), n=9); and (3) sham controls (n=8). In the untreated pacing CHF group, LV fractional shortening was reduced (21+/-2% versus 47+/-2%) and peak wall stress increased (364+/-21 versus 141+/-5 g/cm(2)) from normal control values (P:<0.05). In the GHS group, LV fractional shortening was higher (29+/-2%) and LV peak wall stress lower (187+/-126 g/cm(2)) than untreated CHF values (P:<0.05). With GHS treatment, the ratio of LV mass to body weight increased by 44% from untreated values. Steady-state myocyte velocity of shortening was reduced with pacing CHF compared with controls (38+/-1 versus 78+/-1 microm/s, P:<0.05) and was increased from pacing CHF values with GHS treatment (55+/-7 microm/s, P:<0.05). CONCLUSIONS: The improved LV pump function that occurred with GHS treatment in this model of CHF was most likely a result of favorable effects on LV myocardial remodeling and contractile processes. On the basis of these results, further studies are warranted to determine the potential role of GH secretagogues in the treatment of CHF.

Myocardial bradykinin following acute angiotensin-converting enzyme inhibition, AT1 receptor blockade, or combined inhibition in congestive heart failure.

BACKGROUND: The present study examined the effects of acute angiotensin-converting enzyme inhibition (ACEI), AT(1) receptor blockade (AT(1) block), or combined treatment on in vitro and in vivo bradykinin (BK) levels. METHODS: BK levels were measured in isolated porcine myocyte preparations (n = 13) in the presence of exogenous BK (10(-8) M); with an ACEI (benezaprilat; 0.1 mM) and BK; an AT(1) block (valsartan; 10(-5) M) and BK; and combined treatment and BK. In a second study, myocardial microdialysis was used to measure porcine interstitial BK levels in both normal (n = 14) and pacing-induced congestive heart failure (CHF) (240 beats/min, 3 weeks, n = 16) under the following conditions: baseline, following ACEI (benezaprilat, 0.0625 mg/kg) or AT(1) block (valsartan, 0.1 mg/kg), and a combined treatment (benezaprilat, 0.0625 mg/kg; valsartan, 0.1 mg/kg). RESULTS: In the left ventricular myocyte study, BK levels increased over 93% with all treatments compared to untreated values (P < 0.05). In the in vivo study, basal interstitial BK values were lower in the CHF group than in controls (2.64 +/- 0.57 vs 5.91 +/- 1.4 nM, respectively, P < 0.05). Following acute infusion of the ACEI, BK levels in the CHF state increased from baseline (57% +/- 22; P < 0.05). Following combined ACEI/AT(1) block, BK levels increased from baseline in both control (42% +/- 11) and CHF groups (60% +/- 22; P < 0.05 for both). CONCLUSION: These findings suggest that ACEI, or combined ACEI/AT(1) block increased BK at the level of the myocyte and potentiated BK levels in the CHF myocardial interstitium.

Effects of combined angiotensin II and endothelin receptor blockade with developing heart failure: effects on left ventricular performance.

BACKGROUND: The goal of this study was to determine the comparative effects of angiotensin II type 1 (AT(1)) receptor inhibition alone, endothelin-1 (ET) receptor blockade alone, and combined receptor blockade on left ventricular (LV) function, contractility, and neurohormonal system activity in a model of congestive heart failure (CHF). METHODS AND RESULTS: Pigs were randomly assigned to each of 5 groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n=9), (2) concomitant AT(1) receptor blockade (valsartan, 3 mg/kg per day) and rapid pacing (n=8), (3) concomitant ET receptor blockade (bosentan, 50 mg/kg BID) and rapid pacing (n=8), (4) concomitant combined AT(1) and ET receptor inhibition and rapid pacing (n=8), and (5) sham-operated control (n=9). LV stroke volume was reduced from the control value after rapid pacing, was unchanged with either AT(1) or ET receptor blockade alone, but was improved with combination treatment. LV peak wall stress was reduced in both groups with ET receptor blockade compared with the rapid pacing group. Plasma norepinephrine levels were increased by >3-fold after rapid pacing, remained increased in the monotherapy groups, but were reduced after combination treatment. LV myocyte velocity of shortening was reduced after rapid pacing-induced CHF, remained reduced after AT(1) receptor blockade, increased after ET receptor blockade (compared with rapid pacing-induced CHF values), and returned to within control values after combined blockade. CONCLUSIONS: Combined AT(1) and the ET receptor blockade in this model of CHF improved LV pump function, and contributory factors included the effects of LV loading conditions, neurohormonal system activity, and myocardial contractile performance. Thus, combined receptor blockade may provide a useful combinatorial therapeutic approach in CHF.

Selective vasopressin, angiotensin II, or dual receptor blockade with developing congestive heart failure.

