Abundant cytomegalovirus (CMV) reactive clonotypes in the CD8(+) T cell receptor alpha repertoire following allogeneic transplantation.

Allogeneic stem cell transplantation is potentially curative, but associated with post-transplantation complications, including cytomegalovirus (CMV) infections. An effective immune response requires T cells recognizing CMV epitopes via their T cell receptors (TCRs). Little is known about the TCR repertoire, in particular the TCR-α repertoire and its clinical relevance in patients following stem cell transplantation. Using next-generation sequencing we examined the TCR-α repertoire of CD8(+) T cells and CMV-specific CD8(+) T cells in four patients. Additionally, we performed single-cell TCR-αß sequencing of CMV-specific CD8(+) T cells. The TCR-α composition of human leucocyte antigen (HLA)-A*0201 CMVpp65- and CMVIE -specific T cells was oligoclonal and defined by few dominant clonotypes. Frequencies of single clonotypes reached up to 11% of all CD8(+) T cells and half of the total CD8(+) T cell repertoire was dominated by few CMV-reactive clonotypes. Some TCR-α clonotypes were shared between patients. Gene expression of the circulating CMV-specific CD8(+) T cells was consistent with chronically activated effector memory T cells. The CD8(+) T cell response to CMV reactivation resulted in an expansion of a few TCR-α clonotypes to dominate the CD8(+) repertoires. These results warrant further larger studies to define the ability of oligoclonally expanded T cell clones to achieve an effective anti-viral T cell response in this setting.

[Medication-induced dysphagia : A review]. / Medikamenteninduzierte Dysphagien : Ein Überblick.

As a highly differentiated physiological process, swallowing may be affected by a variety of confounding factors. Primarily described are swallowing disorders caused by mechanical anatomic changes (e. g., alteration of the cervical spine, goiter), surgery for head and neck tumors, thyroid abnormalities, and neuromuscular disorders. Age-related cerebral neurological and blood vessel-associated changes can also cause dysphagia (so-called presbyphagia) or worsen the condition.Medication-associated dysphagia is recognized far less frequently, not paid due attention, or accepted in silence; particularly in older patients. Furthermore, pharmacological interference of different medications is frequently inadequately considered, particularly in the case of polypharmacy.Initial treatment of medication-induced dysphagia includes a critical review of medication status, with the aim of reducing/discontinuing the causative medication by giving precise instructions regarding its administration; as well as antacid medication, diet, and professional oral stimulation or swallowing training.To date, medication-induced dysphagia has not occupied the focus of physicians and therapists. This is despite the fact that many active agents can have a negative effect on swallowing and medication-induced dysphagia caused by polypharmacy is not uncommon, particularly in old age. This article presents an overview of the different classes of drugs in terms of their direct or indirect negative effects on the swallowing function.

Compromised immune response in infants at risk for type 1 diabetes born by Caesarean Section.

Children born by Caesarean Section have a higher risk for type 1 diabetes. We aimed to investigate whether Caesarean Section leads to alterations of the immune response in children with familial risk for type 1 diabetes. We examined measures of innate and adaptive immune responses in 94 prospectively followed children, including 40 born by Caesarean Section. Proinflammatory serum cytokine concentrations were determined at age 6 months. As a measure of vaccine response, IgG1, IgG2, and IgG4 tetanus antibody titers and CD4(+) T cell proliferation against tetanus toxoid were quantified. Compared to infants born by vaginal delivery, infants born by Caesarean Section had lower concentrations of the cytokines IFN-É£ (p=0.014) and IL-8 (p=0.005), and weaker CD4(+) T cell responses to tetanus measured in the first (p=0.007) and second year (p=0.047) of life. Overall, our findings provide evidence that the mode of delivery influences the immune status and responsiveness during childhood.

[How reliable are non-instrumental assessment tools for dysphagia?]. / Welche Aussagekraft haben nichtinstrumentelle Diagnoseverfahren bei Dysphagie?