With developing congestive heart failure (CHF), activation of the vasopressin V(1a) and angiotensin II type 1 (AT(1)) receptors can occur. In the present study, we examined the direct effects of V(1a) receptor blockade (V(1a) block), selective AT(1) receptor blockade (AT(1) block), and dual V(1a)/AT(1) receptor blockade (dual block) with respect to left ventricular (LV) function and contractility during the progression of CHF. LV and myocyte functions were examined in pigs with pacing CHF (rapid pacing, 240 beats/min, 3 weeks, n = 10), pacing CHF with concomitant V(1a) block (SR49059, 60 mg/kg, n = 8), pacing CHF with concomitant AT(1) block (irbesartan, 30 mg/kg, n = 7), or pacing CHF with dual block (n = 7). LV end-diastolic dimension and peak wall stress were reduced in all receptor blockade groups compared with CHF values. However, LV fractional shortening was increased only in the dual block group compared with CHF values (29 +/- 3 versus 21 +/- 2, P <.05). Basal LV myocyte percent shortening increased in the dual block group compared with CHF values (3.44 +/- 0.23 versus 2.88 +/- 0.11, P <. 05). Although V(1a) or AT(1) block reduced LV loading conditions, only dual block resulted in improved LV and myocyte shortening.

ET-1 in the myocardial interstitium: relation to myocyte ECE activity and expression.

Increased plasma levels of endothelin-1 (ET-1) have been identified in congestive heart failure (CHF), but local myocardial interstitial ET-1 levels and the relation to determinants of ET-1 synthesis remain to be defined. Accordingly, myocardial interstitial ET-1 levels and myocyte endothelin-converting enzyme (ECE)-1 activity and expression with the development of CHF were examined. Pigs were instrumented with a microdialysis system to measure myocardial interstitial ET-1 levels with pacing CHF (240 beats/min, 3 wk; n = 9) and in controls (n = 14). Plasma ET-1 was increased with CHF (15 +/- 1 vs. 9 +/- 1 fmol/ml, P < 0.05) as was total myocardial ET-1 content (90 +/- 15 vs. 35 +/- 5 fmol/g, P < 0.05). Paradoxically, myocardial interstitial ET-1 was decreased in CHF (32 +/- 4 vs. 21 +/- 2 fmol/ml, P < 0.05), which indicated increased ET-1 uptake by the left ventricular (LV) myocardium with CHF. In isolated LV myocyte preparations, ECE-1 activity was increased by twofold with CHF (P < 0.05). In LV myocytes, both ECE-1a and ECE-1c mRNAs were detected, and ECE-1a expression was upregulated fivefold in CHF myocytes (P < 0.05). In conclusion, this study demonstrated compartmentalization of ET-1 in the myocardial interstitium and enhanced ET-1 uptake with CHF. Thus a local ET-1 system exists at the level of the myocyte, and determinants of ET-1 biosynthesis are selectively regulated within this myocardial compartment in CHF.

Effects of angiotensin type-I receptor blockade on pericardial fibrosis.

BACKGROUND: Reoperative cardiac surgical procedures are associated with a significantly greater complication rate than that of the initial procedure. Enhanced collagen synthesis can occur due to increased production of angiotensin II (Ang-II) and subsequent activation of Ang AT(1) receptor. Accordingly, the goal of the current study is to test the hypothesis that increased Ang AT(1) receptor activity following pericardiotomy contributes to pericardial thickening and fibrosis. MATERIALS AND METHODS: Adult pigs were randomly assigned to three protocols: (1) pericardiotomy with 28-day recovery period (n = 5); (2) pericardiotomy with Ang AT(1) receptor blockade instituted throughout the 28-day recovery period using 60 mg/day valsartan (n = 5); and (3) sham controls (n = 6). Pericardium samples were collected and analyzed by biochemical and histomorphometrical methods. Pericardial fibrosis occurred postpericardiotomy as indicated by increased hydroxyproline content from normal value of 50 +/- 3 microg/mg to 75 +/- 4 microg/mg (P < 0. 05). RESULTS: Pericardial thickness was increased postpericardiotomy to 2.7 +/- 0.4 mm compared to normal values of 0.4 +/- 0.05 mm (P < 0.05). Ang AT(1) receptor blockade reduced pericardial thickness by 50% and the relative degree of fibrosis was comparable to that of the normal group. CONCLUSIONS: The results from this pericardial fibrosis animal model suggest that Ang AT(1) receptor activation contributes to the development of pericardial thickening and collagen accumulation in the postoperative period. Thus, Ang AT(1) receptor inhibition may provide a novel therapeutic strategy to prevent pericardial fibrosis that follows cardiac surgical procedures.

Angiotensin-converting enzyme and matrix metalloproteinase inhibition with developing heart failure: comparative effects on left ventricular function and geometry.