BACKGROUND: The requirement for otorhinolaryngologists and phoniatricians to diagnose dysphagia and evaluate its extent is on the rise, particularly in light of demographic changes. The gold standards in confirmatory diagnostics are fiberoptic endoscopic evaluation of swallowing (FEES) and the videofluoroscopic swallowing examination (VFS). Standardized assessments, such as questionnaires or assessments involving probatory swallows are often applied as screening or supportive measures. This article aims to give a critical overview of the assessment tools frequently used in clinical routine. Test quality is assessed, particularly compared to FEES and VFS. METHODS: A selective literature search using PubMed has been conducted. RESULTS: On the basis of this lierature search, 48 assessment tools were identified. These can be classified into screening tools, instrument-based tools (implementation standards and evaluation protocols) and questionnaire-based assessment inventories. DISCUSSION: In order to diagnose and evaluate dysphagia on the basis of assessment critieria, clinicians should be aware of indications for, as well as the advantages, disadvantages and test quality of the assessment tools. Considering the different assessment tools for anamnesis and probatory swallowing, rather low sensitivities and specificities for possible penetration and aspiration are evident. In cases where these symptoms of dysphagia are not evident and reliably assessable, confirmatory assessment via FEES or VFS is essential.

Single bunch X-ray pulses on demand from a multi-bunch synchrotron radiation source.

Synchrotron radiation facilities routinely operate in a multi-bunch regime, but applications relying on time-of-flight schemes require single bunch operation. Here we show that pulse picking by resonant excitation in a storage ring creates in addition to the multi-bunch operation a distinct and separable single bunch soft X-ray source. It has variable polarization, a photon flux of up to 10(7)-10(9) ph s(-1)/0.1%BW at purity values of 10(4)-10(2) and a repetition rate of 1.25 MHz. The quasi-resonant excitation of incoherent betatron oscillations of electrons allows horizontal pulse separation at variable (also circular) polarization accessible for both, regular 30 ps pulses and ultrashort pulses of 2-3 ps duration. Combined with a new generation of angularly resolving electron spectrometers this creates unique opportunities for time-resolved photoemission studies as confirmed by time-of-flight spectra. Our pulse picking scheme is particularly suited for surface physics at diffraction-limited light sources promising ultimate spectral resolution.

[Endoscopic video imaging of configuration changes in the larynx and pharynx during selected swallowing techniques]. / Videoendoskopische Darstellung der Konfigurationsänderungen im Larynx und Pharynx bei definierten Schluckmanövern.

BACKGROUND: Traditional dysphagia therapy (TDT) aims to improve swallowing by means of compensatory strategies including postural changes or swallowing maneuvers. These techniques are mainly applied in order to modify swallowing by affecting bolus transport to facilitate safe swallowing. Videos demonstrating actual, laryngoscopically verified effects on the pharyngeal and laryngeal structures involved are rare in the current literature. This paper aims to assess various maneuvers used in TDT endoscopically. METHOD: A selective literature search for endoscopic imaging of swallowing maneuvers and postural changes applied in TDT was performed in PubMed. RESULTS: Each of the techniques commonly used in TDT influenced the pharyngeal or laryngeal structures distinctly. DISCUSSION: All of the techniques examined for this paper represent techniques commonly applied in traditional dysphagia therapy. The specific changes observed endoscopically of the anatomic structures involved are distinct, but sometimes seem only marginal in comparison to the initial configurations. It should hence not be surprising that these swallowing techniques occasionally only slightly improve swallowing. The videos included in this article demonstrate the actual impact of the swallowing techniques and may therefore be of use to physicians prescribing and implementing TDT.

[Assessment inventories for hearing aid outcome]. / Fragebogenassessments für die Hörgerätekontrolle.

BACKGROUND: At the beginning of 2012 new fee schedule positions have been introduced to the ambulatory physician fee schedule ("Einheitlicher Bewertungsmaßstab", EBM) regarding the hearing aid fittings of youngsters and adults. With regards to quality assurance the use of a hearing aid outcome self-assessment inventory is made compulsive. This article aims to review available hearing aid (self-) assessment inventories as well as the evaluations regarding criteria for test quality implemented. METHOD: For this systematic review a selective literature research in PubMed has been carried out. RESULTS: There are various self assessment inventories measuring hearing aid benefit. Many of the studies evaluating these inventories were implemented during the 1980ies and early 90ies when analogue hearing aids were commonly used. These results cannot automatically be transferred to the nowadays common digital devices. Only a small amount of studies investigated German translations of the mostly originally English inventories. DISCUSSION: In order to be able to identify the actual meaning of resulting values from these inventories, it is important for ENT doctors and audiologists to be well informed of the tests' quality criteria.

Perifoveal exudative vascular anomalous complex.

PURPOSE: To report the angiographic and optical coherence tomography (OCT) features of isolated "perifoveal exudative vascular anomalous complex (PEVAC)", a peculiar clinical entity. METHODS: A complete ophthalmologic examination was performed in two patients (a 82-year old woman [case 1]; a 52-year old man [case 2]) that were referred to our department for unilateral blurred vision. RESULTS: In both cases, fundus examination of the right eye showed a perifoveal isolated large aneurismal change, accompanied by small hemorrhages, intraretinal exudation, and small hard exudates accumulation. Both FA and ICGA revealed the absence of any other retinal or choroidal vascular abnormality associated. OCT showed a round hyperreflective lesion in correspondence of the perifoveal vascular anomalous complex, surrounded by intraretinal cystic spaces. In case 2, the lesion remained unchanged despite 3 monthly intravitreal injections of ranibizumab. CONCLUSION: PEVAC may develop in absence of capillary ischemia or inflammation, probably due to progressive retinal endothelial cell degeneration. This could explain the unresponsiveness to anti-VEGF treatments.

Second generation proteasome inhibitors: carfilzomib and immunoproteasome-specific inhibitors (IPSIs).

The ubiquitin-proteasome pathway (UPP) is an attractive chemotherapeutic target due to its intrinsically stringent regulation of cell cycle, pro-survival, and anti-apoptotic regulators that disproportionately favor survival and proliferation in malignant cells. A reversible first-in-class proteasome inhibitor, bortezomib, is Food and Drug Administration approved for multiple myeloma and relapsed/refractory mantle cell lymphoma and has proven to be extremely effective, both as a single agent and in combination. An irreversible second generation proteasome inhibitor, carfilzomib, has shown preclinical effectiveness against hematological and solid malignancies both in vitro and in vivo. Carfilzomib, a peptidyl-epoxyketone functions similarly to bortezomib through primary inhibition of chymotrypsin-like (ChT-L) activity at the b5 subunits of the core 20S proteasome. Carfilzomib is also currently achieving successful response rates within the clinical setting. In addition to conventional proteasome inhibitors, a novel approach may be to specifically target the hematological-specific immunoproteasome, thereby increasing overall effectiveness and reducing negative off-target effects. The immunoproteasome-specific inhibitor, IPSI-001, was shown to have inhibitory preference over the constitutive proteasome, and display enhanced efficiency of apoptotic induction of tumor cells from a hematologic origin. Herein, we discuss the preclinical and clinical development of carfilzomib and explore the potential of immunoproteasome-specific inhibitors, like IPSI-001, as a rational approach to exclusively target hematological malignancies.

Perioperative concentrations of catecholamines in the cerebrospinal fluid and plasma during spinal anesthesia.