The progression of congestive heart failure (CHF) is left ventricular (LV) myocardial remodeling. The matrix metalloproteinases (MMPs) contribute to tissue remodeling and therefore MMP inhibition may serve as a useful therapeutic target in CHF. Angiotensin converting enzyme (ACE) inhibition favorably affects LV myocardial remodeling in CHF. This study examined the effects of specific MMP inhibition, ACE inhibition, and combined treatment on LV systolic and diastolic function in a model of CHF. Pigs were randomly assigned to five groups: 1) rapid atrial pacing (240 beats/min) for 3 weeks (n = 8); 2) ACE inhibition (fosinopril, 2.5 mg/kg b.i.d. orally) and rapid pacing (n = 8); 3) MMP inhibition (PD166793 2 mg/kg/day p.o.) and rapid pacing (n = 8); 4) combined ACE and MMP inhibition (2.5 mg/kg b.i.d. and 2 mg/kg/day, respectively) and rapid pacing (n = 8); and 5) controls (n = 9). LV peak wall stress increased by 2-fold with rapid pacing and was reduced in all treatment groups. LV fractional shortening fell by nearly 2-fold with rapid pacing and increased in all treatment groups. The circumferential fiber shortening-systolic stress relation was reduced with rapid pacing and increased in the ACE inhibition and combination groups. LV myocardial stiffness constant was unchanged in the rapid pacing group, increased nearly 2-fold in the MMP inhibition group, and was normalized in the ACE inhibition and combination treatment groups. Increased MMP activation contributes to the LV dilation and increased wall stress with pacing CHF and a contributory downstream mechanism of ACE inhibition is an effect on MMP activity.

Structure-function relationships within peripheral nerves in diabetic neuropathy: the hydration hypothesis.

To define the quantitative relationship between peripheral nerve structure and function imposed by endoneurial oedema in the diabetic state, we determined values for sural nerve hydration structure as measured by magnetic resonance spectroscopy, and for neurological function with scores for nerve conduction properties (NCV-score), neuropathic symptoms (NS-score), and examination signs (NE-score). The coefficient of sural nerve hydration was elevated to 30 +/- 6% (p < 0.05) in 79 symptomatic neuropathic diabetic subjects with an average of 15 years of diabetes mellitus, compared to a value of 25 +/- 3% in 72 non-diabetic control subjects. In contrast, in 75 asymptomatic diabetic subjects with an average of 6 additional years of diabetes, the mean hydration coefficient was only 28 +/- 5% (p < 0.05). A nerve hyperhydration state was identified with a prevalence of 25% within the asymptomatic group characterized by nerve hydration greater than the 95th percentile, early changes in nerve electrophysiology and neurological examination, but with no symptomatology of neuropathy. Stratification of the symptomatic neuropathic group by worsening nerve electrophysiology, demonstrates a coincident deterioration in neurological examination (RR = 5.39 at maximum NCV-score), and neuropathy symptomatology (RR = 4.80 at maximum NE-score). The present data are consistent with the hypothesis that endoneurial oedema initiates deterioration sequentially in nerve electrophysiology, followed by abnormal findings on neurological examination, preceding the patient's final perception of symptomatic stocking glove peripheral diabetic neuropathy.

Suicide attempt history in depressed patients with and without a history of panic attacks.

This study of 346 depressed outpatients found a significant difference in the frequency of suicide attempts in those with a history of panic attacks (26.9%) compared with those without (16.8%). Further investigation showed that depressed patients with a history of infrequent panic attacks had a higher incidence of suicide attempts (32.3%) than those with panic disorder (21.5%). However, multiple regression analysis including a number of sociodemographic and diagnostic variables revealed that female gender and history of psychosis (but not panic attack history) significantly contributed to the variance in the history of suicide attempts. These data for depressed patients are compared with data from other studies regarding the association of panic attacks and suicidal behavior.

Sural nerve water in vivo in normal humans measured by magnetic resonance spectroscopy: relation to age, height, gender, and neurological profile.

To enable the quantitative assessment of peripheral nerve structure and function, we determined the normal values for sural nerve hydration structure as measured by magnetic resonance proton imaging, and for neurological function with scores for neuropathic symptoms, signs, and nerve conduction properties. Normal human sural nerves contain 24.8 +/- 3.4% water. The structural water content of the nerves did not vary systematically in relation to age, height, gender, sural nerve conduction, neurologic symptoms, or examination deficits. In contrast, the neurological function scores were significantly influenced by age and selectively by height. Both nerve structure and function were stable over a 1-year interval. Measurement of human sural nerve water content in vivo by magnetic resonance proton imaging, and quantitation of the neurological profile of symptoms, signs, and conduction velocity are useful, noninvasive tools for the investigation of diseases in which changes in nerve structure may be related to alterations in nerve function.

Meningococcal carriage, meningococcal disease and vaccination.

Group A meningococcal carriage rates were determined 6 months before and 6 and 18 months after a mass vaccination campaign with a combined group A and group C meningococcal polysaccharide vaccine in a rural area of The Gambia. During the first pre-vaccination survey, performed during an outbreak of meningococcal disease, the carriage rate was high (16%). The carriage rate remained high during a second survey made 6 months after a vaccination campaign that covered approximately 90% of the study population. A year later very few group A meningococcal carriers were found. Membrane protein patterns of isolates obtained before and after vaccination were similar. We conclude that vaccination had little influence on the carriage rate of group A meningococci but that this was influenced by changes in herd immunity or by other unidentified factors.