BACKGROUND: Catecholamine release is a physiological response to stress. The extent to which perioperative stress provokes the central release of catecholamines, which modulate pain perception in the spinal cord, still remains unknown. The perioperative course of catecholamine concentrations in the cerebrospinal fluid (CSF) and plasma was examined. METHODS: A prospective study was performed in 25 patients (ASA III, 60-84 years) undergoing elective hip joint replacement in spinal catheter anesthesia. The concentrations of dopamine, epinephrine and norepinephrine in the CSF and plasma were measured before anesthesia, immediately after surgery, and 6 and 24 h post-operatively. RESULTS: In most patients, dopamine and epinephrine were not detectable in CSF. CSF-norepinephrine concentrations decreased from median [interquartile-range] 159 [124;216] pre-anesthesia to 116 [79;152] pmol/l immediately post-operatively and were slightly elevated 24 h post-operatively (180 [134;302] pmol/l) (P=0.05). Dopamine plasma concentrations were not detectable or were barely above the detection threshold. Plasma epinephrine increased from 61 [28;77] pmol/l pre-anesthesia to 112 [69;138] pmol/l 6 h post-operatively and returned to baseline 24 h post-operatively (P=0.001). Plasma norepinephrine concentrations increased intra-operatively from 298 [249;422] to 556 [423;649] pmol/l and remained elevated 24 h after surgery (P=0.009). There was no association between changes in CSF or plasma norepinephrine or epinephrine concentrations and changes in heart rate (HR) or mean arterial pressure (MAP). CONCLUSION: During spinal anesthesia for elective hip joint replacement, norepinephrine concentrations were greater in plasma than in CSF. CSF dopamine and epinephrine concentrations were essentially undetectable. The changes in CSF-norepinephrine concentrations and the changes of plasma norepinephrine concentrations showed no association with each other; nor were there correlations between clinical stress parameters (HR, MAP) or visual analog scale pain, and the changes in CSF norepinephrine concentrations.

Perioperative changes in cerebral ischemic markers in the cerebrospinal fluid after preoperative nimodipine treatment.

BACKGROUND: Elderly patients with previous organ damage are at risk for minor neurologic deficits after major surgery. Spinal catheter analgesia is used whenever possible in this group and enables regular cerebrospinal fluid (CSF) sampling. Nimodipine, a calcium blocker, may have neuroprotective effects. We examined whether preoperative treatment with nimodipine affects ischemic markers in the CSF during extracranial surgery. METHODS: We performed a prospective, randomized, placebo-controlled, double-blind study in patients (ASA III or IV, 65-85 years) that underwent elective implantation surgery of the hip joint with intrathecal catheter anesthesia. Starting 15 h before surgery, patients received either 30 microg x kg(-1) h(-1) of nimodipine (n = 20) or 0.9% saline solution (placebo, n = 23) as a central venous infusion. The concentrations of neuron-specific enolase, hypoxanthine, creatine-kinase, lactate and pH in the CSF were determined before and immediately after surgery as well as 6 and 24 h after surgery. RESULTS: Before surgery, the baseline CSF pH was normal in all patients. Immediately after surgery it fell significantly to 7.08 +/- 0.29 in the placebo group and non-significantly to 7.27 +/- 0.38 in the treatment group; all values were normalized at 6 and 24 h after surgery in both groups. In the placebo group, lactate levels rose significantly from 1.48 +/- 0.28 mmol l(-1) before surgery to 1.77 +/- 0.27 mmol l(-1) immediately after surgery, and to 2.03 +/- 0.32 mmol l(-1) 24 h after surgery. In the treatment group, lactate concentrations remained stable up to 6 h after surgery (1.55-1.62 mmol l-1), while an increase to 2.10 +/- 0.48 mmol l(-1) was observed 24 h after the operation. Neuron-specific enolase, hypo-xanthine and creatine-kinase showed no change in either group. CONCLUSION: In conclusion, preoperative nimodipine treatment reduced intraoperative CSF acidosis and delayed surgery-related increases in lactate concentration in the CSF by several hours in elderly, comorbid patients at risk for minor postoperative neurologic deficits.

Indoor mold, toxigenic fungi, and Stachybotrys chartarum: infectious disease perspective.

Damp buildings often have a moldy smell or obvious mold growth; some molds are human pathogens. This has caused concern regarding health effects of moldy indoor environments and has resulted in many studies of moisture- and mold-damaged buildings. Recently, there have been reports of severe illness as a result of indoor mold exposure, particularly due to Stachybotrys chartarum. While many authors describe a direct relationship between fungal contamination and illness, close examination of the literature reveals a confusing picture. Here, we review the evidence regarding indoor mold exposure and mycotoxicosis, with an emphasis on S. chartarum. We also examine possible end-organ effects, including pulmonary, immunologic, neurologic, and oncologic disorders. We discuss the Cleveland infant idiopathic pulmonary hemorrhage reports in detail, since they provided important impetus for concerns about Stachybotrys. Some valid concerns exist regarding the relationship between indoor mold exposure and human disease. Review of the literature reveals certain fungus-disease associations in humans, including ergotism (Claviceps species), alimentary toxic aleukia (Fusarium), and liver disease (Aspergillys). While many papers suggest a similar relationship between Stachybotrys and human disease, the studies nearly uniformly suffer from significant methodological flaws, making their findings inconclusive. As a result, we have not found well-substantiated supportive evidence of serious illness due to Stachybotrys exposure in the contemporary environment. To address issues of indoor mold-related illness, there is an urgent need for studies using objective markers of illness, relevant animal models, proper epidemiologic techniques, and examination of confounding factors.

Shorter discharge time after regional or intravenous anaesthesia in combination with laryngeal mask airway compared with balanced anaesthesia with endotracheal intubation.

BACKGROUND AND OBJECTIVE: The efficiency of operating room times can be significantly improved using rapid changes between operative procedures. We performed a retrospective analysis using electronic anaesthesia charts that compared anaesthesia-related times between the three most frequently performed types of anaesthesia (for orthopaedic surgery) to evaluate the potential for a quicker turn-around between cases. METHODS: A total of 5614 anaesthetic procedures in trauma-related orthopaedic surgery were performed from 1997 to 1999. All were documented with an automatic record-keeping system. Data were compared for intravenous anaesthesia with the laryngeal mask airway, balanced anaesthesia with tracheal intubation and regional anaesthesia. The primary outcome measure was the time needed for emergence from anaesthesia after the end of surgery. Statistical evaluation was performed with matched triples for all three types of anaesthesia (155 triples for ambulatory surgery, 249 triples for in-patient care). RESULTS: For ambulatory surgery, the induction time was significantly shorter for general anaesthesia (23.7 min for intravenous anaesthesia, 22.7 min for balanced anaesthesia techniques) compared with regional anaesthesia (27.2 min). The time from the end of the surgical procedure to transfer of the patient out of the operating room was shortest for regional anaesthesia (6.3 min) compared with intravenous anaesthesia (9.0 min) and balanced anaesthesia (12.5 min) techniques. Results were comparable for in-patients: regional anaesthesia required significantly longer for its induction, but less time for patient discharge from the operating room. CONCLUSIONS: The use of a regional anaesthesia technique or one involving intravenous anaesthesia in combination with the laryngeal mask airway may lead to a reduction in discharge time compared with a balanced anaesthesia technique with endotracheal intubation. Thus, improved use of resources may be achieved.

Antifungal susceptibility of Candida biofilms: unique efficacy of amphotericin B lipid formulations and echinocandins.

Biofilms, likely the predominant mode of device-related microbial infection, exhibit resistance to antimicrobial agents. Evidence suggests that Candida biofilms have dramatically reduced susceptibility to antifungal drugs. We examined antifungal susceptibilities of Candida albicans and Candida parapsilosis biofilms grown on a bioprosthetic model. In addition to conventional agents, we determined if new antifungal agents (triazoles, amphotericin B lipid formulations, and echinocandins) have activities against Candida biofilms. We also explored effects of preincubation of C. albicans cells with subinhibitory concentrations (sub-MICs) of drugs to see if they could modify subsequent biofilm formation. Finally, we used confocal scanning laser microscopy (CSLM) to image planktonic- and biofilm-exposed blastospores to examine drug effects on cell structure. Candida biofilms were formed on silicone elastomer and quantified by tetrazolium and dry weight (DW) assays. Susceptibility testing of fluconazole, nystatin, chlorhexidine, terbenafine, amphotericin B (AMB), and the triazoles voriconazole (VRC) and ravuconazole revealed resistance in all Candida isolates examined when grown as biofilms, compared to planktonic forms. In contrast, lipid formulations of AMB (liposomal AMB and AMB lipid complex [ABLC]) and echinocandins (caspofungin [Casp] and micafungin) showed activity against Candida biofilms. Preincubation of C. albicans cells with sub-MIC levels of antifungals decreased the ability of cells to subsequently form biofilm (measured by DW; P < 0.0005). CSLM analysis of planktonic and biofilm-associated blastospores showed treatment with VRC, Casp, and ABLC resulted in morphological alterations, which differed with each agent. In conclusion, our data show that Candida biofilms show unique susceptibilities to echinocandins and AMB lipid formulations.

[New therapies for the treatment of age-related macular degeneration]. / Nouvelles thérapeutiques dans le traitement de la dégénérescence maculaire liée à l'âge.

Age-related macular degeneration has a natural progression from the precursors (the drusen) towards atrophic or neovascular complications. Choroidal neovascularization is undoubtedly the aspect of the disease that benefits most from new therapeutical approaches. Destructive photocoagulation based on fluorescein angiography has demonstrated since 20 years its efficiency on choroidal neovascularization. The same approach based on indocyanine green (ICG) angiography would increase the number of patients available to therapy. Very recently photodynamic therapy has demonstrated its efficiency to stabilize visual acuity at least at two years in patients with choroidal new vessels predominantly well defined. Other treatment developments are considered, such as refinement of photocoagulation techniques or of surgery. Until now, none has demonstrated its efficiency although they raise justified hopes. The future approaches rely upon the progress of the research both in physiopathology of the disease and on the angiogenic process requiring a constant interaction with all thematics of research. Finally, palliative treatments will be required before heading up to a preventive treatment.

Identifying feeding problems in mentally retarded persons: development and reliability of the screening tool of feeding problems (STEP).

Feeding problems are extremely common among individuals with mental retardation. Palmer, Thompson, and Linscheid (1975) estimate that 33% of persons with mental retardation have severe feeding difficulties or problems. Furthermore, the consequences of untreated feeding problems can be severe if not fatal. Despite these numbers, little has been done to systematically identify these problems. The Screening Tool of Feeding Problems (STEP) was developed as a means to identify feeding problems presented by persons with mental retardation, and thus facilitate the process of identifying who would benefit from some type of behavioral or medical intervention. Items included in the STEP target feeding problems identified in the literature, in the areas of risk of aspiration, food selectivity, feeding skills deficits, food refusal and associated behavior problems, and nutrition related behavior problems. The current study describes the construction of this scale, provides psychometric data including test-retest and cross rater reliability, and factor analysis data.

CDKN2A/p16 inactivation is related to pituitary adenoma type and size.

p16 (CDKN2A, MTS1, INK4A) status at genomic and protein levels was analysed and correlated with clinico-pathological features in 72 pituitary adenomas. Methylation of CpG islands of promoter/exon 1 sequences was found in most gonadotroph, lactotroph, plurihormonal, and null cell adenomas (36 of 44, 82%), but it was rare in somatotroph (1 of 13 cases, 8%) and corticotroph adenomas (1 of 15 cases, 7%). Homozygous CDKN2A deletion was restricted to rare somatotroph (15%) and corticotroph adenomas (13%). Immunohistochemical p16 protein expression was observed in the normal adenohypophysis, whereas it was absent in 60 of 72 (83%) tumours and reduced in another ten (14%) tumours. Staining for p16 was only seen in 5 of 15 (33%) corticotroph, 3 of 13 (23%) somatotroph, 3 of 5 (60%) plurihormonal, and 1 of 19 (5%) null cell adenomas. p16 immunonegativity without CDKN2A methylation or deletion occurred in 22 tumours, including most somatotroph and corticotroph adenomas (15 of 28, 54%). Both CDKN2A alterations and p16 negativity were related to larger tumour size. Patients with p16-negative tumours were older than patients with p16-positive tumours. These data suggest that p16 down-regulation is common in all adenoma types. The mechanisms of p16 down-regulation probably involve CDKN2A methylation in most types, but remain to be determined in somatotroph and corticotroph adenomas. These findings also suggest that p16 down-regulation is usually not an initial event, but is acquired during adenoma progression.

Iron transport into mycobacterium avium-containing phagosomes from an Nramp1(Gly169)-transfected RAW264.7 macrophage cell line.

Nramp1 is an important determinant of innate resistance of macrophages to the growth of intracellular microorganisms. We previously showed that Nramp1 functions to transport iron from the cytoplasm into phagosomes of Mycobacterium avium-infected macrophages. The purpose of this investigation was to further characterize the factors that regulate Nramp1-mediated iron transport into phagosomes. Treatment of Nramp1(Gly169) macrophages with the lysomotrophic agents chloroquine or ammonium chloride reduced the import of iron significantly. We found that macrophage-activating cytokines, including TNF-alpha, IFN-gamma, IL-1alpha, and GM-CSF, when added prior to M. avium, increased the transport of iron into the phagosome. This increase in iron transport was not a result of an increased amount of Nramp1 protein in the phagosome nor to new protein synthesis. Treatment of Nramp1(Gly169)-transfected macrophages with inhibitors of protein kinase C (PKC) diminished the import of iron into the phagosomes. Iron import was inhibited by an anti-Nramp1 antibody against the putative fourth outer-loop region of Nramp1 but not by an anti-Nramp1 antibody against the carboxy terminus. The significance of these results on the orientation of Nramp1 in the phagosome membrane and on the transport of iron is discussed.

Tetrahydrobiopterin enhances apoptotic PC12 cell death following withdrawal of trophic support.

(6R)-Tetrahydro-l-biopterin (BH(4)) is the rate-limiting cofactor in the production of catecholamine and indoleamine neurotransmitters and is also essential for the synthesis of nitric oxide by nitric-oxide synthase. We have previously reported that BH(4) administration induces PC12 cell proliferation and that nerve growth factor- or epidermal growth factor-induced PC12 cell proliferation requires the elevation of intracellular BH(4) levels. We show here that BH(4) accelerates apoptosis in undifferentiated PC12 cells deprived of serum and in differentiated neuron-like PC12 cells after nerve growth factor withdrawal. Increased production of catecholamines or nitric oxide cannot account for the enhancement of apoptosis by BH(4). Furthermore, increased calcium influx by exogenous BH(4) administration is not involved in the BH(4) proapoptotic effect. Our data also argue against the possibility that increased oxidative stress, due to BH(4) autoxidation, is responsible for the observed BH(4) effects. Instead, they are consistent with the hypothesis that BH(4) induces apoptosis by increasing cell cycle progression. Elevation of intracellular BH(4) during serum withdrawal increased c-Myc (and especially Myc S) expression earlier than serum withdrawal alone. Furthermore, N-acetylcysteine and the cyclin-dependent kinase inhibitor olomoucine ameliorated the BH(4) proapoptotic effect. These data suggest that BH(4) affects c-Myc expression and cell cycle-dependent events, possibly accounting for its effects on promoting cell cycle progression or apoptosis.